TW202448949A - Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies - Google Patents

Abstract

The invention provides methods of dosing for the treatment of cancers, such as multiple myelomas, with anti-fragment crystallizable receptor-like 5 (FcRH5)/anti-cluster of differentiation 3 (CD3) bispecific antibodies.

Description

Administration of anti-FCRH5/anti-CD3 bispecific antibodies for treatment

The present invention relates to the treatment of cancer, such as B-cell proliferative disorders. More specifically, the present invention relates to the treatment of human patients with multiple myeloma (MM) using anti-fragment crystallizable receptor-like 5 (FcRH5)/anti-cluster of differentiation 3 (CD3) bispecific antibodies.

Cancer remains one of the most deadly threats to human health. In the United States, cancer affects more than 1.7 million new patients each year and is the second leading cause of death after heart disease, accounting for approximately one in four deaths.

Hematologic cancers in particular are the second leading cause of cancer-related death. Hematologic cancers include multiple myeloma (MM), a tumor characterized by the proliferation and accumulation of malignant plasma cells. Worldwide, approximately 160,000 people are diagnosed with MM each year. Despite advances in treatment, MM remains incurable, with an estimated median survival of 8-10 years for standard-risk myeloma and 2-3 years for high-risk disease, despite autologous stem cell transplantation. Although patient survival has improved significantly over the past 20 years, only 10%-15% of patients survive as or longer than expected compared to the matched general population. The introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies has resulted in improved survival. Despite this, most, if not all, patients eventually relapse, and after becoming refractory or ineligible for proteasome inhibitors or IMiDs, outcomes for MM patients are poor, with survival of less than 1 year.

Therefore, relapsed or refractory (R/R) MM in particular remains a significant unmet medical need, and novel therapeutic agents and treatments are needed.

In particular, provided herein are methods of treating cancer (eg, B-cell proliferative disorders such as MM), as well as related compositions, uses and articles of manufacture for use.

In one aspect, the invention provides a method of treating an individual with multiple myeloma (MM), the method comprising administering (e.g., intravenously (IV)) to the individual a bispecific antibody that binds to Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), wherein the individual does not have (i) a history of macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH), (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic coronavirus disease 2019 (COVID-19) infection or the need for treatment with intravenous antiviral agents.

In another aspect, the invention provides a bispecific antibody that binds to FcRH5 and CD3 for use in treating an individual with MM, the treatment comprising administering (e.g., IV) a bispecific antibody that binds to FcRH5 and CD3 to the individual, wherein the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

In another aspect, the invention provides a method of treating a subject having MM, the method comprising administering (e.g., IV) a bispecific antibody that binds to FcRH5 and CD3 to the subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the subject every week (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the subject every four weeks (Q4W). The bispecific antibody is administered to the individual, wherein the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

In another aspect, the invention provides a bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising administering (e.g., IV) the bispecific antibody to the subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the subject every week (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the subject every four weeks (Q2W). (Q4W) administering the bispecific antibody to the individual, wherein the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

In some aspects, each dosing cycle is a 28-day dosing cycle.

In some embodiments, the first phase includes at least two dosing cycles.

In some embodiments, the first phase includes a first dosing cycle (C1) and a second dosing cycle (C2).

In some embodiments, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and day 22 of C1.

In some embodiments, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and day 22 of C2.

In some aspects, for each administration during the first phase, a target dose of the bispecific antibody (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject.

In some aspects, the first phase comprises administering to the individual a first step-up dose of the bispecific antibody.

In some aspects, the first escalating dose is administered to the subject on day 1 of C1.

In some aspects, a target dose (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject on days 8, 15, and 22 of C1.

In some aspects, the target dose (e.g., 90 mg, 132 mg, or 160 mg) is further administered to the subject on day 1, day 8, day 15, and day 22 of C2.

In some aspects, the first incremental dose is about 4% of the target dose.

In some aspects, the first phase comprises administering to the subject a first increasing dose and a second increasing dose of the bispecific antibody.

In some aspects, the first escalating dose is administered to the subject on day 1 of C1, and the second escalating dose is administered to the subject on day 8 of C1.

In some aspects, a target dose (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject on days 15 and 22 of C1.

In some aspects, the target dose (e.g., 90 mg, 132 mg, or 160 mg) is further administered to the subject on day 1, day 8, day 15, and day 22 of C2.

In some aspects: (i) the first incremental dose is 0.33% of the target dose; and (ii) the second incremental dose is about 4% of the target dose.

In some aspects, the first incremental dose is 3.6 mg.

In some aspects, the first increasing dose is 0.3 mg and the second increasing dose is 3.6 mg.

In some embodiments, the second phase includes at least two dosing cycles, at least three dosing cycles, or at least four dosing cycles.

In some embodiments, the second phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4).

In some embodiments, the second phase comprises administering the bispecific antibody to the individual on day 1 and day 15 of C1, C2, C3, and/or C4.

In some aspects, for each administration during the second phase, a target dose of the bispecific antibody (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject.

In some aspects, the third phase includes at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, or at least seven dosing cycles.

In some embodiments, the third phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7).

In some embodiments, the third phase comprises administering the bispecific antibody to the individual on day 1 of C1, C2, C3, C4, C5, C6, and/or C7.

In some embodiments, for each administration during the third phase, a target dose of the bispecific antibody (e.g., 90 mg, 132 mg, or 160 mg) is administered to the individual.

In some aspects, the target dose is 90 mg.

In some aspects, the bispecific antibody is administered to a subject as a single therapy.

In some aspects, the bispecific antibody is administered intravenously to a subject.

In another aspect, the present invention provides a method for treating an individual with MM, the method comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 and an immunomodulatory drug (IMiD) in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W), wherein the individual does not have (i) a history of MAS or HLH, (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with intravenous antivirals.

In another aspect, the present invention provides a bispecific antibody that binds to FcRH5 and CD3 for use in treating an individual with MM, the treatment comprising administering the bispecific antibody and an IMiD to the individual in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W), wherein the individual does not have (i) a history of MAS or HLH, and (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with intravenous antivirals.

In some aspects, each dosing cycle of the first phase and the second phase is a 28-day dosing cycle.

In some aspects, the dosing regimen further comprises a preliminary phase prior to the first phase, which comprises one or more dosing cycles.

In some aspects, the pre-phase comprises administering the bispecific antibody to the individual weekly (QW).

In some aspects, each dosing cycle in the preliminary phase is a 21-day dosing cycle.

In some aspects, the pre-phase includes one dosing cycle (C1).

In some aspects, the pre-phase comprises administering the bispecific antibody to the individual on day 1, day 8, and day 15 of C1.

In some aspects, for each administration in the pre-phase, a target dose of the bispecific antibody (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject.

In some aspects, the preliminary phase comprises administering to the individual a first increasing dose of the bispecific antibody.

In some aspects, the first escalating dose is administered to the subject on day 1 of C1.

In some aspects, a target dose (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject on days 8 and 15 of C1.

In some aspects, the first incremental dose is about 2.73% of the target dose. In some aspects, the first incremental dose is about 4% of the target dose.

In some aspects, the first incremental dose is 3.6 mg.

In some aspects, the preliminary phase comprises administering to the individual a first increasing dose and a second increasing dose of the bispecific antibody.

In some aspects: (i) the first incremental dose is an amount of about 0.23% of the target dose; and (ii) the second incremental dose is an amount of about 2.73% of the target dose.

In some aspects: (a) the first incremental dose is an amount that is 0.33% of the target dose; and (b) the second incremental dose is an amount that is about 4% of the target dose.

In some aspects, the first increasing dose is 0.3 mg and the second increasing dose is 3.6 mg.

In some aspects: (a) the first incremental dose is an amount of 0.23% of the target dose; and (b) the second incremental dose is an amount of about 2.73% of the target dose.

In some aspects: (a) the first incremental dose is an amount that is 0.33% of the target dose; and (b) the second incremental dose is an amount that is about 4% of the target dose.

In some aspects, the first increasing dose is 0.3 mg and the second increasing dose is 3.3 mg.

In some aspects, the first escalating dose is administered to the subject on day 1 of C1, and the second escalating dose is administered to the subject on day 8 of C1.

In some aspects, the target dose (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject on day 8 of C1. In some aspects, the target dose (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject on day 15 of C1.

In some aspects, each dosing cycle in the preliminary phase is a 14-day dosing cycle.

In some aspects, the pre-phase includes one dosing cycle (C1).

In some aspects, the pre-phase comprises administering the bispecific antibody to the individual on: (a) day 1, day 2, and day 8 of C1; (b) day 1, day 3, and day 8 of C1; or (c) day 1, day 4, and day 8 of C1.

In some aspects, if the individual has an adverse reaction to the bispecific antibody, the bispecific antibody is administered to the individual on days 1, 3, and 8 of C1 or on days 1, 4, and 9 of C1.

In some aspects: (a) the first incremental dose is an amount of 0.23% of the target dose; and (b) the second incremental dose is an amount of about 2.5% of the target dose.

In some aspects: (a) the first incremental dose is an amount of 0.33% of the target dose; and (b) the second incremental dose is an amount of about 3.6% of the target dose.

In some aspects, the first increasing dose is 0.3 mg and the second increasing dose is 3.3 mg.

In some aspects, the first escalating dose is administered on day 1 of C1 and the second escalating dose is administered on day 2 of C1; (b) the first escalating dose is administered on day 1 of C1 and the second escalating dose is administered on day 3 of C1; or (c) the first escalating dose is administered on day 1 of C1 and the second escalating dose is administered on day 4 of C1.

In some aspects, the target dose is administered to the subject on day 8 of C1.

In some aspects, the target dose is administered to the subject on day 15 of C1.

In some aspects, the first phase includes at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, or at least six dosing cycles.

In some aspects, the first phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6).

In some aspects, the first phase comprises administering the bispecific antibody to the individual on day 1 and day 15 of C1, C2, C3, C4, C5 and/or C6.

In some aspects, for each administration during the first phase, a target dose of the bispecific antibody (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject.

In some aspects, the second phase includes at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, or at least seven dosing cycles.

In some embodiments, the second phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7).

In some aspects, the second phase comprises administering the bispecific antibody on day 1 of C1, C2, C3, C4, C5, C6 and/or C7.

In some embodiments, for each administration during the second phase, a target dose of the bispecific antibody (e.g., 90 mg, 132 mg, or 160 mg) is administered to the individual.

In some aspects, the target dose is 132 mg. In some aspects, the target dose is 90 mg.

In some aspects, the bispecific antibody is administered intravenously to the individual.

In some aspects, the IMiD is administered to the subject on day 1 to day 21 of each dosing cycle in the first phase and/or the second phase.

In some aspects, the IMiD is pomalidomide.

In some aspects, pomalidomide is administered to the subject in an amount of about 2 to 4 mg (e.g., 2 mg, 3 mg, or 4 mg). In some aspects, pomalidomide is administered to the subject in an amount of about 2 mg. In some aspects, pomalidomide is administered to the subject in an amount of about 3 mg. In some aspects, pomalidomide is administered to the subject in an amount of about 4 mg.

In some aspects: (a) during the first phase C2, the dose of pomalidomide of about 2 mg is increased to about 4 mg; and (b) the subject has an absolute neutrophil count greater than or equal to 1000/µl and platelets greater than or equal to 75000/µl.

In some aspects, pomalidomide is administered to the subject orally (PO).

In some aspects, the dosing regimen further comprises administering a corticosteroid to the individual during the pre-phase, the first phase, and/or the second phase.

In some aspects, the corticosteroid is administered QW to the subject during the pre-phase, the first phase, and/or the second phase.

In some aspects, the corticosteroid is administered to a subject intravenously or orally.

In some aspects, the corticosteroid is administered to the subject during the pre-phase on day 1, day 8, and day 15 of C1.

In some aspects, the corticosteroid is administered intravenously to the subject during the pre-phase on day 1, day 8, and day 15 of C1.

In some aspects, the corticosteroid is administered to the subject on day 1, day 8, day 15, and day 22 of C1, C2, C3, and/or C4 during the first phase.

In some aspects, the corticosteroid is administered to the subject: (i) intravenously on days 1 and 15 of C1, C2, C3, and/or C4 during the first phase; and (ii) orally on days 8 and 22 of C1, C2, C3, and/or C4 during the first phase.

In some aspects, the corticosteroid is administered to the subject during the pre-phase on: (a) day 1, day 2, and day 8 of C1; (b) day 1, day 3, and day 8 of C1; or (C) day 1, day 4, and day 8 of C1.

In some aspects, the corticosteroid is administered intravenously to the subject during the pre-phase on days 1, 2, and 8 of C1.

In some aspects, the corticosteroid is administered to the subject on day 1, day 8, day 15, and day 22 of C1, C2, C3, and/or C4 during the first phase.

In some aspects, the corticosteroid is administered to the subject: (a) intravenously on days 1 and 15 of C1 during the first phase; and (b) orally on days 8 and 22 of C1 during the first phase.

In some aspects, the corticosteroid is further administered to the subject during the first phase on day 1, day 8, day 15 and/or day 22 of C5, C6, C7, C8 and/or C9.

In some aspects, the corticosteroid is administered to the subject: (i) intravenously on day 1 and/or day 15 of C5 and/or C6 during the first phase; and (ii) orally on day 8 and/or day 22 of C5 and/or C6 during the first phase.

In some aspects, the corticosteroid is further administered to the subject during the second phase on day 1, day 8, day 15 and/or day 22 of C1, C2, C3, C4, C5, C6, C7, C8 and/or C9.

In some aspects, the corticosteroid is administered to the subject: (i) intravenously or orally on Day 1 of C1, C2, C3, C4, C5, C6, C7, C8 and/or C9 during the Second Phase; and (ii) orally on Day 8, Day 15 and/or Day 22 of C1, C2, C3, C4, C5, C6, C7, C8 and/or C9 during the Second Phase.

In some aspects, a corticosteroid is administered intravenously to a subject prior to administration of the bispecific antibody.

In some aspects, the corticosteroid is administered intravenously to the subject about 1 hour prior to administration of the bispecific antibody.

In some aspects, the corticosteroid is dexamethasone or methylprednisolone.

In some aspects, the corticosteroid is dexamethasone.

In some aspects, dexamethasone is administered to the subject in an amount of about 20 mg. In some aspects, dexamethasone is administered to the subject in an amount of about 15 mg. In some aspects, dexamethasone is administered to the subject in an amount of about 4 mg.

In some aspects, methylprazosin is administered to a subject in an amount of about 80 mg.

In another aspect, the present invention provides a method for treating an individual with MM, the method comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 and an anti-cluster of differentiation 38 (CD38) antibody in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every three weeks (Q3W); and (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W), wherein the individual does not have (i) a history of MAS or HLH, (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with intravenous antivirals.

In another aspect, the present invention provides a bispecific antibody that binds to FcRH5 and CD3 for use in treating an individual with MM, the treatment comprising administering the bispecific antibody and an anti-CD38 antibody to the individual in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every three weeks (Q3W); and (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W), wherein the individual does not have (i) a history of MAS or HLH, and (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with intravenous antivirals.

In some aspects, each dosing cycle of the run-in phase is a 21-day dosing cycle.

In some aspects, each dosing cycle of the second phase is a 28-day dosing cycle.

In some aspects, the dosing regimen further comprises an introduction phase prior to the first phase, which comprises one or more dosing cycles.

In some aspects, the introduction phase comprises administering the bispecific antibody to the individual weekly (QW).

In some aspects, each dosing cycle of the first phase is a 21-day dosing cycle.

In some aspects, the introduction phase includes one dosing cycle (C1).

In some aspects, the introduction phase comprises administering the bispecific antibody to the individual on: (i) day 2, day 9, and day 16 of C1; or (ii) day 3, day 9, and day 16 of C1.

In some aspects, if the individual has an adverse reaction to the anti-CD38 antibody, the bispecific antibody is administered to the individual on days 3, 9, and 16 of C1.

In some aspects, for each administration during the introduction phase, a target dose of the bispecific antibody (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject.

In some aspects, the introduction phase comprises administering to the individual a first increasing dose of the bispecific antibody.

In some aspects, the first escalating dose is administered to the subject on day 2 of C1 or on day 3 of C1.

In some aspects, a target dose (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject on days 9 and 16 of C1.

In some aspects, the first incremental dose is about 2.25% of the target dose.

In some aspects, the first incremental dose is 3.6 mg.

In some embodiments, the introduction phase comprises administering the bispecific antibody to the individual on: (a) days 9, 10, and 16 of C1; (b) days 9, 11, and 16 of C1; or (c) days 9, 12, and 16 of C1.

In some aspects, if the individual has an adverse reaction to the bispecific antibody, the bispecific antibody is administered to the individual on days 9, 11, and 16 of C1 or on days 9, 12, and 16 of C1.

In some aspects: (a) the first incremental dose is about 0.19% of the target dose; and (b) the second incremental dose is about 2.1% of the target dose.

In some embodiments, the first increasing dose is 0.3 mg and the second increasing dose is 3.3 mg. In some embodiments: (a) the first increasing dose is administered to the subject on day 2 of C1 or on day 3 of C1; and (b) the second increasing dose is administered to the subject on day 9 of C1.

In some aspects: (a) the first incremental dose is about 0.19% of the target dose; and (b) the second incremental dose is about 2.25% of the target dose.

In some aspects, the first increasing dose is 0.3 mg and the second increasing dose is 3.6 mg.

In some aspects: (a) the first escalating dose is administered to the subject on day 9 of C1; and (b) the second escalating dose is administered to the subject on day 10, day 11, or day 12 of C1.

In some aspects, if the individual has an adverse reaction to the bispecific antibody, the bispecific antibody is administered to the individual on days 9, 11, and 16 of C1 or on days 9, 12, and 16 of C1.

In some aspects, the introduction phase comprises administering to the subject a first increasing dose and a second increasing dose of the bispecific antibody.

In some aspects: (a) the first incremental dose is about 0.19% of the target dose; and (b) the second incremental dose is about 2.1% of the target dose.

In some aspects: (a) the first escalating dose is administered to the subject on day 9 of C1; and (b) the second escalating dose is administered to the subject on day 10, day 11, or day 12 of C1.

In some aspects, the target dose (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject on day 16 of C1.

In some embodiments, the first stage includes a first sub-stage and a second sub-stage.

In some embodiments, the first subphase of the first phase includes at least two dosing cycles.

In some embodiments, the first sub-phase of the first phase includes a first dosing cycle (C1) and a second dosing cycle (C2).

In some aspects, the first subphase of the first phase comprises administering the bispecific antibody on day 1 of C1 and C2.

In some aspects, for each administration during the first subphase of the first phase, a target dose of the bispecific antibody (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject.

In some embodiments, the second subphase includes at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, or at least five dosing cycles.

In some embodiments, the second sub-phase of the first phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5).

In some aspects, the second subphase of the first phase comprises administering the bispecific antibody on day 1 of C1, C2, C3, C4 and/or C5.

In some aspects, for each administration during the second subphase of the first phase, a target dose of the bispecific antibody (e.g., 90 mg, 132 mg, or 160 mg) is administered to the subject.

In some embodiments, the second phase includes at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, or at least five dosing cycles.

In some embodiments, the second phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5).

In some aspects, the second phase comprises administering the bispecific antibody on day 1 of C1, C2, C3, C4 and/or C5.

In some embodiments, for each administration during the second phase, a target dose of the bispecific antibody (e.g., 90 mg, 132 mg, or 160 mg) is administered to the individual.

In some aspects, the target dose is 160 mg.

In some aspects, the bispecific antibody is administered intravenously to a subject.

In some aspects, the anti-CD38 antibody is administered to the subject during the introduction phase.

In some aspects, the introduction phase comprises a first dosing cycle (C1) and the anti-CD38 antibody is administered to the subject during the introduction phase on day 1, day 8, and day 15 of C1.

In some aspects, the anti-CD38 antibody is administered to the subject during a first subphase of the first phase.

In some aspects, the anti-CD38 antibody is administered to the subject on day 1, day 8, and day 15 of C1 and/or C2 during the first subphase of the first phase.

In some aspects, the anti-CD38 antibody is administered to the subject during the second subphase of the first phase.

In some aspects, the anti-CD38 antibody is administered to the subject on day 1 of C1, C2, C3, C4 and/or C5 during the second subphase of the first phase.

In some aspects, the anti-CD38 antibody is administered to the subject during the second phase.

In some aspects, the anti-CD38 antibody is administered to the subject on day 1 of C1, C2, C3, C4 and/or C5 during the second phase.

In some aspects, the anti-CD38 antibody is administered to the individual subcutaneously (SC).

In some aspects, the anti-CD38 antibody is daratumumab or isatuximab.

In some aspects, the anti-CD38 antibody is daratumumab.

In some aspects, daratumumab is administered to the subject at a dose of about 1800 mg.

In some aspects, the dosing regimen further comprises administering a corticosteroid to the subject during any dosing period within the introduction phase, the first phase, and/or the second phase.

In some aspects, the corticosteroid is administered to the subject during the introduction phase.

In some aspects, the run-in phase comprises a first dosing cycle (C1) and the corticosteroid is administered to the subject during the run-in phase on day 1, day 2, day 8, day 9, day 15, and day 16 of C1.

In some aspects, the corticosteroid is further administered to the subject during the run-in phase on day 3, day 10, day 11, or day 12 of C1.

In some aspects, the corticosteroid is administered to the subject QW during the first subphase of the first phase.

In some aspects, the corticosteroid is administered to the subject on day 1, day 8, and day 15 of C1 during the first subphase of the first phase.

In some aspects, the corticosteroid is administered to the subject on day 1 of C2 during the first subphase of the first phase.

In some aspects, the corticosteroid is administered to the subject Q3W during the second subphase of the first phase.

In some aspects, the corticosteroid is administered to the subject on day 1 of C1, C2, C3, C4, C5 during the second subphase of the first phase.

In some aspects, the corticosteroid is administered to the subject Q4W during the second phase.

In some aspects, the corticosteroid is administered to the subject on day 1 of C1, C2, C3, C4, and/or C5 during the second phase.

In some aspects, the corticosteroid is administered to the individual intravenously and/or orally.

In some aspects, the corticosteroid is administered to the subject as follows: (a) intravenously or orally on day 1, day 8, and day 15 of C1 during the run-in phase; (b) intravenously on day 2, day 9, and day 16 of C1 during the run-in phase; (c) intravenously on day 1 of C1 during the first subphase of the first phase; (d) intravenously or orally on day 8 and day 15 of C1 during the first subphase of the first phase; (e) intravenously or orally on day 1 of C2 during the first subphase of the first phase; and (f) Administer intravenously or orally on Day 1 of C1 during the second subphase of this first phase.

In some aspects, the corticosteroid is administered to the subject as follows: (a) intravenously or orally on Day 1, Day 2, Day 3, Day 8, and Day 15 of C1 during the run-in phase; (b) intravenously on Day 9 and Day 16 of C1 during the run-in phase; (c) intravenously on Day 1 of C1 during the first subphase of Phase 1; (d) intravenously or orally on Day 8 and Day 15 of C1 during the first subphase of Phase 1; and (e) intravenously or orally on Day 1 of C2 during the first subphase of Phase 1.

In some aspects, the corticosteroid is further administered to the subject intravenously or orally on day 1 of C1, C2, C3, C4, and/or C5 during the second subphase of the first phase.

In some aspects, the corticosteroid is further administered intravenously or orally to the subject on day 1 of C2, C3, C4, and/or C5 during the second phase.

In some aspects, the corticosteroid is administered intravenously to the individual as premedication of the bispecific antibody.

In some aspects, the corticosteroid is administered to the subject about 1 hour prior to administration of the bispecific antibody: (a) on day 2 or day 3 of C1 during the run-in phase; (b) on day 9 and day 16 of C1 during the run-in phase; and (c) on day 1 of C2 during the first subphase of the first phase.

In some aspects, the corticosteroid is administered to the subject about 1 hour prior to administration of the bispecific antibody on: (a) day 9 of C1 during the run-in phase; (b) day 10, day 11, or day 12 of C1 during the run-in phase; (c) day 16 of C1 during the run-in phase; and (d) day 1 of C2 during the first subphase of the first phase.

In some aspects, the corticosteroid is dexamethasone or methylprednisolone.

In some aspects, the corticosteroid is dexamethasone.

In some aspects, dexamethasone is administered to the subject in an amount of about 20 mg. In some aspects, dexamethasone is administered to the subject in an amount of about 15 mg. In some aspects, dexamethasone is administered to the subject in an amount of about 4 mg.

In some aspects, the methylprazosin is administered to the subject in an amount of about 80 mg.

In some embodiments, the bispecific antibody includes an anti-FcRH5 arm, the anti-FcRH5 arm includes a first binding domain, the first binding domain includes the following six highly variable regions (HVRs): (a) HVR-H1, which includes the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2, which includes the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3, which includes the amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1, which includes the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2, which includes the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3, which includes The amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

In some aspects, the bispecific antibody comprises an anti-FcRH5 arm, the anti-FcRH5 arm comprising a first binding domain, the first binding domain comprising: (a) a heavy chain variable (VH) domain, the heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain, the light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b).

In some aspects, the first binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 7; and a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

In some aspects, the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising the following six HVRs: (i) HVR-H1 comprising an amino acid sequence of SYYIH (SEQ ID NO: 9); (ii) HVR-H2 comprising an amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (iii) HVR-H3 comprising an amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (iv) HVR-L1 comprising an amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (v) HVR-L2 comprising an amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (vi) HVR-L3 comprising KQSFILRT (SEQ ID NO: 14) of the amino acid sequence.

In some aspects, the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b).

In some aspects, the second binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 15; and a VL domain comprising the amino acid sequence of SEQ ID NO: 16.

In some aspects, the bispecific antibody comprises: an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1); and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein: (i) H1 comprises the amino acid sequence of SEQ ID NO: 35; (ii) L1 comprises the amino acid sequence of SEQ ID NO: 36; (iii) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (iv) L2 comprises the amino acid sequence of SEQ ID NO: 38.

In some aspects, the bispecific antibody comprises a deglycosylation site mutation.

In some aspects, the deglycosylation site mutation reduces the effector function of the bispecific antibody.

In some aspects, the deglycosylation site mutation is a substitution mutation.

In some aspects, the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.

In some aspects, the bispecific antibody is a monoclonal antibody.

In some aspects, the bispecific antibody is a humanized antibody.

In some aspects, the bispecific antibody is a chimeric antibody.

In some aspects, the bispecific antibody is an antibody fragment that binds FcRH5 and CD3.

In some aspects, the antibody fragment is selected from the group consisting of Fab, Fab'-SH, Fv, scFv and (Fab') ₂ fragments.

In some aspects, the bispecific antibody is a full-length antibody.

In some aspects, the bispecific antibody is an IgG antibody.

In some aspects, the IgG antibody is an _IgG1 antibody.

In some aspects, the bispecific antibody comprises one or more heavy chain constitutive domains, wherein the one or more heavy chain constitutive domains are selected from a first CH1 (CH1 ₁ ) domain, a first CH2 (CH2 ₁ ) domain, a first CH3 (CH3 ₁ ) domain, a second CH1 (CH1 ₂ ) domain, a second CH2 (CH2 ₂ ) domain, and a second CH3 (CH3 ₂ ) domain.

In some aspects, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

In some embodiments, the _CH3.1 domain and the _CH3.2 domain each include a protuberance or a cavity, and wherein the protuberance or the cavity in the _CH3.1 domain can be positioned in the cavity or the protuberance in the _CH3.2 domain, respectively.

In some embodiments, the CH3 ₁ domain and the CH3 ₂ domain meet at the interface between the protuberance and the cavity.

In some aspects, the CH2 ₁ domain and the CH2 ₂ domain each include a protuberance or a cavity, and wherein the protuberance or the cavity in the CH2 ₁ domain can be positioned in the cavity or the protuberance in the CH2 ₂ domain, respectively.

In some embodiments, the CH2 ₁ and the CH2 ₂ domains meet at the interface between the protuberance and the cavity.

In some aspects, the anti-FcRH5 arm comprises the protuberance and the anti-CD3 arm comprises the cavity.

In some aspects, the CH3 domain of the anti-FcRH5 arm comprises a protuberance comprising a T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

In some aspects, the bispecific antibody is cevostamab.

In some aspects, the bispecific antibody is administered to a subject concurrently with one or more additional therapeutic agents.

In some aspects, the bispecific antibody is administered to a subject prior to administration of one or more additional therapeutic agents.

In some aspects, the bispecific antibody is administered to a subject after administration of one or more additional therapeutic agents.

In some aspects, the one or more additional therapeutic agents comprises an effective amount of tocilizumab.

In some aspects, tocilizumab is administered to a subject by intravenous infusion.

In some aspects: (i) the individual weighs ≥ 30 kg and tocilizumab is administered to the individual at a dose of 8 mg/kg; (ii) the individual weighs < 30 kg and tocilizumab is administered to the individual at a dose of 12 mg/kg; or (iii) wherein the final dose administered does not exceed 800 mg.

In some aspects, tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody.

In some aspects, the one or more additional therapeutic agents comprises an effective amount of a B cell maturation antigen (BCMA) directed therapy.

In some aspects, the individual has a cytokine release syndrome (CRS) event, and the method further comprises treating the symptoms of the CRS event while discontinuing treatment with the bispecific antibody.

In some aspects, the method further comprises administering to the individual an effective amount of tocilizumab to treat the CRS event.

In some aspects, tocilizumab is administered intravenously to a subject as a single dose of about 8 mg/kg.

In some aspects, the CRS event does not resolve or worsens within 24 hours of treating symptoms of the CRS event, and the method further comprises administering to the individual one or more additional doses of tocilizumab to control the CRS event.

In some aspects, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg/kg.

In some aspects, the one or more additional therapeutic agents comprises an effective amount of acetaminophen or paracetamol.

In some aspects, acetaminophen or acetaminophen is administered to the subject in an amount between about 500 mg and about 1000 mg.

In some aspects, acetaminophen or acetaminophen is administered orally to the subject.

In some aspects, the one or more additional therapeutic agents includes an effective amount of diphenhydramine.

In some aspects, diphenhydramine is administered to the subject in an amount between about 25 mg and about 50 mg.

In some aspects, diphenhydramine is administered orally to the subject.

In some aspects, the MM is relapsed or refractory (R/R) MM.

In some aspects, the individual has received at least three prior lines of treatment for MM.

In some aspects, the individual has received at least four prior lines of treatment for the MM.

In some aspects, the subject has been exposed to prior therapy including a proteasome inhibitor, an IMiD, and/or an anti-CD38 therapy.

In some aspects, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib.

In some aspects, the IMiD is thalidomide, lenalidomide, or pomalidomide.

In some aspects, the anti-CD38 therapy is daratumumab, MOR202, or isatuximab.

In some aspects, the anti-CD38 therapeutic agent is daratumumab.

In some aspects, the individual has received prior treatment including autologous stem cell transplantation (ASCT) or CAR-T cell therapy, wherein the last administration of the CAR-T cell therapy was at least 12 weeks before initiation of the regimen.

In some aspects, the subject has: (a) an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) less than or equal to 2.5 times the upper limit of normal (ULN); and/or (b) a platelet count greater than or equal to 75,000/mm ³ .

In another aspect, the present invention provides a method of treating a subject having MM, the method comprising administering (e.g., IV) a monotherapy of ceftriaxone to the subject in a dosing regimen comprising: (i) a first phase comprising a first dosing cycle (C1) and a second dosing cycle (C2); (ii) a second phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); and (iii) a third phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle. (C7), wherein each dosing cycle of the first phase, the second phase, and the third phase is a 28-day dosing cycle, and ceftriaxone is administered to the individual as follows: A) (i) at escalating doses on Day 1 of C1 during the first phase; (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 8, Day 15, and Day 22 of C1 during the first phase; (iii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1, Day 8, Day 15, and Day 22 of C2 during the first phase; (iv) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1, Day 8, Day 15, and Day 22 of C2 during the first phase; or 160 mg) on Day 1 and Day 15 of C1, C2, C3, and C4 during Phase II; and (v) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of C1, C2, C3, C4, C5, C6, and C7 during Phase III; or B) (i) at a first escalating dose on Day 1 of C1 during Phase I and as a second escalating dose on Day 8 of C1 during Phase I; (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 15 and Day 22 of C1 during Phase I; (iii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on days 1, 8, 15, and 22 of C2 during Phase 1; (iv) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on days 1 and 15 of C1, C2, C3, and C4 during Phase 2; and (v) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on day 1 of C1, C2, C3, C4, C5, C6, and C7 during Phase 3, wherein the individual does not have (i) a history of MAS or HLH, (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with an intravenous antiviral. In some aspects, the booster dose is 3.6 mg and the target dose is 90 mg. In some aspects, the first booster dose is 0.3 mg, the second booster dose is 3.6 mg, and the target dose is 90 mg.

In another aspect, the present invention provides ceftriaxone for use in treating an individual with MM, the treatment comprising administering (e.g., IV) ceftriaxone to the individual as a monotherapy in a dosing regimen comprising: (i) a first phase comprising a first dosing cycle (C1) and a second dosing cycle (C2); (ii) a second phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); and (iii) a third phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6). and a seventh dosing cycle (C7), wherein each of the dosing cycles of the first phase, the second phase, and the third phase is a 28-day dosing cycle, and ceftriaxone is administered to the subject as follows: A) (i) at escalating doses on Day 1 of C1 during the first phase; (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 8, Day 15, and Day 22 of C1 during the first phase; (iii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1, Day 8, Day 15, and Day 22 of C2 during the first phase; (iv) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 and Day 15 of C1, C2, C3, and C4 during Phase II; and (v) at the target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of C1, C2, C3, C4, C5, C6, and C7 during Phase III; or B) (i) at the first escalating dose on Day 1 of C1 during Phase I and as the second escalating dose on Day 8 of C1 during Phase I; (ii) at the target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 15 and Day 22 of C1 during Phase I (iii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on days 1, 8, 15, and 22 of C2 during Phase 1; (iv) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on days 1 and 15 of C1, C2, C3, and C4 during Phase 2; and (v) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on day 1 of C1, C2, C3, C4, C5, C6, and C7 during Phase 3, wherein the individual does not have (i) a history of MAS or HLH, and (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with an intravenous antiviral. In some aspects, the booster dose is 3.6 mg and the target dose is 90 mg. In some aspects, the first booster dose is 0.3 mg, the second booster dose is 3.6 mg, and the target dose is 90 mg.

In another aspect, the present invention provides a method for treating an individual with MM, the method comprising administering ceftriaxone, pomalidomide, and dexamethasone to the individual in a dosing regimen, the dosing regimen comprising: (i) a pre-stage comprising a 21-day dosing cycle (C1); (ii) a first stage after the pre-stage comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6), wherein each dosing cycle of the first stage is a 28-day dosing cycle; and (iii) a second stage after the first stage comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6). (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), wherein each dosing cycle of the second phase is a 28-day dosing cycle, wherein ceftriaxone is administered (e.g., IV) to the individual as follows: (i) at a first escalating dose on day 1 of C1 during the pre-phase and as a second escalating dose on day 8 of C1 during the pre-phase; (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on day 15 of C1 during the pre-phase; (iii) at a target dose on day 2 of C1 during the first phase; C1, C2, C3, C4, C5, and C6 on Days 1 and 15 during Phase 1; and (iv) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of C1, C2, C3, C4, C5, C6, and C7 during Phase 2; pomalidomide is administered to the subject (e.g., PO) as follows: (i) at a dose of about 2-4 mg (e.g., 2 mg, 3 mg, or 4 mg) on Days 1 through 21 of C1, C2, C3, C4, C5, and C6 during Phase 1; and (ii) at a dose of about 2-4 mg (e.g., 2 mg, 3 mg, or 4 mg) on Days 1 through 21 of C1, C2, C3, C4, C5, and C6 during Phase 2 C1, C2, C3, C4, C5, C6 and C7 on days 1 to 21; and dexamethasone is administered to the subject (e.g., IV and/or PO) as follows: (i) at a dose of about 20 mg on days 1, 8 and 15 of C1 during the Pre-Phase; and (ii) at a dose of about 20 mg on days 1, 8, 15 and 22 of C1, C2, C3 and C4 during the First Phase, as appropriate, wherein dexamethasone is administered to the subject as follows: (iii) at a dose of about 20 mg on days 1, 8, 15 and 22 of C5 and C6 during the First Phase and (iv) administered at a dose of about 20 mg on Day 1, Day 8, Day 15, and Day 22 of C1, C2, C3, C4, C5, C6, and C7 during a second phase, wherein the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent. In some aspects, the first booster dose is 0.3 mg, the second booster dose is 3.6 mg, and the target dose is 132 mg. In some aspects, the first incremental dose is 0.3 mg, the second incremental dose is 3.6 mg, and the target dose is 90 mg.

In another aspect, the present invention provides ceftriaxone for use in treating an individual with MM, the treatment comprising administering ceftriaxone, pomalidomide and dexamethasone to the individual in a dosing regimen, the dosing regimen comprising: (i) a pre-stage comprising a 21-day dosing cycle (C1); (ii) a first stage after the pre-stage comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5) and a sixth dosing cycle (C6), wherein each dosing cycle of the first stage is a 28-day dosing cycle; and (iii) a second stage after the first stage comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), wherein each dosing cycle of the second phase is a 28-day dosing cycle, and wherein ceftriaxone is administered (e.g., IV) to the individual as follows: (i) at a first escalating dose on day 1 of C1 during the pre-phase and as a second escalating dose on day 8 of C1 during the pre-phase; (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on day 15 of C1 during the pre-phase; (iii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 and Day 15 of C1, C2, C3, C4, C5, and C6 during Phase 1; and (iv) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of C1, C2, C3, C4, C5, C6, and C7 during Phase 2; pomalidomide is administered to the subject (e.g., PO) as follows: (i) at a dose of about 2-4 mg (e.g., 2 mg, 3 mg, or 4 mg) on Day 1 through Day 21 of C1, C2, C3, C4, C5, and C6 during Phase 1; and (ii) at a dose of about 2-4 mg (e.g., 2 and (ii) about 20 mg on days 1, 8, 15, and 22 of C1, C2, C3, C4, C5, C6, and C7 during the First Phase, as appropriate, wherein dexamethasone is administered to the subject as follows: (iii) about 20 mg on days 1, 8, 15, and 22 of C1, C2, C3, and C4 during the First Phase; and (iv) about 20 mg on days 1, 8, 15, and 22 of C1, C2, C3, and C4 during the First Phase. and (iv) about 20 mg on days 1, 8, 15, and 22 of C1, C2, C3, C4, C5, C6, and C7 during a second phase, wherein the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or the need for treatment with an intravenous antiviral agent. In some embodiments, the first increment is 0.3 mg, the second increment is 3.6 mg, and the target dose is 132 mg. In some embodiments, the first increment is 0.3 mg, the second increment is 3.6 mg, and the target dose is 90 mg.

In another aspect, the present invention provides a method for treating an individual with MM, the method comprising administering ceftriaxone, pomalidomide, and dexamethasone to the individual in a dosing regimen, the dosing regimen comprising: (i) a pre-stage comprising a 14-day dosing cycle (C1); (ii) a first stage after the pre-stage comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6), wherein each dosing cycle of the first stage is a 28-day dosing cycle; and (iii) a second stage after the first stage comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6). (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), wherein each dosing cycle of the second phase is a 28-day dosing cycle, wherein ceftriaxone is administered to the subject (e.g., IV) as follows: (i) at a first escalating dose on day 1 of C1 during the pre-phase, and as a second escalating dose on day 2, day 3, or day 4 of C1 during the pre-phase; (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on day 8 of C1 during the pre-phase; (iii) at a target dose pomalidomide is administered to the subject (e.g., PO): (i) at a dose of about 2-4 mg on Days 1 to 21 of C1, C2, C3, C4, C5, and C6 during Phase 1; and (ii) at a dose of about 2-4 mg on Days 1 to 21 of C1, C2, C3, C4, C5, and C6 during Phase 2. C1, C2, C3, C4, C5, C6 and C7 on days 1 to 21; and dexamethasone is administered to the subject (e.g., IV and/or PO) as follows: (i) at a dose of about 20 mg on days 1 and 8 of C1 during the pre-phase; (ii) at a dose of about 20 mg on days 2, 3 or 4 of C1 during the pre-phase; (iii) at a dose of about 20 mg on days 1, 8, 15 and 22 of C1, C2, C3 and C4 during the first phase, as appropriate, wherein dexamethasone is administered to the subject as follows: (iv) at a dose of about 20 mg and (v) about 20 mg on days 1, 8, 15, and 22 of C1, C2, C3, C4, C5, C6, and C7 during Phase 2, wherein the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or the need for treatment with intravenous antivirals. In some embodiments, the first increment is 0.3 mg, the second increment is 3.6 mg, and the target dose is 132 mg. In some embodiments, the first increment is 0.3 mg, the second increment is 3.6 mg, and the target dose is 90 mg.

In another aspect, the present invention provides ceftriaxone for use in treating an individual with MM, the treatment comprising administering ceftriaxone, pomalidomide and dexamethasone to the individual in a dosing regimen, the dosing regimen comprising: (i) a pre-stage comprising a 14-day dosing cycle (C1); (ii) a first stage after the pre-stage comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5) and a sixth dosing cycle (C6), wherein each dosing cycle of the first stage is a 28-day dosing cycle; and (iii) a second stage after the first stage comprising a first dosing cycle The invention relates to a method of treating a subject with cefotaxime (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), wherein each dosing cycle of the second phase is a 28-day dosing cycle, wherein cefotaxime (C6) is administered to the subject (e.g., IV) as follows: (i) at a first escalating dose on day 1 of C1 during the pre-phase, and as a second escalating dose on day 2, day 3, or day 4 of C1 during the pre-phase; and (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on day 8 of C1 during the pre-phase. pomalidomide is administered to the subject (e.g., PO): (i) at a dose of about 2-4 mg on days 1 to 21 of C1, C2, C3, C4, C5, and C6 during Phase 1; and (ii) at a dose of about 2-4 mg on days 1 to 21 of C1, C2, C3, C4, C5, and C6 during Phase 1. and dexamethasone is administered to the subject as follows: (i) at a dose of about 20 mg on days 1 and 8 of C1 during the pre-phase; (ii) at a dose of about 20 mg on days 2, 3, or 4 of C1 during the pre-phase; (iii) at a dose of about 20 mg on days 1, 8, 15, and 22 of C1, C2, C3, and C4 during the first phase, as appropriate, wherein dexamethasone is administered to the subject as follows (e.g., IV and/or PO): (iv) about 20 mg on Day 1, Day 8, Day 15, and Day 22 of C5 and C6 during Phase 1; and (v) about 20 mg on Day 1, Day 8, Day 15, and Day 22 of C1, C2, C3, C4, C5, C6, and C7 during Phase 2, wherein the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or the need for treatment with an intravenous antiviral agent. In some embodiments, the first increment is 0.3 mg, the second increment is 3.6 mg, and the target dose is 132 mg. In some embodiments, the first increment is 0.3 mg, the second increment is 3.6 mg, and the target dose is 90 mg.

In another aspect, the present invention provides a method for treating an individual suffering from MM, the method comprising administering ceftriaxone, daratumumab and dexamethasone to the individual in a dosing regimen, the dosing regimen comprising: (i) an introduction phase, which comprises a 21-day dosing cycle (C1); (ii) a first phase after the introduction phase, which comprises a first sub-phase and a second sub-phase, wherein the first sub-phase comprises a first dosing cycle (C1) and a second dosing cycle (C2), and the second sub-phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4) and a fifth dosing cycle (C5), wherein each dosing cycle of the first phase is 21 days; day dosing cycle; and (iii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, wherein the bispecific antibody is administered (e.g., IV) to the subject as follows: (i) at a first escalating dose on day 2 of C1 during the run-in phase and as a second escalating dose on day 9 of C1 during the run-in phase; (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on day 9 of C1 during the run-in phase daratumumab is administered to the subject (e.g., IV) as follows: (i) at a dose of about 1800 mg on Day 1, Day 8, and Day 15 of C1 during the Run-In Phase; (ii) at a dose of about 1800 mg on Day 1, Day 8, and Day 15 of C1 and C2 during the First Sub-Phase of the First Phase; (iii) at a dose of about 1800 mg on Day 1, Day 8, and Day 15 of C1 and C2 during the First Sub-Phase of the First Phase; and (iv) at a dose of about 1800 mg (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of each cycle during the Second Phase. and (iii) dexamethasone is administered to the subject (e.g., IV and/or PO): (i) at a dose of about 20 mg on Day 1, Day 2, Day 8, Day 9, Day 15, and Day 16 of C1 during the Run-In Phase; (ii) at a dose of about 20 mg on Day 1, Day 8, and Day 15 of C1 and C2 during the First Subphase of Phase I; and (iii) at a dose of about 20 mg on Day 1 of C1, C2, C3, C4, and C5 during the Second Subphase of Phase I. The subject is administered dexamethasone as follows: (iv) at about 20 mg on day 1 of C1, C2, C3, C4, and C5 during the second phase. In some aspects, the subject does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral. In some aspects, the first booster dose is 0.3 mg, the second booster dose is 3.6 mg, and the target dose is 160 mg.

In another aspect, the present invention provides ceftriaxone for use in treating an individual with MM, the treatment comprising administering ceftriaxone, daratumumab and dexamethasone to the individual in a dosing regimen, the dosing regimen comprising: (i) an introduction phase, which comprises a 21-day dosing cycle (C1); (ii) a first phase after the introduction phase, which comprises a first sub-phase and a second sub-phase, wherein the first sub-phase comprises a first dosing cycle (C1) and a second dosing cycle (C2), and the second sub-phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4) and a fifth dosing cycle (C5), wherein each dosing cycle of the first phase is and (iii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, wherein the bispecific antibody is administered to the subject (e.g., IV) as follows: (i) at a first escalating dose on day 2 of C1 during the run-in phase and as a second escalating dose on day 9 of C1 during the run-in phase; (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) daratumumab is administered to the subject (e.g., IV) as follows: (i) at a dose of about 1800 mg on Day 1, Day 8, and Day 15 of C1 during the Run-in Phase; (ii) at a dose of about 1800 mg on Day 1, Day 8, and Day 15 of C1 during the first subphase of Phase 1; and (iii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of each cycle during Phase 1; and (iv) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of each cycle during Phase 2. and (iii) at a dose of about 1800 mg on Day 1 of C1, C2, C3, C4, and C5 during the second subphase of Phase 1; and dexamethasone is administered to the subject (e.g., PO) as follows: (i) at a dose of about 20 mg on Day 1, Day 2, Day 8, Day 9, Day 15, and Day 16 of C1 during the run-in phase; (ii) at a dose of about 20 mg on Day 1, Day 8, and Day 15 of C1 and C2 during the first subphase of Phase 1; and (iii) at a dose of about 20 mg on Day 1 of C1, C2, C3, C4, and C5 during the second subphase of Phase 1. C1, C2, C3, C4 and C5 on day 1, as appropriate, wherein dexamethasone is administered to the subject as follows: (iv) at about 20 mg on day 1 of C1, C2, C3, C4 and C5 during the second phase. In some aspects, the subject does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or the need for treatment with an intravenous antiviral agent. In some aspects, the first booster dose is 0.3 mg, the second booster dose is 3.6 mg, and the target dose is 160 mg.

In another aspect, the present invention provides a method for treating an individual suffering from MM, the method comprising administering ceftriaxone, daratumumab and dexamethasone to the individual in a dosing regimen, the dosing regimen comprising: (i) an introduction phase, which comprises a 21-day dosing cycle (C1); (ii) a first phase after the introduction phase, which comprises a first sub-phase and a second sub-phase, wherein the first sub-phase comprises a first dosing cycle (C1) and a second dosing cycle (C2), and the second sub-phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4) and a fifth dosing cycle (C5), wherein each dosing cycle of the first phase is 21 days; day dosing cycle; and (iii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, wherein the bispecific antibody is administered to the subject (e.g., IV) as follows: (i) at a first escalating dose on day 9 of C1 during the run-in phase, and as a second escalating dose on day 10, day 11, or day 12 of C1 during the run-in phase; (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) daratumumab is administered to the subject (e.g., IV) as follows: (i) at a dose of about 1800 mg on Day 1, Day 8, and Day 15 of C1 during the Run-in Phase; (ii) at a dose of about 1800 mg on Day 1, Day 8, and Day 15 of C1 during the First Sub-Phase of the First Phase; and (iii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of each cycle during the First Sub-Phase; and (iv) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of each cycle during the Second Sub-Phase. and (iii) about 1800 mg on Day 1 of C1, C2, C3, C4, and C5 during the second subphase of Phase I; and dexamethasone is administered to the subject (e.g., IV and/or PO) as follows: (i) about 20 mg on Day 1, Day 8, Day 15, and Day 16 of C1 during the Run-in Phase; (ii) about 4 mg on Day 2 and Day 3 of C1 during the Run-in Phase; (iii) about 15 mg on Day 9 of C1 during the Run-in Phase; (iv) about 20 mg (v) about 20 mg on Day 1 of C1 during the first subphase of Phase 1, and (vi) about 20 mg on Day 1 of C2 during the first subphase of Phase 1, as appropriate, wherein dexamethasone is administered to the subject as follows: (vii) about 20 mg on Day 1 of C1, C2, C3, C4, and C5 during the second subphase of Phase 1, and wherein the subject does not have (i) a history of MAS or HLH, (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with an intravenous antiviral agent. In some aspects, the first booster dose is 0.3 mg, the second booster dose is 3.6 mg, and the target dose is 160 mg.

In another aspect, the present invention provides ceftriaxone for use in treating an individual with MM, the treatment comprising administering ceftriaxone, daratumumab and dexamethasone to the individual in a dosing regimen, the dosing regimen comprising: (i) an introduction phase, which comprises a 21-day dosing cycle (C1); (ii) a first phase after the introduction phase, which comprises a first sub-phase and a second sub-phase, wherein the first sub-phase comprises a first dosing cycle (C1) and a second dosing cycle (C2), and the second sub-phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4) and a fifth dosing cycle (C5), wherein each dosing cycle of the first phase is and (iii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, wherein the bispecific antibody is administered to the subject (e.g., IV) as follows: (i) at a first escalating dose on day 9 of C1 during the run-in phase and as a second escalating dose on day 10, day 11, or day 12 of C1 during the run-in phase; (ii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 16 of C1 during the Run-In Phase; (iii) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of each cycle during Phase I; and (iv) at a target dose (e.g., 90 mg, 132 mg, or 160 mg) on Day 1 of each cycle during Phase II; daratumumab is administered (e.g., IV) to the subject as follows: (i) at a dose of about 1800 mg on Day 1, Day 8, and Day 15 of C1 during the Run-In Phase; (ii) at a dose of about 1800 mg on Day 1 of C1 and C2 during the first subphase of Phase I and (iii) about 1800 mg on Day 1 of C1, C2, C3, C4, and C5 during the second subphase of Phase I; and dexamethasone is administered to the subject (e.g., IV and/or PO) as follows: (i) about 20 mg on Day 1, Day 8, Day 15, and Day 16 of C1 during the Run-in Phase; (ii) about 4 mg on Day 2 and Day 3 of C1 during the Run-in Phase; (iii) about 15 mg on Day 9 of C1 during the Run-in Phase; (iv) about 20 mg (v) about 20 mg on Day 1 of C1 during the first subphase of Phase 1, and (vi) about 20 mg on Day 1 of C2 during the first subphase of Phase 1, as appropriate, wherein dexamethasone is administered to the subject as follows: (vii) about 20 mg on Day 1 of C1, C2, C3, C4, and C5 during the second subphase of Phase 1, and wherein the subject does not have (i) a history of MAS or HLH, (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with an intravenous antiviral agent. In some aspects, the first booster dose is 0.3 mg, the second booster dose is 3.6 mg, and the target dose is 160 mg.

Sequence Listing

This application contains a sequence listing that has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy was created on April 29, 2024, is named "50474-330TW2_Sequence_Listing_4_29_24", and is 45,056 bytes in size. I. Definitions

As used herein, the term "about" refers to the usual error range of each value that is readily known to those skilled in the art. In this document, the value or parameter referred to as "about" includes (and describes) the state that refers to the value or parameter itself.

It should be understood that aspects and embodiments of the present invention described herein include "comprising," "consisting of," and "consisting essentially of."

As used herein, the term "FcRH5" or "fragment crystallizable receptor-like 5" refers to any native FcRH5 from any vertebrate source, including mammals, such as primates (e.g., humans) and rodents (e.g., mice and rats), and unless otherwise indicated, includes "full-length" unprocessed FcRH5, as well as any form of FcRH5 resulting from processing in cells. The term also encompasses naturally occurring FcRH5 variants, such as splice variants or allelic variants. FcRH5 includes, for example, the human FcRH5 protein (UniProtKB/Swiss-Prot ID: Q96RD9.3), which is 977 amino acids in length.

The terms "anti-FcRH5 antibody" and "antibody that binds to FcRH5" refer to an antibody that is capable of binding to FcRH5 with sufficient affinity such that the antibody can be used as a diagnostic and/or therapeutic agent targeting FcRH5. In one embodiment, the extent to which an anti-FcRH5 antagonist antibody binds to an unrelated, non-FcRH5 protein is less than about 10% of the binding of the antibody to FcRH5, as measured by, for example, a radioimmunoassay (RIA). In certain embodiments, the dissociation constant ( _KD ) of the antibody that binds to FcRH5 is ≤ 1 μM, ≤ 250 nM, ≤ 100 nM, ≤ 15 nM, ≤ 10 nM, ≤ 6 nM, ≤ 4 nM, ≤ 2 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., ^10-8 M or lower, such as ^10-8 M to ^10-13 M, such as ^10-9 M to ^10-13 M). In certain embodiments, the anti-FcRH5 antagonist antibody binds to an antigenic determinant of FcRH5 that is conserved in FcRH5 of different species.

As used herein, the term "cluster of differentiation 3" or "CD3" refers to any native CD3 from any vertebrate source, including mammals, such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, including, for example, CD3ε, CD3γ, CD3α and CD3β chains. The term encompasses "full-length," unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ) as well as any form of CD3 obtained in cell manipulation. The term also encompasses naturally occurring CD3 variants, such as splice variants or allelic variants. CD3 includes, for example, a human CD3ε protein having a length of 207 amino acids (NCBI RefSeq No. NP_000724) and a human CD3γ protein having a length of 182 amino acids (NCBI RefSeq No. NP_000064).

The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that is capable of binding to CD3 with sufficient affinity to render the antibody useful as a diagnostic and/or therapeutic agent targeting CD3. In one embodiment, the extent to which an anti-CD3 antagonist antibody binds to an unrelated, non-CD3 protein is less than about 10% of the binding of the antibody to CD3, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the dissociation constant ( _KD ) of the antibody that binds to CD3 is ≤ 1 μM, ≤ 250 nM, ≤ 100 nM, ≤ 15 nM, ≤ 10 nM, ≤ 5 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., ^10-8 M or lower, such as ^10-8 M to ^10-13 M, such as ^10-9 M to ^10-13 M). In certain embodiments, the anti-CD3 antagonist antibody binds to an antigenic determinant of CD3 that is conserved in CD3 of different species.

For purposes herein, "ceftazidimeb" is also referred to as BFCR4350A or RO7187797, an Fc-engineered, humanized, full-length non-glycosylated IgG1 κ T cell-dependent bispecific antibody (TDB) that binds to FcRH5 and CD3 and comprises: an anti-FcRH5 arm comprising a heavy chain polypeptide sequence of SEQ ID NO: 35 and a light chain polypeptide sequence of SEQ ID NO: 36; and an anti-CD3 arm comprising a heavy chain polypeptide sequence of SEQ ID NO: 37 and a light chain polypeptide sequence of SEQ ID NO: 38. Ceftamizumab contains an amino acid substitution of threonine to tryptophan (T366W) at position 366 of the heavy chain of the anti-FcRH5 arm using EU numbering of amino acid residues in the Fc region, and three amino acid substitutions (tyrosine to valine at position 407, threonine to serine at position 366, and leucine to alanine at position 368) (Y407V, T366S, and L368A) on the heavy chain of the anti-CD3 arm using EU numbering of amino acid residues in the Fc region to drive heterodimerization of the two arms (half-antibodies). Ceftamizumab also contains an amino acid substitution (glycine for asparagine) at position 297 on each heavy chain (N297G) using the EU numbering of the amino acid residues in the Fc region, which results in an aglycosylated antibody that minimally binds to Fc (Fcγ) receptors and thus prevents Fc effector function. Ceftamizumab is also described in the WHO Drug Information (International Nonproprietary Names of Drug Substances), Recommended INN: List 84, Vol. 34, No. 3, published in 2020 (see page 701).

The term "antibody" herein is used in the broadest sense and covers various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies) and antibody fragments, as long as they exhibit the intended antigen-binding activity.

"Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, "binding affinity" as used herein refers to the intrinsic binding affinity that reflects a 1:1 interaction between the members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be expressed by a dissociation constant ( _KD ). Affinity can be measured by conventional methods known in the art, including those described herein. Specific illustrative and exemplary aspects for measuring binding affinity are described below.

An "affinity matured" antibody is one that has one or more changes in one or more hypervariable regions (HVRs) that result in an improvement in the affinity of the antibody for antigen compared to a parent antibody that does not possess those changes.

The terms "full length antibody", "intact antibody" and "whole antibody" are used interchangeably herein and refer to an antibody having a structure substantially similar to a native antibody structure or having a heavy chain containing an Fc region as defined herein.

"Antibody fragment" refers to a molecule other than an intact antibody, which comprises a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, biFab, Fv, Fab, Fab'-SH, F(ab') ₂ , bifunctional antibodies, linear antibodies, single-chain antibody molecules (e.g., scFv, scFab), and multispecific antibodies formed from antigen fragments.

"Single-domain antibodies" are antibody fragments that contain all or part of the heavy chain variable domain of an antibody or all or part of the light chain variable domain of an antibody. In certain embodiments, the single-domain antibody is a human single-domain antibody ( see , e.g., U.S. Patent No. 6,248,516 B1). Examples of single-domain antibodies include, but are not limited to, VHH.

The "Fab" fragment is an antigen-binding fragment produced by papain digestion of an antibody and consists of an intact L chain and the variable region of the H chain (VH) and the first constant domain (CH1) of the heavy chain. Papain digestion of an antibody produces two identical Fab fragments. Pepsin treatment of the antibody produces a single large F(ab') ₂ fragment that roughly corresponds to two disulfide-bonded Fab fragments that have divalent antigen-binding activity and are still able to cross-link antigen. The Fab' fragment differs from the Fab fragment in having a few additional residues at the carboxyl terminus of the CH1 domain, which include one or more cysteines from the hinge region of the antibody. Fab'-SH refers to Fab' in which the cysteine residue of the constant domain carries a free thiol group. F(ab') ₂ antibody fragments originally were produced as pairs of Fab' fragments, which have hinge cysteines. Other chemical couplings of antibody fragments are also known.

"Fv" consists of a dimer of one heavy chain variable region and one light chain variable region in tight, non-covalent association. Folding of these two domains produces six highly variable loops (3 loops each in the H and L chains) that form the amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary slightly, the Fc region of a human IgG heavy chain is generally defined as extending from the amino acid residue at position Cys226 or Pro230 to its carboxyl terminus. For example, the C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed during antibody production or purification, or by recombinant engineering of the nucleic acid encoding the antibody heavy chain. Therefore, the composition of the complete antibody may include an antibody population with all Lys447 residues removed, an antibody population with no Lys447 residues removed, and an antibody population having a mixture of antibodies with and without Lys447 residues.

A "functional Fc fragment" possesses an "effector function" of a native sequence Fc region. Exemplary "effector functions" include C1q binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor; BCR); B cell activation, etc. Such effector functions generally require an Fc region in combination with a binding domain (e.g., an antibody variable domain), and can be assessed using various assays as disclosed, for example, in the definitions herein.

A "native sequence Fc region" comprises an amino acid sequence that is identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes); native sequence human IgG2 Fc regions; native sequence human IgG3 Fc regions; and native sequence human IgG4 Fc regions, and naturally occurring variants thereof.

A "variant Fc region" comprises an amino acid sequence that differs from a native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution compared to the native sequence Fc region or the Fc region of a parent polypeptide, for example, about one to about ten amino acid substitutions in the native sequence Fc region or the Fc region of a parent polypeptide, preferably about one to about five amino acid substitutions. The variant Fc region herein preferably has at least about 80% homology with the native sequence Fc region and/or the Fc region of a parent polypeptide, most preferably has at least about 90% homology therewith, and preferably has at least about 95% homology therewith.

As used herein, "Fc complex" refers to the CH3 domains of two Fc regions interacting together to form a dimer, or as in certain aspects, two Fc regions interacting to form a dimer, wherein the cysteine residues in the hinge region and/or the CH3 domain interact via bonds and/or forces (e.g., Van der Waals forces, hydrophobic forces, hydrogen bonds, electrostatic forces or disulfide bonds).

The "hinge region" is usually defined as stretching from approximately residues 216 to 230 of IgG (EU numbering), from approximately residues 226 to 243 of IgG (Kabat numbering), or from approximately residues 1 to 15 of IgG (IMGT unique numbering).

"Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native sequence human FcR. Further preferred FcRs are those that bind IgG antibodies (gamma receptors) and include receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and splice forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. The activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (see M. Daëron, Annu. Rev. Immunol. 15:203-234 (1997) for a review). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). The term "FcR" herein encompasses other FcRs, including those to be identified in the future. The term also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

As referred to herein, the term "knob-into-hole" or "KnH" technology refers to a technique for directing the pairing of two polypeptides together in vitro or in vivo by introducing a knob (knob) into one polypeptide and a cavity (hole) into the other polypeptide at their interactive interface. For example, KnH has been introduced into the Fc:Fc interaction interface, CL:CH1 interface, or VH/VL interface of antibodies (e.g., US2007/0178552, WO 96/027011, WO 98/050431, and Zhu et al., (1997) Protein Science 6:781-788). In the production of multispecific antibodies, this is particularly useful for driving the pairing of two different heavy chains together. For example, a multispecific antibody having KnH in its Fc regions may further comprise a single variable domain linked to each Fc region, or further comprise different heavy chain variable domains paired with the same, similar or different light chain variable domains. KnH technology can also be used to pair together two different receptor extracellular domains or any other polypeptide sequences containing different target recognition sequences.

"Framework" or "FR" refers to the variable domain residues excluding the hypervariable region (HVR) residues. The FR of the variable domain is usually composed of four FR domains: FR1, FR2, FR3, and FR4. Therefore, HVR and FR sequences usually appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

A "CH1 region" or "CH1 domain" comprises residues stretching from about residue 118 to residue 215 of IgG (EU numbering), from about residue 114 to 223 of IgG (Kabat numbering), or from about residue 1.4 to residue 121 of IgG (IMGT unique numbering) (Lefranc et al., IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015 Jan;43(Database Special Issue):D413-22).

The "CH2 domain" of the human IgG Fc region typically extends from about residue 244 to about residue 360 of IgG (Kabat numbering), from about residue 231 to about residue 340 of IgG (EU numbering), or from about residue 1.6 to about residue 125 of IgG (IGMT unique numbering). The CH2 domain is unique in that it is not tightly paired with another domain. Instead, two N-linked branched carbohydrate chains are inserted between the two CH2 domains of the intact native IgG molecule. It is speculated that the carbohydrates may provide an alternative to this domain-domain pairing and help stabilize the CH2 domain. Burton, Molec. Immunol. 22:161-206 (1985).

The “CH3 domain” comprises the C-terminal residue extension of the CH2 domain in the Fc region (i.e., from about amino acid residue 361 to about amino acid residue 478 of IgG (Kabat numbering), from about amino acid residue 341 to about amino acid residue 447 of IgG (EU numbering), or about amino acid residue 1.4 to about amino acid residue 130 of IgG (IGMT unique numbering)).

The "CL domain" or "constant light domain" comprises the C-terminal residue extension of the light chain variable domain (VL). The light chain (LC) of an antibody can be a kappa (κ) ("Cκ") or lambda (λ) ("Cλ") light chain region. The Cκ region typically extends from about residue 108 to residue 214 of IgG (Kabat or EU numbering) or from about residue 1.4 to residue 126 of IgG (IMGT unique numbering). The Cλ residues typically extend from about residue 107a to residue 215 (Kabat numbering) or from about residue 1.5 to residue 127 (IMGT unique numbering) (Lefranc et al., supra ).

The term "chimeric" antibody refers to an antibody in which a portion of the heavy chain and/or light chain is derived from a particular source or species, while the remainder of the heavy chain and/or light chain is derived from a different source or species.

The "class" of an antibody refers to the type of constant domain or region of its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these classes can be further divided into subclasses (isotypes), such as IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ , and IgA ₂ . The constant domains of the heavy chains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

A "human antibody" is an antibody having an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by a human or human cell or derived from a non-human source using the human antibody repertoire or other human antibody encoding sequences. This definition of human antibody specifically excludes humanized antibodies that contain non-human antigen binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol. 227:381, 1991; Marks et al., J. Mol. Biol. 222:581, 1991. Methods for preparing human monoclonal antibodies are also described in Cole et al., Monoclonal Antibodies and Cancer Therapy , Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol. , 147(1):86-95, 1991. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74, 2001. Human antibodies can be prepared by administering antigen to transgenic animals that have been modified to produce such antibodies in response to antigenic challenge but whose endogenous loci have been disabled, such as immunized xenogeneic mice (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 for XENOMOUSE ^™ technology). See also, e.g., Li et al., Proc. Natl. Acad. Sci. USA . 103:3557-3562, 2006, regarding human antibodies generated by human B cell hybridoma technology.

A "human common framework" is a framework that represents the most common amino acid residues in a series of human immunoglobulin VL or VH framework sequences. Typically, the selection of human immunoglobulin VL or VH sequences comes from a subgroup of variable domain sequences. Typically, the subgroup of sequences is a subgroup such as in Kabat et al. Sequences of Proteins of Immunological Interest , Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1-3 . In one aspect, for VL, the subgroup is subgroup κ I as described by Kabat et al. in the above-mentioned literature. In one aspect, for VH, the subgroup is subgroup III, such as Kabat et al. above.

A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will include substantially all of at least one (and usually two) variable domains, wherein all or substantially all HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all FRs correspond to those of a human antibody. In certain aspects, wherein all or substantially all FRs of a humanized antibody correspond to those of a human antibody, any FR of the humanized antibody may comprise one or more amino acid residues from a non-human FR (e.g., one or more Vernier residues of a FR). A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody (e.g., a non-human antibody) refers to an antibody that has undergone humanization.

The term "variable region" or "variable domain" refers to the domain of the heavy or light chain of an antibody that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of natural antibodies generally have similar structures, and each domain comprises four conserved framework regions (FRs) and three highly variable regions (HVRs). (See, e.g., Kindt et al., Kuby Immunology , 6th ed. WH Freeman and Co., p. 91 (2007).) A single VH or VL domain may be sufficient to confer antigen binding specificity. In addition, VH or VL domains can be used to separate antibodies that bind to a specific antigen from antibodies that bind to the antigen to screen libraries of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887, 1993; Clarkson et al. Nature 352:624-628, 1991.

As used herein, the term "hypervariable region" or "HVR" refers to each region of hypervariability in the sequence of an antibody variable domain ("complementarity determining region" or "CDR"). Typically, an antibody includes six CDRs: three in VH (CDR-H1, CDR-H2, CDR-H3), and three in VL (CDR-L1, CDR-L2, CDR-L3). As used herein, exemplary CDRs include: (a) CDRs present at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917, 1987); (b) CDRs present at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al. Sequences of Proteins of Immunological Interest , 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) antigenic contacts at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745, 1996).

Unless otherwise indicated, HVR residues and other residues in variable domains (eg, FR residues) are numbered herein according to Kabat et al., supra .

"Single-chain Fv", also referred to as "sFv" or "scFv", is an antibody fragment comprising VH and VL antibody domains linked in a single polypeptide chain. Preferably, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains that enables the scFv to form the desired structure for antigen binding. For a review of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore, eds., Springer-Verlag, New York, pp. 269-315 (1994); Malmborg et al., J. Immunol. Methods 183:7-13, 1995.

The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous antibody population, i.e., the individual antibodies comprising the population are identical and/or bind to the same antigenic determinant, except for possible variant antibodies that contain naturally occurring mutations or that arise during the production of the monoclonal antibody preparation, such variants are generally present in small amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (antigenic determinants), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on the antigen. Therefore, the modifier "monoclonal" indicates that the characteristics of the antibody are obtained from a substantially homogeneous antibody population, and should not be interpreted as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies intended for use in accordance with the present invention may be produced by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals with genes comprising all or part of the human immunoglobulin loci, these methods and other exemplary methods for making monoclonal antibodies are described herein.

The term "multispecific antibody" is used in the broadest sense and specifically encompasses antibodies with multiple antigenic determinant specificities. In one aspect, a multispecific antibody binds two different targets (e.g., a bispecific antibody). Such multispecific antibodies include, but are not limited to, antibodies comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH/VL unit has polyepitopic specificity, antibodies having two or more VL and VH domains, each VH/VL unit binding to a different epitope, antibodies having two or more single variable domains, each single variable domain binding to a different epitope, full-length antibodies, antibody fragments such as Fab, Fv, dsFv, scFv, diabodies, bispecific diabodies and terabodies, antibody fragments that have been covalently or non-covalently linked. "Polyepitopic specificity" refers to the ability to bind specifically to two or more different epitopes on the same or different targets. "Monospecificity" relates to the ability to bind only one antigen. In one aspect, a monospecific bi-epitope antibody binds two different epitopes on the same target/antigen. In one aspect, a monospecific multi-epitope antibody binds multiple different epitopes on the same target/antigen. According to one aspect, the multispecific antibody is an IgG antibody that binds to each epitope with an affinity of 5 μM to 0.001 pM, 3 μM to 0.001 pM, 1 μM to 0.001 pM, 0.5 μM to 0.001 pM, or 0.1 μM to 0.001 pM.

"Native antibodies" refer to naturally occurring immunoglobulin molecules with different structures. For example, the Ig natural IgG antibody is a heterotetrameric glycoprotein of approximately 150,000 daltons composed of two identical light chains and two identical heavy chains bonded by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also known as a variable heavy chain domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also known as a variable light chain domain or a light chain variable domain, followed by a light chain constant (CL) domain. Based on the amino acid sequence of their homeodomains, the light chains of antibodies can be classified into one of two types, called kappa (κ) and lambda (λ).

As used herein, the term "immunoadhesin" indicates a molecule that has the binding specificity of binding to a heterologous protein ("adhesin") and the effector function of an immunoglobulin constant domain. Structurally, an immunoadhesin comprises a fusion of an amino acid sequence having the desired binding specificity and an immunoglobulin constant domain sequence (e.g., CH2 and/or CH3 sequence of IgG), wherein the amino acid sequence is different from the antigen recognition and binding site of the antibody (i.e., "heterologous" compared to the constant region of the antibody). The adhesin and the immunoglobulin constant domain are optionally separated by an amino acid spacer. Exemplary adhesin sequences include a continuous amino acid sequence that comprises a portion of a receptor or ligand that binds to the protein of interest. Adhesin sequences can also be sequences that bind to a protein of interest but are not receptor or ligand sequences (e.g., adhesin sequences in peptibodies). Such polypeptide sequences can be selected or identified by a variety of methods, including phage display technology and high-throughput sorting methods. The immunoglobulin constant domain sequence in the immunoadhesin can be obtained from any immunoglobulin, such as IgG1, IgG2, IgG3, or IgG4 subtypes, IgA (including IgA1 and IgA2), IgE, IgD, or IgM.

"Chemotherapeutic agents" include chemical compounds used to treat cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldermycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitinib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin, and tadalafil. (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa, and CYTOXAN® Cyclophosphamides, alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodepa, carboquinone, metodepa and uredepa; ethylimides and methylmelamines, including altretamine, triethylmelamine, triethylphosphatamide, triethylthiophosphatamide and trihydroxymethylmelamine; annona lactones (especially bratacin and bratacinone); camptothecins (including topotecan and irinotecan); lichenistatin; callystatin; CC-1065 (including its synthetic analogs adolesin, carzelesin and biszelesin); nostocs (especially nostoc 1 and nostoc 8); adrenocortical steroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase (including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc, duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); acanthopanax; sarcodictyin; a sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, isocyclophosphamide, mechlorethamine, nitrogen mustard hydrochloride mechlorethamine oxide hydrochloride, melphalan, new nitrogen mustard, phenacetin, pyrimethamine, trofosfamide, uracil nitrogen mustard; nitrosoureas, such as carmustine, chloranil, fotemustine, lomustine, nimustine and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1I and calicheamicin omega 1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); anthracycline antibiotics (dynemicins, including anthracycline antibiotics A; bisphosphonates such as clodronate; esperamicin; and neocarcinogenes and related chromoprotein enediyne antibiotic chromophores), aclatomycin, actinomycin, anthramycin, diazoserine, bleomycin, actinomycin C, carabicin, carmomycin, carmomycin, chromomycin, actinomycin D, daunorubicin, detoximum cytoplasm, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolido-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, mesilomycin, mitomycins such as mitomycin C, mycophenolic acid, noramycin, oleamicin, pelomycin, porfiramycin, puromycin, triferroadriamycin, rhodorubicin, streptomycin, streptozocin, tuberculin, ubenimex, nastatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as folinic acid, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-hydroxypurine, thioguanine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dihydrouridine, doxifluridine , enocitabine, floxuridine; androgens, such as calutrone, drostanolone propionate, cyclothiocarb, melastane, testolactone; antiadrenergics, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; aceglucuronolide; aldophosphamide glycoside; aminoacetyl propionic acid; eniluracil; amsacrine, betribucil bestrabucil; bisantrene; edatrexate; defosfoamide; demeclocycline; diazocine; elfomithine; elliptolide; ebotoxetine; etogluconate; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansine alkaloids, such as maytansine and anstomectin; mitoguanidine; mitoxantrone; mopidarol; diamine nitrazolium; pentostatin; methamine mustard; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; radimycin; sisofilam; spirogermanium; streptomycin; triazoline; 2,2',2''-trichlorotriethylamine; trichothecenes (particularly T-2 toxin, verrucosporin A, bacitracin A, and serpentin); uracil; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromocerol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Oncology, Pharmaceutical Partners, Schaumberg, Ill.) and TAXOTERE® (docetaxel; Sanofi-Aventis); chloranil; GEMZAR® (gemcitabine); 6-thioguanine; oxazolidinone; methotrexate; platinum analogs, such as cis-platinum and carboplatin, vinblastine; etoposide (VP-16); isocyclic phosphamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); nabendazim; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitors RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Chemotherapy agents also include (i) antihormones that have a modulating or inhibitory effect on the hormones of the tumor, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, troxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazole, aminoglutaramide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, flumethyltestosterone, all-trans retinoic acid, fenretinide, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) Antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways associated with abnormal cell proliferation, such as, for example, PKC-Alpha, Ralf and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as ALLOVECTIN®, LEUVECTIN® and VAXID®; PROLEUKIN®, rIL-2; topoisomerase 1 inhibitors, such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Chemotherapy agents also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and antibody-drug conjugates such as gemtuzumab (MYLOTARG®, Wyeth). Other humanized monoclonal antibodies with therapeutic potential that bind to the compounds of the present invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, panvituzumab felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, peficizumab pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, tocilizumab (toralizumab), tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and anti-interleukin 12 (ABT-874/J695, Wyeth Research and Abbott Laboratories), a full-length IgG1 lambda antibody specific to human sequence that has been genetically engineered to recognize the interleukin 12 p40 protein.

Chemotherapeutic agents also include "EGFR inhibitors," which are compounds that bind to or directly interact with EGFR and prevent or reduce its signal transduction activity, or "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Patent No. 4,943,533) and variants thereof, such as chimeric 225 (C225 or cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human EGFR targeting antibody (Imclone); antibodies that bind to type II mutant EGFR (U.S. Patent No. 5,212,290 ); humanized and chimeric antibodies that bind to EGFR as described in U.S. Patent No. 5,891,996; and human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al., Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody against EGFR that competes with EGF and TGF-α for binding to EGFR (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); a fully human antibody, referred to as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). Anti-EGFR antibodies can be conjugated to cytotoxic agents to generate immunoconjugates (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as the compounds described in the following U.S. Patent Nos.: 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008 and 5,747,498, and compounds described in the following PCT publications: WO98/14451, WO98/50038, WO99/09016, and WO99/24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-acrylamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-oxolinyl)propoxy]-6-quinazolinyl]-dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-oxolinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimidin[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynylamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)-2-butenylamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapitinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2-methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamide).

Chemotherapy agents also include "tyrosine kinase inhibitors", including the EGFR-targeted agents mentioned in the previous paragraph; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724,714, which is an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors that preferentially bind EGFR but inhibit both HER2 and EGFR overexpressing cells, such as EKB-569 (available from Wyeth); lapatinib (GSK572016, available from Glaxo-SmithKline), which is an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033, Pharmacia); Raf-1 inhibitors, such as ISIS-5132, an antisense agent that inhibits Raf-1 signaling, available from ISIS Pharmaceuticals; non-HER-targeted TK inhibitors, such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261, and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines; curcumin (diferulylmethane, 4,5-bis(4-fluoroanilino)-phthalimide); tyrphostine containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (such as those that bind to nucleic acids encoding HER); quinoxalines (U.S. Patent No. 5,804,396) ; tryphostin (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®) or as described in any of the following patent publications: U.S. Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapy also includes dexamethasone, interferon, colchicine, chlorpheniramine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, norron, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate disodium, pegastatin, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valfloxacin, zoledronic acid and zoledronic acid and their pharmaceutically acceptable salts.

Chemotherapy agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone ethanol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinonide acetate, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fluocortolone hexanoate, fluocortolone trimethylacetate, and fluprednidene acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamic acid-glycine (FEG) and its D-isomer form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs, such as azathioprine, cyclosporine A), D-penicillin, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor α (TNFα) inhibitors such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), interleukin 1 (IL-1) inhibitors such as anakinra (Kineret), T cell costimulation inhibitors such as abatacept (Orencia), interleukin 6 (IL-6) inhibitors such as tocilizumab (ACTEMRA®); interleukin 13 (IL-13) inhibitors such as lebrikizumab; interferon α (IFN) inhibitors such as rontalizumab; β7-integrin inhibitors such as rhuMAb β7; IgE pathway inhibitors such as anti-M1 prime; secretory homotrimeric LTa3 and membrane-bound heterotrimeric LTa1/β2 inhibitors such as anti-lymphotoxin α (LTa); radioisotopes (e.g., At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and radioactive isotopes of Lu); miscellaneous investigational agents, such as thioplatin, PS-341, phenyl butyrate, ET-18- OCH3 or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, proanthocyanidins, birchic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; birchic acid; acetylcamptothecin, scopolectin and 9-aminocamptopine); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates, such as clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronic acid (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines, such as THERATOPE® vaccines; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors, such as oblimersen sodium (GENASENSE®), pixantrone; farnesyl transferase inhibitors, such as lonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing; and combinations of two or more of the foregoing, such as CHOP (an acronym for the combination therapy of cyclophosphamide, doxorubicin, vincristine and penicillin) and FOLFOX (an acronym for the combination therapy of oxaliplatin (ELOXATIN ^™ ) with 5-FU and leucovorin).

Chemotherapy also includes nonsteroidal anti-inflammatory drugs that have analgesic, antipyretic and anti-inflammatory properties. NSAIDs include nonselective inhibitors of cyclooxygenase. Specific examples of NSAIDs include: aspirin; propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen; acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac; enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam; fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid and fenamic acid. NSAIDs are used to relieve symptoms of rheumatoid arthritis, osteoarthritis, inflammatory arthritis, ankylosing spondylitis, psoriasis, Reiter's syndrome, acute gout, menstrual pain, metastatic bone pain, headaches and migraines, postoperative pain, mild to moderate pain caused by inflammation and tissue damage, fever, intestinal obstruction, and angina.

As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and Lu radioisotopes of ), chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin (ADRIAMYCIN®), vinca alkaloids (vincristine, vinblastine, etoposide), mycophenolate mofetil, mitomycin C, chloramphenicol, daunomycin or other intercalating agents), growth inhibitors, enzymes and fragments thereof, such as nucleases, antibiotics, toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof, and various antitumor or anticancer agents disclosed below.

A "disorder" is any condition that would benefit from treatment, including but not limited to chronic and acute conditions or diseases, including those pathological symptoms that predispose the mammal to the disease. In one aspect, the disorder is cancer, such as a B-cell proliferative disorder, such as MM, such as relapsed or refractory MM.

The terms "cell proliferative disorder" and "proliferative disorder" refer to a disorder associated with some degree of abnormal cell proliferation. In one aspect, the cell proliferative disorder is cancer. In one aspect, the cell proliferative disorder is a tumor.

As used herein, the term "tumor" refers to all proliferative cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms "cancer", "cancerous", "cell proliferative disorder", "proliferative disorder" and "tumor" are not mutually exclusive in this context.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Aspects of cancer include solid tumor cancers and non-solid tumor cancers. Examples of cancer include, but are not limited to, B cell proliferative disorders, such as MM, which can be relapsed or refractory MM. MM can be, for example, classical MM (e.g., immunoglobulin G (IgG) MM, IgA MM, IgD MM, IgE MM, or IgM MM), light chain MM (LCMM) (e.g., lambda light chain MM or kappa light chain MM), or non-secretory MM. MM can have one or more cytogenetic features (e.g., high-risk cytogenetic features), such as t(4;14), t(11;14), t(14;16), and/or del(17p), as described in Table 1 and in the International Myeloma Working Group (IMWG) guidelines provided in Sonneveld et al., Blood , 127(24): 2955-2962, 2016; and/or 1q21, as described in Chang et al., Bone Marrow Transplantation , 45: 117-121, 2010. Cytogenetic features can be detected, for example, using fluorescent in situ hybridization (FISH). Table 1. Cytogenetic features of MM Major genetic events Minor genetic events IgH translocation Gene Missing Gene t(4;14) FGFR3 / MMSET 1p CDKN2C, FAF1, FAM46C t(6;14) CCND3 6q t(11;14) CCND1 8p t(14;16) MAF 13 RB1, DIS3 t(14;20) MAFB 11q BIRC2/BIRC3 14q TRAF3 16q WWOX, CYLD 17p TP53 Hyperdiploid improve Chromosomes 3, 5, 7, 9, 11, 15, 19, 21 1q CKS1B, ANP32E

The term "B cell proliferative disorder" or "B cell malignancy" refers to a disorder associated with some degree of abnormal B cell proliferation, and includes, for example, lymphoma, leukemia, myeloma (e.g., multiple myeloma (MM), e.g., relapsed or refractory (R/R) MM), and myelodysplastic syndrome. In one embodiment, the B cell proliferative disorder is a lymphoma, such as non-Hodgkin's lymphoma (NHL), including, for example, diffuse large B cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL). In another embodiment, the B cell proliferative disorder is a leukemia, such as chronic lymphocytic leukemia (CLL). Other specific examples of cancer include germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL), activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), zonal lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt’s lymphoma (BL), B Prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma/leukemia, unclassifiable, splenic diffuse erythromedullary small B-cell lymphoma, aberrant hairy cell leukemia, heavy chain disease (α-chain disease, γ-chain disease, μ-chain disease), plasma cell myeloma, solitary plasmacytoma of bone, extraplasmocytoma of bone, mucosa-associated lymphoid tissue extranodal zone lymphoma (MALT lymphoma), lymph node marginal zone lymphoma, pediatric lymph node marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicular center lymphoma, T-cell/tissue cell-rich large B-cell B-cell lymphoma, primary DLBCL of the CNS, primary DLBCL of the skin, leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, lymphomatoid granuloma, primary septal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to multicentric Castleman disease associated with HHV8, primary effusion lymphoma: B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt's lymphoma, and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt's lymphoma and classical Hodgkin's lymphoma. Additional examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies, including B-cell lymphomas. More specific examples of such cancers include, but are not limited to, low-grade/follicular NHL; small lymphocytic (SL) NHL; intermediate-grade/follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-cleaved cell NHL; bulky NHL; AIDS-related lymphomas; and acute lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Examples of solid tumors include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric/stomach cancer (including gastrointestinal cancer and gastrointestinal stromal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urethral cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colon-rectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer (kidney/renal cancer), ovarian cancer, liver cancer, bladder cancer, urethral cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colon-rectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer (kidney/renal cancer), cancer), prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, melanoma, superficial spreading melanoma, malignant lentigo melanoma, acral lentigo melanoma, nodular melanoma, and abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), Meigs' syndrome, brain cancer, and head and neck cancer and related metastases. In certain embodiments, cancers suitable for treatment with the antibodies of the invention include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkin's lymphoma (NHL), kidney cell carcinoma, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid, head and neck cancer, ovarian cancer and mesothelioma.

"Complement-dependent cytotoxicity" or "CDC" involves the lysis of target cells in the presence of complement. Activation of the canonical complement pathway is initiated by binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) bound to its cognate antigen. To assess complement activation, a CDC assay may be performed, for example as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996).

"Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig binds to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages), enabling these cytotoxic effector cells to specifically bind to target cells bearing the antigen and subsequently kill the target cells with cytotoxic agents. Antibody "arming" the cytotoxic cells is absolutely necessary for this killing. The primary cells that mediate ADCC, natural killer (NK) cells, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcRs on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Annu. Rev. Immunol. 9:457-92, 1991. To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in U.S. Patent Nos. 5,500,362 or 5,821,337, may be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively or additionally, ADCC activity of the molecule of interest can be assessed in vivo, for example in an animal model, as disclosed in Clynes et al., Proc. Natl. Acad . Sci. USA. 95:652-656, 1998.

As used herein, "complex" or "complexed" refers to an association of two or more molecules that interact with each other via bonds other than peptide bonds and/or forces (e.g., van der Waals forces, hydrophobic forces, hydrophilic forces). In one aspect, the complex is a heteromultimer. It should be understood that the term "protein complex" or "polypeptide complex" as used herein includes complexes with non-protein entities bound to proteins in the protein complex (e.g., including but not limited to chemical molecules such as toxins or detection agents).

As used herein, "delaying progression" of a disorder or disease means delaying, impeding, slowing, retarding, stabilizing and/or postponing the development of a disease or disorder, such as a cell proliferative disorder, such as cancer (e.g., MM). Such a delay may be of varying lengths of time, depending on the disease being treated and/or the individual's medical history. As will be apparent to one skilled in the art, a substantial or significant delay may actually encompass prevention, such that the individual does not develop the disease. For example, advanced cancers, such as the development of metastases, may be delayed.

An "effective amount" of a compound of the invention (e.g., anti-FcRH5/anti-CD3 T cell-dependent bispecific antibody (TDB)) or a composition thereof (e.g., a pharmaceutical composition) is at least the minimum amount required to achieve a desired therapeutic or preventive result, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, such as cancer). The effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in an individual. An effective amount is also an amount in which any toxic or detrimental effects of the treatment are outweighed by the beneficial effects of the treatment. For preventive use, beneficial or desired results include, for example, eliminating or reducing the risk, reducing the severity or delaying the onset of a disease, including the biochemical, histological and/or behavioral symptoms of the disease, its complications and the intermediate pathological phenotypes that occur during the development of the disease. For therapeutic use, beneficial or desired results include clinical results such as the following: reducing one or more symptoms caused by the disease, improving the quality of life of the patient, reducing the amount of other drugs required to treat the disease, enhancing the effect of another agent (such as through targeting), delaying the progression of the disease and/or prolonging survival. In the case of cancer or tumors, an effective amount of a drug may have the following effects: reduce the number of cancer cells; reduce the size of tumors; inhibit (i.e., slow down to some extent or, ideally, stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow down to some extent or, ideally, stop) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate to some extent one or more of the symptoms associated with the disease. An effective amount may be administered in one or more administrations. For the purposes of the present invention, an effective amount of a drug, compound, or drug composition is an amount sufficient to accomplish preventive or therapeutic treatment directly or indirectly. As understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may be achieved with or without combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if it can achieve or has achieved the desired result in combination with one or more other agents.

As used herein, "overall survival" or "OS" refers to the percentage of individuals in a group who are likely to be alive after a specified duration.

As used herein, "objective response rate" (ORR) refers to the sum of strict complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) rates determined using the International Myeloma Working Group response criteria (e.g., see Tables 11A and 11B in Example 1).

The term "antigenic determinant" refers to a specific site on an antigen molecule to which an antibody binds. In some embodiments, the specific site on an antigen molecule to which an antibody binds is determined by hydroxyl radical footprint analysis. In some embodiments, the specific site on an antigen molecule to which an antibody binds is determined by crystallography.

As used herein, "growth inhibitor" refers to a compound or composition that inhibits cell growth in vitro or in vivo . In one aspect, the growth inhibitor is a growth inhibitory antibody that prevents or reduces the proliferation of cells expressing the antigen to which the antibody binds. In another aspect, the growth inhibitor can be an inhibitor that significantly reduces the percentage of cells in the S phase. Aspects of growth inhibitors include agents that block cell cycle progression (other than the S phase), such as agents that induce G1 arrest and M phase arrest. Typical M-phase arrest agents include the vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors, such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest G1 also extend to S-phase arrest, such as DNA alkylating agents, such as tamoxifen, prednisone, dacarbazine, nitrogen mustard, cisplatin, methotrexate, 5-fluorouracil, and ara-C. For more information, see Mendelsohn and Israel, eds., The Molecular Basis of Cancer, Chapter 1, entitled “Cell cycle regulation, oncogenes, and antineoplastic drugs”, Murakami et al. (WB Saunders, Philadelphia, 1995), e.g., p. 13. Taxanes (paclitaxel and docetaxel) are both anticancer drugs derived from the taxus. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer) is derived from the European taxus and is a semisynthetic analog of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote microtubule assembly of tubulin dimers and stabilize microtubules by preventing depolymerization, thereby inhibiting cell mitosis.

An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to a cytotoxic agent.

The term "immunomodulator" or "IMiD" refers to a class of molecules that modify immune system responses or immune system functions. Immunomodulators include, but are not limited to, POMALYST® (pomalidomide), thalidomide (α-N-o-phenylenediamine-glutaramide) and its analogs, OTEZLA® (apremilast), REVLIMID® (lenalidomide), and PD-1 axis binding antagonists, and pharmaceutically acceptable salts or acids thereof.

An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, the individual or subject is a human. The subject may be a patient.

An "isolated" protein or polypeptide is one that is separated from the components of its natural environment. In some aspects, the protein or peptide is purified to greater than 95% or 99% purity as determined, for example, by electrophoresis (e.g., sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. Isolated nucleic acids include nucleic acid molecules contained in cells that normally contain the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from the natural chromosomal location.

The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners, thereby eliminating T cell dysfunction caused by signaling of the PD-1 signaling axis, resulting in restoration or enhancement of T cell function (e.g., proliferation, cytokine production and/or target cell killing). As used herein, PD-1 axis binding antagonists include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. In some cases, a PD-1 axis binding antagonist includes a PD-L1 binding antagonist or a PD-1 binding antagonist. In a preferred aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates or interferes with signal transduction caused by the interaction of PD-L1 with any one or more of its binding partners (such as PD-1 and/or B7-1). In some examples, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In a specific aspect, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and/or B7-1. In some examples, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners (e.g., PD-1 or B7-1). In one example, the PD-L1 binding antagonist reduces negative co-stimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes (through PD-L1-mediated signaling), thereby reducing the dysfunction of the dysfunctional T cells (e.g., enhancing effector responses to antigen recognition). In some cases, the PD-L1 binding antagonist binds to PD-L1. In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, envafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodalimab (lodapolimab), FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. In some embodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one embodiment, the PD-L1 binding antagonist is MDX-1105. In another embodiment, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another embodiment, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other embodiments, the PD-L1 binding antagonist can be a small molecule, for example, GS-4224, INCB086550, MAX-10181, INCB090244, CA-170 or ABSK041, which can be administered orally in some examples. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003 and JS-003. In a preferred embodiment, the PD-L1 binding antagonist is atezolizumab. Atezolizumab is also described in the WHO Drug Information (International Nonproprietary Drug Name), Proposed INN: List 112, Vol. 28, No. 4, published on January 16, 2015 (see page 485).

The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates or interferes with signal transduction caused by the interaction of PD-1 with one or more of its binding partners (such as PD-L1 and/or PD-L2). PD-1 (programmed death 1) is also known in the art as "programmed cell death 1", "PDCD1", "CD279" and "SLEB2". Exemplary human PD-1 is shown in UniProtKB/Swiss-Prot Accession No. Q15116. In some instances, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signal transduction caused by the interaction of PD-1 with PD-L1 and/or PD-L2. In one example, a PD-1 binding antagonist reduces negative co-stimulatory signals mediated by or expressed by cell surface proteins expressed on T lymphocytes (via PD-1 mediated signaling), thereby reducing dysfunction of dysfunctional T cells (e.g., enhancing effector responses to antigen recognition). In some instances, a PD-1 binding antagonist binds to PD-1. In some instances, a PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody). Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, batilimab In one embodiment, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In another embodiment, the PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g., AMP-224. In another embodiment, the PD-1 binding antagonist is MED1-0680. In another embodiment, the PD-1 binding antagonist is PDR001 (spartalizumab). In another embodiment, the PD-1 binding antagonist is REGN2810 (simiprilimab). In another embodiment, the PD-1 binding antagonist is BGB-108. In another embodiment, the PD-1 binding antagonist is proglitinomab. In another embodiment, the PD-1 binding antagonist is carrelizumab. In another embodiment, the PD-1 binding antagonist is sintilimab. In another embodiment, the PD-1 binding antagonist is tislelizumab. In another embodiment, the PD-1 binding antagonist is toripalimab. Other additional exemplary PD-1 binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates or interferes with signal transduction caused by the interaction of PD-L2 with any one or more of its binding partners, such as PD-1. PD-L2 (programmed death ligand 2) is also known in the art as "programmed cell death 1 ligand 2", "PDCD1LG2", "CD273", "B7-DC" and "PDL2". An exemplary human PD-L2 is shown in UniProtKB/Swiss-Prot Accession No. Q9BQ51. In some instances, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, a PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signal transduction resulting from the interaction of PD-L2 with any one or more of its binding partners (such as PD-1). In one aspect, a PD-L2 binding antagonist reduces negative co-stimulatory signals mediated by or expressed by cell surface proteins expressed on T lymphocytes (via PD-L2-mediated signaling), thereby reducing dysfunction of dysfunctional T cells (e.g., enhancing effector responses to antigen recognition). In some aspects, a PD-L2 binding antagonist binds to PD-L2. In some aspects, a PD-L2 binding antagonist is an immunoadhesin. In other aspects, a PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.

Unless otherwise indicated, the term "protein" as used herein refers to any native protein from any vertebrate source, including mammals, such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed protein as well as any form of the protein produced by processing in cells. The term also encompasses naturally occurring protein variants, such as splice variants or allelic variants.

"Percentage (%) of amino acid sequence identity" relative to a reference polypeptide sequence refers to the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a reference polypeptide sequence, after aligning the sequences and introducing differences (if necessary), the maximum percentage of sequence identity that can be achieved, and any conservative substitutions are not considered as part of the sequence identity. Alignment for the purpose of determining percentage of amino acid sequence identity can be achieved by various means within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or the FASTA program suite. A person skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm required to achieve maximum alignment over the entire length of the sequences being compared. Alternatively, percent identity values may be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was developed by ALIGN-2, Inc., and its source code is filed with user documentation in the U.S. Copyright Office, Washington, D.C. 20559, registered (U.S. Copyright Registration No. TXU510087) and described in WO 2001/007611.

Unless otherwise noted, for the purposes of this article, percent amino acid sequence identity values were generated using the ggsearch program from the FASTA suite, version 36.3.8c or later, and the BLOSUM50 comparison matrix. The FASTA package was developed by W. R. W. R. Pearson and D. J. Lipman (1988), “Improved Tools for Biological Sequence Analysis,” PNAS 85:2444-2448; W. R. Pearson (1996) “Effective protein sequence comparison,” Meth. Enzymol. 266:227- 258; and Pearson et al. (1997) Genomics 46:24-36, and is publicly available at fasta.bioch.virginia.edu/fasta_www2/fasta_down.shtml or ebi.ac.uk/Tools/sss/fasta. Alternatively, sequences can be compared using a public server accessed through fasta.bioch.virginia.edu/fasta_www2/index.cgi using the ggsearch (global protein:protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) to ensure that a global rather than a local alignment is performed. The percentage of amino acid identity is provided in the output alignment header.

The term "pharmaceutical formulation" refers to a preparation which is in such form as to permit the biological activity of the active ingredient contained therein to be effective and which contains no other components which are unacceptably toxic to the subject to which the formulation is to be administered.

"Pharmaceutically acceptable carriers" refer to ingredients in pharmaceutical formulations other than active ingredients that are non-toxic to individuals. Pharmaceutically acceptable carriers include but are not limited to buffers, excipients, stabilizers or preservatives.

"Radiotherapy" means the use of directed gamma or beta rays to induce sufficient damage to cells to limit their ability to function normally or to destroy the cells completely. It will be appreciated that there are many ways in the art to determine the dosage and duration of treatment. Typical treatment is a single administration, and typical dosages range from 10 to 200 Grays per day.

As used herein, "treatment" (and grammatical variants such as "treat" or "treating") refers to clinical intervention intended to alter the natural course of a disease in the individual being treated, and can be performed either preventively or during the course of clinical pathology. Desired therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of a disease, alleviating symptoms, alleviating any direct or indirect pathological consequences of a disease, preventing metastasis, reducing the rate of disease progression, ameliorating or reducing the disease state, relieving or improving prognosis. In some aspects, the antibodies of the invention (e.g., the anti-FcRH5/anti-CD3 TDB of the invention) are used to delay the development of a disease or slow the progression of a disease.

"Reducing or inhibiting" means the ability to cause an overall reduction, preferably 20% or greater, more preferably 50% or greater, and most preferably 75%, 85%, 90%, 95% or greater. In certain aspects, reduction or inhibition may refer to antibody effector functions mediated by the antibody Fc region, such effector functions specifically include CDC, ADCC and ADCP.

According to the present invention, the term "vaccine" relates to a pharmaceutical preparation (pharmaceutical composition) or product that, upon administration, induces an immune response, particularly a cellular immune response, which recognizes and attacks pathogens or diseased cells such as cancer cells. Vaccines can be used to prevent or treat diseases. The vaccine may be a cancer vaccine. As used herein, a "cancer vaccine" is a composition that stimulates an individual to produce an immune response against cancer. Cancer vaccines typically consist of a source of cancer-related substances or cells (antigens), which may be autologous (from oneself) or allogeneic (from elsewhere) to the individual; and other components (such as adjuvants) to further stimulate and enhance the immune response against the antigen. Cancer vaccines stimulate an individual's immune system to produce antibodies against one or more specific antigens and/or to produce killer T cells to attack cancer cells that have those antigens.

As used herein, "administering" refers to a method of administering a dose of a compound (e.g., an anti-FcRH5/anti-CD3 TDB, such as ceftriaxone, an IMiD (e.g., pomalidomide), an anti-CD38 antibody (e.g., daratumumab), or a corticosteroid (e.g., dexamethasone)) to a subject. In some embodiments, the composition used in the methods herein is administered intravenously. For example, the compositions used in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, transdermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intracapsularly, intramucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, topically, by inhalation, by injection, by infusion, by continuous infusion, by local direct perfusion of target cells, by catheter, by lavage, by cream or lipid composition. The method of administration can vary depending on a variety of factors (e.g., the compound or composition being administered and the severity of the condition, disease or disorder to be treated).

Unless otherwise indicated, as used herein, "CD38" refers to a glycoprotein found on the surface of many immune cells, including CD4+, CD8+, B lymphocytes, and natural killer (NK) cells, and includes any native CD38 from any vertebrate source, including mammals, such as primates (e.g., humans) and rodents (e.g., mice and rats). CD38 is generally expressed at higher levels and more uniformly on myeloma cells than on normal lymphocytes and myeloid cells. The term encompasses "full-length," unprocessed CD38 as well as any form of CD38 produced by processing in the cell. The term also encompasses natural CD38 variants, such as splice variants or allelic variants. CD38 is also referred to in the art as cluster of differentiation 38, ADP-ribosyl cyclase 1, cADPr hydrolase 1, and cyclic ADP-ribose hydrolase 1. CD38 is encoded by the CD38 gene. The nucleic acid sequence of an exemplary human CD38 is shown in NCBI Reference Sequence: NM_001775.4 or SEQ ID NO: 33. The amino acid sequence of an exemplary human CD38 protein encoded by CD38 is shown in UniProt Accession No. P28907 or SEQ ID NO: 34.

The term "anti-CD38 antibody" encompasses all antibodies that bind CD38 with sufficient affinity to allow the antibody to be used as a therapeutic agent targeting cells expressing the antigen and that do not significantly cross-react with other proteins, such as negative control proteins in the assays described below. For example, an anti-CD38 antibody can bind to CD38 on the surface of MM cells and mediate cell lysis via activated complement-dependent cytotoxicity, ADCC, antibody-dependent cellular phagocytosis (ADCP), and Fc-crosslinking-mediated apoptosis, leading to depletion of malignant cells and reduction of overall cancer burden. Anti-CD38 antibodies can also modulate CD38 enzymatic activity by inhibiting ribosyl cyclase activity and stimulating cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain aspects, the dissociation constant ( _KD ) of the anti-CD38 antibody binding to CD38 is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., ^10-8 M or less, such as ^10-8 M to ^10-13 M, such as ^10-9 to ^10-13 M). In certain aspects, the anti-CD38 antibody can bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies also include anti-CD38 antagonist antibodies. Also encompassed are bispecific antibodies in which one arm of the antibody binds to CD38. This definition of anti-CD38 antibodies also includes functional fragments of the aforementioned antibodies. Examples of antibodies that bind to CD38 include: Daratumumab (DARZALEX®) (U.S. Patent No.: 7,829,673 and U.S. Publication No.: 20160067205 A1); "MOR202" (U.S. Patent No.: 8,263,746); and isatuximab (SAR-650984).

As used herein, the term "macrophage activation syndrome" or "MAS" refers to a condition characterized by inappropriate activation of an individual's immune system, including uncontrolled activation and proliferation of macrophages and/or T lymphocytes, which is often associated with rheumatic diseases such as systemic juvenile idiopathic arthritis and adult-onset Still's disease. Viral infections (e.g., Epstein Barr virus (EBV), cytomegalovirus (CMV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), autoimmune diseases, and malignancies (e.g., multiple myeloma) may contribute to symptoms of MAS. Exemplary, non-limiting symptoms of MAS include persistent high fever, hepatosplenomegaly, lymphadenopathy, and hemorrhagic manifestations.

As used herein, the term "hemophagocytic lymphohistiocytosis" or "HLH" refers to a rare and potentially fatal condition characterized by inappropriate activation of the immune system in which certain white blood cells (e.g., tissue cells (e.g., macrophages) and lymphocytes) accumulate in and damage organs (e.g., bone marrow, liver, and/or spleen) and destroy other blood cells. HLH can be inherited (e.g., primary or familial HLH (FHL)) or acquired (e.g., secondary HLH). Viral infections (e.g., EBV, CMV, and SARS-CoV-2), autoimmune diseases, and malignant tumors (e.g., multiple myeloma) may contribute to the symptoms of HLH. Exemplary, non-limiting symptoms of HLH include an enlarged liver, swollen lymph nodes, rash, jaundice, difficulty breathing, vomiting, diarrhea, headache, difficulty walking, and visual impairment.

It is understood that MAS and HLH are closely related conditions that may have overlapping manifestations (see, e.g., Halyabar et al. Pediatric Rheumatology 17(7):1-12, 2019). In some cases, the diagnosis of HLH/MAS uses the HLH-2004 criteria, which require the presence of at least five of the following eight criteria: (1) fever ≥38.5°C; (2) splenomegaly; (3) peripheral blood cytopenia affecting at least two cell lines (hemoglobin <9 g/dL, platelets <100,000/µL and/or absolute neutrophil count <1000/µL); (4) fasting triglycerides >265 mg/dL and/or fibrinogen <150 mg/dL; (5) hemophagocytosis in the bone marrow, spleen, lymph nodes, or liver; (6) low or absent NK cell activity; (7) ferritin >500 ng/mL; (8) Soluble interleukin-2 (IL-2) receptor (soluble CD25) is elevated by two standard deviations above the laboratory-specified normal range (see, e.g., McClain and Eckstein. “Clinical Features and Diagnosis of Hemoph, wagocytic Lymphohistiocytosis.” UpToDate, May 6, 2022). II. Treatment

The present disclosure provides methods for treating individuals with cancer (e.g., multiple myeloma (MM)) using anti-fragment crystallizable receptor-like 5 (FcRH5)/anti-cluster of differentiation 3 (CD3) bispecific antibodies. The present invention is based, at least in part, on the development of dosing regimens as disclosed herein. The invention is also based, at least in part, on reducing or inhibiting unwanted treatment effects by excluding from treatment subjects with one or more of the following: (i) a history of macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH), (ii) positive and quantifiable Epstein-Barr virus (EBV) or cytomegalovirus (CMV), or (iii) active symptomatic coronavirus disease 2019 (COVID-19) infection or a need for treatment with intravenous antivirals. The methods utilize dosing regimens using anti-FcRH5/anti-CD3 bispecific antibodies, including fractionated, dose-escalating dosing regimens and split dose-escalating regimens. The present invention provides monotherapy dosing regimens of ceftriaxone and combinations of ceftriaxone with: 1) pomalidomide and dexamethasone (Pd), and 2) daratumumab and dexamethasone (Dd). Exemplary dosing regimens described herein are ceftriaxone as a single agent in a dose-dense dosing regimen, wherein ceftriaxone is administered in 28-day cycles, wherein ceftriaxone is administered Q1W for the first two cycles (C1 and C2), Q2W for cycles 3 to 6, and Q4W for cycles 7 to 13. Another exemplary dosing regimen described herein is the use of ceftriaxone with Pd in a 28-day cycle, wherein ceftriaxone is administered Q2W for the first 24 weeks (cycles 1-6) and then (cycle 7 onwards) Q4W. Another exemplary dosing regimen described herein is also the use of ceftriaxone with Dd in a 21-day cycle, wherein ceftriaxone is administered Q3W for the first 24 weeks (cycles 1-8) and then (cycle 9 onwards) Q4W. The methods disclosed herein can, for example, facilitate consistency in dosing schedules with combination therapy partners. Such approaches are expected to reduce or inhibit unwanted treatment effects, including interleukin-driven toxicities (e.g., interleukin release syndrome (CRS)), infusion-related reactions (IRRs), macrophage activation syndrome (MAS), hemophagocytic lymphohistiocytosis (HLH), neurologic toxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, and/or elevated liver enzymes. Thus, such approaches are useful for treating individuals while achieving a more favorable benefit-risk profile.

The present invention provides methods useful for treating an individual with cancer (e.g., multiple myeloma), wherein the individual does not have one or more of the following: a history of MAS and/or HLH; active (e.g., positive and quantifiable) EBV, CMV, or SARS-CoV-2 infection; or active symptomatic COVID-19 infection or need for treatment with an intravenous antiviral agent. The methods include administering to the individual a bispecific antibody that binds to FcRH5 and CD3 (i.e., an anti-FcRH5/anti-CD3 antibody), e.g., in a divided, dose-escalating dosing regimen, as a monotherapy or in combination with one or more additional therapeutic agents (e.g., an IMiD (e.g., pomalidomide), an anti-CD38 antibody (e.g., daratumumab), a corticosteroid (e.g., dexamethasone), or a combination thereof). A. Dosing Regimen i. Non-escalating Dosing Regimen

In some aspects, the invention provides methods of treating an individual having cancer (e.g., multiple myeloma (MM)) comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen without administering any booster doses.

In some aspects, the invention provides a method of treating a subject having MM, comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1D1) of the bispecific antibody, wherein C1D1 is between about 0.15 mg and about 1000 mg (e.g., between about 0.5 mg and about 800 mg, between about 1 mg and about 700 mg, between about 5 mg and about 500 mg, between about 10 mg and about 400 mg, between about 25 mg and about 300 mg, between about 40 mg and about 200 mg, between about 50 mg and about 1000 mg, to about 100 mg, between about 75 mg to about 100 mg, or between about 85 mg to about 100 mg).

In some aspects, the invention provides a method of treating a subject having cancer (e.g., MM) comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1D1) of the bispecific antibody between about 0.15 mg and about 1000 mg (e.g., between about 0.5 mg and about 800 mg, between about 1 mg and about 700 mg, between about 5 mg and about 500 mg, between about 10 mg and about 400 mg, between about 25 mg and about 300 mg, between about 40 mg and about 200 mg, between about 50 mg and about 1000 mg, between about 25 mg and about 300 mg, between about 40 mg and about 200 mg, between about 50 mg and about 1000 mg, between about 20 ... to about 100 mg, between about 75 mg to about 100 mg, or between about 85 mg to about 100 mg).

In some aspects, C1D1 is between about 20 mg and about 600 mg (e.g., between about 30 mg and 500 mg, 40 mg and 400 mg, 60 mg and 350 mg, 80 mg and 300 mg, 100 mg and 200 mg, or 140 mg and 180 mg, e.g., about 20, 40, 60, 80, 90, 100, 120, 130, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, C1D1 is 90 mg. In some aspects, C1D1 is 132 mg. In some aspects, C1D1 is 160 mg.

In some embodiments of any of the foregoing aspects, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody , or ( iii ) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

In some aspects, the invention provides methods of treating an individual having cancer (e.g., MM) comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 in a single boosting dosing regimen.

In some aspects, the present invention provides a method of treating a subject having MM, comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose of the bispecific antibody (C1D1) and a second dose of the bispecific antibody (C1D2), wherein C1D1 is between about 0.05 mg and about 180 mg (e.g., between about 0.1 mg and about 160 mg, between about 0.5 mg and about 140 mg, between about 1 mg and about 120 mg, between about 1.5 mg and about 100 mg, between about 2.0 mg and about 80 mg, between about 2.5 mg and about 50 mg, between about 3.0 mg and about 25 mg, between about 3.0 mg and about 15 mg, between about 3.0 mg and about 10 mg, or between about 3.0 mg and about 5 mg, and C1D2 is between about 0.15 mg and about 1000 mg (e.g., between about 0.5 mg and about 800 mg, between about 1 mg and about 700 mg, between about 5 mg and about 500 mg, between about 10 mg and about 400 mg, between about 25 mg and about 300 mg, between about 40 mg and about 200 mg, between about 50 mg and about 100 mg). between about 75 mg and about 100 mg, or between about 85 mg and about 100 mg).

In some aspects, the present invention provides a method for treating an individual having cancer (e.g., MM), comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first dose of the bispecific antibody (C1D1; cycle 1, dose 1) and a second dose of the bispecific antibody (C1D2; cycle 1, dose 2), wherein C1D1 is less than C1D2, and wherein C1D1 is between about 0.05 mg and about 180 mg (e.g., between about 0.1 mg and about 160 mg, between about 0.5 mg and about 160 mg, between about 0.6 mg and about 160 mg, between about 0.7 mg and about 160 mg, between about 0.9 mg and about 180 mg, between about 1.1 mg and about 1.2 mg, between about 2.0 mg and about 2.0 mg, between about 3.5 mg and about 3.0 mg, between about 4.5 mg and about 5.0 mg, between about 5. between about 100 mg and about 140 mg, between about 1 mg and about 120 mg, between about 1.5 mg and about 100 mg, between about 2.0 mg and about 80 mg, between about 2.5 mg and about 50 mg, between about 3.0 mg and about 25 mg, between about 3.0 mg and about 15 mg, between about 3.0 mg and about 10 mg, or between about 3.0 mg and about 5 mg, and C1D2 is between about 0.15 mg and about 1000 mg (e.g., between about 0.5 mg and about 800 mg, between about 1 mg and about 700 mg, between about 5 mg and about 500 mg, between about 10 mg and about 400 mg). mg, between about 25 mg and about 300 mg, between about 40 mg and about 200 mg, between about 50 mg and about 100 mg, between about 75 mg and about 100 mg, or between about 85 mg and about 100 mg); and (b) a second dosing cycle comprises a single dose of the bispecific antibody (C2D1; Cycle 2, Dose 1), wherein C2D1 is equal to or greater than C1D2 and is between about 0.15 mg and about 1000 mg (e.g., between about 0.5 mg and about 800 mg, between about 1 mg and about 700 mg, between about 5 mg and about 500 mg, between about 10 mg to about 400 mg, between about 25 mg to about 300 mg, between about 40 mg to about 200 mg, between about 50 mg to about 100 mg, between about 75 mg to about 100 mg, or between about 85 mg to about 100 mg).

In some aspects, (a) C1D1 is between about 0.5 mg and about 19.9 mg (e.g., between about 1 mg and about 18 mg, between about 2 mg and about 15 mg, between about 3 mg and about 10 mg, between about 3.3 mg and about 6 mg, or between about 3.4 mg and about 4 mg, for example, about 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 13 mg mg, 13.2 mg, 13.4 mg, 13.6 mg, 13.8 mg, 14 mg, 14.2 mg, 14.4 mg, 14.6 mg, 14.8 mg, 15 mg, 15.2 mg, 15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg, 18.2 mg, 18.4 mg, 18.6 (b) C1D2 is between about 20 mg and about 600 mg (e.g., between about 30 mg and 500 mg, 40 mg and 400 mg, 60 mg and 350 mg, 80 mg and 300 mg, 100 mg and 200 mg, or 140 mg and 180 mg, e.g., about 20, 40, 60, 80, 90, 100, 120, 130, 132, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg).

In some aspects, C1D1 is between about 1.2 mg and about 10.8 mg and C1D2 is between about 80 mg and about 300 mg. In some aspects, C1D1 is between 1.2 mg and 10.8 mg and C1D2 is between 80 mg and 300 mg. In some aspects, C1D1 is 3.6 mg and C1D2 is 90 mg. In some aspects, C1D1 is 3.6 mg and C1D2 is 132 mg. In some aspects, C1D1 is 3.6 mg and C1D2 is 160 mg.

In some cases, the above methods may include a first dosing cycle of four weeks or 28 days. In some instances, the methods may include administering C1D1 and C1D2 to a subject on or about days 1 and 8, respectively, of the first dosing cycle.

In some cases, the above methods may include a first dosing cycle of three weeks or 21 days. In some instances, the methods may include administering C1D1 and C1D2 to a subject on or about days 1 and 8, respectively, of the first dosing cycle.

In some cases, the above methods may include a first dosing cycle of three weeks or 21 days. In some instances, the methods may include administering C1D1 and C1D2 to a subject on or about days 2 and 9, respectively, of the first dosing cycle.

In some cases, the above methods may include a first dosing cycle of three weeks or 21 days. In some instances, the methods may include administering C1D1 and C1D2 to a subject on or about days 3 and 9, respectively, of the first dosing cycle.

In some embodiments of any of the foregoing aspects, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody , or ( iii ) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

In other aspects, the invention provides methods of treating an individual having cancer (e.g., MM) comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 in a double boost dosing regimen.

In some aspects, the present disclosure provides a method of treating a subject having cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen that comprises at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1D1) of the bispecific antibody, a second dose (C1D2) of the bispecific antibody, and a third dose (C1D3) of the bispecific antibody, wherein C1D1 is between about 0.2 mg and about 0.4 mg (e.g., about 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, 0.30 mg, 0.31 mg, 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, 0.38 mg, 0.39 mg, 0.40 mg, 0.41 mg, 0.42 mg, 0.43 mg, 0.44 mg, 0.45 mg, 0.46 mg, 0.47 mg, 0.48 mg, 0.49 mg, 0.50 mg, 0.51 mg, 0.52 mg, 0.53 mg, 0.54 mg, 0.55 mg, 0.56 mg, 0.57 mg, 0.58 mg, 0.59 mg, 0.60 mg, 0.61 mg, 0.62 mg, 0.63 mg, 0.64 mg, 0.65 mg, 0.66 mg, 0.67 mg, 0.68 mg, 0.69 mg, 0.70 mg, 0.71 mg, 0. In some aspects, C1D1 is about 0.3 mg.

In some aspects, C1D1 is 0.2 mg to 0.4 mg (e.g., 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, 0.30 mg, 0.31 mg, 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, 0.38 mg, 0.39 mg, or 0.40 mg). In some aspects, C1D1 is 0.3 mg.

In some aspects, the present disclosure provides a method of treating a subject having cancer (e.g., MM) comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), wherein C1D1 is between about 0.01 mg and about 2.9 mg, C1D2 is between about 3 mg and about 19.9 mg, and C1D3 is between about 20 mg and about 600 mg.

In some aspects, the present invention provides a method of treating an individual having cancer (e.g., MM), comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1D1) of the bispecific antibody, a second dose (C1D2) of the bispecific antibody, and a third dose (C1D3) of the bispecific antibody, wherein C1D1 and C1D2 are each less than C1D3, and wherein C1D1 is between about 0.01 mg and about 2.9 mg, C1D2 is between about 3 mg and about 19.9 mg, and C1D3 is between about 20 mg and about 19.9 mg. and (b) the second dosing cycle comprises a single dose (C2D1) of the bispecific antibody, wherein C2D1 is equal to or greater than C1D3 and is between about 20 mg and about 600 mg.

In some aspects, C1D1 is about 0.05 mg to about 2.5 mg, about 0.1 mg to about 2 mg, about 0.2 mg to about 1 mg, or about 0.2 mg to about 0.4 mg (e.g., about 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, or 2.9 mg). In some aspects, C1D1 is about 0.3 mg.

In some aspects, C1D1 is 0.05 mg to 2.5 mg, 0.1 mg to 2 mg, 0.2 mg to 1 mg, or 0.2 mg to 0.4 mg (e.g., 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, or 2.9 mg). In some aspects, C1D1 is 0.3 mg.

In some aspects, C1D2 is about 3 mg to about 19.9 mg (e.g., about 3 mg to about 18 mg, about 3.1 mg to about 15 mg, about 3.2 mg to about 10 mg, about 3.3 mg to about 6 mg, or about 3.4 mg to about 4 mg, such as about 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 10.2 mg, 10.4 mg, 10.6 mg, 10.8 mg, 11 mg, 11.2 mg, 11.4 mg, 11.6 mg, 11.8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg, 12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 13.8 mg, 14 mg, 14.2 mg, 14.4 mg, 14.6 mg, 14.8 mg, 15 mg, 15.2 mg, 15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg, 18.2 mg, 18.4 mg, 18.6 mg, 18.8 mg, 19 mg, 19.2 In some aspects, C1D2 is between about 3.2 mg and about 10 mg. In some aspects, C1D2 is about 3.6 mg. In some aspects, C1D2 is between about 3 mg and about 4 mg. In some aspects, C1D2 is about 3.3 mg.

In some aspects, C1D2 is about 3 mg to 19.9 mg (e.g., 3 mg to 18 mg, 3.1 mg to 15 mg, 3.2 mg to 10 mg, 3.3 mg to 6 mg, or 3.4 mg to 4 mg, for example, 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 10.2 mg, 10.4 mg, 10.6 mg, 10.8 mg, 11 mg, 11.2 mg, 11.4 mg, 11.6 mg, 11.8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg, 12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 13.8 mg, 14 mg, 14.2 mg, 14.4 mg, 14.6 mg, 14.8 mg, 15 mg, 15.2 mg, 15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg, 18.2 mg, 18.4 mg, 18.6 mg, 18.8 mg, 19 mg, 19.2 mg, 19.4 mg, 19.6 mg or In some aspects, C1D2 is between 3.2 mg and 10 mg. In some aspects, C1D2 is 3.6 mg. In some aspects, C1D2 is between 3 mg and 4 mg. In some aspects, C1D2 is 3.3 mg.

In some aspects, C1D3 is about 20 mg to about 600 mg (e.g., about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, such as about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, C1D3 is between about 80 mg and about 300 mg. In some aspects, C1D3 is about 90 mg. In some aspects, C1D3 is about 132 mg. In some aspects, C1D3 is about 160 mg.

In some aspects, C1D3 is 20 mg to 600 mg (e.g., 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, C1D3 is between 80 mg and 300 mg. In some aspects, C1D3 is 90 mg. In some aspects, C1D3 is 132 mg. In some aspects, C1D3 is 160 mg.

In some aspects, the method comprises only a single dosing cycle of the bispecific antibody (e.g., a dosing cycle comprising C1D1, C1D2, and C1D3).

In other aspects, the dosing regimen further comprises a second dosing cycle comprising at least a single dose of the bispecific antibody (C2D1). In some aspects, C2D1 is equal to or greater than C1D3 and is about 20 mg to about 600 mg (e.g., about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, such as about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, C2D1 is between about 80 mg and about 300 mg. In some aspects, C2D1 is about 90 mg. In some aspects, C2D1 is about 132 mg. In some aspects, C2D1 is about 160 mg.

In some aspects, C2D1 is 20 mg to 600 mg (e.g., 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some aspects, C2D1 is between 80 mg and 300 mg. In some aspects, C2D1 is 90 mg. In some aspects, C2D1 is 132 mg. In some aspects, C2D1 is 160 mg.

Alternatively, in any of the above embodiments, C1D1 can be between about 0.01 mg and about 60 mg (e.g., between about 0.05 mg and about 50 mg, between about 0.01 mg and about 40 mg, between about 0.1 mg and about 20 mg, between about 0.1 mg and about 10 mg, between about 0.1 mg and about 5 mg, between about 0.1 mg and about 2 mg, between about 0.1 mg and about 1.5 mg, between about 0.1 mg and about 1.2 mg, between about 0.1 mg and about 0.5 mg, or between about 0.2 mg and about 0.4 mg, e.g., about 0.3 mg, e.g., 0.3 mg), and C1D2 can be between about 0.01 mg and about 60 mg (e.g., between about 0.05 mg and about 50 mg, between about 0.01 mg and about 40 mg, between about 0.1 mg and about 20 mg, between about 0.1 mg and about 5 mg, between about 0.1 mg and about 2 mg, between about 0.1 mg and about 1.5 mg, between about 0.1 mg and about 1.2 mg, between about 0.1 mg and about 0.5 mg, or between about 0.2 mg and about 0.4 mg, e.g., about 0.3 mg, e.g., 0.3 mg). The dosage may be between about 0.05 mg and about 180 mg (e.g., between about 0.1 mg and about 160 mg, between about 0.5 mg and about 140 mg, between about 1 mg and about 120 mg, between about 1.5 mg and about 100 mg, between about 2.0 mg and about 80 mg, between about 2.5 mg and about 50 mg, between about 3.0 mg and about 25 mg, between about 3.0 mg and about 15 mg, between about 3.0 mg and about 10 mg, between about 3.0 mg and about 5 mg, or between about 3.0 mg and about 4.0 mg, for example, about 3.3 mg or about 3.6 mg, for example. or 3.6 mg), and C1D3 may be between about 0.15 mg and about 1000 mg (e.g., between about 0.5 mg and about 800 mg, between about 1 mg and about 700 mg, between about 5 mg and about 500 mg, between about 10 mg and about 400 mg, between about 25 mg and about 300 mg, between about 40 mg and about 200 mg, between about 50 mg and about 190 mg, between about 140 mg and about 180 mg, or between about 150 mg and about 170 mg, e.g., about 160 mg, e.g., 160 mg); and in an aspect comprising a second dosing cycle, C2D1 may be between about 0.15 mg and about 1000 mg (e.g., between about 0.5 mg and about 800 mg, between about 1 mg and about 700 mg, between about 5 mg and about 500 mg, between about 10 mg and about 400 mg, between about 25 mg and about 300 mg, between about 40 mg and about 200 mg, between about 50 mg and about 190 mg, between about 140 mg and about 180 mg, or between about 150 mg and about 170 mg, e.g., about 160 mg, e.g., 160 mg). to about 1000 mg (e.g., between about 0.5 mg to about 800 mg, between about 1 mg to about 700 mg, between about 5 mg to about 500 mg, between about 10 mg to about 400 mg, between about 25 mg to about 300 mg, between about 40 mg to about 200 mg, between about 50 mg to about 190 mg, between about 140 mg to about 180 mg, or between about 150 mg to about 170 mg, e.g., about 90 mg, about 132 mg, or about 160 mg, e.g., 90 mg, 132 mg, or 160 mg).

In some examples, the length of the first dosing cycle is three weeks or 21 days. In some examples, the methods may include administering C1D1, C1D2, and C1D3 to a subject on or about day 1, day 8, and day 15 of the first dosing cycle, respectively.

In some examples, the length of the first dosing cycle is three weeks or 21 days. In some examples, the methods may include administering C1D1, C1D2, and C1D3 to the subject on or about day 2, day 9, and day 16 of the first dosing cycle, respectively.

In some examples, the length of the first dosing cycle is three weeks or 21 days. In some examples, the methods may include administering C1D1, C1D2, and C1D3 to the subject on or about day 3, day 9, and day 16 of the first dosing cycle, respectively.

In some examples, the length of the first dosing cycle is three weeks or 21 days. In some examples, the methods may include administering C1D1, C1D2, and C1D3 to the subject on or about day 9, day 10, and day 16 of the first dosing cycle, respectively.

In some examples, the length of the first dosing cycle is three weeks or 21 days. In some examples, the methods may include administering C1D1, C1D2, and C1D3 to the subject on or about day 9, day 11, and day 16 of the first dosing cycle, respectively.

In some examples, the length of the first dosing cycle is three weeks or 21 days. In some examples, the methods may include administering C1D1, C1D2, and C1D3 to the subject on or about day 9, day 12, and day 16 of the first dosing cycle, respectively.

In some cases, the length of the first dosing cycle is two weeks or 14 days. In some examples, the methods may include administering C1D1, C1D2, and C1D3 to the subject on or about day 1, day 2, and day 8 of the first dosing cycle, respectively.

In some cases, the length of the first dosing cycle is two weeks or 14 days. In some examples, the methods may include administering C1D1, C1D2, and C1D3 to the subject on or about day 1, day 3, and day 8 of the first dosing cycle, respectively.

In some cases, the length of the first dosing cycle is two weeks or 14 days. In some examples, the methods may include administering C1D1, C1D2, and C1D3 to the subject on or about day 1, day 4, and day 8 of the first dosing cycle, respectively.

In some embodiments of any of the foregoing aspects, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or the need for treatment with intravenous antivirals. iv. Additional dosing cycles

In some instances, the methods described above may include a second dosing cycle of three weeks or 21 days. In some instances, the methods described above may include a second dosing cycle of four weeks or 28 days. In some instances, the methods may include administering C2D1 to the subject on or about day 1 of the second dosing cycle.

In some examples where the methods include at least a second administration cycle, the methods may include one or more additional administration cycles. In some embodiments, the dosing regimen comprises 1 to 17 additional dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 additional dosing cycles, such as 1-3 additional dosing cycles, 1-5 additional dosing cycles, 3-8 additional dosing cycles, 5-10 additional dosing cycles, 8-12 additional dosing cycles, 10-15 additional dosing cycles, 12-17 additional dosing cycles, or 15-17 additional dosing cycles, i.e., the dosing regimen includes one or more additional dosing cycles C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18 and C19.

In some embodiments, the length of each of the one or more additional dosing cycles is 7 days, 14 days, 21 days, or 28 days. In some embodiments, the length of each of the one or more additional dosing cycles is 5 days to 30 days, such as 5 to 9 days, 7 to 11 days, 9 to 13 days, 11 to 15 days, 13 to 17 days, 15 to 19 days, 17 to 21 days, 19 to 23 days, 21 to 25 days, 23 to 27 days, or 25 to 30 days. In some cases, the length of each of the one or more additional dosing cycles is three weeks or 21 days. In some cases, each of the one or more additional dosing cycles is four weeks or 28 days in length.

In some instances, each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is equal to C2D1, for example, about 20 mg to about 600 mg (e.g., about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, for example about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580 or 600 mg). In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is about 90 mg. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is about 132 mg. In some embodiments, the dose of the bispecific antibody in the one or more additional dosing cycles is about 160 mg. In some embodiments, the dose of the bispecific antibody in the one or more additional dosing cycles is equal to C2D1, for example, between 20 mg and 600 mg (e.g., between 30 mg and 500 mg, 40 mg and 400 mg, 60 mg and 350 mg, 80 mg and 300 mg, 100 mg and 200 mg, or 140 mg and 180 mg). In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is 90 mg. In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is 132 mg. In some aspects, the dose of the bispecific antibody in one or more additional dosing cycles is about 160 mg.

In some cases, the method comprises administering to the individual a single dose of the bispecific antibody on or about day 1 of the one or more additional dosing cycles. In some cases, the method comprises administering to the individual a single dose of the bispecific antibody on or about day 1 and day 15 of the one or more additional dosing cycles. In some cases, the method comprises administering to the individual a single dose of the bispecific antibody on or about day 1, day 8, and day 15 of the one or more additional dosing cycles. In some cases, the method comprises administering to the individual a single dose of the bispecific antibody on or about day 1, day 8, day 15, and day 22 of one or more additional dosing cycles.

In some aspects, the bispecific antibody is administered to the individual every 7 days (QW) until progressive disease is observed, for up to 18 cycles, or until minimal residual disease (MRD) is observed. In some aspects, the bispecific antibody is administered to the individual every 14 days (Q2W) until progressive disease is observed, for up to 18 cycles, or until minimal residual disease (MRD) is observed. In some aspects, the bispecific antibody is administered to the individual every 21 days (Q3W) until progressive disease is observed, for up to 18 cycles, or until minimal residual disease (MRD) is observed. In some aspects, the bispecific antibody is administered to an individual every 28 days (Q4W) until progressive disease is observed, for up to 18 cycles, or until minimal residual disease (MRD) is observed.

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject as a monotherapy. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject in combination with another therapeutic agent. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject in combination with an anti-CD38 antibody. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject in combination with a corticosteroid. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject in combination with an immunomodulatory drug (IMiD). In some cases, a bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject in combination with an anti-CD38 antibody and a corticosteroid. In some cases, a bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject in combination with an IMiD and a corticosteroid. Exemplary anti-CD38 antibodies for use in combination therapy include daratumumab and isatuximab. Exemplary corticosteroids for use in combination therapy include dexamethasone and methylprednisolone. Exemplary IMiDs for use in combination therapy include pomalidomide and lenalidomide.

In some cases, the bispecific anti-FcRH5/anti-CD3 antibody is ceftriaxone. In some cases, ceftriaxone is administered to an individual as a monotherapy. In some cases, ceftriaxone is administered to an individual in combination with pomalidomide (P). In some cases, ceftriaxone is administered to an individual in combination with dexamethasone (d). In some cases, ceftriaxone is administered to an individual in combination with pomalidomide and dexamethasone (Pd). In some cases, ceftriaxone is administered to an individual in combination with daratumumab (D). In some cases, ceftriaxone is administered to an individual in combination with daratumumab and dexamethasone (Dd).

In some embodiments of any of the foregoing aspects, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent. B. Dosing Regimen

The present disclosure describes a method of treating an individual with cancer (e.g., multiple myeloma (MM)), wherein the individual does not have one or more of the following: a history of MAS and/or HLH; active (e.g., positive and quantifiable) EBV, CMV, or SARS-CoV-2 infection; or active symptomatic COVID-19 infection or need for treatment with intravenous antivirals. The methods may include the step of administering to the individual a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen described herein. In some examples, the dosing regimen comprises a first phase comprising one or more dosing cycles, a second phase comprising one or more dosing cycles, and a third phase comprising one or more dosing cycles. In some instances, each dosing cycle is a 14-day dosing cycle. In some instances, each dosing cycle is a 21-day dosing cycle. In some instances, each dosing cycle is a 28-day dosing cycle. The first phase may include administering the bispecific antibody to the individual every week (QW), the second phase may include administering the bispecific antibody to the individual every two weeks (Q2W), and/or the third phase may include administering the bispecific antibody to the individual every four weeks (Q4W).

For example, provided herein are methods for treating an individual having cancer (e.g., MM) comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 using a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every week (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and/or (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the individual every four weeks (Q4W). In some instances, the dosing regimen includes a first phase. In some instances, the dosing regimen includes a second phase. In some instances, the dosing regimen includes a third phase. In some instances, the dosing regimen includes a first phase and a second phase. In some instances, the dosing regimen includes a first phase and a third phase. In some instances, the dosing regimen includes a second phase and a third phase. In some instances, the dosing regimen includes a second phase and a third phase. In some instances, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with intravenous antivirals.

In another example, provided herein are bispecific antibodies that bind to FcRH5 and CD3 for use in treating an individual with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to the individual using a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every week (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and/or (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the individual every four weeks (Q4W). A bispecific antibody is administered to an individual. In some instances, the dosing regimen includes a first phase. In some instances, the dosing regimen includes a second phase. In some instances, the dosing regimen includes a third phase. In some instances, the dosing regimen includes a first phase and a second phase. In some instances, the dosing regimen includes a first phase and a third phase. In some instances, the dosing regimen includes a second phase and a third phase. In some instances, the dosing regimen includes a second phase and a third phase. In some instances, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with an intravenous antiviral agent.

In another example, provided herein is a use of a bispecific antibody that binds to FcRH5 and CD3 in the manufacture of a medicament for treating an individual with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to the individual in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every week (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and/or (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the individual every four weeks (Q4W). A bispecific antibody is administered to an individual. In some instances, the dosing regimen includes a first phase. In some instances, the dosing regimen includes a second phase. In some instances, the dosing regimen includes a third phase. In some instances, the dosing regimen includes a first phase and a second phase. In some instances, the dosing regimen includes a first phase and a third phase. In some instances, the dosing regimen includes a second phase and a third phase. In some instances, the dosing regimen includes a second phase and a third phase. In some instances, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or need for treatment with an intravenous antiviral agent.

The first phase may include any suitable number of dosing cycles. For example, in some embodiments, the first phase may include at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles or more dosing cycles.

In some examples, the first phase includes a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a second dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6) and seventh dosing cycle (C7); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7) and eighth dosing cycle (C8); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7) and eighth dosing cycle (C8); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8) and the ninth dosing cycle (C9); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9) and the tenth dosing cycle (C10); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9) and the tenth dosing cycle (C10). (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10) and the eleventh dosing cycle (C11); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11) and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11) and the twelfth dosing cycle (C12). (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12) and the thirteenth dosing cycle (C13).

The bispecific antibody can be administered on any suitable day of a given dosing cycle. For example, for a 28-day dosing cycle, the bispecific antibody can be administered on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21, day 22, day 23, day 24, day 25, day 26, day 27, or day 28. In another example, for a 21-day dosing cycle, the bispecific antibody can be administered on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, or day 21. In another example, for a 14-day dosing cycle, the bispecific antibody can be administered on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, or day 14. In another example, for a 7-day dosing cycle, the bispecific antibody can be administered on day 1, day 2, day 3, day 4, day 5, day 6, or day 7.

In some examples, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C1. In further examples, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C2. In further examples, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C3. In further examples, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C4. In a further example, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C5. In a further example, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C6. In a further example, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C7. In a further example, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C8. In a further example, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C9. In a further example, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C10. In a further example, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C11. In a further example, the first phase comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C12. In further embodiments, the first phase comprises administering a bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C13.

In some instances, for each administration during the first phase, a target dose of a bispecific antibody is administered to the subject.

In some examples, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C1. In further examples, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C2. In further examples, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C3. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C4. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C5. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C6. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C7. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C8. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C9. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C10. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C11. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, day 15, and/or day 22 of C12. In further embodiments, the first phase comprises administering a target dose of a bispecific antibody to the subject on day 1, day 8, day 15, and/or day 22 of C13.

In some examples, the first phase comprises administering to the subject a first ascending dose and a target dose of the bispecific antibody. The first ascending dose can be administered to the subject on day 1 of C1, on day 2 of C1, on day 3 of C1, on day 4 of C1, on day 5 of C1, on day 6 of C1, on day 7 of C1, on day 8 of C1, on day 9 of C1, on day 10 of C1, on day 11 of C1, or on day 12 of C1 during the first phase. The target dose can be administered to the subject on day 8, day 15, and/or day 22 of C1 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C2 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C3 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C4 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C5 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C6 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C7 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C8 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C9 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C10 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C11 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C12 during the first phase. In further examples, the target dose may be administered to the subject on day 1, day 8, day 15, and/or day 22 of C13 during the first phase.

In some embodiments, the first incremental dose is about 0.3% to about 8% of the target dose. In some embodiments, the first incremental dose is about 0.19%, about 0.3%, about 0.33%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.1%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, or about 8% of the target dose.

In some examples, the first incremental dose is 0.19%, 0.3%, 0.33%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.1%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, or 8% of the target dose. In some examples, the first incremental dose is 4% of the target dose.

In some instances, the first incremental dose is about 3.3 mg. In some instances, the first incremental dose is about 3.6 mg. In some instances, the first incremental dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.3 mg, about 3.5 mg, about 3.6 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

In some instances, the first incremental dose is 3.3 mg. In some instances, the first incremental dose is 3.6 mg. In some instances, the first incremental dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.3 mg, 3.5 mg, 3.6 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

In some examples, the first phase comprises administering to the subject a first and a second incrementing dose of a bispecific antibody. In some examples, the first incrementing dose is administered to the subject on day 1 of C1 during the first phase, and the second incrementing dose is administered on day 2 of C1. In some examples, the first incrementing dose is administered to the subject on day 1 of C1 during the first phase, and the second incrementing dose is administered on day 3 of C1. In some examples, the first incrementing dose is administered to the subject on day 1 of C1 during the first phase, and the second incrementing dose is administered on day 4 of C1. In some examples, a first bolus dose is administered to a subject on day 9 of C1 during the first phase, and a second bolus dose is administered on day 10 of C1. In some examples, a first bolus dose is administered to a subject on day 9 of C1 during the first phase, and a second bolus dose is administered on day 11 of C1. In some examples, a first bolus dose is administered to a subject on day 9 of C1 during the first phase, and a second bolus dose is administered on day 12 of C1. In some examples, a first bolus dose is administered to a subject on day 1 of C1 during the first phase, and a second bolus dose is administered on day 8 of C1. In some examples, a first bolus dose is administered to a subject on day 2 of C1 during the first phase, and a second bolus dose is administered on day 9 of C1. In some examples, a first bolus dose is administered to a subject on day 3 of C1 during the first phase, and a second bolus dose is administered on day 10 of C1. In some examples, a first bolus dose is administered to a subject on day 4 of C1 during the first phase, and a second bolus dose is administered on day 11 of C1. In some examples, a first bolus dose is administered to a subject on day 5 of C1 during the first phase, and a second bolus dose is administered on day 12 of C1. In some examples, a first bolus dose is administered to a subject on day 6 of C1 during the first phase, and a second bolus dose is administered to a subject on day 13 of C1. In some examples, a first bolus dose is administered to a subject on day 7 of C1 during the first phase, and a second bolus dose is administered to a subject on day 14 of C1. In some examples, a first bolus dose is administered to a subject on day 8 of C1 during the first phase, and a second bolus dose is administered to a subject on day 15 of C1. In some examples, a first bolus dose is administered to a subject on day 9 of C1 during the first phase, and a second bolus dose is administered to a subject on day 16 of C1. In some examples, a first bolus dose is administered to a subject on day 10 of C1 during the First Phase, and a second bolus dose is administered on day 17 of C1. In some examples, a first bolus dose is administered to a subject on day 11 of C1 during the First Phase, and a second bolus dose is administered on day 18 of C1. In some examples, a first bolus dose is administered to a subject on day 12 of C1 during the First Phase, and a second bolus dose is administered on day 19 of C1. In some examples, a first bolus dose is administered to a subject on day 13 of C1 during the First Phase, and a second bolus dose is administered on day 20 of C1. In some instances, a first escalating dose is administered to a subject on day 14 of C1 and a second escalating dose is administered on day 21 of C1 during the first phase.

In further examples, the target dose is administered to the subject during the first phase after the second escalating dose is administered. In some examples, the target dose is administered to the subject on day 8 of C1. In some examples, the target dose is administered to the subject on day 15 of C1. In some examples, the target dose is administered to the subject on day 16 of C1. In some examples, the target dose is administered to the subject on day 15 and/or day 22 of C1. In some examples, the target dose is administered to the subject on day 16 and/or day 23 of C1. In some examples, the target dose is administered to the subject on day 17 and/or day 24 of C1. In some instances, the target dose is administered to the subject on day 18 and/or day 25 of C1. In some instances, the target dose is administered to the subject on day 19 and/or day 26 of C1. In some instances, the target dose is administered to the subject on day 20 and/or day 27 of C1. In some instances, the target dose is administered to the subject on day 21 and/or day 28 of C1.

In a further example, the target dose is further administered to the subject on day 1, day 8, day 15, and/or day 22 of C2 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and/or day 22 of C3 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and/or day 22 of C4 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and/or day 22 of C5 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and/or day 22 of C6 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and day 22 of C7 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and/or day 22 of C8 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and/or day 22 of C9 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and/or day 22 of C10 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and/or day 22 of C11 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and/or day 22 of C12 during the first phase. In a further example, the target dose is administered to the subject on day 1, day 8, day 15, and/or day 22 of C13 during the first phase.

In some examples, the first incremental dose is about 0.1% to about 2% of the target dose, and the second incremental dose is about 3% to about 8% of the target dose. In some examples, the first incremental dose is about 0.19%, about 0.23%, about 0.3%, about 0.33%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.1%, or about 2.5% of the target dose, and the second incremental dose is about 2.1%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, or about 8% of the target dose. In some examples, the first incremental dose is about 0.33% of the target dose and the second incremental dose is about 4% of the target dose. In some examples, the first incremental dose is about 0.19% of the target dose and the second incremental dose is about 2.1% of the target dose. In some examples, the first incremental dose is about 0.23% of the target dose and the second incremental dose is about 2.5% of the target dose.

In some examples, the first incremental dose is 0.19%, 0.23%, 0.3%, 0.33%, 0.5%, 1%, 1.5%, 2%, or 2.1% of the target dose, and the second incremental dose is 2.1%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, or 8% of the target dose. In some examples, the first incremental dose is 0.33% of the target dose and the second incremental dose is 4% of the target dose. In some examples, the first incremental dose is 0.19% of the target dose and the second incremental dose is 2.1% of the target dose. In some examples, the first incremental dose is 0.23% of the target dose and the second incremental dose is 2.5% of the target dose.

In some instances, the first incrementing dose is about 0.3 mg and the second incrementing dose is about 3.3 mg. In some instances, the first incrementing dose is about 0.3 mg and the second incrementing dose is about 3.6 mg. In some examples, the first incremental dose is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, or about 1 mg, and the second incremental dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

In some examples, the first increment amount is 0.3 mg and the second increment amount is 3.3 mg. In some examples, the first increment amount is 0.3 mg and the second increment amount is 3.6 mg. In some examples, the first increment amount is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg, and the second increment amount is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

In any of the foregoing examples, the second phase may include at least two dosing cycles, at least three dosing cycles, or at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven dosing cycles, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles or more dosing cycles.

Phase II may include any suitable number of dosing cycles. For example, in some examples, the second phase may include a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a second dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5) and the sixth dosing cycle (C6); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6) and the seventh dosing cycle (C7); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7) and the eighth dosing cycle (C8); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), and the ninth dosing cycle (C9); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10). (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), and the eleventh dosing cycle (C11); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12) and the thirteenth dosing cycle (C13).

In some examples, a target dose of the bispecific antibody can be administered to a subject on day 1 and/or day 15 of C1 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to a subject on day 1 and/or day 15 of C2 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to a subject on day 1 and/or day 15 of C3 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to a subject on day 1 and/or day 15 of C4 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C5 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C6 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C7 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C8 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C9 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C10 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C11 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C12 during the second phase. In a further example, a target dose of a bispecific antibody can be administered to a subject on day 1 and/or day 15 of C13 during the second phase.

In some instances, for each administration during the second phase, a target dose of the bispecific antibody is administered to the individual.

The pre-phase may include any suitable number of dosing cycles. For example, in any of the foregoing examples, the third phase may include at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven dosing cycles, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles or more dosing cycles.

In some examples, the third phase includes a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a second dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6) and seventh dosing cycle (C7); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7) and eighth dosing cycle (C8); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7) and eighth dosing cycle (C8); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8) and the ninth dosing cycle (C9); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9) and the tenth dosing cycle (C10); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9) and the tenth dosing cycle (C10). (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10) and the eleventh dosing cycle (C11); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11) and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11) and the twelfth dosing cycle (C12). (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12) and the thirteenth dosing cycle (C13).

In some examples, the third phase comprises administering the bispecific antibody to the individual on day 1 of C1. In further examples, the third phase comprises administering the bispecific antibody to the individual on day 1 of C2. In further examples, the third phase comprises administering the bispecific antibody to the individual on day 1 of C3. In further examples, the third phase comprises administering the bispecific antibody to the individual on day 1 of C4. In further examples, the third phase comprises administering the bispecific antibody to the individual on day 1 of C5. In further examples, the third phase comprises administering the bispecific antibody to the individual on day 1 of C6. In a further example, the third phase comprises administering the bispecific antibody to the individual on day 1 of C7. In a further example, the third phase comprises administering the bispecific antibody to the individual on day 1 of C8. In a further example, the third phase comprises administering the bispecific antibody to the individual on day 1 of C9. In a further example, the third phase comprises administering the bispecific antibody to the individual on day 1 of C10. In a further example, the third phase comprises administering the bispecific antibody to the individual on day 1 of C11. In a further example, the third phase comprises administering the bispecific antibody to the individual on day 1 of C12. In further embodiments, the third phase comprises administering a bispecific antibody to the individual on day 1 of C13.

In some instances, for each administration during the third phase, a target dose of a bispecific antibody is administered to the individual.

In any of the foregoing examples, the target dose can be about 45 mg to about 180 mg. In some examples, the target dose is about 50 mg to about 175 mg. In some examples, the target dose is about 55 mg to about 165 mg. In some examples, the target dose is about 60 mg to about 160 mg. In some examples, the target dose is about 65 mg to about 155 mg. In some examples, the target dose is about 70 mg to about 150 mg. In some examples, the target dose is about 75 mg to about 145 mg. In some examples, the target dose is about 80 mg to about 140 mg. In some instances, the target dose is about 85 mg to about 135 mg. In some instances, the target dose is about 90 mg to about 130 mg. In some instances, the target dose is about 90 mg. In some instances, the target dose is about 132 mg. In some instances, the target dose is about 160 mg.

In some instances, the target dose is about 45 mg. In some instances, the target dose is about 50 mg. In some instances, the target dose is about 55 mg. In some instances, the target dose is about 60 mg. In some instances, the target dose is about 65 mg. In some instances, the target dose is about 70 mg. In some instances, the target dose is about 75 mg. In some instances, the target dose is about 80 mg. In some instances, the target dose is about 85 mg. In some instances, the target dose is about 90 mg. In some instances, the target dose is about 95 mg. In some instances, the target dose is about 100 mg. In some instances, the target dose is about 105 mg. In some instances, the target dose is about 110 mg. In some instances, the target dose is about 115 mg. In some instances, the target dose is about 120 mg. In some instances, the target dose is about 125 mg. In some instances, the target dose is about 130 mg. In some instances, the target dose is about 132 mg. In some instances, the target dose is about 135 mg. In some instances, the target dose is about 140 mg. In some instances, the target dose is about 145 mg. In some instances, the target dose is about 150 mg. In some instances, the target dose is about 155 mg. In some instances, the target dose is about 160 mg. In some instances, the target dose is about 165 mg. In some instances, the target dose is about 170 mg. In some instances, the target dose is about 175 mg. In some instances, the target dose is about 180 mg.

In some instances, the target dose is 45 mg to 180 mg. In some instances, the target dose is 50 mg to 175 mg. In some instances, the target dose is 55 mg to 165 mg. In some instances, the target dose is 60 mg to 160 mg. In some instances, the target dose is 65 mg to 155 mg. In some instances, the target dose is 70 mg to 150 mg. In some instances, the target dose is 75 mg to 145 mg. In some instances, the target dose is 80 mg to 140 mg. In some instances, the target dose is 85 mg to 135 mg. In some instances, the target dose is 90 mg to 130 mg. In some instances, the target dose is 90 mg. In some instances, the target dose is 132 mg. In some instances, the target dose is 160 mg.

In some instances, the target dose is 45 mg. In some instances, the target dose is 50 mg. In some instances, the target dose is 55 mg. In some instances, the target dose is 60 mg. In some instances, the target dose is 65 mg. In some instances, the target dose is 70 mg. In some instances, the target dose is 75 mg. In some instances, the target dose is 80 mg. In some instances, the target dose is 85 mg. In some instances, the target dose is 90 mg. In some instances, the target dose is 95 mg. In some instances, the target dose is 100 mg. In some instances, the target dose is 105 mg. In some instances, the target dose is 110 mg. In some instances, the target dose is 115 mg. In some instances, the target dose is 120 mg. In some instances, the target dose is 125 mg. In some instances, the target dose is 130 mg. In some instances, the target dose is 132 mg. In some instances, the target dose is 135 mg. In some instances, the target dose is 140 mg. In some instances, the target dose is 145 mg. In some instances, the target dose is 150 mg. In some instances, the target dose is 155 mg. In some instances, the target dose is 160 mg. In some instances, the target dose is 165 mg. In some instances, the target dose is 170 mg. In some instances, the target dose is 175 mg. In some instances, the target dose is 180 mg.

In some instances, bispecific antibodies are administered to an individual as a single therapy.

In some instances, the bispecific antibody is administered intravenously to a subject. In some instances, the bispecific antibody is administered subcutaneously to a subject.

In one example, the disclosure describes a method of treating an individual with cancer (e.g., MM), wherein the individual does not have one or more of: a history of MAS and/or HLH; active (e.g., positive and quantifiable) EBV, CMV, or SARS-CoV-2 infection; or active symptomatic COVID-19 infection or need for treatment with intravenous antivirals. The methods include administering to the individual a bispecific antibody that binds to FcRH5 and CD3 and an immunomodulatory drug (IMiD) in a dosing regimen described herein. The dosing regimen may include a preliminary phase comprising one or more dosing cycles, a first phase comprising one or more dosing cycles, and/or a second phase comprising one or more dosing cycles. Each dosing cycle of the pre-phase may be a 21-day dosing cycle, and each dosing cycle of the first phase and the second phase may be a 28-day dosing cycle. The pre-phase may include administering the bispecific antibody to the individual every week (QW). The first phase may include administering the bispecific antibody to the individual every two weeks (Q2W). The second phase may include administering the bispecific antibody to the individual every four weeks (Q4W). In some instances, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

In another example, provided herein is a method of treating an individual with cancer (e.g., MM), the method comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering a bispecific antibody to the individual every two weeks (Q2W); and/or (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering a bispecific antibody to the individual every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some examples, the dosing regimen comprises the first phase and the second phase. In some instances, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

In another example, provided herein is a bispecific antibody that binds to FcRH5 and CD3 for use in treating an individual with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to the individual in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and/or (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some instances, the dosing regimen includes a first phase and a second phase. In some instances, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

In another example, provided herein is a use of a bispecific antibody that binds to FcRH5 and CD3 in the manufacture of a medicament for treating an individual with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to the individual in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and/or (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some instances, the dosing regimen includes a first phase and a second phase. In some instances, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

The pre-phase may include any suitable number of dosing cycles. For example, in some examples, the pre-phase may include at least one dosing cycle, at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles or more dosing cycles.

In some examples, the preliminary phase includes a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a second dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5) and the sixth dosing cycle (C6); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6) and the seventh dosing cycle (C7); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7) and the eighth dosing cycle (C8); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), and the ninth dosing cycle (C9); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10). (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), and the eleventh dosing cycle (C11); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12) and the thirteenth dosing cycle (C13).

In some examples, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C1 . In further examples, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C2. In further examples, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C3. In further examples, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C4. In further examples, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C5. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8 and/or day 15 of C6. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8 and/or day 15 of C7. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8 and/or day 15 of C8. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8 and/or day 15 of C9. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8 and/or day 15 of C10. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C11. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C12. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C13. In some examples, for each administration of the pre-stage, the individual is administered a target dose of the bispecific antibody.

In some examples, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C1. In further examples, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C2. In further examples, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C3. In further examples, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C4. In a further example, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C5. In a further example, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C6. In a further example, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C7. In a further example, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C8. In a further example, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C9. In a further example, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C10. In a further example, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C11. In a further example, the pre-stage comprises administering a target dose of the bispecific antibody to the individual on day 1, day 8, and/or day 15 of C12. In a further example, the pre-phase comprises administering a target dose of a bispecific antibody to the subject on day 1, day 8, and/or day 15 of C13.

In some examples, the pre-phase comprises administering to the subject a first ascending dose and a target dose of the bispecific antibody. The first ascending dose can be administered to the subject during the pre-phase on day 1 of C1, on day 2 of C1, on day 3 of C1, on day 4 of C1, on day 5 of C1, on day 6 of C1, on day 7 of C1, on day 8 of C1, on day 9 of C1, on day 10 of C1, on day 11 of C1, or on day 12 of C1. The target dose can be administered to the subject during the pre-phase on day 8 and/or day 15 of C1. In further examples, the target dose may be administered to the subject on day 1, day 8, and/or day 15 of C2 during the pre-phase. In further examples, the target dose may be administered to the subject on day 1, day 8, and/or day 15 of C3 during the pre-phase. In further examples, the target dose may be administered to the subject on day 1, day 8, and/or day 15 of C4 during the pre-phase. In further examples, the target dose may be administered to the subject on day 1, day 8, and/or day 15 of C5 during the pre-phase. In further examples, the target dose may be administered to the subject on day 1, day 8, and/or day 15 of C6 during the pre-phase. In further examples, the target dose may be administered to the subject on day 1, day 8, and/or day 15 of C7 during the pre-phase. In further examples, the target dose may be administered to the subject on day 1, day 8, and/or day 15 of C8 during the pre-phase. In further examples, the target dose may be administered to the subject on day 1, day 8, and/or day 15 of C9 during the pre-phase. In further examples, the target dose may be administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C10. In further examples, the target dose may be administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C11. In further examples, the target dose may be administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C12. In further examples, the target dose may be administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C13.

In some embodiments, the first incremental dose is about 0.1% to about 10% of the target dose. In some embodiments, the first incremental dose is about 0.19%, 0.23%, about 0.3%, about 0.33%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 2.73%, about 3%, about 3.5%, about 3.6%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% of the target dose.

In some examples, the first incremental dose is 0.1% to 10% of the target dose. In some examples, the first incremental dose is 0.19%, 0.23%, 0.3%, 0.33%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.5%, 1%, 2.73%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% of the target dose.

In some instances, the first incremental dose is about 3.3 mg. In some instances, the first incremental dose is about 3.6 mg. In some instances, the first incremental dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

In some instances, the first increasing dose is 3.3 mg. In some instances, the first increasing dose is 3.6 mg. In some instances, the first increasing dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

In some examples, the pre-phase comprises administering to the subject a first and a second incrementing dose of a bispecific antibody. In some examples, the first incrementing dose is administered to the subject on day 1 of C1 during the pre-phase, and the second incrementing dose is administered on day 2 of C1. In some examples, the first incrementing dose is administered to the subject on day 1 of C1 during the pre-phase, and the second incrementing dose is administered on day 3 of C1. In some examples, the first incrementing dose is administered to the subject on day 1 of C1 during the pre-phase, and the second incrementing dose is administered on day 4 of C1. In some examples, a first bolus dose is administered to a subject on day 9 of C1 during the pre-phase, and a second bolus dose is administered on day 10 of C1. In some examples, a first bolus dose is administered to a subject on day 9 of C1 during the pre-phase, and a second bolus dose is administered on day 11 of C1. In some examples, a first bolus dose is administered to a subject on day 9 of C1 during the pre-phase, and a second bolus dose is administered on day 12 of C1. In some examples, a first bolus dose is administered to a subject on day 1 of C1 during the pre-phase, and a second bolus dose is administered on day 8 of C1. In some examples, a first bolus dose is administered to a subject on day 2 of C1 during the pre-phase, and a second bolus dose is administered on day 9 of C1. In some examples, a first bolus dose is administered to a subject on day 3 of C1 during the pre-phase, and a second bolus dose is administered on day 10 of C1. In some examples, a first bolus dose is administered to a subject on day 4 of C1 during the pre-phase, and a second bolus dose is administered on day 11 of C1. In some examples, a first bolus dose is administered to a subject on day 5 of C1 during the pre-phase, and a second bolus dose is administered on day 12 of C1. In some examples, a first bolus dose is administered to a subject on day 6 of C1 during the pre-phase, and a second bolus dose is administered on day 13 of C1. In some examples, a first bolus dose is administered to a subject on day 7 of C1 during the pre-phase, and a second bolus dose is administered on day 14 of C1. In some examples, a first bolus dose is administered to a subject on day 8 of C1 during the pre-phase, and a second bolus dose is administered on day 15 of C1.

In a further example of the pre-phase, the target dose is administered to the subject after the second escalating dose is administered during the pre-phase. In some examples, the target dose is administered to the subject on day 8, day 9, day 10, day 11, day 12, day 12, day 14, day 15, day 16, day 17, day 18, day 19, day 20, or day 21 of C1 during the run-in phase.

In a further example of the pre-phase, the target dose is further administered to the subject on day 1, day 8, and/or day 15 of C2 during the pre-phase. In a further example, the target dose is administered to the subject on day 1, day 8, and/or day 15 of C3 during the pre-phase. In a further example, the target dose is administered to the subject on day 1, day 8, and/or day 15 of C4 during the pre-phase. In a further example, the target dose is administered to the subject on day 1, day 8, and/or day 15 of C5 during the pre-phase. In a further example, the target dose is administered to the subject on day 1, day 8, and/or day 15 of C6 during the pre-phase. In a further example, the target dose is administered to the subject on day 1, day 8, and/or day 15 of C7 during the pre-phase. In a further example, the target dose is administered to the subject on day 1, day 8, and/or day 15 of C8 during the pre-phase. In a further example, the target dose is administered to the subject on day 1, day 8, and/or day 15 of C9 during the pre-phase. In further examples, the target dose is administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C10. In further examples, the target dose is administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C11. In further examples, the target dose is administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C12. In further examples, the target dose is administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C13.

In some examples, the first incremental dose is about 0.1% to about 2% of the target dose, and the second incremental dose is about 3% to about 10% of the target dose. In some examples, the first incremental dose is about 0.23%, about 0.33%, about 0.5%, about 1%, about 1.5%, or about 2% of the target dose, and the second incremental dose is about 2.5%, about 2.73%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, or about 8% of the target dose. In some examples, the first incremental dose is about 0.23% of the target dose and the second incremental dose is about 2.73% of the target dose. In some examples, the first incremental dose is about 0.33% of the target dose and the second incremental dose is about 4% of the target dose. In some examples, the first incremental dose is about 0.19% of the target dose and the second incremental dose is about 2.1% of the target dose. In some examples, the first incremental dose is about 0.23% of the target dose and the second incremental dose is about 2.5% of the target dose.

In some examples, the first incremental dose is 0.1% to 2% of the target dose and the second incremental dose is 3% to 10% of the target dose. In some examples, the first incremental dose is 0.23%, 0.33%, 0.5%, 1%, 1.5%, or 2% of the target dose and the second incremental dose is 2.5%, 2.73%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, or 8% of the target dose. In some examples, the first incremental dose is 0.23% of the target dose and the second incremental dose is 2.73% of the target dose. In some examples, the first incremental dose is 0.33% of the target dose and the second incremental dose is 4% of the target dose. In some examples, the first incremental dose is 0.19% of the target dose and the second incremental dose is 2.1% of the target dose. In some examples, the first incremental dose is 0.23% of the target dose and the second incremental dose is 2.5% of the target dose.

In some instances, the first incrementing dose is about 0.3 mg and the second incrementing dose is about 3.3 mg. In some instances, the first incrementing dose is about 0.3 mg and the second incrementing dose is about 3.6 mg. In some examples, the first incremental dose is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, or about 1 mg, and the second incremental dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

In some examples, the first increment amount is 0.3 mg and the second increment amount is 3.3 mg. In some examples, the first increment amount is 0.3 mg and the second increment amount is 3.6 mg. In some examples, the first increment amount is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg, and the second increment amount is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

The first phase may include any suitable number of dosing cycles. For example, in any of the foregoing examples, the first phase may include at least two dosing cycles, at least three dosing cycles, or at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles or more dosing cycles.

In some examples, the first phase includes a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a first dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a first dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a first dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a first dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6); first dosing cycle (C1), first dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6) and seventh dosing cycle (C7); first dosing cycle (C1), first dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7) and eighth dosing cycle (C8); first dosing cycle (C1), first dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7) and eighth dosing cycle (C8); first dosing cycle (C1), first dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8) and the ninth dosing cycle (C9); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9) and the tenth dosing cycle (C10); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9) and the tenth dosing cycle (C10). (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10) and the eleventh dosing cycle (C11); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11) and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11) and the twelfth dosing cycle (C12). (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12) and the thirteenth dosing cycle (C13).

In some examples, a target dose of the bispecific antibody can be administered to a subject on day 1 and/or day 15 of C1 during the first phase. In further examples, a target dose of the bispecific antibody can be administered to a subject on day 1 and/or day 15 of C2 during the first phase. In further examples, a target dose of the bispecific antibody can be administered to a subject on day 1 and/or day 15 of C3 during the first phase. In further examples, a target dose of the bispecific antibody can be administered to a subject on day 1 and/or day 15 of C4 during the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C5 during the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C6 during the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C7 during the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C8 during the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C9 during the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C10 during the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C11 during the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and/or day 15 of C12 during the first phase. In a further example, a target dose of a bispecific antibody can be administered to a subject on day 1 and/or day 15 of C13 during the first phase.

In some instances, for each administration during the first phase, a target dose of the bispecific antibody is administered to the individual.

In any of the foregoing examples, the second phase may include at least two dosing cycles, at least three dosing cycles, or at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven dosing cycles, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles or more dosing cycles.

In some examples, the second phase includes a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a second dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6) and seventh dosing cycle (C7); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7) and eighth dosing cycle (C8); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7) and eighth dosing cycle (C8); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8) and the ninth dosing cycle (C9); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9) and the tenth dosing cycle (C10); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9) and the tenth dosing cycle (C10). (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10) and the eleventh dosing cycle (C11); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11) and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11) and the twelfth dosing cycle (C12). (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12) and the thirteenth dosing cycle (C13).

In some examples, a target dose of the bispecific antibody can be administered to the individual on day 1 of C1 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to the individual on day 1 of C2 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to the individual on day 1 of C3 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to the individual on day 1 of C4 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to the individual on day 1 of C5 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the individual on day 1 of C6 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the individual on day 1 of C7 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the individual on day 1 of C8 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the individual on day 1 of C9 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the individual on day 1 of C10 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C11 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C12 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C13 during the second phase.

In some instances, for each administration during the second phase, a target dose of a bispecific antibody is administered to the individual.

In any of the foregoing examples, the target dose is about 65 mg to about 270 mg. In some examples, the target dose is about 75 mg to about 260 mg. In some examples, the target dose is about 85 mg to about 250 mg. In some examples, the target dose is about 95 mg to about 240 mg. In some examples, the target dose is about 95 mg to about 230 mg. In some examples, the target dose is about 95 mg to about 220 mg. In some examples, the target dose is about 105 mg to about 210 mg. In some examples, the target dose is about 115 mg to about 200 mg. In some instances, the target dose is about 125 mg to about 190 mg. In some instances, the target dose is about 130 mg to about 180 mg. In some instances, the target dose is about 90 mg. In some instances, the target dose is about 132 mg. In some instances, the target dose is about 160 mg.

In some instances, the target dose is about 65 mg. In some instances, the target dose is about 70 mg. In some instances, the target dose is about 75 mg. In some instances, the target dose is about 80 mg. In some instances, the target dose is about 85 mg. In some instances, the target dose is about 90 mg. In some instances, the target dose is about 95 mg. In some instances, the target dose is about 100 mg. In some instances, the target dose is about 105 mg. In some instances, the target dose is about 110 mg. In some instances, the target dose is about 115 mg. In some instances, the target dose is about 120 mg. In some instances, the target dose is about 125 mg. In some instances, the target dose is about 130 mg. In some instances, the target dose is about 132 mg. In some instances, the target dose is about 135 mg. In some instances, the target dose is about 140 mg. In some instances, the target dose is about 145 mg. In some instances, the target dose is about 150 mg. In some instances, the target dose is about 155 mg. In some instances, the target dose is about 160 mg. In some instances, the target dose is about 165 mg. In some instances, the target dose is about 170 mg. In some instances, the target dose is about 175 mg. In some instances, the target dose is about 180 mg. In some instances, the target dose is about 185 mg. In some instances, the target dose is about 190 mg. In some instances, the target dose is about 195 mg. In some instances, the target dose is about 200 mg. In some instances, the target dose is about 205 mg. In some instances, the target dose is about 210 mg. In some instances, the target dose is about 215 mg. In some instances, the target dose is about 220 mg. In some instances, the target dose is about 225 mg. In some instances, the target dose is about 230 mg. In some instances, the target dose is about 235 mg. In some instances, the target dose is about 240 mg. In some instances, the target dose is about 245 mg. In some instances, the target dose is about 250 mg. In some instances, the target dose is about 255 mg. In some instances, the target dose is about 260 mg.

In some instances, the target dose is 65 mg to 270 mg. In some instances, the target dose is 75 mg to 260 mg. In some instances, the target dose is 85 mg to 250 mg. In some instances, the target dose is 95 mg to 240 mg. In some instances, the target dose is 95 mg to 230 mg. In some instances, the target dose is 95 mg to 220 mg. In some instances, the target dose is 105 mg to 210 mg. In some instances, the target dose is 115 mg to 200 mg. In some instances, the target dose is 125 mg to 190 mg. In some instances, the target dose is 130 mg to 180 mg. In some instances, the target dose is 90 mg. In some instances, the target dose is 132 mg. In some instances, the target dose is 160 mg.

In some instances, the target dose is 65 mg. In some instances, the target dose is 70 mg. In some instances, the target dose is 75 mg. In some instances, the target dose is 80 mg. In some instances, the target dose is 85 mg. In some instances, the target dose is 90 mg. In some instances, the target dose is 95 mg. In some instances, the target dose is 100 mg. In some instances, the target dose is 105 mg. In some instances, the target dose is 110 mg. In some instances, the target dose is 115 mg. In some instances, the target dose is 120 mg. In some instances, the target dose is 125 mg. In some instances, the target dose is 130 mg. In some instances, the target dose is 132 mg. In some instances, the target dose is 135 mg. In some instances, the target dose is 140 mg. In some instances, the target dose is 145 mg. In some instances, the target dose is 150 mg. In some instances, the target dose is 155 mg. In some instances, the target dose is 160 mg. In some instances, the target dose is 165 mg. In some instances, the target dose is 170 mg. In some instances, the target dose is 175 mg. In some instances, the target dose is 180 mg. In some instances, the target dose is 185 mg. In some instances, the target dose is 190 mg. In some instances, the target dose is 195 mg. In some instances, the target dose is 200 mg. In some instances, the target dose is 205 mg. In some instances, the target dose is 210 mg. In some instances, the target dose is 215 mg. In some instances, the target dose is 220 mg. In some instances, the target dose is 225 mg. In some instances, the target dose is 230 mg. In some instances, the target dose is 235 mg. In some instances, the target dose is 240 mg. In some instances, the target dose is 245 mg. In some instances, the target dose is 250 mg. In some instances, the target dose is 255 mg. In some instances, the target dose is 260 mg.

The bispecific antibody can be administered by any suitable route of administration. In some instances, the bispecific antibody is administered intravenously to a subject. In some instances, the bispecific antibody is administered subcutaneously to a subject.

In any of the foregoing examples, the IMiD can be administered to the subject on any appropriate day of any dosing cycle. For example, in some examples, the IMiD is administered to the subject on Day 1 to Day 21 of each dosing cycle in the Pre-Phase. In some examples, the IMiD is administered to the subject on Day 1 to Day 21 of each dosing cycle in the First Phase. In some examples, the IMiD is administered to the subject on Day 1 to Day 21 of each dosing cycle in the Second Phase. In some examples, the IMiD is administered to the subject on Day 1 to Day 21 of each dosing cycle in the Pre-Phase, the First Phase, and the Second Phase. In some instances, the IMiD is administered to the subject on Day 1 to Day 21 of each dosing cycle in Phase I and Phase II.

IMiDs can be administered by any suitable route of administration. In some instances, IMiDs are administered to a subject orally. In some instances, IMiDs are administered to a subject intravenously.

In some instances, the IMiD is lenalidomide. In some instances, the IMiD is pomalidomide.

In some instances, pomalidomide is administered to a subject in an amount of about 1 mg to about 8 mg. In some instances, pomalidomide is administered to a subject in an amount of about 2 mg to about 4 mg. In some instances, pomalidomide is administered to a subject in an amount of about 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, or 8 mg. In some instances, pomalidomide is administered to a subject in an amount of about 4 mg. In some instances, pomalidomide is administered to a subject in an amount of about 4 mg. In some instances, an initial dose of about 2 mg is administered to a subject, followed by subsequent doses of about 4 mg. When the pomalidomide dose is less than 4 mg (e.g., 2 mg or 3 mg), the dose may be increased to 4 mg, for example, if the individual demonstrates an absolute neutrophil count (ANC) greater than or equal to 1000/µl and platelets greater than or equal to 75,000/µl. If an adverse event occurs after a dose increase from 2 mg to 4 mg, the pomalidomide dose adjustment may be made as outlined in Example 1 (e.g., see Table 14).

In some instances, pomalidomide is administered to a subject in an amount of 1 mg to 8 mg. In some instances, pomalidomide is administered to a subject in an amount of 2 mg to 4 mg. In some instances, pomalidomide is administered to a subject in an amount of 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, or 8 mg. In some instances, pomalidomide is administered to a subject in an amount of 2 mg. In some instances, pomalidomide is administered to a subject in an amount of 4 mg.

In any of the foregoing examples, the dosing regimen further comprises administering a corticosteroid to the individual during the pre-phase, the first phase, and/or the second phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the individual during the pre-phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the individual during the first phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the individual during the second phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the individual during the pre-phase and the first phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the individual during the pre-phase and the second phase. In some instances, the dosing regimen further comprises administering a corticosteroid to the individual during the first phase and the second phase.

In some instances, a corticosteroid is administered to a subject QW, e.g., during the pre-phase, the first phase, and/or the second phase.

Corticosteroids can be administered by any suitable route of administration. In some instances, corticosteroids are administered intravenously to a subject. In some instances, corticosteroids are administered orally to a subject. In some instances, corticosteroids can be administered intravenously or orally to a subject.

In some instances, a corticosteroid is administered to a subject (e.g., IV and/or orally) during the pre-phase on day 1, day 8, and/or day 15 of C1. In some instances, a corticosteroid is administered to a subject during the pre-phase on day 1, day 2, and/or day 8 of C1. In some instances, a corticosteroid is administered to a subject during the pre-phase on day 1, day 3, and/or day 8 of C1. In some instances, a corticosteroid is administered to a subject during the pre-phase on day 1, day 4, and/or day 8 of C1. In some instances, a corticosteroid is administered to a subject during the pre-phase on day 9, day 10, and/or day 16 of C1. In some instances, a corticosteroid is administered to a subject during the pre-phase on day 9, day 11, and/or day 16 of C1. In some instances, a corticosteroid is administered to a subject during the pre-phase on day 9, day 12, and/or day 16 of C1. In further instances, a corticosteroid is administered to a subject during the pre-phase on day 1, day 8, and/or day 15 of C2 . In further instances, a corticosteroid is administered to a subject during the pre-phase on day 1, day 8, and/or day 15 of C3. In further instances, a corticosteroid is administered to a subject during the pre-phase on day 1, day 8, and/or day 15 of C4. In further examples, the corticosteroid is administered to the individual during the pre-phase on day 1, day 8, and/or day 15 of C5. In further examples, the corticosteroid is administered to the individual during the pre-phase on day 1, day 8, and/or day 15 of C6. In further examples, the corticosteroid is administered to the individual during the pre-phase on day 1, day 8, and/or day 15 of C7. In further examples, the corticosteroid is administered to the individual during the pre-phase on day 1, day 8, and/or day 15 of C8. In further examples, the corticosteroid is administered to the individual during the pre-phase on day 1, day 8, and/or day 15 of C9. In a further example, the corticosteroid is administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C10. In a further example, the corticosteroid is administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C11. In a further example, the corticosteroid is administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C12. In a further example, the corticosteroid is administered to the subject during the pre-phase on day 1, day 8, and/or day 15 of C13.

In some examples, a corticosteroid is administered to a subject during the first phase on day 1, day 8, day 15, and/or day 22 of C1. In further examples, a corticosteroid is administered to a subject during the first phase on day 1, day 8, day 15, and/or day 22 of C2 . In further examples, a corticosteroid is administered to a subject during the first phase on day 1, day 8, day 15, and/or day 22 of C3. In further examples, a corticosteroid is administered to a subject during the first phase on day 1, day 8, day 15, and/or day 22 of C4. In further examples, the corticosteroid is administered to the subject on day 1, day 8, day 15, and/or day 22 of C5 during the first phase. In further examples, the corticosteroid is administered to the subject on day 1, day 8, day 15, and/or day 22 of C6 during the first phase. In further examples, the corticosteroid is administered to the subject on day 1, day 8, day 15, and/or day 22 of C7 during the first phase. In further examples, the corticosteroid is administered to the subject on day 1, day 8, day 15, and/or day 22 of C8 during the first phase. In further examples, the corticosteroid is administered to the subject during the First Phase on Day 1, Day 8, Day 15, and/or Day 22 of C9. In further examples, the corticosteroid is administered to the subject during the First Phase on Day 1, Day 8, Day 15, and/or Day 22 of C10. In further examples, the corticosteroid is administered to the subject during the First Phase on Day 1, Day 8, Day 15, and/or Day 22 of C11. In further examples, the corticosteroid is administered to the subject during the First Phase on Day 1, Day 8, Day 15, and/or Day 22 of C12. In further examples, the corticosteroid is administered to the subject during Phase 1 on Day 1, Day 8, Day 15, and/or Day 22 of C13.

In some instances, a corticosteroid is administered intravenously to a subject prior to administration of the bispecific antibody. In some instances, a corticosteroid is administered intravenously to a subject approximately 1 hour prior to administration of the bispecific antibody.

Any suitable corticosteroid can be used, such as any corticosteroid described herein. In some instances, the corticosteroid is dexamethasone or methylprednisolone. In some instances, the corticosteroid is dexamethasone.

In some instances, dexamethasone is administered to a subject in an amount of about 10 mg to about 40 mg. In some instances, dexamethasone is administered to a subject in an amount of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg. In some instances, dexamethasone is administered to a subject in an amount of about 20 mg. In some instances, dexamethasone is administered to a subject in an amount of about 15 mg. In some instances, dexamethasone is administered to a subject in an amount of about 4 mg.

In some instances, dexamethasone is administered to a subject in an amount of 10 mg to 40 mg. In some instances, dexamethasone is administered to a subject in an amount of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. In some instances, dexamethasone is administered to a subject in an amount of 20 mg. In some instances, dexamethasone is administered to a subject in an amount of 15 mg. In some instances, dexamethasone is administered to a subject in an amount of 4 mg.

In some instances, methylprednisolone is administered to a subject in an amount of about 40 mg to about 160 mg. In some instances, methylprednisolone is administered to a subject in an amount of about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, or about 160 mg. In some instances, methylprednisolone is administered to a subject in an amount of about 80 mg.

In some instances, methylprednisolone is administered to a subject in an amount of 40 mg to 160 mg. In some instances, methylprednisolone is administered to a subject in an amount of 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, or 160 mg. In some instances, methylprednisolone is administered to a subject in an amount of 80 mg.

In another example, the disclosure describes a method of treating an individual with cancer (e.g., MM), wherein the individual does not have one or more of the following: a history of MAS and/or HLH; active (e.g., positive and quantifiable) EBV, CMV, or SARS-CoV-2 infection; or active symptomatic COVID-19 infection or a need for treatment with intravenous antivirals. The methods include administering to the individual a bispecific antibody that binds to FcRH5 and CD3 and an anti-cluster of differentiation 38 (CD38) antibody in a dosing regimen as described herein. The dosing regimen may include: an introduction phase comprising one or more dosing cycles; a first phase comprising one or more dosing cycles, wherein the first phase comprises a first subphase and a second subphase; and/or a second phase comprising one or more dosing cycles. Each dosing cycle of the introduction phase and the first phase may be a 21-day dosing cycle, and each dosing cycle of the second phase may be a 28-day dosing cycle. The introduction phase may include administering the bispecific antibody to the individual every week (QW). The first phase may include administering the bispecific antibody to the individual every three weeks (Q3W). The second phase may involve administering the bispecific antibody to the individual every four weeks (Q4W).

For example, provided herein is a method of treating an individual with cancer (e.g., MM) comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering a bispecific antibody to the individual every three weeks (Q3W); and/or (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering a bispecific antibody to the individual every four weeks (Q4W). In some instances, the dosing regimen comprises a first phase. In some instances, the dosing regimen comprises a second phase. In some instances, the dosing regimen comprises a first phase and a second phase. In some instances, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

In another example, provided herein is a bispecific antibody that binds to FcRH5 and CD3 for use in treating an individual with cancer (e.g., MM), wherein the individual does not have one or more of the following: a history of MAS and/or HLH; active (e.g., positive and quantifiable) EBV, CMV, or SARS-CoV-2 infection; or active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent, the treatment comprising administering the bispecific antibody to the individual in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises dosing every three weeks (Q3W) administering the bispecific antibody to the individual; and/or (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W). In some instances, the dosing regimen comprises a first phase. In some instances, the dosing regimen comprises a second phase. In some instances, the dosing regimen comprises a first phase and a second phase.

In another example, provided herein is a use of a bispecific antibody that binds to FcRH5 and CD3 in the manufacture of a medicament for treating an individual with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to the individual in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every three weeks (Q3W); and/or (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some instances, the dosing regimen includes a first phase and a second phase. In some instances, the individual does not have (i) a history of MAS or HLH, (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody, or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent.

The first phase can include any suitable number of dosing cycles. For example, in some examples, the introduction phase includes at least one dosing cycle, at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles or more dosing cycles.

In some examples, the introduction phase includes a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a second dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5) and the sixth dosing cycle (C6); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6) and the seventh dosing cycle (C7); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7) and the eighth dosing cycle (C8); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), and the ninth dosing cycle (C9); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10). (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), and the eleventh dosing cycle (C11); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12) and the thirteenth dosing cycle (C13).

In some examples, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C1. In some examples, the pre-stage comprises administering the bispecific antibody to the individual on day 3, day 9, and/or day 16 of C1. In further examples, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C2 . In further examples, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C3. In further examples, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C4. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9 and/or day 16 of C5. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9 and/or day 16 of C6. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9 and/or day 16 of C7. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9 and/or day 16 of C8. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9 and/or day 16 of C9. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C10. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C11. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C12. In a further example, the pre-stage comprises administering the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C13. In some examples, for each administration of the pre-stage, the subject is administered a target dose of the bispecific antibody.

In some instances, if the individual has an adverse reaction to an anti-CD38 antibody, the individual is administered a bispecific antibody on day 3, day 9, and/or day 16 of C1.

In some instances, for each administration during the introduction phase, a target dose of a bispecific antibody is administered to a subject.

In some examples, the introduction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C1. In some examples, the introduction phase comprises administering a target dose of the bispecific antibody to the individual on day 3, day 9, and/or day 16 of C1. In further examples, the introduction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C2. In further examples, the introduction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C3. In a further example, the induction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C4. In a further example, the induction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C5. In a further example, the induction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C6. In a further example, the induction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C7. In a further example, the introduction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C8. In a further example, the introduction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C9. In a further example, the introduction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C10. In a further example, the introduction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C11. In a further example, the introduction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and/or day 16 of C12. In a further example, the introduction phase comprises administering a target dose of the bispecific antibody to the individual on day 2, day 9, and day 16 of C13.

In some examples, the run-in phase comprises administering to the subject a first booster dose and a target dose of the bispecific antibody. The first booster dose can be administered to the subject on day 1 of C1, on day 2 of C1, on day 3 of C1, on day 4 of C1, on day 5 of C1, on day 6 of C1, on day 7 of C1, or on day 8 of C1 during the run-in phase. The target dose can be administered to the subject on day 9 and/or day 16 of C1 during the run-in phase. In further examples, the target dose can be administered to the subject on day 2, day 9, and/or day 16 of C2 during the run-in phase. In further examples, the target dose may be administered to the subject on day 2, day 9, and/or day 16 of C3 during the run-in phase. In further examples, the target dose may be administered to the subject on day 2, day 9, and/or day 16 of C4 during the run-in phase. In further examples, the target dose may be administered to the subject on day 2, day 9, and/or day 16 of C5 during the run-in phase. In further examples, the target dose may be administered to the subject on day 2, day 9, and/or day 16 of C6 during the run-in phase. In further examples, the target dose may be administered to the subject on day 2, day 9, and/or day 16 of C7 during the run-in phase. In further examples, the target dose may be administered to the subject on day 2, day 9, and/or day 16 of C8 during the run-in phase. In further examples, the target dose may be administered to the subject on day 2, day 9, and/or day 16 of C9 during the run-in phase. In further examples, the target dose may be administered to the subject on day 2, day 9, and/or day 16 of C10 during the run-in phase. In further examples, the target dose can be administered to the subject on day 2, day 9, and/or day 16 of C11 during the run-in phase. In further examples, the target dose can be administered to the subject on day 2, day 9, and/or day 16 of C12 during the run-in phase. In further examples, the target dose can be administered to the subject on day 2, day 9, and/or day 16 of C13 during the run-in phase.

In some examples, the first incremental dose is about 0.1% to about 10% of the target dose. In some examples of the introduction phase, the first incremental dose is about 0.19%, 0.23%, about 0.3%, about 0.33%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.25%, about 2.5%, about 3%, about 3.5%, about 3.6%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% of the target dose. In some examples, the first incremental dose is about 2.25% of the target dose.

In some examples, the first incremental dose is 0.1% to 10% of the target dose. In some examples of the introduction phase, the first incremental dose is 0.19%, 0.23%, 0.3%, 0.33%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.25%, 2.5%, 3%, 3.5%, 3.6%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% of the target dose. In some examples, the first incremental dose is 2.25% of the target dose.

In some examples, the first incremental dose is about 3.3 mg. In some examples, the first incremental dose is about 3.6 mg. In some examples of the lead-in phase, the first incremental dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

In some examples, the first incremental dose is 3.3 mg. In some examples, the first incremental dose is 3.6 mg. In some examples of the lead-in phase, the first incremental dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

In some examples, the run-in phase comprises administering to the subject a first booster dose and a second booster dose of the bispecific antibody. In some examples, the first booster dose is administered to the subject on day 1 of C1 during the run-in phase, and the second booster dose is administered on day 2 of C1. In some examples, the first booster dose is administered to the subject on day 1 of C1 during the run-in phase, and the second booster dose is administered on day 3 of C1. In some examples, the first booster dose is administered to the subject on day 1 of C1 during the run-in phase, and the second booster dose is administered on day 4 of C1. In some examples, a first bolus dose is administered to a subject on day 9 of C1 during the run-in phase, and a second bolus dose is administered on day 10 of C1. In some examples, a first bolus dose is administered to a subject on day 9 of C1 during the run-in phase, and a second bolus dose is administered on day 11 of C1. In some examples, a first bolus dose is administered to a subject on day 9 of C1 during the run-in phase, and a second bolus dose is administered on day 12 of C1. In some examples, a first bolus dose is administered to a subject on day 2 of C1 during the run-in phase, and a second bolus dose is administered on day 9 of C1. In some examples, a first bolus dose is administered to a subject on day 3 of C1 during the run-in phase, and a second bolus dose is administered on day 10 of C1. In some examples, a first bolus dose is administered to a subject on day 4 of C1 during the run-in phase, and a second bolus dose is administered on day 11 of C1. In some examples, a first bolus dose is administered to a subject on day 5 of C1 during the run-in phase, and a second bolus dose is administered on day 12 of C1. In some examples, a first bolus dose is administered to a subject on day 6 of C1 during the run-in phase, and a second bolus dose is administered on day 13 of C1. In some instances, a first bolus dose is administered to a subject on day 7 of C1 during the run-in phase, and a second bolus dose is administered on day 14 of C1. In some instances, a first bolus dose is administered to a subject on day 8 of C1 during the run-in phase, and a second bolus dose is administered on day 15 of C1.

In further examples, the target dose is administered to the subject after the second escalating dose is administered during the run-in phase. In some examples, the target dose is administered to the subject on day 16, day 17, day 18, day 19, day 20, or day 21 of C1 during the run-in phase.

In a further example, the target dose is further administered to the subject on day 2, day 9, and/or day 16 of C2 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C3 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C4 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C5 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C6 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C7 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C8 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C9 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C10 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C11 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C12 during the run-in phase. In a further example, the target dose is administered to the subject on day 2, day 9, and/or day 16 of C13 during the run-in phase.

In some examples of the introduction phase, the first incremental dose is about 0.1% to about 1% of the target dose, and the second incremental dose is about 2% to about 10% of the target dose. In some examples of the introduction phase, the first incremental dose is about 0.19%, about 0.33%, about 0.5%, about 0.7%, about 1%, and the second incremental dose is about 1.5%, about 2%, about 2.25%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% of the target dose. In some examples of the introduction phase, the first incremental dose is about 0.19% of the target dose, and the second incremental dose is about 2.25% of the target dose. In some examples of the introduction phase, the first incremental dose is about 0.33% of the target dose and the second incremental dose is about 4% of the target dose. In some examples, the first incremental dose is about 0.19% of the target dose and the second incremental dose is about 2.1% of the target dose. In some examples, the first incremental dose is 0.23% of the target dose and the second incremental dose is about 2.5% of the target dose.

In some examples of the introduction phase, the first incremental dose is 0.1% to 1% of the target dose, and the second incremental dose is 2% to 10% of the target dose. In some examples of the introduction phase, the first incremental dose is 0.19%, 0.33%, 0.5%, 0.7%, 1% of the target dose, and the second incremental dose is 1.5%, 2%, 2.25%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% of the target dose. In some examples of the introduction phase, the first incremental dose is 0.19% of the target dose and the second incremental dose is 2.25% of the target dose. In some examples of the introduction phase, the first incremental dose is 0.3% of the target dose and the second incremental dose is 4% of the target dose. In some examples, the first incremental dose is 0.19% of the target dose and the second incremental dose is 2.1% of the target dose. In some examples, the first incremental dose is 0.23% of the target dose and the second incremental dose is 2.5% of the target dose.

In some examples of the lead-in phase, the first escalating dose is about 0.3 mg and the second escalating dose is about 3.6 mg. In some examples, the first incremental dose is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, or about 1 mg, and the second incremental dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

In some examples of the run-in phase, the first escalating dose is 0.3 mg and the second escalating dose is 3.3 mg. In some examples of the run-in phase, the first escalating dose is 0.3 mg and the second escalating dose is 3.6 mg. In some examples, the first incremental dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg and the second incremental dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

In any of the foregoing examples, the first subphase of the first phase may include at least two dosing cycles, at least three dosing cycles, or at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles or more dosing cycles.

In some examples, the first sub-phase of the first phase includes a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a first dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a first dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a first dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a first dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5) and the sixth dosing cycle (C6); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6) and the seventh dosing cycle (C7); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7) and the eighth dosing cycle (C8); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), and the ninth dosing cycle (C9); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10). (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), and the eleventh dosing cycle (C11); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12) and the thirteenth dosing cycle (C13).

In some examples, a target dose of the bispecific antibody can be administered to a subject on day 1 of C1 during the first subphase of the first phase. In further examples, a target dose of the bispecific antibody can be administered to a subject on day 1 of C2 during the first subphase of the first phase. In further examples, a target dose of the bispecific antibody can be administered to a subject on day 1 of C3 during the first subphase of the first phase. In further examples, a target dose of the bispecific antibody can be administered to a subject on day 1 of C4 during the first subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C5 during the first subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C6 during the first subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C7 during the first subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C8 during the first subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C9 during the first subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C10 during the first subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C11 during the first subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C12 during the first subphase of the first phase. In a further example, a target dose of a bispecific antibody can be administered to a subject on day 1 of C13 during the first subphase of the first phase.

In some instances, for each administration during the first subphase of the phase, a target dose of the bispecific antibody is administered to the subject.

In any of the foregoing examples, the second subphase of the first phase may include at least two dosing cycles, at least three dosing cycles, or at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles or more dosing cycles.

In some examples, the second sub-phase of the first phase includes the first dosing cycle (C1); the first dosing cycle and the second dosing cycle (C2); the first dosing cycle, the first dosing cycle (C2), and the third dosing cycle (C3); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), and the fourth dosing cycle (C4); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), and the fifth dosing cycle (C5); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), and the fifth dosing cycle (C5) and the sixth dosing cycle (C6); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6) and the seventh dosing cycle (C7); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7) and the eighth dosing cycle (C8); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), and the ninth dosing cycle (C9); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10). (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), and the eleventh dosing cycle (C11); the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the first dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12) and the thirteenth dosing cycle (C13).

In some examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C1 during the second subphase of the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C2 during the second subphase of the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C3 during the second subphase of the first phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C4 during the second subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C5 during the second subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C6 during the second subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C7 during the second subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C8 during the second subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C9 during the second subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C10 during the second subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C11 during the second subphase of the first phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C12 during the second subphase of the first phase. In a further example, a target dose of a bispecific antibody can be administered to a subject on day 1 of C13 during the second subphase of the first phase.

In some instances, for each administration during the second subphase of the phase, a target dose of the bispecific antibody is administered to the subject.

In any of the foregoing examples, the second phase may include at least two dosing cycles, at least three dosing cycles, or at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven dosing cycles, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles or more dosing cycles.

In some examples, the second phase includes a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a second dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6) and seventh dosing cycle (C7); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7) and eighth dosing cycle (C8); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7) and eighth dosing cycle (C8); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8) and the ninth dosing cycle (C9); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9) and the tenth dosing cycle (C10); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9) and the tenth dosing cycle (C10). (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10) and the eleventh dosing cycle (C11); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11) and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11) and the twelfth dosing cycle (C12). (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12) and the thirteenth dosing cycle (C13).

In some examples, a target dose of the bispecific antibody can be administered to the individual on day 1 of C1 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to the individual on day 1 of C2 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to the individual on day 1 of C3 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to the individual on day 1 of C4 during the second phase. In further examples, a target dose of the bispecific antibody can be administered to the individual on day 1 of C5 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the individual on day 1 of C6 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the individual on day 1 of C7 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the individual on day 1 of C8 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the individual on day 1 of C9 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the individual on day 1 of C10 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C11 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C12 during the second phase. In a further example, the target dose of the bispecific antibody can be administered to the subject on day 1 of C13 during the second phase.

In some instances, for each administration during the second phase, a target dose of a bispecific antibody is administered to the individual.

In any of the foregoing examples, the target dose is about 75 mg to about 325 mg. In some examples, the target dose is about 80 mg to about 320 mg. In some examples, the target dose is about 85 mg to about 310 mg. In some examples, the target dose is about 95 mg to about 300 mg. In some examples, the target dose is about 105 mg to about 290 mg. In some examples, the target dose is about 110 mg to about 280 mg. In some examples, the target dose is about 115 mg to about 270 mg. In some examples, the target dose is about 125 mg to about 260 mg. In some instances, the target dose is about 135 mg to about 250 mg. In some instances, the target dose is about 145 mg to about 240 mg. In some instances, the target dose is about 155 mg to about 230 mg. In some instances, the target dose is about 160 mg to about 220 mg. In some instances, the target dose is about 160 mg to about 210 mg. In some instances, the target dose is about 160 mg to about 200 mg. In some instances, the target dose is about 90 mg. In some instances, the target dose is about 132 mg. In some instances, the target dose is about 160 mg.

In some instances, the target dose is about 65 mg. In some instances, the target dose is about 70 mg. In some instances, the target dose is about 75 mg. In some instances, the target dose is about 80 mg. In some instances, the target dose is about 85 mg. In some instances, the target dose is about 90 mg. In some instances, the target dose is about 95 mg. In some instances, the target dose is about 100 mg. In some instances, the target dose is about 105 mg. In some instances, the target dose is about 110 mg. In some instances, the target dose is about 115 mg. In some instances, the target dose is about 120 mg. In some instances, the target dose is about 125 mg. In some instances, the target dose is about 130 mg. In some instances, the target dose is about 132 mg. In some instances, the target dose is about 135 mg. In some instances, the target dose is about 140 mg. In some instances, the target dose is about 145 mg. In some instances, the target dose is about 150 mg. In some instances, the target dose is about 155 mg. In some instances, the target dose is about 160 mg. In some instances, the target dose is about 165 mg. In some instances, the target dose is about 170 mg. In some instances, the target dose is about 175 mg. In some instances, the target dose is about 180 mg. In some instances, the target dose is about 185 mg. In some instances, the target dose is about 190 mg. In some instances, the target dose is about 195 mg. In some instances, the target dose is about 200 mg. In some instances, the target dose is about 205 mg. In some instances, the target dose is about 210 mg. In some instances, the target dose is about 215 mg. In some instances, the target dose is about 220 mg. In some instances, the target dose is about 225 mg. In some instances, the target dose is about 230 mg. In some instances, the target dose is about 235 mg. In some examples, the target dose is about 240 mg. In some examples, the target dose is about 245 mg. In some examples, the target dose is about 250 mg. In some examples, the target dose is about 255 mg. In some examples, the target dose is about 260 mg. In some examples, the target dose is about 265 mg. In some examples, the target dose is about 270 mg. In some examples, the target dose is about 275 mg. In some examples, the target dose is about 280 mg. In some examples, the target dose is about 285 mg. In some examples, the target dose is about 290 mg. In some examples, the target dose is about 295 mg. In some examples, the target dose is about 300 mg. In some examples, the target dose is about 305 mg. In some examples, the target dose is about 310 mg. In some examples, the target dose is about 315 mg. In some examples, the target dose is about 320 mg. In some examples, the target dose is about 325 mg. In some examples, the target dose is about 330 mg. In some examples, the target dose is about 335 mg. In some examples, the target dose is about 340 mg. In some examples, the target dose is about 345 mg. In some examples, the target dose is about 350 mg. In some examples, the target dose is about 355 mg. In some instances, the target dose is about 360 mg.

In some instances, the target dose is 65 mg. In some instances, the target dose is 70 mg. In some instances, the target dose is 75 mg. In some instances, the target dose is 80 mg. In some instances, the target dose is 85 mg. In some instances, the target dose is 90 mg. In some instances, the target dose is 95 mg. In some instances, the target dose is 100 mg. In some instances, the target dose is 105 mg. In some instances, the target dose is 110 mg. In some instances, the target dose is 115 mg. In some instances, the target dose is 120 mg. In some instances, the target dose is 125 mg. In some instances, the target dose is 130 mg. In some instances, the target dose is 132 mg. In some instances, the target dose is 135 mg. In some instances, the target dose is 140 mg. In some instances, the target dose is 145 mg. In some instances, the target dose is 150 mg. In some instances, the target dose is 155 mg. In some instances, the target dose is 160 mg. In some instances, the target dose is 165 mg. In some instances, the target dose is 170 mg. In some instances, the target dose is 175 mg. In some instances, the target dose is 180 mg. In some instances, the target dose is 185 mg. In some instances, the target dose is 190 mg. In some instances, the target dose is 195 mg. In some instances, the target dose is 200 mg. In some instances, the target dose is 205 mg. In some instances, the target dose is 210 mg. In some instances, the target dose is 215 mg. In some instances, the target dose is 220 mg. In some instances, the target dose is 225 mg. In some instances, the target dose is 230 mg. In some instances, the target dose is 235 mg. In some instances, the target dose is 240 mg. In some instances, the target dose is 245 mg. In some instances, the target dose is 250 mg. In some instances, the target dose is 255 mg. In some instances, the target dose is 260 mg. In some instances, the target dose is 265 mg. In some instances, the target dose is 270 mg. In some instances, the target dose is 275 mg. In some instances, the target dose is 280 mg. In some instances, the target dose is 285 mg. In some instances, the target dose is 290 mg. In some instances, the target dose is 295 mg. In some instances, the target dose is 300 mg. In some instances, the target dose is 305 mg. In some instances, the target dose is 310 mg. In some instances, the target dose is 315 mg. In some instances, the target dose is 320 mg. In some instances, the target dose is 325 mg. In some instances, the target dose is 330 mg. In some instances, the target dose is 335 mg. In some instances, the target dose is 340 mg. In some instances, the target dose is 345 mg. In some instances, the target dose is 350 mg. In some instances, the target dose is 355 mg. In some instances, the target dose is 360 mg.

In some instances, for each administration during the second phase, a target dose of the bispecific antibody is administered to the individual.

In some instances, the bispecific antibody is administered intravenously to a subject. In some instances, the bispecific antibody is administered subcutaneously to a subject.

In any of the foregoing examples, the anti-CD38 antibody is administered to the subject on day 1, day 8, and/or day 15 of each dosing cycle in the introduction phase. In a further example, the anti-CD38 antibody is administered to the subject on day 1, day 8, and/or day 15 of each dosing cycle in the first subphase of the first phase. In a further example, the anti-CD38 antibody is administered to the subject on day 1 of each dosing cycle in the second subphase of the first phase. In a further example, the anti-CD38 antibody is administered to the subject on day 1 of each dosing cycle in the second phase.

Anti-CD38 antibodies can be administered by any suitable route of administration. In some instances, anti-CD38 antibodies are administered to a subject subcutaneously. In some instances, anti-CD38 antibodies are administered to a subject intravenously.

In some instances, the anti-CD38 antibody is daratumumab or isatuximab.

In some instances, the anti-CD38 antibody is daratumumab.

In some examples, daratumumab can be administered in an amount of about 900 mg to about 3600 mg (e.g., about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about In some embodiments, daratumumab is administered to a subject in an amount of about 1800 mg.

In any of the foregoing examples, the dosing regimen further comprises administering a corticosteroid to the individual during the introduction phase, the first phase (e.g., the first subphase and/or the second subphase), and/or the second phase. For example, in some examples, the dosing regimen further comprises administering a corticosteroid to the individual during the introduction phase. In another example, the dosing regimen further comprises administering a corticosteroid to the individual during the first phase (e.g., the first subphase and/or the second subphase). In another example, the dosing regimen further comprises administering a corticosteroid to the individual during the second phase. For example, in some examples, the dosing regimen further comprises administering a corticosteroid to the individual during the introduction phase and the first phase (e.g., the first subphase and/or the second subphase). In other examples, the dosing regimen further comprises administering a corticosteroid to the individual during the introduction phase and the second phase. In other examples, the dosing regimen further comprises administering a corticosteroid to the individual during the first phase (e.g., the first subphase and/or the second subphase) and the second phase.

In some instances, the corticosteroid is administered to the subject QW during the introduction phase and the first subphase of the first phase. In further aspects, the corticosteroid is administered to the subject Q3W during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the subject Q4W during the second phase.

Corticosteroids can be administered by any suitable route of administration. In some instances, corticosteroids are administered intravenously to a subject. In some instances, corticosteroids are administered orally to a subject. In some instances, corticosteroids can be administered intravenously and/or orally to a subject.

In some instances, a corticosteroid is administered to a subject during the pre-phase on day 1, day 2, and/or day 8 of C1. In some instances, a corticosteroid is administered to a subject during the pre-phase on day 1, day 3, and/or day 8 of C1. In some instances, a corticosteroid is administered to a subject during the pre-phase on day 1, day 4, and/or day 8 of C1. In some instances, a corticosteroid is administered to a subject during the pre-phase on day 9, day 10, and/or day 16 of C1. In some instances, a corticosteroid is administered to a subject during the pre-phase on day 9, day 11, and/or day 16 of C1. In some instances, a corticosteroid is administered to a subject during the Pre-Phase on day 9, day 12, and/or day 16 of C1. In some instances, a corticosteroid is administered to a subject during the Run-In Phase on day 1, day 2, day 8, day 9, day 15, and/or day 16 of C1. In further aspects, a corticosteroid is administered to a subject during the Run-In Phase on day 1, day 2, day 8, day 9, day 15, and/or day 16 of C2 . In further aspects, a corticosteroid is administered to a subject during the Run-In Phase on day 1, day 2, day 8, day 9, day 15, and/or day 16 of C3. In further aspects, the corticosteroid is administered to the subject during the run-in phase on day 1, day 2, day 8, day 9, day 15, and/or day 16 of C4. In further aspects, the corticosteroid is administered to the subject during the run-in phase on day 1, day 2, day 8, day 9, day 15, and/or day 16 of C5. In further aspects, the corticosteroid is administered to the subject during the run-in phase on day 1, day 2, day 8, day 9, day 15, and/or day 16 of C6. In further aspects, the corticosteroid is administered to the subject during the run-in phase on day 1, day 2, day 8, day 9, day 15, and/or day 16 of C7. In further aspects, the corticosteroid is administered to the subject during the Run-In Phase on Day 1, Day 2, Day 8, Day 9, Day 15, and/or Day 16 of C8. In further aspects, the corticosteroid is administered to the subject during the Run-In Phase on Day 1, Day 2, Day 8, Day 9, Day 15, and/or Day 16 of C9. In further aspects, the corticosteroid is administered to the subject during the Run-In Phase on Day 1, Day 2, Day 8, Day 9, Day 15, and/or Day 16 of C10. In further aspects, the corticosteroid is administered to the subject during the Run-In Phase on Day 1, Day 2, Day 8, Day 9, Day 15, and/or Day 16 of C11. In further aspects, the corticosteroid is administered to the subject during the Run-In Phase on Day 1, Day 2, Day 8, Day 9, Day 15, and/or Day 16 of C12. In further aspects, the corticosteroid is administered to the subject during the Run-In Phase on Day 1, Day 2, Day 8, Day 9, Day 15, and/or Day 16 of C13.

In some instances, a corticosteroid is administered to a subject during the first subphase of the first phase on day 1, day 8, and/or day 15 of C1. In further aspects, a corticosteroid is administered to a subject during the first subphase of the first phase on day 1, day 8, and/or day 15 of C2 . In further aspects, a corticosteroid is administered to a subject during the first subphase of the first phase on day 1, day 8, and/or day 15 of C3. In further aspects, a corticosteroid is administered to a subject during the first subphase of the first phase on day 1, day 8, and/or day 15 of C4. In further aspects, the corticosteroid is administered to the subject on day 1, day 8, and/or day 15 of C5 during the first subphase of the first phase. In further aspects, the corticosteroid is administered to the subject on day 1, day 8, and/or day 15 of C6 during the first subphase of the first phase. In further aspects, the corticosteroid is administered to the subject on day 1, day 8, and/or day 15 of C7 during the first subphase of the first phase. In further aspects, the corticosteroid is administered to the subject on day 1, day 8, and/or day 15 of C8 during the first subphase of the first phase. In further aspects, the corticosteroid is administered to the subject during the first subphase of the first phase on day 1, day 8, and/or day 15 of C9. In further aspects, the corticosteroid is administered to the subject during the first subphase of the first phase on day 1, day 8, and/or day 15 of C10. In further aspects, the corticosteroid is administered to the subject during the first subphase of the first phase on day 1, day 8, and/or day 15 of C11. In further aspects, the corticosteroid is administered to the subject during the first subphase of the first phase on day 1, day 8, and/or day 15 of C12. In a further aspect, the corticosteroid is administered to the subject during the first subphase of the first phase on day 1, day 8, and/or day 15 of C13.

In some instances, the corticosteroid is administered to the subject on day 1 of C1 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the subject on day 1 of C2 during the second subphase of the first phase . In further aspects, the corticosteroid is administered to the subject on day 1 of C3 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the subject on day 1 of C4 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the subject on day 1 of C5 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the individual on day 1 of C6 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the individual on day 1 of C7 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the individual on day 1 of C8 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the individual on day 1 of C9 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the individual on day 1 of C10 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the subject on day 1 of C11 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the subject on day 1 of C12 during the second subphase of the first phase. In further aspects, the corticosteroid is administered to the subject on day 1 of C13 during the second subphase of the first phase.

In some instances, a corticosteroid is administered to a subject on Day 1 of C1 during the Second Phase. In further aspects, a corticosteroid is administered to a subject on Day 1 of C2 during the Second Phase . In further aspects, a corticosteroid is administered to a subject on Day 1 of C3 during the Second Phase. In further aspects, a corticosteroid is administered to a subject on Day 1 of C4 during the Second Phase. In further aspects, a corticosteroid is administered to a subject on Day 1 of C5 during the Second Phase. In further aspects, a corticosteroid is administered to a subject on Day 1 of C6 during the Second Phase. In further aspects, a corticosteroid is administered to a subject on Day 1 of C7 during the Second Phase. In further aspects, the corticosteroid is administered to the individual on Day 1 of C8 during the Second Phase. In further aspects, the corticosteroid is administered to the individual on Day 1 of C9 during the Second Phase. In further aspects, the corticosteroid is administered to the individual on Day 1 of C10 during the Second Phase. In further aspects, the corticosteroid is administered to the individual on Day 1 of C11 during the Second Phase. In further aspects, the corticosteroid is administered to the individual on Day 1 of C12 during the Second Phase. In further aspects, the corticosteroid is administered to the individual on Day 1 of C13 during the Second Phase.

In some instances, a corticosteroid is administered intravenously to a subject prior to administration of the bispecific antibody. In some instances, a corticosteroid is administered intravenously to a subject approximately 1 hour prior to administration of the bispecific antibody.

In some instances, the corticosteroid is dexamethasone or methylprednisolone. In some instances, the corticosteroid is dexamethasone.

In some instances, dexamethasone is administered to a subject in an amount of about 10 mg to about 40 mg. In some instances, dexamethasone is administered to a subject in an amount of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg. In some instances, dexamethasone is administered to a subject in an amount of about 20 mg. In some instances, dexamethasone is administered to a subject in an amount of about 15 mg. In some instances, dexamethasone is administered to a subject in an amount of about 4 mg.

In some instances, dexamethasone is administered to a subject in an amount of 10 mg to 40 mg. In some instances, dexamethasone is administered to a subject in an amount of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. In some instances, dexamethasone is administered to a subject in an amount of 20 mg. In some instances, dexamethasone is administered to a subject in an amount of 15 mg. In some instances, dexamethasone is administered to a subject in an amount of 4 mg.

In some instances, methylprednisolone is administered to a subject in an amount of about 40 mg to about 160 mg. In some instances, methylprednisolone is administered to a subject in an amount of about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, or about 160 mg. In some instances, methylprednisolone is administered to a subject in an amount of about 80 mg.

In some instances, methylprednisolone is administered to a subject in an amount of 40 mg to 160 mg. In some instances, methylprednisolone is administered to a subject in an amount of 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, or 160 mg. In some instances, methylprednisolone is administered to a subject in an amount of 80 mg. C. Combination Therapy

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject as a combination therapy. For example, the bispecific anti-FcRH5/anti-CD3 antibody can be co-administered with one or more additional therapeutic agents described herein. i. Anti- CD38 Antibodies

In some cases, the bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject in combination with an anti-CD38 antibody. The anti-CD38 antibody can be administered to a subject by any suitable route of administration, such as intravenous (IV) or subcutaneous (SC). In some aspects, the anti-CD38 antibody is daratumumab (e.g., daratumumab/rHuPH20). Daratumumab can be administered in an amount of about 900 mg to about 3600 mg (e.g., about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg). or about 3600 mg) to a subject. Daratumumab can be administered to a subject in a dose of about 1800 mg. In some aspects, daratumumab is administered by intravenous infusion (e.g., over 3-5 hours) at a dose of 16 mg/kg once a week, once every two weeks, or once every four weeks. In some aspects, daratumumab is administered by intravenous infusion (e.g., over 3-5 hours) at a dose of 16 mg/kg. In other aspects, the anti-CD38 antibody is isatuximab. In some embodiments, an anti-CD38 antibody (e.g., daratumumab or isatuximab) is administered to a subject prior to administration of a bispecific anti-FcRH5/anti-CD3 antibody, e.g., one day prior to administration of a bispecific anti-FcRH5/anti-CD3 antibody. In some embodiments, an anti-CD38 antibody (e.g., daratumumab or isatuximab) is administered to a subject concurrently with administration of a bispecific anti-FcRH5/anti-CD3 antibody. ii. Corticosteroids

In some cases, the bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject in combination with a corticosteroid. The corticosteroid can be administered to a subject by any suitable route of administration (e.g., intravenously or orally). In some instances, the corticosteroid is administered to a subject orally. In other instances, the corticosteroid is administered to a subject intravenously. Any suitable corticosteroid can be used, such as dexamethasone, methylprednisolone, prednisone, penicillin, betamethasone, hydrocortisone, etc. In some embodiments, the corticosteroid is methylprednisolone. Methylprednisolone can be administered to a subject in an amount of about 80 mg. In other aspects, the corticosteroid is dexamethasone. Dexamethasone can be administered to the subject at a dose of about 20 mg, about 15 mg, and/or about 4 mg during treatment. In some aspects, the corticosteroid (e.g., methylprednisolone or dexamethasone) is administered to the subject prior to administration of the bispecific anti-FcRH5/anti-CD3 antibody, for example, one hour prior to administration of the bispecific anti-FcRH5/anti-CD3 antibody. In some aspects, the corticosteroid (e.g., methylprednisolone or dexamethasone) is administered to the subject about one day prior to administration of the bispecific anti-FcRH5/anti-CD3 antibody. In some embodiments, a corticosteroid (e.g., methylprednisolone or dexamethasone) is administered to the subject concurrently with the administration of the bispecific anti-FcRH5/anti-CD3 antibody. iii. Immunomodulatory drugs (IMiDs)

In some cases, the bispecific anti-FcRH5/anti-CD3 antibody is administered to a subject in combination with an immunomodulatory drug (IMiD). The IMiD can be administered by any suitable route of administration, such as orally to a subject. The IMiD can be administered intravenously to a subject. In some aspects, the IMiD is pomalidomide. Pomalidomide can be administered to a subject in an amount of about 2 mg to about 4 mg (e.g., 2 mg, 3 mg, or 4 mg). Pomalidomide can be administered to a subject in an amount of about 4 mg. Pomalidomide can be administered to a subject in an amount of about 3 mg. Pomalidomide can be administered to a subject in an amount of about 2 mg. In other aspects, the IMiD is lenalidomide. In some embodiments, an IMiD (e.g., pomalidomide or lenalidomide) is administered to a subject prior to administration of a bispecific anti-FcRH5/anti-CD3 antibody, e.g., one hour prior to administration of a bispecific anti-FcRH5/anti-CD3 antibody. In some embodiments, an IMiD (e.g., pomalidomide or lenalidomide) is administered to a subject concurrently with administration of a bispecific anti-FcRH5/anti-CD3 antibody. In some embodiments, an IMiD (e.g., pomalidomide or lenalidomide) is administered daily between doses of a bispecific anti-FcRH5/anti-CD3 antibody. iv. Tocilizumab and Treatment of CRS

In one instance, the additional therapeutic agent is an effective amount of tocilizumab (ACTEMRA®). In some instances, the subject has a cytokine release syndrome (CRS) event (e.g., a CRS event after treatment with a bispecific antibody, such as a CRS event after C1D1, C1D2, C1D3, C2D1, or an additional dose of a bispecific antibody), and the method further comprises treating the symptoms of the CRS event (e.g., by administering an effective amount of tocilizumab to the subject to treat the CRS event) while discontinuing treatment with the bispecific antibody. In some aspects, tocilizumab is administered intravenously to the subject in a single dose of about 8 mg/kg. In some aspects, the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further comprises administering to the individual one or more additional doses of tocilizumab to control the CRS event, e.g., administering one or more additional doses of tocilizumab intravenously to the individual at a dose of about 8 mg/kg.

In some aspects, treating the symptoms of a CRS event further comprises treatment with a high-dose vasopressor (e.g., norepinephrine, dopamine, norepinephrine, epinephrine, or vasopressin and norepinephrine), e.g., as described in Tables 2A, 2B, and 8.

In other examples, tocilizumab is administered as a premedication, e.g., prior to administration of a bispecific anti-FcRH5/anti-CD3 antibody to a subject. In some instances, tocilizumab is administered as a premedication in cycle 1, e.g., prior to a first dose (C1D1) of a bispecific antibody, a second dose (C1D2) of a bispecific antibody, and/or a third dose (C1D3) of a bispecific anti-FcRH5/anti-CD3 antibody. In some aspects, tocilizumab is administered intravenously to a subject in a single dose of about 8 mg/kg. v. Symptoms and Grading of CRS

CRS can be graded according to a modified cytokine release syndrome grading system developed by Lee et al., Blood, 124: 188-195, 2014 or Lee et al., Biol Blood Marrow Transplant , 25(4): 625-638, 2019, as described in Table 2A. In addition to the diagnostic criteria, Tables 2A and 2B also provide and reference recommendations for the management of CRS based on severity, including early intervention with corticosteroids and/or anti-interleukin therapy. Table 2A. Cytokine Release Syndrome Grading System Level Revised cytokine release syndrome grading system ASTCT consensus grading system Level 1 Symptoms are not life-threatening and require only symptomatic treatment (e.g., fever, nausea, fatigue, headache, myalgia, malaise) Body temperature ≥38℃ No hypotension No hypoxia Level 2 Symptoms requiring moderate intervention for which the oxygen requirement is <40%; or hypotension responsive to fluids or low-dose ^a vasopressor; or grade 2 organ toxicity Temperature ≥ 38°C* with hypotension not requiring vasopressors and/or ^† hypoxia requiring low-flow nasal cannula ^‡ or air leak Level 3 Symptoms requiring invasive intervention with reactive oxygen requirement ≥ 40%; or hypotension requiring high- ^doseb or multiple vasopressors; or grade 3 organ toxicity or grade 4 transaminitis Temperature ≥ 38°C* with hypotension requiring vasopressors with or without vasopressors and/or ^† hypoxia requiring high-flow nasal cannula ^‡ , face mask, non-rebreather mask, or Venturi mask Level 4 Life-threatening symptoms requiring ventilatory support or grade 4 organ toxicity (excluding transaminitis) Temperature ≥ 38°C* with hypotension requiring multiple vasopressors (excluding vasopressin) and/or ^† hypoxia requiring positive pressure (e.g. CPAP, BiPAP, intubation, and mechanical ventilation) Level 5 die die Table 2B. High-dose vasopressors High-dose vasopressors ( duration ≥ 3 hours ) Boosters Dosage Norepinephrine monotherapy ≥ 20 µg/min Dopamine monotherapy ≥ 10 µg/kg/min Phenylephrine monotherapy ≥ 200 µg/min Epinephrine monotherapy ≥ 10 µg/min If vasopressin is used Then vasopressin + norepinephrine equivalents ≥ 10 µg/min ^a If using combination or vasopressor (non-vasopressin) Norepinephrine equivalents ≥ 20 µg/min ^a

Mild to moderate manifestations of CRS and/or infusion-related reactions (IRRs) may include symptoms such as fever, headache, and myalgia, and may be treated symptomatically with analgesics, antipyretics, and antihistamines as indicated. Severe or life-threatening manifestations of CRS and/or IRRs (e.g., hypotension, tachycardia, dyspnea, or chest discomfort) should be treated aggressively with supportive and resuscitative measures as indicated, including high-dose corticosteroids, intravenous fluids, ICU admission, and other supportive measures. Severe CRS may be associated with other clinical sequelae such as chronic intravascular coagulation, capillary leak syndrome, or macrophage activation syndrome (MAS). Standards of care for severe or life-threatening CRS due to immune-based therapies have not been established; case reports and recommendations for the use of anticytokine therapy (such as tocilizumab) have been published (Teachey et al., Blood , 121: 5154-5157, 2013; Lee et al., Blood, 124: 188-195, 2014; Maude et al., New Engl J Med , 371: 1507-1517, 2014).

As shown in Table 2A, even individuals with extensive comorbidities who present with moderate manifestations of CRS should be closely monitored and considered for ICU admission and tocilizumab. vi. Tocilizumab as premedication

In some aspects, an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab (ACTEMRA®/ROACTEMRA®)) is administered as a premedication (prophylaxis), e.g., to a subject prior to administration of the bispecific antibody (e.g., administered about 2 hours prior to administration of the bispecific antibody). Administration of tocilizumab as a premedication can reduce the frequency or severity of CRS. In some aspects, tocilizumab is administered as a premedication in cycle 1, e.g., prior to the first dose (C1D1; cycle 1, dose 1), the second dose (C1D2; cycle 1, dose 2), and/or the third dose (C1D3; cycle 1, dose 3) of the bispecific antibody. In some aspects, tocilizumab is administered intravenously to a subject in a single dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some aspects, tocilizumab is administered intravenously to a subject in a single dose of about 8 mg/kg. In some aspects, tocilizumab is administered intravenously to a subject in a single dose of about 8 mg/kg for patients weighing 30 kg or more (maximum 800 mg) and about 12 mg/kg for patients weighing less than 30 kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061), SA-237, and variants thereof.

For example, in one embodiment, the bispecific antibody is co-administered with tocilizumab (ACTEMRA®/ROACTEMRA®), wherein tocilizumab (ACTEMRA®/ROACTEMRA®) is administered first to the subject, and then the bispecific antibody is administered separately (e.g., the subject is pretreated with tocilizumab (ACTEMRA®/ROACTEMRA®)).

In some aspects, the incidence of CRS (e.g., Grade 1 CRS, Grade 2 CRS, and/or Grade 3+ CRS) is reduced in patients treated with tocilizumab as a premedication compared to patients not treated with tocilizumab as a premedication. In some aspects, patients treated with tocilizumab as a premedication require less intervention to treat CRS (e.g., less need for additional tocilizumab, IV fluids, steroids, or _O2 ) compared to patients not treated with tocilizumab as a premedication. In some aspects, the severity of CRS symptoms is reduced (e.g., limited to fever and stiffness) in patients treated with tocilizumab as a premedication compared to patients not treated with tocilizumab as a premedication. vii. Tocilizumab for the treatment of CRS

In some aspects, the subject experiences a CRS event during treatment with a therapeutic bispecific antibody and an effective amount of an IL-6R antagonist (e.g., an anti-IL-6R antibody such as tocilizumab (ACTEMRA®/ROACTEMRA®)) is administered to control the CRS event.

In some aspects, the subject has a CRS event (e.g., has a CRS event after treatment with a bispecific antibody, such as after a first dose or a subsequent dose of the bispecific antibody), and the method further comprises treating symptoms of the CRS event upon discontinuation of the bispecific antibody treatment.

In some aspects, the subject experiences a CRS event, and the method further comprises administering to the subject an effective amount of an interleukin 6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab (ACTEMRA®/ROACTEMRA®)) to control the CRS event while discontinuing bispecific antibody treatment. In some aspects, the IL-6R antagonist (e.g., tocilizumab) is administered intravenously to the subject in a single dose of about 1 mg/kg to about 15 mg/kg, such as about 4 mg/kg to about 10 mg/kg, such as about 6 mg/kg to about 10 mg/kg, such as about 8 mg/kg. In some aspects, tocilizumab is administered intravenously to the subject in a single dose of about 8 mg/kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061), SA-237 and its variants.

In some aspects, the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further comprises administering to the individual one or more additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to control the CRS event, e.g., administering one or more additional doses of tocilizumab intravenously to the individual at a dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some aspects, the one or more additional doses of tocilizumab are administered intravenously to the subject in a single dose of about 8 mg/kg.

In some aspects, the method further comprises administering to the individual an effective amount of a corticosteroid. The corticosteroid can be administered intravenously to the individual. In some aspects, the corticosteroid is methylprednisolone. In some instances, methylprednisolone is administered in an amount of about 1 mg/kg per day to about 5 mg/kg per day, such as about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, dexamethasone is administered in an amount of about 10 mg (e.g., a single dose of about 10 mg intravenously) or in an amount of about 0.5 mg/kg/day.

If administration of an IL-6R antagonist (e.g., tocilizumab) alone does not control the CRS event, a corticosteroid, such as methylprednisolone or dexamethasone, may be administered to the individual. In some embodiments, treating the symptoms of the CRS event further includes treatment with a high-dose vasopressor (e.g., norepinephrine, dopamine, norepinephrine, epinephrine, or vasopressin and norepinephrine), for example, as described in Tables 2A and 2B. Tables 3A and 2A provide detailed information about tocilizumab for the treatment of severe or life-threatening CRS. viii. Control of CRS Events by Grade

Management of CRS events can be tailored based on the grade of CRS (Tables 2A and 3A) and the presence of comorbidities. Table 3A provides recommendations for the management of CRS syndrome by grade. Table 3B provides recommendations for the management of IRR syndrome by grade. Table 3A. Recommendations for the management of cytokine release syndrome (CRS) Event ^{a , b Actions} takenb Grade 1 fever (≥38°C or 100.4°F, not attributable to any other cause) Immediate Actions: ● If ceftriaxone infusion is ongoing, interrupt infusion immediately. ● If needed, call to ensure tocilizumab is readily available. ● Provide supportive care for systemic symptoms. ^c ● If fever and neutropenia are present, treat. ● Fluid balance monitor; administer IV fluids as clinically indicated. ● Consider hospitalization until symptom resolution. ● If global health status declines rapidly or CRS is prolonged (>24 hours), or if the patient has significant symptoms and/or comorbidities (e.g., compromised cardiovascular function, decreased pulmonary reserve, as determined by the investigator), consider IV corticosteroids and tocilizumab or another anticytosteroid based on signs of CRS. Restart Infusion: ● If ceftriaxone infusion is interrupted, wait 30 minutes after the event resolves and then restart at 50% of the original infusion rate. ● If symptoms recur, discontinue the infusion for that dose. Next Dose: ● Pretreat with antihistamines, antipyretics, and/or analgesics. ● Pretreat with IV corticosteroids (dexamethasone 20 mg (preferred) or methylprednisolone 80 mg). ● Consider hospitalization for next dose. ● Consider longer infusion times (slower infusion rates) for subsequent cycles. Grade 2 fever ( ≥38 °C or 100.4°F, not attributable to any other cause) Hypotension: Responds to fluids, does not require vasopressors Hypoxia: requires low-flow nasal cannula or air leak Immediate Actions: ● Follow all Level 1 recommendations. ● Maintain further ceftriaxone therapy until complete resolution of symptoms. ● Hospitalize patient until complete resolution of signs and symptoms. ● Administer tocilizumab 8 mg/kg IV ^d ● Consider treatment with IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or, if neurologic symptoms are present, dexamethasone 10 mg IV every 6 hours as needed). ^b ● Closely monitor cardiac and other organ function. ● Manage systemic symptoms and organ toxicity as needed. ● Provide hemodynamic support via IV bolus infusion of 250-500 mL up to a total of 2000 mL (avoid fluid overload). ● Provide oxygen for hypoxia. ● Admit to ICU as appropriate. ● If no improvement occurs within 8-12 hours of tocilizumab administration, manage as a Grade 3 event: – Notify the Medical Monitor if patient does not improve by 24 hours. – Initiate testing for signs and symptoms of MAS/HLH and assess. Restart infusion: ● Wait 30 minutes after the event resolves and then restart the infusion at up to 25% of the original infusion rate. ● If symptoms recur, stop the infusion immediately. Ceftriaxone should not be restarted. ● If hypotension or hypoxia recurs, manage as a Grade 3 event. Next Cycle: ● If symptoms resolve to ≤ Grade 1 for 3 consecutive days, receive the next dose of ceftriaxone as follows: – Consider hospitalization for at least 24 hours after infusion. – If event occurs during or within 24 hours of infusion, administer ceftriaxone at 50% of the initial infusion rate of the previous cycle. ^e – Pretreat with antihistamines, antipyretics, and/or analgesics. – Pretreat with IV corticosteroids (dexamethasone 20 mg (preferred) or methylprednisolone 80 mg). Subsequent Cycles: ● If ≥ Grade 3 IRR or CRS occurs in any subsequent cycle, permanently discontinue ceftriaxone regardless of recovery (see Grade 3 Management Guidelines). ● If ≤ Grade 2 CRS occurs in a subsequent cycle, manage as indicated by severity (see Grade 1 or 2 management guidelines). Grade 3 Fever (≥38°C or 100.4°F, not attributable to any other cause) Hypotension: Requires vasopressors with or without vasopressors Hypoxia: Requires high-flow nasal cannula, face mask , non-rebreather mask, or Venturi mask Immediate Actions: ● Stop further ceftriaxone infusion. ● Provide supportive care and treat symptomatically as clinically indicated. ^c ● Monitor fluid balance; administer IV bolus infusions of 250-500 mL up to a total of 2000 mL (avoid fluid overload); provide vasopressor support for hypotension at high and repeated doses if needed. ● Hospitalize patient until signs and symptoms resolve completely. ● Treat with IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or, if neurologic symptoms are present, dexamethasone 10 mg IV every 6 hours as needed). ^b ● Administer tocilizumab 8 mg/kg IV. ^d – If no improvement after 8 hours, repeat tocilizumab. – If no improvement within 8-12 hours after second dose of tocilizumab, manage as a Grade 4 event. – Initiate testing for signs and symptoms of MAS/HLH and assess. ● ICU monitoring of cardiopulmonary and organ function is recommended. ● Provide oxygen for hypoxia. ● Notify Medical Monitor. Restart Infusion: ● Do not restart ceftriaxone infusion. Next Cycle: ● Permanently discontinue ceftriaxone if patient had ≥ Grade 2 IRR or CRS in any prior cycle. – Ceftriaxone must be discontinued in patients who experience Grade 3 wheezing, bronchospasm, or generalized urticaria. – If the patient recovers to ≤ Grade 1 for 3 consecutive days, ceftriaxone may be administered in the next cycle as follows: – Hospitalize the patient for at least 24 hours after mask infusion. – If the event occurred during or within 24 hours of the infusion, administer ceftriaxone at 50% of the initial infusion rate of the previous cycle. ^e – Pretreat with antihistamines, antipyretics, and/or analgesics – Pretreat with IV corticosteroids (dexamethasone 20 mg (preferred) or methylprednisolone 80 mg). ● If a patient experiences Grade 3 CRS after dosing on Day 1 of Cycle 1, dose escalation must be repeated. Subsequent cycles: ● If ≥ Grade 3 CRS recurs, permanently discontinue ceftriaxone. ● If Grade 2 CRS occurs in subsequent cycles, manage as indicated by severity (i.e., Grade 1 or 2 management guidelines). Grade 4 fever (≥38°C or 100.4°F, not attributable to any other cause) Hypotension: multiple vasopressors required Hypoxia: positive pressures required (e.g., CPAP, BiPAP, intubation, mechanical ventilation) ● Stop ceftriaxone infusion. ● Follow all Level 3 control guidelines. ● Patients require ICU admission for hemodynamic monitoring, and/or mechanical ventilation, and/or IV fluids and vasopressors as needed. ● Administer tocilizumab 8 mg/kg IV (see footnote). ^d ● Treat with IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or, if neurologic symptoms are present, dexamethasone 10 mg IV every 6 hours as needed) ● For patients refractory to tocilizumab therapy, experimental therapies (e.g., sildenafil, anakinra, emaratumumab, or LCK inhibitors) may be considered based on the investigator’s judgment and institutional guidelines ^b . ● Permanently discontinue study treatment. BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome; HLH = hemophagocytic lymphohistiocytosis; ICU = intensive care unit; IV = intravenous; MAS = macrophage activation syndrome. aSee Table 2A for a full description of the grading of symptoms. ^bGuidelines for the management of CRS are ^based on Lee et al (2019) and Riegler et al (2019). ^cTreat patients with acetaminophen and antihistamines (e.g., diphenhydramine) if they have not been given within the previous 4 hours. Treat bronchospasm, urticaria, or dyspnea according to institutional practice. Treat fever and neutropenia as needed; consider broad-acting antibiotics and/or G-CSF if indicated. ^d Tocilizumab should be administered at a dose of 8 mg/kg IV (8 mg/kg only for patients weighing ≥ 30 kg; 12 mg/kg for patients weighing < 30 kg; doses exceeding 800 mg per infusion are not recommended); repeat every 8 hours as needed (up to a maximum of 4 doses). ^e If the patient does not experience CRS during this next infusion at a 50% reduced rate, the infusion rate may be increased to the initial rate in subsequent cycles. However, if this patient experiences another CRS event, the infusion rate should be reduced by 25%-50% depending on the severity of the event. Table 3B. Management recommendations for ceftriaxone infusion-related reactions (IRRs) Event ^a Actions taken Level 1-2 ​ ​ ​ ● Slow infusion to ≤50% or interrupt infusion. ● Administer supportive care. ^b ● After symptoms resolve, infusion may be resumed at 50% of the starting rate (if interrupted). The infusion must be maintained at a low rate to allow symptoms to resolve over the remainder of the infusion time. ^c ● Premedicate with acetaminophen/pyrazol and an antihistamine (such as diphenhydramine) for all subsequent infusions. Notes: 1. For Grade 2 wheezing or urticaria, patients must be premedicated prior to subsequent dosing. 2. If symptoms recur with equal or greater severity after slowing or interrupting the infusion of ceftriaxone, the infusion must be stopped immediately. Ceftriaxone should not be administered during this cycle. Level 3 ​ ● Discontinue ceftriaxone infusion. Do not restart infusion for the current cycle. ● Administer supportive care. ^b ● ICU admission is recommended to monitor cardiopulmonary and other organ function. ● Provide oxygen for hypoxia and/or provide mechanical ventilation as needed. ● Subsequent cycles of ceftriaxone may be administered with premedication. ● Patients who experience a first episode of Grade 3 wheezing, bronchospasm, or generalized urticaria must discontinue study treatment. Notes: 1. If symptoms recur with equal or greater severity during a subsequent cycle despite premedication, the infusion must be stopped immediately and the patient permanently discontinued from study treatment. Level 4 ​ ● Immediately stop the infusion. ● Provide supportive treatment. ^b ● Admit to ICU to monitor cardiopulmonary and other organ functions. ● Provide oxygen for hypoxia and/or provide mechanical ventilation as needed. ● Permanently stop study treatment. ICU = Intensive Care Unit; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. ^a Symptom grading is based on NCI CTCAE v5.0. ^b Supportive care: Patients should be treated with acetaminophen/pyrazol and antihistamines (e.g., diphenhydramine) if they have not been treated within the previous 4 hours. Intravenous fluids (e.g., saline) may be administered as clinically indicated. For bronchospasm, urticaria, or dyspnea, antihistamines, oxygen, corticosteroids (e.g., 100 mg IV penicillin or equivalent), and/or bronchodilators may be administered as per institutional practice. Provide fluid and vasopressor support for hypotension if necessary. ^cSubsequent ceftriaxone infusions may be started at the original rate. ix. Management of Grade 2 CRS Events

If an individual has a Grade 2 CRS event following administration of a therapeutic bispecific antibody (e.g., a Grade 2 CRS event with no comorbidities or with minimal comorbidities), the approach may further include treating the symptoms of the Grade 2 CRS event while discontinuing treatment with the bispecific antibody. If the Grade 2 CRS event subsequently resolves to ≤ Grade 1 CRS events for at least three consecutive days, the approach may further include resuming treatment with the bispecific antibody without changing the dose. On the other hand, if the Grade 2 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 2 CRS event or worsens to a Grade ≥ 3 CRS event, the method can further comprise administering to the individual an effective amount of an interleukin 6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab (ACTEMRA® / ROACTEMRA®)) to control the Grade 2 or Grade ≥ 3 CRS event. In some examples, tocilizumab is administered intravenously to the individual in a single dose of about 8 mg/kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061), SA-237 and its variants.

If the individual has a Grade 2 CRS event in the presence of extensive comorbidities following administration of a therapeutic bispecific antibody, the method can further include administering to the individual a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab (ACTEMRA® / ROACTEMRA®)) to control the Grade 2 CRS event while discontinuing treatment with the bispecific antibody. In some instances, the first dose of tocilizumab is administered intravenously to the individual at a dose of about 8 mg/kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061), SA-237, and variants thereof. In some instances, if a Grade 2 CRS event resolves to a Grade 1 CRS event within two weeks, the method further comprises restarting treatment with a reduced dose of the bispecific antibody. In some instances, if the event occurred during an infusion or within 24 hours of it, the lower dose is 50% of the initial infusion rate of the previous cycle. On the other hand, if the Grade 2 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 2 CRS event or worsens to a Grade ≥ 3 CRS event, the method may further comprise administering to the individual one or more (e.g., one, two, three, four, five, or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab) to control the Grade 2 or Grade ≥ 3 CRS event. In some specific instances, the Grade 2 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 2 CRS event or worsens to a Grade ≥ 3 CRS event, and the method may further comprise administering to the individual one or more additional doses of tocilizumab to control the Grade 2 or Grade ≥ 3 CRS event. In some cases, one or more additional doses of tocilizumab are administered intravenously to the subject in an amount of about 1 mg/kg to about 15 mg/kg (e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg). In some instances, the method further comprises administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered before, after, or simultaneously with the one or more additional doses of tocilizumab or other anti-IL-6R antibody. In some instances, the corticosteroid is administered intravenously to the subject. In some instances, the corticosteroid is methylprednisolone. In some instances, methylprednisolone is administered in an amount of about 1 mg/kg per day to about 5 mg/kg per day, such as about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, dexamethasone is administered in an amount of about 10 mg (e.g., a single dose of about 10 mg intravenously) or in an amount of about 0.5 mg/kg/day. x. Control of Grade 3 CRS Events

If the individual has a Grade 3 CRS event following administration of the therapeutic bispecific antibody, the method can further include administering to the individual a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab (ACTEMRA® / ROACTEMRA®)) to control the Grade 3 CRS event while discontinuing treatment with the bispecific antibody. In some instances, the first dose of tocilizumab is administered intravenously to the individual at a dose of about 8 mg/kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061), SA-237, and variants thereof. In some instances, the subject recovers (e.g., is afebrile and off vasopressors) within 8 hours of treatment with the bispecific antibody, and the method further comprises resuming treatment with the bispecific antibody at a reduced dose. In some instances, if the event occurred during an infusion or within 24 hours thereof, the reduced dose is 50% of the initial infusion rate of the previous cycle. In other examples, if a Grade 3 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 3 CRS event or worsens to a Grade 4 CRS event, the method may further include administering to the individual one or more (e.g., one, two, three, four, five, or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab) to control the Grade 3 or Grade 4 CRS event. In some specific examples, a Grade 3 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 3 CRS event or worsens to a Grade 4 CRS event, and the method further includes administering to the individual one or more additional doses of tocilizumab to control the Grade 3 or Grade 4 CRS event. In some cases, one or more additional doses of tocilizumab are administered intravenously to the subject in an amount of about 1 mg/kg to about 15 mg/kg (e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg). In some instances, the method further comprises administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered before, after, or simultaneously with the one or more additional doses of tocilizumab or other anti-IL-6R antibody. In some instances, the corticosteroid is administered intravenously to the subject. In some instances, the corticosteroid is methylprednisolone. In some instances, methylprednisolone is administered in an amount of about 1 mg/kg per day to about 5 mg/kg per day, such as about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, dexamethasone is administered in an amount of about 10 mg (e.g., a single dose of about 10 mg intravenously) or in an amount of about 0.5 mg/kg/day. xi. Control of Grade 4 CRS Events

If the individual has a Grade 4 CRS event following administration of the therapeutic bispecific antibody, the method can further include administering to the individual a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab (ACTEMRA® / ROACTEMRA®)) to control the Grade 4 CRS event and permanently discontinuing treatment with the bispecific antibody. In some instances, the first dose of tocilizumab is administered intravenously to the individual at a dose of about 8 mg/kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061), SA-237, and variants thereof. In some instances, a Grade 4 CRS event resolves within 24 hours of treating the symptoms of the Grade 4 CRS event. If the Grade 4 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 4 CRS event, the method may further comprise administering to the individual one or more additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab (ACTEMRA®/ROACTEMRA®)) to manage the Grade 4 CRS event. In some specific instances, the Grade 4 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 4 CRS event, and the method further comprises administering to the individual one or more (e.g., one, two, three, four, or five or more) additional doses of tocilizumab to manage the Grade 4 CRS event. In some instances, one or more additional doses of tocilizumab are administered intravenously to the subject in an amount of about 1 mg/kg to about 15 mg/kg (e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg). In some instances, the method further comprises administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered before, after, or simultaneously with the one or more additional doses of tocilizumab or another anti-IL-6R antibody. In some instances, the corticosteroid is administered intravenously to the subject. In some instances, the corticosteroid is methylprednisolone. In some instances, methylprednisolone is administered in an amount of about 1 mg/kg per day to about 5 mg/kg per day, such as about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, dexamethasone is administered in an amount of about 10 mg (e.g., a single dose of about 10 mg intravenously) or in an amount of about 0.5 mg/kg/day. xii. Acetaminophen or acetaminophen

In another example, the additional therapeutic agent is an effective amount of acetaminophen or acetaminophen. Acetaminophen or acetaminophen can be administered orally to a subject, for example, in an amount of about 500 mg to about 1000 mg. In some aspects, acetaminophen or acetaminophen is administered to a subject as a premedication, for example, prior to administration of a bispecific anti-FcRH5/anti-CD3 antibody. xiii. Diphenhydramine

In another example, the additional therapeutic agent is an effective amount of diphenhydramine. Diphenhydramine can be administered orally to a subject, for example, in an amount between about 25 mg and about 50 mg. In some aspects, diphenhydramine is administered to a subject as a premedication, for example, prior to administration of a bispecific anti-FcRH5/anti-CD3 antibody. xiv. Anti-myeloma Agents

In another example, the additional therapeutic agent is an effective amount of an anti-myeloma agent, such as an anti-myeloma agent that enhances and/or supplements T cell-mediated myeloma cell killing. The anti-myeloma agent can be, for example, pomalidomide, daratumumab, and/or a B cell maturation antigen (BCMA) directed therapy (e.g., an antibody-drug conjugate targeting BCMA (BCMA-ADC)). In some embodiments, the anti-myeloma agent is administered in a four-week cycle. xv. Other Combination Therapies

In some embodiments, the one or more additional therapeutic agents include a PD-1 axis binding antagonist, an immunomodulatory agent, an anti-tumor agent, a chemotherapeutic agent, a growth inhibitor, an anti-angiogenic agent, radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof. xvi. PD-1 axis binding antagonist

In some embodiments, the additional therapeutic agent is a PD-1 axis binding antagonist. PD-1 axis binding antagonists may include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. Any suitable PD-1 axis binding antagonist may be used.

In some cases, a PD-L1 binding antagonist inhibits binding of PD-L1 to one or more of its ligand binding partners. In other cases, PD-L1 binding antagonists inhibit the binding of PD-L1 to PD-1. In still other cases, PD-L1 binding antagonists inhibit the binding of PD-L1 to B7-1. In some cases, PD-L1 binding antagonists inhibit PD-L1 binding to PD-1 and B7-1. PD-L1 binding antagonists may be, but are not limited to, antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, or small molecules. In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041). Antagonists are small molecules that inhibit PD-L1 and VISTA. In some cases, the PD-L1 binding antagonist is CA-170 (also known as AUPM-170). In some cases, the PD-L1 binding antagonist is a small molecule that inhibits In some cases, the small molecule is a compound described in WO 2015/033301 and/or WO 2015/033299.

In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD-L1 antibodies are contemplated and described herein. In any case herein, the isolated anti-PD-L1 antibody can bind to human PD-L1, for example, human PD-L1 shown in UniProtKB/Swiss-Prot Accession No. Q9NZQ7-1, or a variant thereof. In some cases, the anti-PD-L1 antibody can inhibit the binding between PD-L1 and PD-1 and/or between PD-L1 and B7-1. In some cases, the anti-PD-L1 antibody is a monoclonal antibody. In some instances, the anti-PD-L1 antagonist antibody is an antibody fragment selected from the group consisting of: Fab, Fab'-SH, Fv, scFv, and (Fab') ₂ fragments. In some instances, the anti-PD-L1 antibody is a humanized antibody. In some instances, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, envafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. In some instances, the anti-PD-L1 antibody is atezolizumab. Examples of anti-PD-L1 antibodies that can be used in the methods of the present invention and methods for their preparation are described in International Patent Application Publication No. WO 2010/077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.

In some cases, the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

In some instances, the anti-PD-L1 antibody is durvalumab (CAS Registry No.: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1 κ anti-PD-L1 antibody described in WO 2011/066389 and US 2013/034559 (MedImmune, AstraZeneca).

In some instances, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007/005874.

In some cases, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

In some instances, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PD-L1 antibody.

In some cases, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is a single domain antibody (dAB) generated from a camel phage display library.

In some cases, the anti-PD-L1 antibody comprises a cleavable portion or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates the antibody antigen-binding domain to enable it to bind its antigen, e.g., by removing a non-binding steric moiety. In some cases, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

In some cases, the anti-PD-L1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and/or heavy chain variable domains and light chain variable domains of an anti-PD-L1 antibody described in US 20160108123, WO 2016/000619, WO 2012/145493, U.S. Patent No. 9,205,148, WO 2013/181634, or WO 2016/061142.

In some cases, the PD-1 axis binding antagonist is a PD-1 binding antagonist. For example, in some cases, a PD-1 binding antagonist inhibits binding of PD-1 to one or more of its ligand binding partners. In some cases, PD-1 binding antagonists inhibit the binding of PD-1 to PD-L1. In other cases, PD-1 binding antagonists inhibit the binding of PD-1 to PD-L2. In yet other cases, PD-1 binding antagonists inhibit the binding of PD-1 to PD-L1 and PD-L2. PD-1 binding antagonists may be, but are not limited to, antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, or small molecules. In some cases, the PD-1 binding antagonist is an immunoadhesin (e.g., an extracellular or PD-1 comprising PD-L1 or PD-L2 fused to a homeostatic region (e.g., an Fc region of an immunoglobulin sequence) For example, in some cases, the PD-1 binding antagonist is an Fc fusion protein. In some cases, the PD-1 binding antagonist is AMP-224. AMP-224, also known as B7-DCIg is a PD-L2-Fc fused soluble receptor described in WO 2010/027827 and WO 2011/066342. In some cases, the PD-1 binding antagonist is a peptide or a small molecule compound. In some cases, the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). See, e.g., WO 2012/168944, WO 2015/036927, WO 2015/044900, WO 2015/033303, WO 2013/144704, WO 2013/132317 and WO 2011/161699. In some instances, the PD-1 binding antagonist is a small molecule that inhibits PD-1.

In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PD-1 antibodies can be used for the methods and uses disclosed herein. In any case herein, the PD-1 antibody can bind to human PD-1 or a variant thereof. In some cases, the anti-PD-1 antibody is a monoclonal antibody. In some cases, the anti-PD-1 antagonist antibody is an antibody fragment selected from the group consisting of: Fab, Fab', Fab'-SH, Fv, scFv and (Fab') ₂ fragments. In some cases, the anti-PD-1 antibody is a humanized antibody. In other cases, the anti-PD-1 antibody is a human antibody. Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21.

In some instances, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb/Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®, is an anti-PD-1 antibody described in WO 2006/121168.

In some instances, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lanlorizumab, SCH-900475, and KEYTRUDA®, is an anti-PD-1 antibody described in WO 2009/114335.

In some cases, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is PDR001 (CAS Reg. No. 1859072-53-9; Novartis). PDR001 is a humanized IgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.

In some cases, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is BGB-108 (BeiGene).

In some cases, the anti-PD-1 antibody is BGB-A317 (BeiGene).

In some cases, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

In some instances, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is PF-06801591 (Pfizer).

In some cases, the anti-PD-1 antibody is TSR-042 (also known as ANB011; Tesaro/AnaptysBio).

In some cases, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

In some cases, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits the function of PD-1 without blocking the binding of PD-L1 to PD-1.

In some cases, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits the binding of PD-L1 to PD-1.

In some cases, the anti-PD-1 antibody comprises an antibody described in WO 2015/112800, WO 2015/112805, WO 2015/112900, US 20150210769, WO 2016/089873, WO 2015/035606, WO 2015/085847, WO 2014/206107, WO 2012/145493, US 9,205,148, WO 2015/119930, WO 2015/119923, WO 2016/032927, WO 2014/179664, WO 2016/106160, and WO 2014/194302. Six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and/or heavy chain variable domains and light chain variable domains of a PD-1 antibody.

In some cases, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some cases, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand binding partner. In a specific aspect, the PD-L2 binding ligand partner is PD-1. PD-L2 binding antagonists may be, but are not limited to, antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, or small molecules.

In some cases, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In any case herein, the anti-PD-L2 antibody can bind to human PD-L2 or a variant thereof. In some cases, the anti-PD-L2 antibody is a monoclonal antibody. In some cases, the anti-PD-L2 antagonist antibody is an antibody fragment selected from the group consisting of: Fab, Fab', Fab'-SH, Fv, scFv and (Fab') ₂ fragments. In some cases, the anti-PD-L2 antibody is a humanized antibody. In other cases, the anti-PD-L2 antibody is a human antibody. In another specific aspect, the anti-PD-L2 antibody has reduced or minimal effector function. In yet another embodiment, the minimal effector function is derived from a "less effector Fc mutation" or a deglycosylation mutation. In yet another embodiment, the less effector Fc mutation is a N297A or D265A/N297A substitution in the constant region. In some instances, the isolated anti-PD-L2 antibody is aglycosylated. xvii. Growth inhibitors

In some aspects, the additional therapeutic agent is a growth inhibitor. Exemplary growth inhibitors include agents that block cell cycle progression outside of the S phase, such as drugs that induce G1 arrest (e.g., DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, methoxyethylamine, cisplatin, methotrexate, 5-fluorouracil, or ara-C) or drugs that induce M phase arrest (e.g., vincristine, vinblastine, taxanes (e.g., paclitaxel and docetaxel), doxorubicin, epirubicin, daunorubicin, etoposide, or bleomycin). xviii. Radiation therapy

In some embodiments, the additional therapeutic agent is radiation therapy. Radiation therapy involves the use of directed gamma or beta rays to cause sufficient damage to cells to limit their ability to function normally or to destroy the cells completely. Typical treatment is a single administration, and typical doses range from 10 to 200 Grays per day. xix. Cytotoxic Agents

In some aspects, the additional therapeutic agent is a cytotoxic agent, such as a substance that inhibits or prevents cell function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and Lu radioactive isotopes of oxazolidinone); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, mycophenolate mofetil, mitomycin C, chloramphenicol, daunomycin or other intercalating agents); growth inhibitors; enzymes and fragments thereof, such as nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and antitumor or anticancer agents. xx. Anticancer Therapy

In some embodiments, the methods include administering to a subject an anti-cancer therapy (e.g., an anti-tumor agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, radiation therapy, or a cytotoxic agent) in the absence of or in addition to the bispecific anti-FcRH5/anti-CD3 antibody.

In some embodiments, the method further comprises administering to the patient an effective amount of an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of an anti-tumor agent, a chemotherapeutic agent, a growth inhibitor, an anti-angiogenic agent, a radiotherapy, a cytotoxic agent, and a combination thereof. In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with chemotherapy or a chemotherapeutic agent. In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with a radiotherapy agent. In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with a targeted therapy or a targeted therapy. In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an immunotherapy or an immunotherapeutic agent, such as a monoclonal antibody. In some embodiments, the additional therapeutic agent is an agonist against a co-stimulatory molecule. In some embodiments, the additional therapeutic agent is an antagonist against a co-inhibitory molecule.

Without wishing to be bound by theory, it is believed that enhancing T cell stimulation by promoting co-stimulatory molecules or by inhibiting co-inhibitory molecules can promote tumor cell death, thereby treating cancer or slowing cancer progression. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an agonist against a co-stimulatory molecule. In some instances, the co-stimulatory molecule can include CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127. In some instances, the agonist against a co-stimulatory molecule is an agonist antibody that binds to CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antagonist against a co-inhibitory molecule. In some instances, the co-inhibitory molecule can include CTLA-4 (also known as CD152), TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA/B, or arginase. In some instances, the antagonist against a co-inhibitory molecule is an antagonist antibody that binds to CTLA-4, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA/B, or arginase.

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antagonist to CTLA-4 (also known as CD152), such as a blocking antibody. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with ipilimumab (also known as MDX-010, MDX-101, or YERVOY®). In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with tremelimumab (also known as ticilimumab or CP-675,206). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antagonist against B7-H3 (also known as CD276), such as a blocking antibody. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with MGA271. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antagonist against TGF-β , such as metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), or LY2157299.

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with a therapy comprising the adoptive transfer of T cells expressing a chimeric antigen receptor (CAR), such as cytotoxic T cells or CTLs. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with a therapy comprising the adoptive transfer of T cells comprising a dominant negative TGF β receptor, such as a dominant negative TGF β type II receptor. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with a therapy comprising the HERCREEM regimen (see, e.g., ClinicalTrials.gov identifier NCT00889954).

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with an agonist for CD137 (also known as TNFRSF9, 4-1BB, or ILA), such as an activating antibody. In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with urelumab (also known as BMS-663513). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with an agonist for CD40 , such as an activating antibody. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with CP-870893. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with an agonist against OX40 (also known as CD134), such as an activating antibody. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with an anti-OX40 antibody (e.g., AgonOX). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with an agonist against CD27, such as an activating antibody. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with CDX-1127. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antagonist against indoleamine-2,3-dioxygenase (IDO). In some instances, the IDO antagonist is 1-methyl-D-tryptophan (also known as 1-D-MT).

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antibody-drug conjugate. In some instances, the antibody-drug conjugate comprises maytansine or monomethyl auristatin E (MMAE). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an anti-NaPi2b antibody-MMAE conjugate (also known as DNIB0600A or RG7599). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with trastuzumab emtansine (also known as T-DM1, ado-trastuzumab emtansine, or KADCYLA®, Genentech). In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with DMUC5754A. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antibody-drug conjugate targeting endothelin B receptor (EDNBR), such as an antibody against EDNBR conjugated to MMAE.

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an anti-angiogenic agent. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antibody directed against VEGF, such as VEGF-A. In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with bevacizumab (also known as AVASTIN®, Genentech). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antibody directed against angiopoietin 2 (also known as Ang2). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with MEDI3617.

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an anti-tumor agent. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an agent that targets CSF-1R (also known as M-CSFR or CD115). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with anti-CSF-1R (also known as IMC-CS4). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an interferon, such as interferon alpha or interferon gamma. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with Roferon-A (also known as recombinant interferon alpha-2a). In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with GM-CSF (also known as recombinant human granulocyte macrophage colony stimulating factor, rhu GM-CSF, sargramostim, or LEUKINE®). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with IL-2 (also known as aldesleukin or PROLEUKIN®). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with IL-12. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antibody targeting CD20. In some instances, the antibody targeting CD20 is obinutuzumab (also known as GA101 or GAZYVA®) or rituximab. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an antibody targeting GITR. In some instances, the antibody targeting GITR is TRX518.

In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with a cancer vaccine. In some instances, the cancer vaccine is a peptide cancer vaccine, in some cases a personalized peptide vaccine. In some instances, the peptide cancer vaccine is a dendritic cell vaccine of multivalent long peptides, polypeptides, peptide mixtures, hybrid peptides, or peptide pulses (see, e.g., Yamada et al., Cancer Sci. 104:14-21, 2013). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an adjuvant. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with a therapy comprising a TLR agonist, such as Poly-ICLC (also known as HILTONOL®), LPS, MPL, or CpG ODN. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with tumor necrosis factor (TNF) α. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with IL-1. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with HMGB1. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an IL-10 antagonist. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an IL-4 antagonist. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an IL-13 antagonist. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an HVEM antagonist. In some examples, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an ICOS agonist, for example, by administering ICOS-L or an agonist antibody to ICOS. In some cases, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with a therapy that targets CX3CL1. In some cases, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with a therapy that targets CXCL9. In some cases, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with a therapy that targets CXCL10. In some cases, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with a therapy that targets CCL5. In some cases, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with an LFA-1 or ICAM1 agonist. In some cases, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with a selectin agonist.

In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with a targeted therapy. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with a B-Raf inhibitor. In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with vemurafenib (also known as ZELBORAF®). In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with dabrafenib (also known as TAFINLAR®). In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with erlotinib (also known as TARCEVA®). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with a MEK inhibitor, such as MEK1 (also known as MAP2K1) or MEK2 (also known as MAP2K2). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with cobimetinib (also known as GDC-0973 or XL-518). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with trametinib (also known as MEKINIST®). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with a K-Ras inhibitor. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with a c-Met inhibitor. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with onartuzumab (also known as MetMAb). In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an Alk inhibitor. In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with AF802 (also known as CH5424802 or alectinib). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with a phosphatidylinositol 3-kinase (PI3K) inhibitor. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with BKM120. In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with idelalisib (also known as GS-1101 or CAL-101). In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with perifosine (also known as KRX-0401). In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an Akt inhibitor. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with MK2206. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with GSK690693. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with GDC-0941. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with an mTOR inhibitor. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with sirolimus (also known as rapamycin). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with temsirolimus (also known as CCI-779 or TORISEL®). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody may be administered in combination with everolimus (also known as RAD001). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with ridaforolimus (also known as AP-23573, MK-8669, or deforolimus). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with OSI-027. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with AZD8055. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with INK128. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with a dual PI3K/mTOR inhibitor. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with XL765. In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with GDC-0980. In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with BEZ235 (also known as NVP-BEZ235). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with BGT226. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with GSK2126458. In some cases, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with PF-04691502. In certain instances, the bispecific anti-FcRH5/anti-CD3 antibody can be administered in combination with PF-05212384 (also known as PKI-587).

In some instances, the bispecific anti-FcRH5/anti-CD3 antibodies can be administered in combination with chemotherapeutics. Chemotherapeutics are compounds that can be used to treat cancer. Exemplary chemotherapeutic agents include, but are not limited to, erlotinib (TARCEVA®, Genentech/OSI Pharm.), antihormonal agents used to modulate or inhibit hormonal effects on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), antibodies, such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech) or trastuzumab (HERCEPTIN®, Genentech), EGFR inhibitors (EGFR antagonists), tyrosine kinase inhibitors, and chemotherapy also includes nonsteroidal anti-inflammatory drugs (NSAIDs) with analgesic, antipyretic and anti-inflammatory effects.

The methods described herein involve combination therapy, such as in the examples of specific combination therapy mentioned above, the combination therapy includes co-administration of a bispecific anti-FcRH5/anti-CD3 antibody and one or more additional therapeutic agents, and such co-administration can be a combined administration (wherein the two or more therapeutic agents are contained in the same or separate formulations) or a separate administration, in which case, the administration of the bispecific anti-FcRH5/anti-CD3 antibody can occur before, simultaneously with, and/or after the administration of one or more additional therapeutic agents. In one embodiment, administration of the bispecific anti-FcRH5/anti-CD3 antibody and administration of the additional therapeutic agent or exposure to radiation therapy can occur within about one month of each other, or within about one, two, or three weeks, or within about one, two, three, four, five, or six days.

In some aspects, the individual does not have an increased risk for CRS (e.g., has not experienced Grade 3+ CRS during treatment with a bispecific antibody or CAR-T therapy; does not have detectable circulating plasma cells; and/or does not have extensive extramedullary disease).

In some aspects, the individual has an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) less than or equal to 2.5 times the upper limit of normal (ULN). In some aspects, the individual has a platelet count greater than or equal to 75,000/mm ^3. D. Cancer

Any of the methods of the invention described herein can be used to treat cancer, such as a B-cell proliferative disorder, including multiple myeloma (MM), which can be relapsed or refractory (R/R) MM. In some aspects, the patient has received at least three prior lines of treatment for a B-cell proliferative disorder (e.g., MM), such as three, four, five, six, or more than six prior lines of treatment. In some aspects, the patient has received at least three prior lines of treatment for a B-cell proliferative disorder, wherein the treatment is 4L+ treatment. For example, the patient may have been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), an autologous stem cell transplant (ASCT), an anti-CD38 therapy (e.g., an anti-CD38 antibody therapy, such as daratumumab therapy), a CAR-T therapy, or a therapy comprising a bispecific antibody. In some instances, the patient has been exposed to all three of PI, IMiD, and anti-CD38 therapy. Other examples of B cell proliferative disorders/malignancies suitable for treatment with bispecific anti-FcRH5/anti-CD3 antibodies according to the methods described herein include, but are not limited to, non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), which may be relapsed or refractory DLBCL, and other cancers including germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL), activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), rim lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, splenic rim lymphoma, hairy cell leukemia, splenic lymphoma/leukemia, unclassifiable, splenic diffuse erythroid small B-cell lymphoma, aberrant hairy cell leukemia, Waldenstrom's macroglobulinemia, heavy chain disease (α heavy chain disease, γ heavy chain disease, μ chain disease), plasma cell myeloma, solitary plasmacytoma of bone, extracellular plasmacytoma of bone, mucosa-associated lymphoid tissue extranodal zone lymphoma (MALT lymphoma), lymph node fringeal lymphoma, pediatric lymph node fringeal lymphoma, pediatric follicular lymphoma, primary cutaneous follicular center lymphoma, T cell/tissue cell-rich large B cell lymphoma, primary DLBCL of the CNS, primary cutaneous DLBCL (leg type), EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, lymphomatoid granuloma, primary septal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, ALK Positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HHV8-related multicentric Castleman disease, primary effusion lymphoma: B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt's lymphoma, and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin's lymphoma. Other examples of B-cell proliferative disorders include, but are not limited to, multiple myeloma (MM); low-grade/follicular NHL; small lymphocytic (SL) NHL; intermediate-grade/follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-cleaved cell NHL; bulky NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Additional examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies, including B-cell lymphoma. More specific examples of such cancers include, but are not limited to, low-grade/follicular NHL; small lymphocytic (SL) NHL; intermediate-grade/follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-lytic cell NHL; bulky NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Solid tumors that may be suitable for treatment with bispecific anti-FcRH5/anti-CD3 antibodies according to the methods described herein include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric cancer (gastric/stomach cancer), including gastrointestinal cancer and gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urethral cancer, hepatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer (kidney/renal cancer), ... urethral cancer, hepatic cancer, bladder cancer, urethral cancer, hepatic cancer, breast cancer cancer), prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, melanoma, superficial spreading melanoma, malignant lentigo melanoma, acral lentigo melanoma, nodular melanoma, and abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), Meigs' syndrome, brain cancer, and head and neck cancer and related metastases. In certain embodiments, cancers suitable for treatment with the antibodies of the invention include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkin's lymphoma (NHL), renal cell carcinoma, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid, head and neck cancer, ovarian cancer and mesothelioma. E. Prior Anticancer Therapy

In some aspects, the subject has previously been treated for a B-cell proliferative disorder (e.g., MM). In some aspects, the subject has received at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more than fifteen lines of treatment for a B-cell proliferative disorder. In some aspects, the patient has received at least one prior line of treatment for a B-cell proliferative disorder, e.g., treatment was 2L+, 3L+, 4L+, 5L+, 6L+, 7L+, 8L+, 9L+, 10L+, 11L+, 12L+, 13L+, 14L+, or 15L+ treatment. In some aspects, the subject has received at least three prior lines of treatment for a B-cell proliferative disorder (e.g., MM), e.g., the patient has received 4L+ treatment, e.g., has received three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more than fifteen lines of treatment. In some aspects, the subject has relapsed or refractory (R/R) multiple myeloma (MM), e.g., a patient with R/R MM who is receiving 4L+ treatment for R/R MM.

In some embodiments, the prior line of therapy includes one or more of the following: a proteasome inhibitor (PI), such as bortezomib, carfilzomib, or ixazomib; an immunomodulatory drug (IMiD), such as thalidomide, lenalidomide, or pomalidomide; an autologous stem cell transplant (ASCT); an anti-CD38 agent, such as daratumumab (DARZALEX®) (U.S. Patent No. 7,829,673 and U.S. Publication No. 20160067205 A1), "MOR202" (U.S. Patent No. 8,263,746), isatuximab (SAR-650984); a CAR-T therapy; a therapy comprising a bispecific antibody; an anti-SLAMF7 therapy (e.g., anti-SLAMF7 In some embodiments, the prior line of therapy comprises an antibody-drug conjugate (ADC). In some embodiments, the prior line of therapy comprises a B-cell maturation antigen (BCMA) directed therapy, such as an antibody-drug conjugate targeting BCMA (BCMA-ADC).

In some aspects, prior lines of therapy include all three of a proteasome inhibitor (PI), an IMiD, and an anti-CD38 agent (e.g., daratumumab).

In some embodiments, the B-cell proliferative disorder (e.g., MM) is refractory to treatment with a line of therapy, such as refractory to treatment with one or more of the following: daratumumab, PI, IMiD, ASCT, anti-CD38 agent, CAR-T therapy, therapy including bispecific antibodies, anti-SLAMF7 therapy, nuclear export inhibitor, HDAC inhibitor, ADC or BCMA-directed therapy. In some embodiments, the B-cell proliferative disorder (e.g., MM) is refractory to treatment with daratumumab. F. Risk-Benefit Scenarios

Treatment with a bispecific anti-FcRH5/anti-CD3 antibody, the methods described herein can provide an improved benefit-risk profile for patients with cancer (e.g., multiple myeloma (MM), such as relapsed or refractory (R/R) MM), such as patients with R/R MM who are receiving 4L+ therapy for R/R MM. In some examples, treatment using the methods described herein that result in administration of a bispecific anti-FcRH5/anti-CD3 antibody in the context of a fractionated, dose-escalating dosing regimen can result in a reduction in adverse events (e.g., a reduction of 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more) following treatment with the bispecific anti-FcRH5/anti-CD3 antibody using a fractionated, dose-escalating dosing regimen of the invention relative to treatment with the bispecific anti-FcRH5/anti-CD3 antibody using a non-fractionated dosing regimen. or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more) or complete inhibition (100% reduction) of the drug, such adverse events as interleukin-driven toxicities (e.g., interleukin release syndrome (CRS)), infusion-related reactions (IRRs), macrophage activation syndrome (MAS), nervous system toxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and/or central nervous system (CNS) toxicity. G. Safety and Efficacy i. Safety

In some aspects, less than 15% (e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of patients treated with the methods described herein experience Grade 3 or 4 interleukin release syndrome (CRS). In some aspects, less than 5% of patients treated with the methods described herein experience Grade 3 or 4 CRS.

In some aspects, less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of patients treated using the methods described herein experience Grade 4+ CRS. In some aspects, less than 3% of patients treated using the methods described herein experience Grade 4+ CRS. In some aspects, no patients experience Grade 4+ CRS.

In some aspects, less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of patients treated using the methods described herein experience Grade 3 CRS. In some aspects, less than 5% of patients treated using the methods described herein experience Grade 3 CRS. In some aspects, no patients experience Grade 3 CRS.

In some aspects, Grade 2+ CRS events occur only during the first treatment cycle. In some aspects, Grade 2 CRS events occur only during the first treatment cycle. In some aspects, no Grade 2 CRS events occur.

In some aspects, less than 3% of patients treated using the methods described herein experience Grade 4+ CRS, less than 5% of patients treated using the methods described herein experience Grade 3 CRS, and Grade 2+ CRS events occur only during the first treatment cycle.

In some aspects, no Grade 3+ CRS events occur and Grade 2 CRS events occur only during the first treatment cycle.

In some cases, symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS) are limited to confusion, disorientation, and expressive aphasia and resolve with steroids.

In some aspects, less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of patients treated using the methods described herein experience an epileptic seizure or other grade 3+ neurologic adverse event (AE). In some aspects, less than 5% of patients experience an epileptic seizure or other grade 3+ neurologic adverse event. In some aspects, no patients experience an epileptic seizure or other grade 3+ neurologic adverse event.

In some aspects, all neurological symptoms are self-limited or resolve with steroids and/or tocilizumab therapy. ii. Efficacy

In some aspects, the overall response rate (ORR) of patients treated using the methods described herein is at least 25%, such as at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In some aspects, the ORR is at least 40%. In some aspects, the ORR is at least 45% (e.g., at least 45%, 45.5%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%, 49.5%, or 50%), at least 55%, or at least 65%. In some aspects, the ORR is at least 47.2%. In some aspects, the ORR is about 47.2%. In some aspects, the ORR is 75% or more. In some aspects, at least 1% of patients (e.g., at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51% In some aspects, the ORR is 40%-50%, and 10%-20% of patients have a CR or VGPR. In some aspects, the ORR is at least 40%, and at least 20% of patients have a CR or VGPR.

In some aspects, the mean duration of response (DoR) in patients treated using the methods described herein is at least two months, such as at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, or more. In some aspects, the mean DoR is at least four months. In some aspects, the mean DoR is at least five months. In some aspects, the mean DoR is at least seven months.

In some aspects, the six-month progression-free survival (PFS) rate for patients treated using the methods described herein is at least 10%, such as at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In some aspects, the six-month PFS rate is at least 25%. In some aspects, the six-month PFS rate is at least 40%. In some aspects, the six-month PFS rate is at least 55%. H. Methods of Administration

The method may involve administering the bispecific anti-FcRH5/anti-CD3 antibody (and/or any additional therapeutic agent) by any suitable means, including parenteral, intrapulmonary, and intranasal, and if local treatment is desired, including intralesional administration. Parenteral infusion includes intravenous, subcutaneous, intramuscular, intraarterial, and intraperitoneal routes of administration. In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody is administered by intravenous infusion. In other examples, the bispecific anti-FcRH5/anti-CD3 antibody is administered subcutaneously.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody administered by intravenous injection exhibits less toxicity (i.e., fewer undesirable effects) in a patient than the same bispecific anti-FcRH5/anti-CD3 antibody administered by subcutaneous injection, or vice versa.

In some aspects, the bispecific anti-FcRH5/anti-CD3 antibody is administered intravenously within 4 hours (± 15 minutes), e.g., the first dose of the antibody is administered within 4 hours ± 15 minutes.

In some aspects, the first and second doses of the antibody are administered intravenously with a median infusion time of less than four hours (e.g., less than three hours, less than two hours, or less than one hour), and the additional dose of the antibody is administered intravenously with a median infusion time of less than 120 minutes (e.g., less than 90 minutes, less than 60 minutes, or less than 30 minutes).

In some aspects, the first and second doses of the antibody are administered intravenously with a median infusion time of less than three hours, and the additional dose of the antibody is administered intravenously with a median infusion time of less than 90 minutes.

In some aspects, the first and second doses of the antibody are administered intravenously with a median infusion time of less than three hours, and the additional doses of the antibody are administered intravenously with a median infusion time of less than 60 minutes. In some aspects, the patient is hospitalized (e.g., hospitalized for 72 hours, 48 hours, 24 hours, or less than 24 hours) during one or more administrations of the anti-FcRH5/anti-CD3 antibody, such as C1D1 (Cycle 1, Dose 1) or C1D1 and C1D2 (Cycle 1, Dose 2). In some aspects, the patient is hospitalized for 72 hours after administration of C1D1 and C1D2. In some aspects, the patient is hospitalized for 24 hours after administration of C1D1 and C1D2. In some aspects, the patient is not hospitalized following administration of any dose of anti-FcRH5/anti-CD3 antibody.

For all methods described herein, the bispecific anti-FcRH5/anti-CD3 antibodies will be formulated, dosed, and administered in a manner consistent with good medical practice. In this context, factors to be considered include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the schedule of administration, and other factors known to medical practitioners. The bispecific anti-FcRH5/anti-CD3 antibodies need not be, but are optionally, formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of bispecific anti-FcRH5/anti-CD3 antibody present in the formulation, the type of disorder or treatment, and the other factors mentioned above. The bispecific anti-FcRH5/anti-CD3 antibody may be appropriately administered to the patient over a series of treatments.

Any dose disclosed herein can be administered SC. Any suitable method of SC administration can be used, including injection (e.g., bolus injection) or infusion. For example, a therapeutic agent (e.g., a bispecific anti-FcRH5/anti-CD3 antibody, an anti-CD38 antibody (e.g., daratumumab) or an IMiD (e.g., pomalidomide)) can be administered SC using a pump (e.g., a patch pump, a syringe pump (e.g., a syringe pump with an infusion set) or an infusion pump (e.g., an active infusion pump or a fixed infusion pump)), a prefilled syringe, a pen syringe, or an autoinjector.

For example, in any method or use disclosed herein, the therapeutic agent can be administered SC using a pump. In some examples, the pump can be used for the benefit of the patient or health care provider (HCP), improved safety data (e.g., in terms of the mechanism of action of the drug or the risk of IV-related infection), and/or for combined therapy. Any suitable pump can be used, such as a patch pump, a syringe pump (e.g., a syringe pump with an infusion set), an infusion pump (e.g., an active infusion pump or a fixed infusion pump), or a LVP. In a specific example, the therapeutic agent can be administered SC using a patch pump. In some examples, the pump (e.g., a patch pump) can be a wearable or surface pump (e.g., a wearable or surface patch pump), such as the Enable ENFUSE® surface infusion set or the West SMARTDOSE® wearable injector (e.g., the West SMARTDOSE® 10 wearable injector). In other examples, the therapeutic agent can be administered SC using a syringe pump (e.g., a syringe pump with an infusion set).

Other exemplary devices suitable for SC delivery include: syringes (including pre-filled syringes); injection devices (such as INJECT-EASE™ and GENJECT™ devices); infusion pumps (such as Accu-Chek™); injection pens (such as GENPEN™); needle-free devices (such as MEDDECTOR™ and BIOJECTOR™); autoinjectors, subcutaneous patch delivery systems, etc. I. Anti- FcRH5/ anti- CD3 bispecific antibodies

The methods described herein include administering a bispecific antibody that binds FcRH5 and CD3 (i.e., a bispecific anti-FcRH5/anti-CD3 antibody) to an individual having cancer (e.g., multiple myeloma, e.g., R/R multiple myeloma).

In some cases, any of the methods described herein may comprise administering a bispecific antibody comprising an anti-FcRH5 arm having a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising an amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising an amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising an amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 comprising an amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 comprising SGSYRYS (SEQ ID NO: 5); NO: 5); and (f) HVR-L3, which comprises the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). In some cases, the bispecific anti-FcRH5/anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, which comprise the sequences of SEQ ID NOs: 17 to 20, respectively; and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, which comprise the sequences of SEQ ID NOs: 21 to 24, respectively.

In some examples, any of the methods described herein may include administering a bispecific antibody comprising an anti-FcRH5 arm having a first binding domain comprising the following six HVRs: (a) HVR-H1 comprising an amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising an amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising an amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 comprising an amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 comprising an amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3 comprising an amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). In some cases, the bispecific anti-FcRH5/anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, comprising the sequences of SEQ ID NOs: 17 to 20, respectively; and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, comprising the sequences of SEQ ID NOs: 21 to 24, respectively.

In some cases, the bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 7, or the sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 8, or (c) a VH domain as in (a) and a VL domain as in (b). Thus, in some cases, the first binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 7; and a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

In some cases, any of the methods described herein may comprise administering a bispecific anti-FcRH5/anti-CD3 antibody comprising an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six HVRs selected from: (a) HVR-H1 comprising an amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising an amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising an amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising an amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3, which comprises the amino acid sequence of KQSFILRT (SEQ ID NO: 14). In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, which comprise the sequences of SEQ ID NOs: 25 to 28, respectively; and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, which comprise the sequences of SEQ ID NOs: 29 to 32, respectively.

In some examples, any of the methods described herein may comprise administering a bispecific anti-FcRH5/anti-CD3 antibody comprising an anti-CD3 arm having a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising an amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising an amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising an amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising an amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising an amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3 comprising In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, comprising the sequences of SEQ ID NOs: 25 to 28, respectively; and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, comprising the sequences of SEQ ID NOs: 29 to 32, respectively.

In some cases, the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising: (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 15, or the sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 16, or the sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b). Thus, in some cases, the second binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 15; and a VL domain comprising the amino acid sequence of SEQ ID NO: 16.

In some cases, any of the methods described herein may comprise administering a bispecific antibody comprising: (1) an anti-FcRH5 arm having a first binding domain comprising at least one, two, three, four, five, or six HVRs selected from: (a) HVR-H1 comprising an amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising an amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising an amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 comprising an amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 comprising SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3 comprising an amino acid sequence of QQHYSPPYT (SEQ ID NO: 6), and (2) an anti-CD3 arm having a second binding domain, the second binding domain comprising at least one, two, three, four, five or six HVRs selected from the following: (a) HVR-H1 comprising an amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising an amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising an amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising an amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

In some examples, any of the methods described herein may include administering a bispecific antibody comprising (1) an anti-FcRH5 arm having a first binding domain comprising the following six HVRs: (a) HVR-H1 comprising an amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising an amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising an amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 comprising an amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 comprising an amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3 comprising The invention relates to an anti-CD3 arm having an amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 having an amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 having an amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 having an amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 having an amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3 having an amino acid sequence of KQSFILRT (SEQ ID NO: 14). 14) of the amino acid sequence.

In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises: (1) at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, each comprising a sequence of SEQ ID NOs: 17 to 20; and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, each comprising a sequence of SEQ ID NOs: 21 to 24; and (2) at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, each comprising a sequence of SEQ ID NOs: 25 to 26. and/or at least one (e.g., 1, 2, 3 or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3 and FR-L4, which comprise the sequences of SEQ ID NOs: 29 to 32, respectively. In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises: (1) all four of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, which comprise the sequences of SEQ ID NOs: 17 to 20, respectively; and/or all four of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, which comprise the sequences of SEQ ID NOs: 21 to 24, respectively, and (2) all four of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, which comprise the sequences of SEQ ID NOs: 25 to 28, respectively; and/or all four of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, which comprise the sequences of SEQ ID NOs: 26 to 29, respectively. All four (e.g., 1, 2, 3 or 4) of the sequences described herein comprise the sequences of SEQ ID NOs: 29 to 32, respectively.

In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises: (1) an anti-FcRH5 arm comprising a first binding domain comprising: (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO:7, or the sequence of SEQ ID NO:7; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO:8, or the sequence of SEQ ID NO:8; or (c) an anti-FcRH5 arm comprising a first binding domain comprising: (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO:8, or the sequence of SEQ ID NO:8. (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 15, or the sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 16, or the sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b), and (2) an anti-CD3 arm comprising a second binding domain, the second binding domain comprising: (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 15, or the sequence of SEQ ID NO: 15; In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises: (1) a first binding domain comprising: a VH domain comprising the amino acid sequence of SEQ ID NO: 7; and a VL domain comprising the amino acid sequence of SEQ ID NO: 8, and (2) a second binding domain comprising: a VH domain comprising the amino acid sequence of SEQ ID NO: 15; and a VL domain comprising the amino acid sequence of SEQ ID NO: 16.

In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1), wherein (a) H1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 35, or the sequence of SEQ ID NO: 35; and/or (b) L1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 36, or the sequence of SEQ ID NO: 36.

In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1), wherein (a) H1 comprises the amino acid sequence of SEQ ID NO: 35; and/or (b) L1 comprises the amino acid sequence of SEQ ID NO: 36.

In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein (a) H2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 37, or the sequence of SEQ ID NO: 37; and/or (b) L2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 38, or the sequence of SEQ ID NO: 38.

In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein (a) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (b) L2 comprises the amino acid sequence of SEQ ID NO: 38.

In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein (a) H1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 35, or the sequence of SEQ ID NO: 35; (b) L1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 36. (c) H2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 37, or the sequence of SEQ ID NO: 37; and (d) L2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 38, or the sequence of SEQ ID NO: 38.

In some cases, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein (a) H1 comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody is ceftriaxone.

In some embodiments, the anti-FcRH5/anti-CD3 bispecific antibody according to any of the above embodiments may incorporate any of the features described in Sections 1-7 below, either alone or in combination. 1. Antibody Affinity

In certain embodiments, the dissociation constant ( _KD ) of an antibody provided herein is ≤ 1 μM, ≤ 250 nM, ≤ 100 nM, ≤ 15 nM, ≤ 10 nM, ≤ 6 nM, ≤ 4 nM, ≤ 2 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM or ≤ 0.001 nM (e.g., ^10-8 M or lower, e.g., ^10-8 M to ^10-13 M, e.g., ^10-9 M to ^10-13 M).

In one embodiment, _KD is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, the RIA is performed with a Fab form of the antibody of interest and its antigen. For example, the solution binding affinity of the Fab for the antigen is measured by equilibrating the Fab with a minimal concentration of ( ^125I )-labeled antigen in the presence of a titration series of unlabeled antigen and then capturing the bound antigen with an anti-Fab antibody coated disk (see, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999)). To determine the conditions for the assay, ^MICROTITER® multiwell plates (Thermo Scientific) were coated overnight with 5 μg/ml capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate, pH 9.6, and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23°C). In nonadsorbent plates (Nunc #269620), 100 pM or 26 pM [ ^125I ]-antigen was mixed with serial dilutions of the Fab of interest (e.g., consistent with the evaluation of anti-VEGF antibody Fab-12 described in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight; however, incubation may be continued for longer periods of time (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixture is transferred to a capture plate and incubated at room temperature (e.g., for 1 hour). The solution is then removed and the plate is washed eight times with 0.1% polysorbate 20 (TWEEN-20 ^® ) in PBS. When the plate is dry, scintillator (MICROSCINT-20 ^TM ; Packard) is added at 150 μl/well and counted for ten minutes using a TOPCOUNT ^TM Gamma Counter (Packard). Concentrations of each Fab that provide less than or equal to 20% of the maximum binding concentration are selected for use in competitive binding assays.

According to another example, _KD is measured using ^BIACORE® surface plasmon resonance measurement. For example, the measurement is performed using BIACORE® ^- 2000 or BIACORE® ^- 3000 (BIAcore, Inc., Piscataway, NJ) at 37°C with an immobilized antigen CM5 chip at about 10 reaction units (RU). In one embodiment, a carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) is activated with N -ethyl- N' -(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N -hydroxysuccinimide (NHS) according to the supplier's instructions. Antigen was diluted to 5 μg/ml (approximately 0.2 μM) in 10 mM sodium acetate (pH 4.8) and injected at a flow rate of 5 μl/min to obtain approximately 10 reaction units (RU) of coupled protein. After injection of antigen, 1 M ethanolamine was injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) were injected in PBS containing 0.05% polysorbate 20 (TWEEN-20 ^TM ) surfactant (PBST) at 37°C at a flow rate of approximately 25 μl/min. The association rate (k _on or _ka ) and dissociation rate (k _off or k _d ) were calculated by simultaneously fitting the association and dissociation sensorgrams using a simple one-to-one Langmuir binding model ( ^BIACORE® Evaluation Software Version 3.2). The equilibrium dissociation constant (K _D ) was calculated from the k _off /k _on ratio. See, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on-rate measured by the surface plasmon resonance assay described above exceeds 10 ⁶ M‑ ¹ s‑ ¹ , the on-rate can be determined using the fluorescence quenching technique, which measures the increase or decrease in fluorescence emission intensity (excitation wavelength = 295 nm; emission wavelength = 340 nm, bandpass 16 nm) of 20 nM antigen-antibody (Fab form) in PBS (pH 7.2) at 37°C in the presence of increasing concentrations of antigen. The fluorescence emission intensity can be measured in a spectrophotometer such as a stopped-flow equipped spectrophotometer (Aviv Instruments) or a 8000 Series SLM-AMINCO ^TM spectrophotometer (ThermoSpectronic) (with a stirring cuvette). 2. Antibody fragments

In certain embodiments, the antibodies provided herein (e.g., anti-FcRH5/anti-CD3 TDB) are antibody fragments that bind to FcRH5 and CD3. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab') ₂ , Fv and scFv fragments, as well as other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a general description of scFv fragments, see, for example, Pluckthün, The Pharmacology of Monoclonal Antibodies , Vol. 113, Rosenburg and Moore, eds., Springer-Verlag, New York, pp. 269-315 (1994); see also WO 93/16185; and U.S. Patent Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab') ₂ fragments that contain antigen-binding residues that rescue receptor binding and have increased in vivo half-life, see U.S. Patent No. 5,869,046.

Bifunctional antibodies are antibody fragments with two antigen binding sites (which may be bivalent or bispecific). See, e.g., EP 404,097; WO 1993/01161; Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad . Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003).

A single domain antibody is an antibody fragment that comprises all or part of the heavy chain variable domain of an antibody or all or part of the light chain variable domain of an antibody. In certain embodiments, the single domain antibody is a human single domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 B1 ).

Antibody fragments can be produced by a variety of techniques, including but not limited to proteolytic digestion of intact antibodies as disclosed herein and production in recombinant host cells (e.g., E. coli or bacteriophage). 3. Chimeric and humanized antibodies

In certain embodiments, the antibodies provided herein (e.g., anti-FcRH5/anti-CD3 TDB) are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al. Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In another example, a chimeric antibody is a "class-switched" antibody, in which the class or subclass has been changed compared to its parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

In certain embodiments, chimeric antibodies are humanized antibodies. Typically, non-human antibodies are humanized antibodies to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. In general, humanized antibodies comprise one or more variable domains, wherein HVR (or a portion thereof) is derived, for example, from a non-human antibody, and FR (or a portion thereof) is derived from a human antibody sequence. Humanized antibodies will optionally comprise at least a portion of a human constant region. In certain embodiments, some FR residues in humanized antibodies are substituted with corresponding residues from a non-human antibody (e.g., an antibody from which HVR residues are derived), for example, to restore or improve antibody specificity or affinity.

Humanized antibodies and methods for their preparation are summarized in, for example, Almagro and Fransson, Front.Biosci. 13:1619-1633 (2008), and further described in, for example, Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc.Nat'l Acad.Sci.USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al ., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol.Immunol. 28:489-498 (1991) (describing "surface remodeling");Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005); and Klimka et al., Br. J. Cancer , 83:252-260 (2000) (describing the "guided selection" method of FR shuffling).

Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best fit" method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subset of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al . J. Immunol. , 151:2623 (1993)); human mature (somatic cell mutation) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from a screened FR library (see, e.g., Baca et al. J. Immunol. 151:2347 (1993)). Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)). 4. Human antibodies

In certain embodiments, the antibodies provided herein (e.g., anti-FcRH5/anti-CD3 TDB) are human antibodies. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in: van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20: 450-459 (2008).

Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce complete human antibodies or complete antibodies with human variable regions in response to antigenic challenge. These animals typically contain all or part of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or are present extrachromosomally or randomly integrated into the chromosomes of the animal. In these transgenic mice, the endogenous immunoglobulin loci are usually inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23: 1117-1125 (2005). See also, for example: U.S. Patent Nos. 6,075,181 and 6,150,584 (describing XENOMOUSE ^™ technology); U.S. Patent No. 5,770,429 (describing HuMab® technology); U.S. Patent No. 7,041,870 (describing KM MOUSE® technology); and U.S. Patent Application Publication No. US 2007/0061900 (describing VelociMouse® technology). The human variable regions from intact antibodies generated by these animals can be further modified, for example, by combining with different human constant regions.

Human antibodies can also be prepared by fusion tumor-based methods. Human myeloma and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol. , 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications , pp. 51-63 (Marcel Dekker, Inc., New York., 1987); and Boerner et al., J. Immunol ., 147: 86 (1991).) Human antibodies produced by human B cell fusion tumor technology are also described in Li et al ., Proc. Natl. Acad. Sci. USA, 103: 3557-3562 (2006). Other methods include those described in, for example, U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies by hybridoma cell lines), and Ni, Xiandai Mianyixue , 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in the following references: Vollmers and Brandlein, Histology and Histopathology , 20(3):927-937 (2005); and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology , 27(3):185-91 (2005).

Human antibodies can also be produced by isolating variable domain sequences of Fv clones selected from human phage display libraries. These variable domain sequences can then be combined with the desired human constant domains. The following describes techniques for selecting human antibodies from antibody libraries. 5. Multispecific Antibodies

In any of the above aspects, the anti-FcRH5/anti-CD3 antibodies provided herein are multispecific antibodies, such as bispecific antibodies. Multispecific antibodies are antibodies (e.g., monoclonal antibodies) that have binding specificities to at least two different sites, such as antibodies that have binding specificities to cell surface antigens (e.g., tumor antigens, such as FcRH5) on immune effector cells and target cells other than immune effector cells. In certain aspects, one of the binding specificities is binding specificity to FcRH5, and the other specificity is for CD3.

In some aspects, the cell surface antigen can be expressed at a low copy number on the target cell. For example, in some aspects, the cell surface antigen is expressed or present at less than 35,000 copies per target cell. In some embodiments, the low copy number cell surface antigen is present at between 100 and 35,000 copies per target cell; between 100 and 30,000 copies per target cell; between 100 and 25,000 copies per target cell; between 100 and 20,000 copies per target cell; between 100 and 15,000 copies per target cell; between 100 and 10,000 copies per target cell; between 100 and 5,000 copies per target cell; between 100 and 2,000 copies per target cell; between 100 and 1,000 copies per target cell; between 100 and 500 copies per target cell. The copy number of a cell surface antigen can be determined, for example, using a standard Scatchard plot.

In some embodiments, bispecific antibodies can be used to localize cytotoxic agents to cells expressing tumor antigens (e.g., FcRH5). Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.

Techniques for preparing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/08829 and Traunecker et al., EMBO J. 10: 3655 (1991)), and "knob-in-hole" engineering (see, e.g., U.S. Patent No. 5,731,168). "Knob-in-hole" engineering of multispecific antibodies can be used to generate a first arm comprising a knob and a second arm comprising a hole into which the knob of the first arm can bind. In one embodiment, the knob of the multispecific antibody of the present invention can be an anti-CD3 arm. Alternatively, in one embodiment, the knob of the multispecific antibody of the present invention may be an anti-target/antigen arm. In one embodiment, the hole of the multispecific antibody of the present invention may be an anti-CD3 arm. Alternatively, in one embodiment, the hole of the multispecific antibody of the present invention may be an anti-target/antigen arm.

Multispecific antibodies can also be engineered using immunoglobulin crossover (also known as Fab domain exchange or CrossMab format) technology (see, e.g., WO 2009/080253; Schaefer et al ., Proc. Natl. Acad . Sci. USA, 108:11187-11192 (2011)). Multispecific antibodies can also be prepared by engineering electrostatic manipulation to prepare antibody Fc heterodimer molecules (WO 2009/089004A1); cross-linking two or more antibodies or fragments (see, e.g., U.S. Patent No. 4,676,980, and Brennan et al. , Science , 229: 81 (1985)); using leucine zipper to produce bispecific antibodies (see, e.g., Kostelny et al., J. Immunol. , 148(5):1547-1553 (1992)); using "bifunctional antibody" technology to prepare bispecific antibody fragments (see, e.g., Hollinger et al ., Proc. Natl. Acad. Sci. USA, 90:6444-6448). (1993)); and using single-chain Fv (sFv) dimers (see, e.g., Gruber et al. , J. Immunol. , 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., in Tutt et al., J. Immunol. 147:60 (1991).

Also included herein are engineered antibodies with three or more antigen binding sites, including "Octopus antibodies" (see, e.g., US 2006/0025576A1).

Bispecific antibodies or antigen-binding fragments thereof also include "dual-acting FAbs" or "DAFs," which contain an antigen-binding site that binds to CD3 and another different antigen (eg, a second biomolecule) (see, e.g., US 2008/0069820). 6. Antibody Variants

In some aspects, amino acid sequence variants of the antibodies described herein (e.g., bispecific anti-FcRH5/anti-CD3 antibodies) are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of the antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions may be performed to obtain the final construct, provided that the final construct has the desired characteristics, e.g., antigen binding characteristics. a. Substitution, insertion, and deletion variants

In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Target sites for substitution-induced mutagenesis include CDRs and FRs. Conservative substitutions are listed under the heading "Preferred Substitutions" in Table 4. More substantial changes are provided under the heading "Exemplary Substitutions" in Table 4 and are further described below with reference to amino acid side chain categories. Amino acid substitutions can be introduced into the antibodies of interest and the products screened for desired activity, e.g., retained/improved antigen binding characteristics, reduced immunogenicity, or improved ADCC or CDC. Table 4. Exemplary and Preferred Amino Acid Substitutions Original Residue Exemplary substitutions Better replacement Ala (A) Val; Leu; Ile Val Arg (R) Lys; Gln; Asn Lys Asn(N) Gln; His; Asp; Lys; Arg Gln Asp (D) Glu; Asn Glu Cys (C) Ser; Ala Ser Gln (Q) Asn; Glu Asn Glu (E) Asp; Gln Asp Gly (G) Ala Ala His (H) Asn; Gln; Lys; Arg Arg Ile (I) Leu; Val; Met; Ala; Phe; nor-leucine Leu Leu (L) nor-leucine; Ile; Val; Met; Ala; Phe Ile Lys (K) Arg; Gln; Asn Arg Met (M) Leu; Phe; Ile Leu Phe (F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Val; Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser Phe Val (V) Ile; Leu; Met; Phe; Ala; nor-leucine Leu

Amino acids can be grouped according to common side chain properties: (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basic: His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will entail exchanging a member of one of these classes for a member of another class.

One type of substitution variant involves replacing one or more highly variable region residues of a parent antibody (e.g., a humanized or human antibody). Typically, the resulting variant selected for further study will have modifications (e.g., improvements) and/or substantially retain certain biological properties of the parent antibody relative to the parent antibody (e.g., increased affinity, reduced immunogenicity). Exemplary substitution variants are affinity-matured antibodies, which can be conveniently produced, for example, using affinity maturation techniques based on phage display, such as those described herein. In short, one or more CDR residues are mutated, and the variant antibody is displayed on phage and screened for specific biological activity (e.g., binding affinity).

Changes (e.g., substitutions) can be made in the CDRs to improve antibody affinity. Such changes can be made in CDR "hotspots" (i.e., residues encoded by codons that undergo high frequency mutation during the in vivo maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)) and/or residues that contact the antigen), and the resulting variant VH or VL is tested for binding affinity. Affinity maturation is achieved by constructing and reselecting from secondary libraries, e.g., as described by Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variant genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide directed mutagenesis). A second library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method for introducing diversity is the CDR-directed approach, in which several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues that participate in antigen binding can be specifically identified by, for example, alanine scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.

In certain embodiments, substitutions, insertions or deletions may occur within one or more CDRs, as long as such modifications do not significantly reduce the ability of the antibody to bind to the antigen. For example, conservative changes (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity may be made in the CDRs. For example, such modifications may be outside of antigen contact residues in the CDRs. In certain embodiments of the variant VH and VL sequences provided above, each CDR remains unchanged or contains no more than one, two or three amino acid substitutions.

As described by Cunningham and Wells (1989) ( Science , 244:1081-1085), a useful method for identifying antibody residues or regions that may be induced is called "alanine scanning induction". In this method, residues or groups of target residues (e.g., charged residues such as Arg, Asp, His, Lys and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with the antigen is affected. More substitutions can be introduced at the amino acid position, indicating good functional sensitivity to the initial substitutions. Alternatively or additionally, the crystal structure of the antigen-antibody complex can be used to identify the contact points between the antibody and the antigen. These contact residues and neighboring residues can be targeted or eliminated as candidates for substitution. Variants can be screened to determine whether they contain the desired properties.

Amino acid sequence insertions include amino and/or carboxyl terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertion variants of the antibody molecule include enzymes fused to the N-terminus or C-terminus of the antibody (e.g., for ADEPT) or polypeptides that increase the serum half-life of the antibody. b. Glycosylation variants

In certain embodiments, the antibodies disclosed herein (e.g., bispecific anti-FcRH5/anti-CD3 antibodies) can be altered to increase or decrease the degree of glycosylation of the antibody. Addition or deletion of glycosylation sites in the anti-FcRH5 antibodies of the present invention can be conveniently achieved by altering the amino acid sequence to create or remove one or more glycosylation sites.

When the antibody comprises an Fc region, the carbohydrates attached thereto may be altered. Natural antibodies produced by mammalian cells typically comprise branched bitactinic oligosaccharides that are typically attached to Asn297 of the CH2 domain of the Fc region by an N-bond. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). Oligosaccharides may include a variety of carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc in the "stem" of the bitactinic oligosaccharide structure. In some embodiments, the oligosaccharides in the antibodies of the present invention may be modified to produce antibody variants having certain improved properties.

In one embodiment, antibody variants are provided that have carbohydrate structures lacking fucose linked (directly or indirectly) to the Fc region, such as bispecific anti-FcRH5/anti-CD3 antibody variants. For example, the fucose content in such antibodies may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose relative to the sum of all carbohydrate structures (e.g., complex, hybrid, and high mannose structures) linked to Asn 297 as measured by MALDI-TOF mass spectrometry is determined by calculating the average amount of fucose in the Asn297 carbohydrate chain, for example, as described in WO 2008/077546. Asn297 refers to the asparagine residue located near position 297 of the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300 due to minor sequence variations of the antibody. Such fucosylated variants may have improved ADCC function. See, for example, U.S. Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to "defucosylated" or "fucose-deficient" antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application No. US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially in Example 11); and knockout cell lines, such as CHO cells in which the α-1,6-fucosyltransferase gene FUT8 is knocked out (see, e.g., Yamane-Ohnuki et al . Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al. , Biotechnol. Bioeng ., 94(4):680-688 (2006); and WO2003/085107).

Further provided are antibody variants having bisected oligosaccharides, such as bispecific anti-FcRH5/anti-CD3 antibody variants, such as bispecific anti-FcRH5/anti-CD3 antibody variants, wherein a bi-antenna oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003/011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al. ). Antibody variants having at least one galactose residue attached to the Fc region on the oligosaccharide are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997/30087, WO 1998/58964 and WO 1999/22764. c. Fc region variants

In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody disclosed herein (e.g., a bispecific anti-FcRH5/anti-CD3 antibody) to generate an Fc region variant (see, e.g., 2012/0251531). The Fc region variant may comprise a human Fc region sequence ( e.g. , a human IgG1, IgG2, IgG3, or IgG4 Fc region) comprising an amino acid modification ( e.g. , substitution) at one or more amino acid positions.

In certain embodiments, the present invention contemplates an antibody variant that has some but not all effector functions, e.g., a bispecific anti-FcRH5/anti-CD3 antibody variant, making it a desirable candidate antibody for applications where the antibody half- life in vivo is important but certain effector functions (e.g., complement and ADCC) are unnecessary or detrimental. In vitro and/or in vivo cytotoxicity assays can be performed to confirm reduction/depletion of CDC and/or ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to ensure that the antibody lacks FcγR binding (and therefore may lack ADCC activity) but retains FcRn binding ability. Primary cells that mediate ADCC, NK cells, express only Fc(RIII, whereas monocytes express Fc(RI, Fc(RII), and Fc(RIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for assessing ADCC activity of target molecules are described in U.S. Patent No. 5,500,362 (see, e.g., Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)), and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)). 82:1499-1502 (1985); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays may be used (see, e.g., ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellTechnology, Inc. Mountain View, CA; and CytoTox ^96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model, such as Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody is unable to bind C1q and therefore lacks CDC activity. See, e.g., C1q and C3c binding ELISAs in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al . J. Immunol. Methods 202:163 (1996); Cragg, MS et al. Blood. 101:1045-1052 (2003); and Cragg, MS and MJ Glennie Blood. 103:2738-2743 (2004)). FcRn Binding and in vivo clearance/half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, SB et al. Int'l. Immunol. 18(12):1759-1769 (2006)).

Antibodies with reduced effector function include those in which one or more of the Fc region residues 238, 265, 269, 270, 297, 327, and 329 are substituted (U.S. Patent Nos. 6,737,056 and 8,219,149). Such Fc variants include Fc variants with two or more substitutions at amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc variant in which residues 265 and 297 are substituted with alanine (U.S. Patent Nos. 7,332,581 and 8,219,149).

In certain embodiments, the proline at position 329 of the wild-type human Fc region in the antibody is substituted with glycine or arginine or an amino acid residue that is large enough to disrupt the proline sandwich structure of proline within the Fc/Fcγ receptor interface formed between proline 329 of Fc and tryptophan residues Trp 87 and Trp 110 of FcgRIII (Sondermann et al. Nature. 406, 267-273, 2000). In certain embodiments, the antibody comprises at least one more amino acid substitution. In one example, more amino acids are substituted with S228P, E233P, L234A, L235A, L235E, N297A, N297D or P331S, and in another example, at least one more amino acid is substituted with L234A and L235A of IgG1 Fc region or S228P and L235E of human IgG4 Fc region (see, e.g., US 2012/0251531); and in another example, at least one more amino acid is substituted with L234A and L235A and P329G of human IgG1 Fc region.

Certain antibody variants with improved or reduced binding to FcRs have been described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004/056312 and Shields et al ., J. Biol. Chem. 9(2): 6591-6604 (2001).)

In certain embodiments, the antibody variant comprises an Fc region having one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333 and/or 334 (EU numbering of residues) of the Fc region.

In some embodiments, alterations are made in the Fc region resulting in altered (ie, improved or reduced) C1q binding and/or complement-dependent cytotoxicity (CDC), as described, for example, in U.S. Patent No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

Antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005/0014934A1 (Hinton et al.). Those antibodies comprise an Fc region having one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include those having substitutions at one or more of the Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (U.S. Pat. No. 7,371,826).

See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94/29351 for other examples of Fc region variants.

In some aspects, an antibody, e.g., an anti-FcRH5 and/or anti-CD3 antibody (e.g., a bispecific anti-FcRH5 antibody) comprises an Fc region comprising an N297G mutation (EU numbering). In some aspects, the anti-FcRH5 arm of the bispecific anti-FcRH5 antibody comprises an N297G mutation, and/or the anti-CD3 arm of the bispecific anti-FcRH5 antibody comprises an Fc region comprising an N297G mutation.

In some embodiments, an anti-FcRH5 antibody comprising an N297G mutation comprises an anti-FcRH5 arm comprising a first binding domain and an anti-CD3 arm comprising an N297G mutation, wherein the first binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-CD3 arm comprising the N297G mutation comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 11; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14.

In some embodiments, an anti-FcRH5 antibody comprising an N297G mutation comprises an anti-FcRH5 arm comprising a first binding domain comprising: (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 7, and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 8. In some embodiments, an anti-CD3 arm comprising an N297G mutation comprises: (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 15, and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

In some embodiments, the anti-FcRH5 antibody containing the N297G mutation comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from: a first CH1 (CH1 ₁ ) domain, a first CH2 (CH2 ₁ ) domain, a first CH3 (CH3 ₁ ) domain, a second CH1 (CH1 ₂ ) domain, a second CH2 (CH2 ₂ ) domain, and a second CH3 (CH3 ₂ ) domain. In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some embodiments, the CH3 ₁ and CH3 ₂ domains each comprise a protuberance or a cavity, and wherein the protuberance or the cavity in the CH3 ₁ domain is respectively located in the cavity or the protuberance of the CH3 ₂ domain. In some embodiments, the CH3 ₁ and CH3 ₂ domains are connected at the interface between the protuberance and the cavity. In some embodiments, the CH2 ₁ and CH2 ₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2 ₁ domain is located in the cavity or protuberance of the CH2 ₂ domain, respectively. In other examples, the CH2 ₁ and CH2 ₂ domains are connected at the interface between the protuberance and the cavity. In some embodiments, the anti-FcRH5 antibody is an IgG ₁ antibody.

In some embodiments, an anti-FcRH5 antibody comprising an N297G mutation comprises an anti-FcRH5 arm comprising a first binding domain and an anti-CD3 arm, the first binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 7, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8, wherein (a) the anti-FcRH5 arm comprises T366S, L368A, Y407V, and N297G amino acid substitution mutations (EU numbering), and (b) the anti-CD3 arm comprises T366W and N297G substitution mutations (EU numbering). In some embodiments, the anti-CD3 arm comprising T366W and N297G mutations comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 15, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 16.

In other embodiments, the anti-FcRH5 antibody comprising the N297G mutation comprises an anti-FcRH5 arm comprising a first binding domain and an anti-CD3 arm, the first binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 7, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8, wherein (a) the anti-FcRH5 arm comprises T366W and N297G substitution mutations (EU numbering), and (b) the anti-CD3 arm comprises T366S, L368A, Y407V and N297G substitution mutations (EU numbering). In some embodiments, the anti-CD3 arm comprising the N297G mutation comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 15, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 16. d. Cysteine engineered antibody variants

In certain embodiments, it may be desirable to create a cysteine engineered antibody, e.g., a "thioMAb," in which one or more residues of the antibody are substituted with a cysteine residue. In particular embodiments, the substituted residues occur at accessible sites of the antibody. By replacing those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and can be used to conjugate the antibody to other moieties (e.g., a drug moiety or a linker-drug moiety) to form an immunoconjugate, as further described herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the Fc region of the heavy chain. Cysteine engineered antibodies can be produced, for example, according to the methods described in U.S. Patent No. 7,521,541. e. Antibody Derivatives

In certain embodiments, the antibodies provided herein, such as the bispecific anti-FcRH5/anti-CD3 antibodies provided herein, can be further modified to include additional non-protein moieties that are known in the art and readily available. Moieties suitable for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-triazine, ethylene/maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers) and dextran or poly (n-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may have any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. In general, the amount and/or type of polymer used for derivatization can be determined based on considerations including, but not limited to, the specific properties or functions of the antibody to be improved, whether the antibody derivative will be used for treatment under a given condition, etc.

In another embodiment, a complex of an antibody and a non-protein portion is provided that can be selectively heated by exposure to radiation. In one embodiment, the non-protein portion is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation can be of any wavelength and includes, but is not limited to, a wavelength that does not damage normal cells but heats the non-protein portion to a temperature close to that at which the cells of the antibody-non-protein portion are killed. 7. Charged Region

In some embodiments, the binding domain that binds to FcRH5 or CD3 comprises a VH1 comprising a charged region (CR ₁ ) and a VL1 comprising a charged region (CR ₂ ), wherein CR ₁ in VH1 forms a charge pair with CR ₂ in VL1. In some embodiments, CR ₁ comprises a basic amino acid residue and CR ₂ comprises an acidic amino acid residue. In some embodiments, CR ₁ comprises a Q39K substitution mutation (Kabat numbering). In some embodiments, CR ₁ consists of a Q39K substitution mutation. In some embodiments, CR ₂ comprises a Q38E substitution mutation (Kabat numbering). In some embodiments, CR ₂ consists of a Q38E substitution mutation. In some embodiments, the second binding domain that binds CD3 comprises a VH2 comprising a charged region (CR ₃ ) and a VL2 comprising a charged region (CR ₄ ), wherein CR ₄ in VL2 forms a charge pair with CR ₃ in VH2. In some embodiments, CR ₄ comprises a basic amino acid residue and CR ₃ comprises an acidic amino acid residue. In some embodiments, CR ₄ comprises a Q38K substitution mutation (Kabat numbering). In some embodiments, CR ₄ consists of a Q38K substitution mutation. In some embodiments, CR ₃ comprises a Q39E substitution mutation (Kabat numbering). In some embodiments, CR ₃ consists of a Q39E substitution mutation. In some embodiments, the VL1 domain is connected to the light chain constant domain (CL1) domain, and VH1 is connected to the first heavy chain constant domain (CH1), wherein CL1 comprises a charged region ( _CR5 ), and CH1 comprises a charged region ( _CR6 ), and wherein _CR5 in CL1 forms a charge pair with _CR6 in _CH11 . In some embodiments, _CR5 comprises a basic amino acid residue, and _CR6 comprises an acidic residue. In some embodiments, _CR5 comprises a V133K substitution mutation (EU numbering). In some embodiments, _CR5 consists of a V133K substitution mutation. In some embodiments, _CR6 comprises an S183E substitution mutation (EU numbering). In some embodiments, _CR6 consists of an S183E substitution mutation.

In other aspects, the VL2 domain is connected to the CL domain (CL2), and VH2 is connected to the CH1 domain ( _CH12 ), wherein CL2 comprises a charged region ( _CR7 ), and _CH12 comprises a charged region ( _CR8 ), and wherein _CR8 in _CH12 forms a charge pair with _CR7 in CL2. In some aspects, _CR8 comprises a basic amino acid residue, and _CR7 comprises an acidic amino acid residue. In some aspects, _CR8 comprises an S183K substitution mutation (EU numbering). In some aspects, _CR8 consists of an S183K substitution mutation. In some aspects, _CR7 comprises a V133E substitution mutation (EU numbering). In some aspects, _CR7 consists of a V133E substitution mutation.

In other aspects, the VL2 domain is linked to the CL domain (CL2), and VH2 is linked to the CH1 domain (CH1 ₂ ), wherein (a) CL2 comprises one or more mutations at amino acid residues F116, L135, S174, S176 and/or T178 (EU numbering), and (b) CH1 ₂ comprises one or more mutations at amino acid residues A141, F170, S181, S183 and/or V185 (EU numbering). In some aspects, CL2 comprises one or more of the following substitution mutations: F116A, L135V, S174A, S176F and/or T178V. In some embodiments, CL2 comprises the following substitution mutations: F116A, L135V, S174A, S176F and T178V. In some embodiments, _CH12 comprises one or more of the following substitution mutations: A141I, F170S, S181M, S183A and/or V185A. In some embodiments, _CH12 comprises the following substitution mutations: A141I, F170S, S181M, S183A and V185A.

In other aspects, the binding domain that binds to FcRH5 or CD3 comprises a VH domain (VH1) comprising a charged region ( _CR1 ) and a VL domain (VL1) comprising a charged region ( _CR2 ), wherein _CR2 in _VL1 forms a charge pair with _CR1 in VH1. In some aspects, _CR2 comprises a basic amino acid residue and _CR1 comprises an acidic amino acid residue. In some aspects, _CR2 comprises a Q38K substitution mutation (Kabat numbering). In some aspects, _CR2 consists of a Q38K substitution mutation. In some aspects, _CR1 comprises a Q39E substitution mutation (Kabat numbering). In some aspects, _CR1 consists of a Q39E substitution mutation. In some embodiments, the second binding domain that binds CD3 comprises a VH domain (VH2) comprising a charged region (CR ₃ ) and a VL domain (VL2) comprising a charged region (CR ₄ ), wherein CR ₃ in VH2 forms a charge pair with CR ₄ in VL2. In some embodiments, CR ₃ comprises a basic amino acid residue and CR ₄ comprises an acidic amino acid residue. In some embodiments, CR ₃ comprises a Q39K substitution mutation (Kabat numbering). In some embodiments, CR ₃ consists of a Q39K substitution mutation. In some embodiments, CR ₄ comprises a Q38E substitution mutation (Kabat numbering). In some embodiments, CR ₄ consists of a Q38E substitution mutation. In some embodiments, the VL1 domain is connected to the light chain constant domain (CL1) and the VH1 domain is connected to the first heavy chain constant domain ( _CH11 ), wherein CL1 comprises a charged region ( _CR5 ) and _CH11 comprises a charged region _CR6 , and wherein _CR6 in _CH11 forms a charge pair with _CR5 in CL1. In some embodiments, _CR6 comprises a basic amino acid residue and _CR5 comprises an acidic amino acid residue. In some embodiments, _CR6 comprises an S183K substitution mutation (EU numbering). In some embodiments, _CR6 consists of an S183K substitution mutation. In some embodiments, _CR5 comprises a V133E substitution mutation (EU numbering). In some embodiments, _CR5 consists of a V133E substitution mutation.

In other aspects, the VL2 domain is connected to the CL domain (CL2) and VH2 is connected to the CH1 domain ( _CH12 ), wherein CL2 comprises a charged region ( _CR7 ) and _CH12 comprises a charged region ( _CR8 ), and wherein _CR7 in CL2 forms a charge pair with _CR8 in _CH12 . In some aspects, _CR7 comprises a basic amino acid residue and _CR8 comprises an acidic residue. In some aspects, _CR7 comprises a V133K substitution mutation (EU numbering). In some aspects, _CR7 consists of a V133K substitution mutation. In some aspects, _CR8 comprises an S183E substitution mutation (EU numbering). In some aspects, _CR8 consists of an S183E substitution mutation.

In other aspects, the VL2 domain is linked to the CL domain (CL2), and VH2 is linked to the CH1 domain (CH1 ₂ ), wherein (a) CL2 comprises one or more mutations at amino acid residues F116, L135, S174, S176 and/or T178 (EU numbering), and (b) CH1 ₂ comprises one or more mutations at amino acid residues A141, F170, S181, S183 and/or V185 (EU numbering). In some aspects, CL2 comprises one or more of the following substitution mutations: F116A, L135V, S174A, S176F and/or T178V. In some embodiments, CL2 comprises the following substitution mutations: F116A, L135V, S174A, S176F, and T178V. In some embodiments, _CH12 comprises one or more of the following substitution mutations: A141I, F170S, S181M, S183A, and/or V185A. In some embodiments, _CH12 comprises the following substitution mutations: A141I, F170S, S181M, S183A, and V185A. In some embodiments, the anti-FcRH5 antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH2 domain ( _CH21 ), a first CH3 domain ( _CH31 ), a second CH2 domain ( _CH22 ), and a second CH3 domain ( _CH32 ). In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some embodiments, CH3 ₁ and CH3 ₂ each include a protuberance (P ₁ ) or a cavity (C ₁ ), and wherein the P ₁ or C ₁ in the CH3 ₁ can be positioned in C ₁ or P ₁ in CH3 _2, respectively. In some embodiments, the CH3 ₁ and the CH3 ₂ are connected at the interface between P ₁ and C _1. In some embodiments, CH2 ₁ and CH2 ₂ each include (P ₂ ) or a cavity (C ₂ ), and wherein the P ₂ or C ₂ in the CH2 ₁ can be positioned in C ₂ or P ₂ in CH2 _2, respectively. In some embodiments, the CH2 ₁ and the CH2 ₂ are connected at the interface between P ₂ and C _2. J. Recombination Methods and Compositions

Antibodies disclosed herein, e.g., bispecific anti-FcRH5/anti-CD3 antibodies as disclosed herein, can be produced using recombinant methods and compositions, e.g., as described in U.S. Patent No. 4,816,567. In one embodiment, isolated nucleic acids encoding antibodies described herein, e.g., anti-FcRH5 antibodies (e.g., bispecific anti-FcRH5/anti-CD3 antibodies) are provided. Such nucleic acids encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light chain and/or heavy chain of the antibody). In one embodiment, isolated nucleic acids encoding anti-CD3 antibodies as described herein are provided. Such nucleic acids may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of an antibody (e.g., the light chain and/or the heavy chain of an antibody). In another embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In another embodiment, a host cell comprising such nucleic acids is provided. In this embodiment, the host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of an antibody and an amino acid sequence comprising the VH of an antibody, or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of an antibody and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of an antibody. In one embodiment, the host cell is a eukaryotic cell, e.g., a Chinese hamster ovary (CHO) cell or a lymphoid cell (e.g., a Y0, NS0, Sp20 cell). In one embodiment, a method for preparing an antibody (e.g., a bispecific anti-FcRH5/anti-CD3 antibody) is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding an antibody as provided above under conditions suitable for antibody expression, and optionally recovering the antibody from the host cell (or host cell culture medium).

For recombinant production of antibodies (e.g., bispecific anti-FcRH5/anti-CD3 antibodies), nucleic acids encoding the antibodies, such as those described above, are isolated and inserted into one or more vectors for further cloning and/or expression in host cells. Such nucleic acids can be readily isolated and sequenced by known methods (e.g., using oligonucleotide probes that specifically bind to genes encoding the heavy and light chains of the antibody). 1. Dual Cell Method for Making Bispecific Antibodies

In some aspects, antibodies as disclosed herein (e.g., bispecific anti-FcRH5/anti-CD3 antibodies) are made using a method comprising two host cell lines. In some aspects, a first arm of the antibody (e.g., a first arm comprising a hole region) is produced in a first host cell line, and a second arm of the antibody (e.g., a second arm comprising a knob region) is produced in a second host cell line. The arms of the antibody are purified from the host cell lines and assembled in vitro . 2. Single Cell Methods for Making Bispecific Antibodies

In some aspects, antibodies as disclosed herein (e.g., bispecific anti-FcRH5/anti-CD3 antibodies) are produced using a method comprising a single host cell line. In some aspects, a first arm of the antibody (e.g., a first arm comprising a hole region) and a second arm of the antibody (e.g., a second arm comprising a knob region) are produced and purified in a single host cell line. Preferably, the first arm and the second arm are expressed at comparable levels in the host cell, for example, both are expressed at high levels in the host cell. Similar expression levels increase the likelihood of efficient production of TDB and reduce the likelihood of mispairing of the light chain (LC) of the TDB component. The first arm and the second arm of the antibody may each further comprise an amino acid substitution mutation that introduces a charge pair, as described in Section II(I)(7) herein. Charge pairs promote the pairing of the heavy and light chain homologous pairs in each arm of the bispecific antibody, thereby minimizing mispairing. 3. Host cells

Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, particularly where glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol . 248 (BKC Lo (ed.), Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) After expression, the antibodies can be separated from the soluble portion of the bacterial cell paste and can be further purified.

In addition to prokaryotes, eukaryotic microorganisms (such as filamentous fungi or yeast) are also suitable hosts for the cloning or expression of antibody-encoding vectors, including fungal and yeast strains whose glycosylation pathways have been "humanized", resulting in the production of antibodies with partially or fully human glycosylation patterns. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

Suitable host cells for the expression of glycosylated antibodies also come from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. A number of bacilliform virus strains have been identified that can be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

Plant cell cultures can also be used as hosts. See , e.g., U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing the PLANTIBODIES ^™ technology for producing antibodies in transgenic plants).

Vertebrate cells can also be used as hosts. For example, mammalian cell strains adapted to growth in suspension can be used. Other examples of useful mammalian host cell strains are monkey kidney CV1 strain transformed by SV40 (COS-7); human embryonic kidney strains (such as, for example, 293 or 293 cells as described in Graham et al. , J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (such as, for example, TM4 cells as described in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells (as described, for example, in Mather et al. , Annals NY Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR ^- CHO cells (Urlaub et al. , Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines, such as Y0, NS0 For a review of certain mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol . 248 (BKC Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003). K. Immunoconjugates

The present invention also provides immunoconjugates comprising an antibody as disclosed herein (e.g., a bispecific anti-FcRH5/anti-CD3 antibody disclosed herein) conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitors, toxins (e.g., protein toxins, enzymatically active toxins, or fragments thereof of bacterial, fungal, plant, or animal origin), or radioactive isotopes.

In one embodiment, the immunoconjugate is an antibody-drug conjugate (ADC) in which the antibody is conjugated to one or more drugs, including but not limited to maytansinoids (see U.S. Pat. Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); auristatins, such as the monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Pat. No. 5,635,483); and 5,780,588, and 7,498,298); dolastatin; calicheamicin or its derivatives (see U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)); anthracyclines such as daunorubicin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vindesine; taxanes, such as docetaxel, paclitaxel, larotaxel, tesetaxel and ortataxel; trichothecenes; and CC1065.

In another embodiment, the immunoconjugate comprises an antibody as disclosed herein (e.g., a bispecific anti-FcRH5/anti-CD3 antibody as described herein) that binds to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, a non-binding active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modisin A chain, α-octacapsulosus, Aleurites fordii proteins, Dianthus dianthus proteins, Pokeweed proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcumin, crotonin, saponin, smilax glabra toxin, mitocin, restrictocin, phenomycin, enomycin, and trichothecenes.

In another embodiment, the immunoconjugate comprises an antibody as disclosed herein (e.g., a bispecific anti-FcRH5/anti-CD3 antibody described herein) conjugated to a radioactive atom to form a radioconjugate. A variety of radioisotopes can be used to produce radioconjugates. Examples include radioisotopes of At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and Lu. When a radioactive complex is used for detection, it may contain radioactive atoms such as tc99m or I123 for scintillation imaging studies, or spin labels such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron for nuclear magnetic resonance (NMR) imaging (also called magnetic resonance imaging, MRI).

The complex of the antibody and the cytotoxic agent can be prepared using a variety of bifunctional protein coupling agents, such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), imidosulfane (IT), imido acid The present invention also includes difunctional derivatives of esters (e.g., dimethyl adipate hydrochloride (HCl)), active esters (e.g., bissuccinimidyl suberate), aldehydes (e.g., glutaraldehyde), bis-azido compounds (e.g., bis-(p-azidobenzyl)hexanediamine), bis-diazonium derivatives (e.g., bis-(p-diazoniumbenzyl)-ethylenediamine), diisocyanates (e.g., toluene 2,6-diisocyanate), and bis-active fluorine compounds (e.g., 1,5-difluoro-2,4-dinitrobenzene). For example, ricin immunotoxins can be prepared as described in Vitetta et al., Science 238:1098 (1987). An exemplary chelator for conjugating radionucleotides to antibodies is carbon-14 labeled 1-isothiocyanate benzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA). See WO94/11026. The linker can be a "cleavable linker" that promotes release of the cytotoxic drug in cells. For example, an acid-labile linker, a peptidase-sensitive linker, a photolabile linker, a dimethyl linker, or a disulfide bond-containing linker can be used (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020).

The immunoconjugates or ADCs herein specifically contemplate, but are not limited to, such conjugates made with crosslinking agents, including but not limited to BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfonate)benzoate) commercially available (e.g., commercially available from Pierce Biotechnology, Inc. (Rockford, IL., USA). L. Pharmaceutical Compositions and Formulations

The pharmaceutical compositions and formulations of the therapeutic agents described herein (e.g., anti-FcRH5/anti-CD3 bispecific antibodies, anti-CD38 antibodies (e.g., daratumumab), IMiDs (e.g., pomalidomide and corticosteroids (e.g., dexamethasone or methylprednisolone)) can be prepared by mixing such therapeutic agents having the desired purity with one or more pharmaceutically acceptable carriers selected as appropriate ( Remington's Pharmaceutical Sciences 16th edition, Osol, A. (1980)), prepared as a lyophilized formulation or an aqueous solution. Pharmaceutically acceptable carriers are generally nontoxic to the recipient at the dosages and concentrations employed, and include, but are not limited to, buffers such as L-histidine/glacial acetic acid (e.g., pH 5.8), phosphates, citrates and other organic acids; tonic agents such as sucrose; stabilizers such as L-methionine; antioxidants including N-acetyl-DL-tryptophan, ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethylammonium chloride; benzalkonium chloride; benzylammonium chloride; phenol, butyl alcohol or benzyl alcohol; alkyl parabens such as methyl or propyl parabens; o-catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, aspartic acid, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrin; chelating agents (such as EDTA); sugars, such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter ions, such as sodium; metal complexes ( such as zinc protein complexes); and/or non-ionic surfactants, such as polysorbate 20 Or polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersions, such as soluble neutral active hyaluronidase glycoproteins (sHASEGP), such as human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 ( ^HYLENEX® , Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use (including rHuPH20) are described in U.S. Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, sHASEGP is conjugated to one or more additional glycosaminoglycans such as chondroitinase.

Exemplary lyophilized antibody formulations are described in U.S. Pat. No. 6,267,958. Water-soluble antibody formulations include those described in U.S. Pat. No. 6,171,586 and WO2006/044908, the latter formulations including a histidine-acetate buffer.

The formulations described herein may also contain more than one active ingredient suitable for the specific indication being treated, preferably, they are complementary active ingredients that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent (e.g., a chemotherapeutic agent, a cytotoxic agent, a growth inhibitor and/or an anti-hormonal agent, such as those described herein above). These active ingredients are suitably present in combination in an amount effective for the intended purpose.

The active ingredient can be embedded in microcapsules (e.g., hydroxymethylcellulose microcapsules or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively) prepared, for example, by coacervation techniques or by interfacial polymerization, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980).

Sustained release preparations may be prepared. Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules.

Formulations intended for intravenous administration are generally sterile. Sterility can be readily achieved, for example, by filtration through sterile filter membranes. III. Preparations

In another aspect of the invention, an article of manufacture containing materials useful for treating, preventing and/or diagnosing the above-mentioned conditions is provided. For example, an article of manufacture for use in any of the methods disclosed herein is provided. The article of manufacture includes a container and a label or drug instructions on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The container can be formed from a variety of materials such as glass or plastic. The container can contain a composition that is used by itself or in combination with another composition that is effective in treating, preventing and/or diagnosing the symptoms, and may have a sterile access port (for example, the container may be an intravenous solution bag or tube with a stopper that can be pierced by a hypodermic injection needle). At least one active agent in the composition may be an anti-FcRH5/anti-CD3 bispecific antibody described herein. In some examples, at least one active agent in the composition can be an anti-CD38 antibody (e.g., daratumumab), an IMiD (e.g., pomalidomide), a corticosteroid (e.g., dexamethasone or methylprednisolone), or a combination thereof.

In some aspects, the product comprises at least two containers (e.g., vials), the first container being filled with a composition suitable for C1D1 (cycle 1, dose 1), and the second container being filled with a composition suitable for C1D2 (cycle 1, dose 2). In some aspects, the product comprises at least three containers (e.g., vials), the first container being filled with a composition suitable for C1D1, the second container being filled with a composition suitable for C1D2, and the third container being filled with a composition suitable for C1D3. In some aspects, the containers (e.g., vials) may be of different sizes, for example, they may have a size proportional to the amount of the composition contained therein. Products comprising containers (e.g., vials) proportional to the expected dose may, for example, increase convenience, minimize waste, and/or increase cost-effectiveness. The label or package insert indicates that the composition is used to treat a selected condition (e.g., multiple myeloma (MM), such as relapsed or refractory MM, such as 4L+ treatment for R/R MM), and further includes information related to at least one of the dosing regimens described herein. In addition, the article of manufacture may include (a) a first container containing a composition, wherein the composition comprises an anti-FcRH5/anti-CD3 bispecific antibody described herein; and (b) a second container containing a composition, wherein the composition comprises another cytotoxic agent or other therapeutic agent. Alternatively or additionally, the article of manufacture may further include a second (or third) container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. From a commercial and user perspective, it may further include other materials, including other buffers, diluents, filters, needles and syringes. IV. Examples

The following are examples of the methods of the present invention. It should be understood that various other embodiments can be practiced in light of the general description provided above, and such examples are not intended to limit the scope of the patent application. Example 1. An open-label, multicenter, phase Ib trial evaluating the safety, pharmacokinetics, and activity of ceftriaxone in patients with relapsed or refractory (RR) multiple myeloma (MM)

This case describes GO42552 (CAMMA 1; ClinicalTrials.gov identifier: NCT04910568), a Phase Ib, multicenter, open-label study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ceftriaxone monotherapy (Arm A), ceftriaxone plus pomalidomide and dexamethasone (Pd; Arm B), or ceftriaxone plus daratumumab and dexamethasone (Dd; Arm C) in patients with relapsed or refractory (R/R) multiple myeloma (MM). Patients undergo a screening period, treatment period, and follow-up. The study will initially enroll approximately 184 patients at approximately 35 sites worldwide. This study consists of three arms: ● Arm A (ceftizumab): This arm evaluates the safety, efficacy, pharmacokinetics, and immunogenicity of ceftriaxone monotherapy using a modified weekly schedule. This arm consists of a safety run-in cohort (A1S cohort) and an expansion cohort (A1E cohort). If the safety data from cohorts A1S and A1E are acceptable, an additional expansion cohort may be opened to further evaluate dosing regimens at higher target doses. ● Arm B (ceftizumab + Pd): The evaluation of the combination of ceftriaxone and Pd uses the following dosing schedule: ceftriaxone, administered every 2 weeks (Q2W) until cycle 6, and every 4 weeks (Q4W) thereafter (hereafter referred to as the Q2W/Q4W schedule). This evaluation begins with an initial safety run-in cohort, B1S. Prior to opening the expansion cohort, an additional safety run-in cohort (e.g., B2S) of ceftriaxone with a lower target dose level may be opened to further understand the safety and tolerability of the treatment combination. Based on observed clinical data (e.g., efficacy, safety, tolerability, and PK) from the safety run-in cohort in Arm B and ceftriaxone monotherapy data from Study GO39775 (e.g., ClinicalTrials.gov identifier: NCT03275103), two target dose levels (DL) of ceftriaxone, DL1 and DL-1, were selected for randomization in the expansion cohort to determine the recommended phase 2 dose (RP2D) of ceftriaxone in combination with Pd. The number of randomized patients at each dose level will be approximately 30 patients. ● Arm C (ceftizumab + Dd): The evaluation of the combination of ceftriaxone and Dd uses a ceftriaxone dosing schedule of Q3W until cycle 8, followed by Q4W dosing (hereinafter referred to as the Q3W/Q4W schedule). This evaluation begins with an initial safety run-in cohort, C1S. Similar to the Arm B study design, an additional safety run-in cohort of ceftriaxone with a lower target dose level may be opened prior to opening the expansion cohort to further understand the safety and tolerability of the treatment combination. Based on observed clinical data (e.g., efficacy, safety, tolerability, and PK) from the safety run-in cohort and ceftriaxone monotherapy data from Study GO39775, two target dose levels of ceftriaxone, DL1 and DL-1, were selected for randomization in the expansion cohort to determine the RP2D of ceftriaxone in combination with Dd. The number of randomized patients at each dose level will be approximately 30 patients. A. Objectives and Endpoints

The primary objectives of this study were to evaluate the safety and tolerability of ceftriaxone monotherapy and ceftriaxone in combination with Pd and with Dd on a modified weekly schedule.

In this treatment protocol, "study treatment" refers to the treatment assigned to patients as part of this study: ceftriaxone monotherapy, ceftriaxone plus Pd, or ceftriaxone plus Dd. The specific objectives and corresponding endpoints of the study are summarized in Table 5 below. Table 5. Objectives and Endpoints Main research objectives Corresponding endpoint ● Determine the RP2D for ceftazidimeb plus Pd and ceftazidimeb plus Dd The RP2D will be selected based on the following endpoints assessed in the overall benefit-risk profile: ● Characterization of adverse events and tolerability ● Preliminary assessment of activity ● Characterization of pharmacokinetic PK Main safety goals Corresponding endpoint ● To evaluate the safety and tolerability of single-agent ceftriaxone in a modified weekly schedule● To evaluate the safety and tolerability of ceftriaxone plus Pd● To evaluate the safety and tolerability of ceftriaxone plus Dd ● The incidence, nature, and severity of adverse events, with severity determined according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and the American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Scale ● Tolerability assessed by the incidence of dose interruptions, dose reductions, dose intensity, and treatment discontinuation Active Target Corresponding endpoint ● Preliminary evaluation of the activity of single-agent ceftriaxone in the modified weekly schedule ● Preliminary evaluation of the activity of ceftriaxone plus Pd ● Preliminary evaluation of the activity of ceftriaxone plus Dd NOTE: If assessed by the investigator, the International Myeloma Working Group (IMWG) criteria will be used for the following endpoints. ● Objective response rate (ORR), defined as the proportion of patients with a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR)● CR/sCR rate, defined as the proportion of patients who achieved a CR or sCR● VGPR or better rate, defined as the proportion of patients who achieved a VGPR or better● Progression-free survival (PFS), defined as the time from the start of study treatment to the first date of disease progression or death from any cause, whichever occurs first● Duration of response (DOR; for patients who achieve a PR or better), defined as the number of days from the date of the first documented PR or better response to the first date of disease progression or death from any cause, whichever occurs first● Time to first response (for patients who achieve a PR =The following table contains the following data: ● Time to best response (for patients who achieved a PR or better), defined as the time from the start of study treatment to the first PR or better response ● Time to best response (for patients who achieved a PR or better response), defined as the time from the start of study treatment to the deepest response ● Minimal residual disease (MRD) negativity as defined by next-generation sequencing (NGS) of bone marrow aspirate at the time of suspected CR ● Overall survival (OS), defined as the time from the start of study treatment to death from any cause. Pharmacokinetic targets Corresponding endpoint ● Characterize the pharmacokinetics of ceftriaxone when given as a single agent and when given in combination with Pd and with Dd ● Serum concentrations of ceftriaxone at specified time points ● Pharmacokinetic parameters of ceftriaxone (if applicable) ● Confirm the exposure of pomalidomide and daratumumab when given in combination with ceftriaxone ● Serum concentrations of pomalidomide and daratumumab at designated time points Exploratory pharmacokinetic targets Corresponding endpoint ● Assess potential relationships between selected covariates and exposure to ceftriaxone ● Relationship between selected covariates and serum concentrations or PK parameters of ceftriaxone Immunogenicity Target The corresponding end point ● To assess the immune response to ceftriaxone when given as a single agent and when given in combination with Pd and with Dd ● The incidence of anti-drug antibodies (ADA) to ceftriaxone at baseline and during the study. Exploratory Immunogenicity Targets Corresponding endpoint ● To evaluate the potential impact on ADA of ceftriaxone ● To evaluate the immunogenicity of daratumumab administered subcutaneously (SC) when combined with ceftriaxone ● Relationship between ADA status for ceftriaxone and safety, PK, or activity endpoints ● Incidence of ADA for daratumumab at baseline and during the study Additional exploratory goals Corresponding endpoint ● Preliminary evaluation of the efficacy of tocilizumab (ACTEMRA®/ROACTEMRA®) in improving symptoms of cytokine release syndrome (CRS) after administration of study treatment ● Outcomes of CRS after administration of tocilizumab ● To evaluate the tolerability of ceftriaxone monotherapy and combination with Pd/Dd from the patient's perspective ● Presence, frequency, severity, and/or degree of interference with daily functioning of symptomatic treatment toxicity as assessed using PRO-CTCAE ● Change from baseline in symptomatic treatment toxicity as assessed using PRO-CTCAE ● Evaluate the efficacy of ceftriaxone monotherapy and combination with Pd/Dd from the patient's perspective ● Change from baseline in pain, fatigue, disease symptoms, and general health/quality of life as assessed using the European Organisation for Research and Treatment of Cancer (EORTC) database ADA = antidrug antibodies; ASTCT = American Society for Transplantation and Cellular Therapy; CR = complete response; CRS = cytokine release syndrome; Dd = daratumumab and dexamethasone; DOR = duration of response; EORTC = European Organization for Research and Treatment of Cancer; IMWG = International Myeloma Working Group; MM = multiple myeloma; MRD = minimal residual disease; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0; NGS = next-generation sequencing; ORR = objective response rate; OS = overall survival; Pd = pomalidomide and dexamethasone; PFS = progression-free survival; PK = pharmacokinetics; PR = partial response; PRO-CTCAE = NCI Common Terminology Criteria for Patient-Reported Outcomes Adverse Events; RP2D = recommended phase II dose; R/R = relapsed or refractory; sCR = strict complete response; VGPR = very good partial response. B. Research Design

This is a Phase Ib, multicenter, open-label study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ceftriaxone monotherapy (Arm A), ceftriaxone plus Pd (Arm B), or ceftriaxone plus Dd (Arm C) in patients with R/R MM. Patients undergo a screening period, treatment period, and follow-up. The study will enroll approximately 184 patients at approximately 35 sites worldwide. This study consists of three arms: 1. Arm A (Ceftriaxone): This arm evaluates the safety, efficacy pharmacokinetics, and immunogenicity of ceftriaxone monotherapy using a modified weekly schedule. This arm consists of a safety run-in cohort (A1S cohort) and an expansion cohort (A1E cohort). If the safety data from Cohort A1S and Cohort A1E are acceptable, an additional expansion cohort may be established to further evaluate this dosing regimen using a higher target dose. 2. Arm B (Ceftuzumab + Pd): This arm compares the safety and tolerability of the combination of two dose levels of Ceftuzumab and Pd and evaluates the efficacy, pharmacokinetics, and immunogenicity of the combination. This arm consists of a safety run-in phase and an expansion phase, with two cohorts evaluating two target dose levels of Ceftuzumab. The initial safety run-in cohort will be Cohort B1S. In addition, a lower active target dose level of ceftriaxone in combination with Pd was evaluated in arm B2S to further understand the safety and tolerability of the treatment combination before opening the expansion cohort. Based on the observed efficacy, safety, and PK data from the safety run-in cohort in arm B, two target dose levels of ceftriaxone (DL1 and DL-1) were selected for randomization in the expansion cohort to determine the RP2D of the combination of ceftriaxone and Pd. 3. Arm C (ceftazidimeb + Dd): This arm compares the safety and tolerability of the combination of ceftriaxone and Dd at two dose levels and evaluates the efficacy, pharmacokinetics, and immunogenicity of the combination. This arm will consist of a safety run-in phase and an expansion phase, with two cohorts evaluating two target dose levels of ceftriaxone. The initial safety run-in cohort will be cohort C1S. Similar to the study design of Arm B, an additional safety run-in cohort with a lower target dose level of ceftriaxone may be opened prior to opening the expansion cohort to further understand the safety and tolerability of the treatment combination. Based on observed efficacy, safety, and PK data from the safety run-in cohort in Arm C, two target dose levels of ceftriaxone (DL1 and DL-1) will be selected for randomization in the expansion cohort to determine the RP2D of the combination of ceftriaxone and Dd.

As described in this article, for treatment-induced CRS, tocilizumab was administered as needed. i. Study design of arm B ( ceftizumab + Pd)

The evaluation of the combination of ceftriaxone and Pd (Arm B) uses the following dosing schedule: ceftriaxone, administered every 2 weeks (Q2W) until cycle 6, and then every 4 weeks (Q4W) thereafter (hereinafter referred to as the Q2W/Q4W schedule). This evaluation begins with an initial safety run-in cohort, B1S. Additional safety run-in cohorts (e.g., B2S, etc.) of ceftriaxone with lower target dose levels may be opened before opening expansion cohorts to further understand the safety and tolerability of the treatment combination. Based on observed clinical data (e.g., efficacy, safety, tolerability, and PK) from the safety run-in cohort in Arm B and ceftriaxone monotherapy data from Study GO39775, two target dose levels of ceftriaxone, DL1 and DL-1, were selected for randomization in the expansion cohort to determine the RP2D of the combination of ceftriaxone and Pd. The number of randomized patients at each dose level will be approximately 30 patients. See Figure 1 for the Arm B scheme. ii. Arm C ( Ceftriaxone + Dd) Study Design

The evaluation of the combination of ceftriaxone and Dd (Arm C) uses a ceftriaxone dosing schedule of Q3W until Cycle 8 and Q4W thereafter (hereinafter referred to as the Q3W/Q4W schedule). This evaluation begins with an initial safety run-in cohort, C1S. Similar to the Arm B study design, an additional safety run-in cohort of ceftriaxone with a lower target dose level may be opened prior to opening the expansion cohort to further understand the safety and tolerability of the treatment combination. Based on observed clinical data from the safety run-in cohort and ceftriaxone monotherapy data from study GO39775, two target dose levels of ceftriaxone, DL1 and DL-1, were selected for randomization in the expansion cohort to determine the RP2D of the combination of ceftriaxone and Dd. The number of randomized patients at each dose level will be approximately 30 patients. See Figure 2 for the C-arm scheme. iii. Screening

The screening period lasted up to 28 days for each safety run-in group and expansion group in all treatment arms. Patients who did not meet the criteria for participation in this study (screen failure) were eligible for two rescreening opportunities (three screenings per patient) at the discretion of the investigator. Patients did not need to resign the consent form unless there was new information that might be relevant to the patient's willingness to participate (e.g., additional procedures, new or updated risk information). The investigator maintained a record of the reasons for screening failure in the screening log. iv. Safety Monitoring

All patients were closely monitored for adverse events throughout the study and followed for 90 days after the last dose of study treatment for Arm A (ceftazidimeb monotherapy) and Arm B (ceftazidimeb + Pd) and for 102 days after the last dose of study treatment for Arm C (ceftazidimeb + Dd). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0), except for CRS, which was graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading for cytokine release syndrome (Lee et al., Biol Blood Marrow Transplant, 25:625-638, 2019). v. Single agent ceftriaxone ( Arm A )  

Ceftriaxone is administered in 28-day cycles based on a “modified weekly” schedule as follows: ● For the first two cycles, Ceftriaxone is administered weekly, starting with a single escalating dose on Day 1 of Cycle 1, followed by weekly infusions of the target dose until Cycle 2. ● For Cycles 3 to 6, the target dose is administered every 14 days on Days 1 and 15 of each cycle. ● For Cycles 7 to 13, the target dose is administered every 28 days on Day 1 of each cycle.

The modified weekly schedule with escalating doses and target doses for ceftriaxone monotherapy in Group A1S and Group A1E are shown in Figure 3 .

Patients with acceptable toxicity and evidence of clinical benefit may continue to receive ceftriaxone for a maximum of 13 cycles or until disease progression (as determined by the investigator based on IMWG criteria) or unacceptable toxicity, whichever occurs first. Additional details on managing partial/missed doses are found in this document.

Patients who completed 13 cycles of study treatment continued to have tumor assessments and additional assessments until disease progression, initiation of new anticancer therapy, or withdrawal from study participation, whichever occurred first. In addition, patients were eligible to receive retreatment with ceftriaxone if they met all retreatment criteria specified herein. vi. Ceftriaxone Single-Agent Safety Run-in ( Cohort A1S)

A single-dose safety run-in (Cohort A1S) will assess the safety, tolerability, and pharmacokinetics of ceftriaxone using a modified weekly schedule prior to an open-label expansion (Cohort A1E). Doses of ceftriaxone in the safety run-in (Cohort A1S) will be 3.6 mg and 90 mg for escalating and target doses, respectively.

Approximately 6 patients will be enrolled during the safety run-in period, as long as the stopping rule is not met before all 6 patients are enrolled. Enrollment of safety run-in patients is staggered so that the first 3 patients have their respective Cycle 1 Day 1 treatments administered at least 7 days apart, followed by subsequent patients having their respective Cycle 1 Day 1 treatments administered at least 3 days apart to allow for evaluation of any severe and unexpected acute or subacute drug or infusion-related toxicities.

In Cohort A1S, the safety assessment window is from Cycle 1 Day 1 to the end of Cycle 1. If the safety run-in cohort requires repeated escalation doses, the safety assessment window is extended by 1 week (e.g., from Cycle 1 Day 1 to Cycle 2 Day 7) to cover a minimum of 3 weeks of target dose infusion. Patients who discontinue the study prior to completion of the safety assessment window for reasons other than experiencing a treatment-related adverse event that meets the stopping criteria described herein are considered unevaluable and will be replaced by another patient at the same dose level. Patients who miss any dose during the safety assessment window for reasons other than the criteria mentioned above will also be replaced.

Frequent safety monitoring will be conducted to guide possible early cessation of enrollment in the event of unacceptable toxicity. vii. Ceftizumab Single-Agent Expansion ( Cohort A1E)

The single-agent expansion of this study (Cohort A1E) was designed to obtain additional safety, tolerability, and PK data of ceftriaxone monotherapy.

To further mitigate the risk of potential unexpected adverse events, if an expansion is allowed, patients participating in the expansion should be monitored frequently for safety.

Similar to safety lead-in, stopping rules due to toxicity were implemented. In the absence of safety issues that would preclude further enrollment, enrollment in the study may continue while safety analyses are ongoing.

If the benefit-risk profile of Cohort A1S and Cohort A1E is acceptable, additional expansion cohorts (A2E, etc.) may be opened and a higher target dose of ceftriaxone may be used to further evaluate the dosing regimen. If a higher target dose is chosen for evaluation, the first 6 patients will each be treated strictly 72 hours apart to closely monitor safety events. If the stopping rules are not met and no other safety issues arise, recruitment in the expansion cohorts may continue while safety analysis is ongoing. viii. Combination of ceftriaxone and Pd using a Q2W/Q4W ceftriaxone dosing schedule ( Arm B )

Study treatment with ceftriaxone in combination with Pd was administered in 28-day treatment cycles using a Q2W/Q4W ceftriaxone dosing schedule as follows (see Figure 4 for examples): ● Initially, patients were treated with ceftriaxone monotherapy during a 21-day period before starting pomalidomide treatment. This phase is called the ceftriaxone pre-phase. Combination treatment with ceftriaxone and pomalidomide was initiated in Cycle 1 following this ceftriaxone pre-phase. ● During the pre-phase, a double escalation schedule of ceftriaxone was evaluated, with the 1st escalation dose and the 2nd escalation dose administered on Day 1 and Day 8, respectively, and the first target dose administered on Day 15. ● For Cycles 1 to 6 (e.g., first 6 cycles of combination therapy), ceftriaxone was administered once Q2W on Day 1 and Day 15 of each 28-day cycle. ● For Cycle 7 onwards, ceftriaxone was administered Q4W on Day 1 of each cycle at the target dose. ● Starting in Cycle 1, pomalidomide was administered orally on Days 1 to 21 of each 28-day cycle. ○ For Cohort B1S, pomalidomide was administered at a dose of 4 mg. ○ For Cohort B2S and subsequent cohorts, starting in Cycle 2, the pomalidomide dose was escalated from 2 mg to 4 mg if the following parameters were met: ■ Absolute neutrophil count (ANC) ≥ 1000/µl (ANC ≥ 1000/mm ³ ) and platelets ≥ 75,000 /µl (75,000/mm ³ ). ■ If an AE occurs after dose escalation, pomalidomide dose adjustments should follow the guidance described herein. ● Dexamethasone was administered orally at a dose of 20 mg once weekly on Days 1, 8, 15, and 22 during the first 4 combination study treatment cycles, except that during the first two cycles, on the days of ceftriaxone infusion, if ceftriaxone was premedicated, the oral dose of dexamethasone was omitted. Instead, during the pre-phase and Cycle 1, 20 mg of dexamethasone was administered intravenously (IV) 1 hour before ceftriaxone administration as a premedication. During Cycle 2 and thereafter, dexamethasone IV 20 mg was administered as a premedication for ceftriaxone if the patient experienced CRS on the previous ceftriaxone dose. At the discretion of the investigator, once-weekly dexamethasone may be discontinued starting from Cycle 5. Once-weekly dexamethasone (20 mg) may be restarted at any time if deemed appropriate by the investigator.

The Q2W/Q4W ceftriaxone dosing schedule is applicable to both the safety introduction group and the randomized expansion group.

For Arm B, patients with acceptable toxicity and evidence of clinical benefit may continue to receive the combination of ceftriaxone and Pd (if applicable) until disease progression (as determined by the investigator based on IMWG criteria) or unacceptable toxicity, whichever occurs first. ix. Combination of ceftriaxone and Dd using a Q3W/Q4W ceftriaxone dosing schedule ( Arm C )

Study treatment with ceftriaxone and Dd will be administered in 21-day cycles in Cycles 1 to 8 and 28-day cycles starting in Cycle 9 as follows: ● Patients start ceftriaxone and daratumumab combination treatment during Cycle 1. ● For Cycle 1, the first escalating dose and second escalating dose of ceftriaxone are administered on Days 2 and 9, followed by the first target dose on Day 16 (double escalation dosing every week). If a response related to the administration of daratumumab on Day 1 of Cycle 1 needs to be resumed, ceftriaxone on Day 2 of Cycle 1 can be delayed to Day 3 of Cycle 1; subsequent doses of ceftriaxone and daratumumab can continue as planned. ● For Cycles 2 to 8, administer a target dose of ceftriaxone on Day 1 of each cycle every 21 days. ● For Cycle 9 onwards, administer a target dose of ceftriaxone on Day 1 of each cycle every 28 days. ● For Cycles 1 to 3, daratumumab was administered subcutaneously (SC) at a dose of 1800 mg once weekly on Days 1, 8, and 15 of Cycle 1, Days 1, 8, and 15 of Cycle 2, and Days 1, 8, and 15 of Cycle 3. The first three doses of daratumumab SC (e.g., Day 1, Day 8, and Day 15 of Cycle 1) were staggered so that their respective injections were given 1 day before the ceftriaxone infusion (e.g., Day 2, Day 9, and Day 16 of Cycle 1, respectively) to minimize the risk of infusion-related reactions (IRRs). ● For Cycles 4 to 8, 1800 mg of daratumumab SC was administered on Day 1 of each cycle every 21 days. ● Starting from Cycle 9, 1800 mg of daratumumab SC was administered on Day 1 of each cycle every 28 days. ● Dexamethasone is administered at a dose of 20 mg as follows: – Cycle 1: as an IV or oral premedication to daratumumab on Days 1, 8, and 15 (e.g., see Table 6). • Dexamethasone is administered IV as a postmedication to daratumumab and as a premedication to ceftriaxone on Days 2, 9, and 16. – Cycle 2: as an IV premedication to ceftriaxone and daratumumab on Day 1, and as an IV or oral premedication to daratumumab on Days 8 and 15. – Cycles 3-4: as an IV or oral premedication to daratumumab. Dexamethasone premedication with ceftriaxone is optional. If given as premedication with both ceftriaxone and daratumumab, dexamethasone should be administered IV. – Cycle 5 onwards: Dexamethasone may be withdrawn at the investigator’s discretion. Dexamethasone (20 mg on Day 1 of each cycle) may be resumed at any time if deemed appropriate by the investigator.

The Q3W/Q4W ceftriaxone dosing schedule is applicable to both safety introduction and expansion.

For Arm C, patients with acceptable toxicity and evidence of clinical benefit could continue to receive the combination of ceftriaxone and Dd (if applicable) until disease progression (as determined by the investigator according to IMWG criteria) or unacceptable toxicity, whichever occurred first. Table 6. Dosing and Schedule of Study Treatments in Cycle 1 for Arm C Using Double Ascending Dosing Schedule Cycle 1 ​ Daratumumab Ceftriaxone Dexamethasone Week 1 Day 1 1800 mg SC 20 mg orally or IV Day 2 0.3 mg IV 20 mg IV Week 2 Day 8 1800 mg 20 mg orally or IV Day 9 3.6 mg IV 20 mg IV Week 3 Day 15 1800 mg SC 20 mg orally or IV Day 16 160 mg IV 20 mg IV PO = oral (eg, by mouth) x. Ceftizumab combination safety introduction initial cohort

The safety and tolerability of the combination of ceftriaxone plus Pd (Q2W/Q4W schedule; cohort B1S) and ceftriaxone plus Dd (Q3W/Q4W schedule; cohort C1S) were evaluated prior to selecting ceftriaxone target dose level 1 (DL1) and lower dose level-1 (DL-1) for expansion of Arm B and Arm C, respectively.

In the safety run-in group B1S of ceftriaxone + Pd, the planned doses of ceftriaxone are as follows: ● First escalating dose: 0.3 mg ● Second escalating dose: 3.6 mg ● Target dose (from pre-stage): 132 mg

In the safety run-in cohort C1S (e.g., ceftriaxone + Dd), the planned ceftriaxone doses were as follows: ● First escalating dose: 0.3 mg ● Second escalating dose: 3.6 mg ● Target dose (from cycle 1): 160 mg

Each safety run-in group will enroll approximately 6 patients, as long as the stopping rule is not met before 6 patients are enrolled.

Enrollment of patients in each safety run-in group was staggered so that the first 3 patients were each administered their first study treatment dose at least 7 days apart, followed by subsequent patients each administered their first study treatment dose at least 3 days apart to allow for evaluation of any serious and unexpected acute or subacute drug- or infusion-related toxicities.

The safety assessment window for Arm B was from Pre-Phase Day 1 to the end of Cycle 1, and the safety assessment window for Arm C was from Cycle 1 Day 1 to the end of Cycle 1. If repeated dose escalation was required, the safety assessment window was extended to cover a minimum of two infusions of the target dose of ceftriaxone given in combination with Pd or Dd. In each group, patients who discontinued the study before completion of the safety assessment window for reasons other than experiencing a treatment-related adverse event that met the stopping criteria described herein were considered unevaluable and replaced by other patients at the same dose level. Patients who missed any dose of ceftriaxone or ≥ 5 doses of pomalidomide (eg, Arm B) or ≥ 2 doses of daratumumab SC (eg, Arm C) during the safety assessment window for reasons other than the criteria mentioned above were also substituted.

Frequent safety monitoring will be conducted to guide possible early cessation of enrollment in the event of unacceptable toxicity. xi. Safety Run-in of Ceftizumab Combination: Lower Dose Level Group

Prior to selecting ceftriaxone DL1 and DL-1 target doses for expansion of Arm B and Arm C, respectively, additional combination safety run-in cohorts could be opened to further assess the safety and tolerability of the combinations of ceftriaxone plus Pd (e.g., B2S) and ceftriaxone plus Dd (e.g., C2S).

In the safety run-in group B2S of ceftriaxone + Pd, the planned dose of ceftriaxone is: ● First escalating dose: 0.3 mg ● Second escalating dose: 3.6 mg ● Target dose (from pre-stage): 90 mg

Enrollment of patients in the other safety run-in groups, except B1S and C1S, will not be delayed as lower doses of study treatment will be tested. xii. Ceftriaxone Combination Expansion:

Expansion cohorts of the combinations of ceftriaxone plus Pd (e.g., Arm B) and ceftriaxone plus Dd (e.g., Arm C) evaluated and optimized the ceftriaxone dosing schedule for each respective combination.

Based on observed clinical data (e.g., efficacy, safety, tolerability, and PK) from the safety run-in cohort and ceftriaxone monotherapy data from Study GO39775, two target dose levels of ceftriaxone were selected for randomized expansion to determine the RP2D for each individual arm. After selecting the two dose levels selected for expansion, enrolled patients were randomized 1:1 between the two dose level expansions (DL1 and DL-1) in each individual arm (e.g., see Figures 1 and 2 ). The number of randomized patients for each dose level will be approximately 30 patients.

Similar to the safety run-in, stopping rules due to toxicity have been implemented as described herein. In the absence of safety issues that would preclude further enrollment, enrollment in the study may continue while analysis is ongoing.

See Figures 1 and 2 for the study plans for Arm B (ceftazidimeb + Pd) and Arm C (ceftazidimeb + Dd). xiii. Alternative escalation schedule for Arm B and Arm C: Option to change to split escalation schedule

Based on emerging data from ceftriaxone studies GO39775, CO43476 (e.g., ClinicalTrials.gov identifier: NCT05535244), and GO42552 (e.g., ClinicalTrials.gov identifier: NCT04910568), split-escalation dosing schedules can be implemented to optimize escalation dosing regimens.

For example, if the investigator decides to modify the dosing schedule of ceftriaxone in the pre-phase in Arm B from weekly double escalation dosing to split escalation dosing, ceftriaxone will be administered as a split escalation regimen of 0.3 mg on Day 1 and 3.3 mg on Day 2 (if no CRS event occurs after the initial dose on Day 1). For doses administered 1 day apart, a minimum of 20 hours will be required from the end of the previous dose of ceftriaxone infusion to the start of the next dose. If a patient experiences CRS after a 0.3 mg escalation dose on Day 1 of the pre-phase, the next dose (e.g., 3.3 mg) will be delivered on Day 2, Day 3, or Day 4 after complete resolution of CRS. Additional dose delays may be necessary depending on the clinical presentation of the CRS event. If a fractionated escalation schedule was used during the ceftazidime pre-phase, use only the treatment schedule described herein (e.g., see Figure 6 ) for activity scheduling. ● During the pre-phase, the first target dose was administered on Day 8 ● Beginning with Cycle 1, the treatment schedule for fractionated escalation and weekly double escalation is the same.

In another example, if the investigator decides to modify the dosing schedule of ceftriaxone in Cycle 1 of the C-arm from weekly double escalation dosing to split escalation dosing, the first two doses on Day 9 (e.g., 0.3 mg) and Day 10 (e.g., 3.3 mg) are escalating doses, and the first target dose (e.g., 160 mg) is administered on Day 16. For doses administered 1 day apart, a minimum of 20 hours will be required from the end of the previous dose of ceftriaxone infusion to the start of the next dose. If a patient experiences CRS after the escalation dose on Day 9, the next dose will be delivered on Day 10, Day 11, or Day 12 after complete resolution of the CRS. Additional dose delays may be necessary depending on the clinical presentation of the CRS event. If split-escalation dosing is used during Cycle 1, use only the treatment schedule described herein (e.g., see Figure 7 ) for the activity schedule of ceftriaxone. ● Dexamethasone is administered as follows: ○ Cycle 1 (e.g., see Table 7 ): 20 mg IV or oral premedication with daratumumab on Days 1, 8, and 15. Administer dexamethasone IV or orally at a dose of 4 mg as a postmedication with daratumumab on Days 2 and 3. ● On Day 9, administer dexamethasone at a dose of 15 mg IV as both a post-daratumumab and a pre-dose of ceftriaxone. ● On Day 16, administer dexamethasone at a dose of 20 mg IV as both a post-daratumumab and a pre-dose of ceftriaxone. ○ Cycle 2: Administer dexamethasone at a dose of 20 mg IV as a pre-drug of ceftriaxone and daratumumab on Day 1, and as an IV or oral pre-drug of daratumumab on Days 8 and 15. ○ Cycles 3 to 4: Administer dexamethasone at a dose of 20 mg IV or oral pre-drug of daratumumab. Dexamethasone premedication with ceftriaxone is optional. If given as a premedication with both ceftriaxone and daratumumab, dexamethasone should be administered IV. ○ Cycle 5 onwards: Dexamethasone may be withdrawn at the investigator’s discretion. Dexamethasone (20 mg on Day 1 of each cycle) may be resumed at any time if deemed appropriate by the investigator. Table 7. Exemplary Dosing and Schedule of Study Treatments in Cycle 1 for the C- Arm Using a Split-Ascend Dosing Schedule for Ceftriaxone Cycle 1 ​ Daratumumab Ceftriaxone Dexamethasone Week 1 Day 1 1800 mg SC 20 mg orally or IV Day 2 0.3 mg IV 4 mg PO or IV Day 3 4 mg PO or IV Week 2 Day 8 1800 mg SC 20 mg orally or IV Day 9 3.3 mg IV 15 mg IV Week 3 Day 15 1800 mg SC 20 mg orally or IV Day 16 160 mg IV 20 mg IV PO = oral (e.g., by mouth) xiv. Stopping criteria for safety

Frequent safety monitoring was performed to guide possible early stopping of enrollment in the event of unacceptable toxicity.

Enrollment in the group evaluating a specific study treatment (e.g., ceftriaxone monotherapy (Arm A); ceftriaxone plus Pd (Arm B); or ceftriaxone plus Dd (Arm C)) was suspended if any of the following occurred at any time: ● One patient at safety run-in, or 15% of the patients overall (a minimum of 12 patients evaluated for a specific study treatment and dosing schedule) experienced any of the following during the safety assessment window for the evaluation of the specific study treatment and dosing schedule: – Any Grade 5 adverse event not considered by the investigator to be attributable to another clearly identifiable cause. – Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 Upper limit of normal (ULN) (if baseline is within normal limits) or baseline (if baseline is > ULN) and total bilirubin > 2 Any condition above ULN, except: ○ AST or ALT >3 ULN and total bilirubin>2 ULN, with no individual laboratory value exceeding Grade 3 in the setting of CRS that resolves to ≤ Grade 1 in <7 days. – Any Grade 4 neurologic adverse event. – Any Grade 4 immune-mediated event, including CRS. ○ Immune-mediated events as determined by the Investigator may include colitis, pneumonitis, or other events not attributable to another clearly identifiable cause. – Any Grade ≥3 seizure. – Any Grade ≥3 neurologic adverse event (other than a seizure) that does not resolve within 72 hours with appropriate management and is not considered by the Investigator to be attributable to another clearly identifiable cause. ● Two patients in the safety run-in, or 20% of the patients overall (out of a minimum of 12 patients evaluated for a specific study treatment and dosing schedule) during the safety assessment window for evaluation of a specific study treatment and dosing schedule, experience any of the following: – Any Grade 4 adverse event not considered by the investigator to be attributable to another clearly identifiable cause, with the following exceptions: ○ Grade 4 lymphocytopenia, which may occur based on the mechanism of action of the study treatment. ○ Grade 4 neutropenia that is not associated with elevated temperature (oral or tympanic temperature ≥100.4°F (38°C)) and improves to ≤ Grade 2 (or to ≥80% of baseline ANC, whichever is lower) within 1 week with or without granulocyte colony-stimulating factor (G-CSF). ○ Grade 4 thrombocytopenia that improves to ≤ Grade 2 (or to ≥80% of baseline platelet count, whichever is lower) within 1 week, is not associated with bleeding, and does not require transfusion. ○ Grade 4 AST or ALT that occurs in the setting of CRS and resolves to ≤ Grade 1 or baseline in <7 days. ○ Grade 4 hypophosphatemia. – Any Grade ≥3 CRS.

Enrollment in the study may be suspended if any of the following occurs at any time: ● One patient in any safety run-in group or 10% of the patients overall (minimum 12 patients enrolled in the study) experience any Grade ≥ 4 confirmed HLH/MAS during the safety assessment window for that group. ● One patient in any safety run-in group or 10% of the patients overall (minimum 12 patients enrolled in the study) experience any Grade 5 adverse event during the safety assessment window for that group that is not considered by the investigator to be attributable to another clearly identifiable cause. xv. Rules for continued dosing after Cycle 1

After Cycle 1, patients are eligible to receive additional study treatment if they demonstrate sustained clinical benefit and acceptable toxicity as follows: 1) Sustained clinical benefit: Patients must have no clinical signs or symptoms of disease progression (patients will be clinically assessed for disease progression based on IMWG criteria on Day 1 of each cycle). 2) Acceptable toxicity: Patients who experience an event meeting any of the stopping criteria described herein should discontinue study treatment and should not be retreated. All other study treatment-related adverse events from the previous study treatment infusion must resolve to ≤ Grade 1 or baseline before the next infusion. Exceptions may be permitted based on continued overall clinical benefit after careful assessment by the study investigator and discussion of the benefit-risk with the patient. Any delay in treatment for an adverse event not attributable to study treatment may not require discontinuation of study treatment. Dose reductions or reduced dosing frequency of ceftriaxone may be permitted if it is determined that clinical benefit can be maintained according to the rules described herein. xvi. Re-treatment with ceftriaxone ( Arm A only )

Patients who initially respond to ceftriaxone but subsequently develop recurrent or progressive disease after completion of treatment or after dosing delays greater than 28 days due to non-treatment-related events may benefit from additional cycles of ceftriaxone. Patients are eligible for retreatment with ceftriaxone as described below. Patients enrolled in retreatment were initiated on a modified weekly schedule during Cycle 1 and could continue treatment until disease progression (as determined by the investigator based on IMWG criteria) or unacceptable toxicity (whichever occurred first), provided that the following criteria were met: ● Met relevant eligibility criteria at the time of reinitiating ceftriaxone treatment, with the following exceptions: – Prior therapy with ceftriaxone was permitted. – The investigator and patient wished to continue retreatment with ceftriaxone, despite any new therapy being appropriate and available for the treatment of MM. – Repeat serologic testing to confirm HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV) status is not required unless clinically indicated. Repeat EBV, CMV, and HHV-6 PCR is mandatory. – Immune-related adverse events that were manageable and reversible on initial ceftriaxone therapy are permitted and do not constitute an exclusion history of autoimmune disease. – Radiation therapy is permitted within 4 weeks of retreatment with ceftriaxone. ● Patients must have a documented objective response (e.g., CR, VGPR, or PR) at the end of initial ceftriaxone treatment and at at least one post-treatment tumor assessment after the end of treatment, per IMWG criteria. ● Patients without biochemical disease progression (defined as an increase in a single paraprotein in the absence of organ dysfunction and clinical symptoms) but with clear evidence of recurrent disease (i.e., the development of new bone lesions or scleroblastomas or an increase in the size of existing bone lesions or scleroblastomas) are permitted. ● Patients must not have experienced an event that meets the stopping criteria as described herein. ● Patients who experience grade 2 or 3 adverse events considered to be treatment-related during initial treatment must have had these toxicities resolved to ≤ grade 1. ● Patients will require hospitalization after the first retreatment infusion of ceftriaxone. ● No intervening systemic anticancer therapy was administered between completion of initial ceftriaxone therapy and restart of ceftriaxone therapy. ● Investigators must discuss with patients any standard of care options that may exist in favor of restarting ceftriaxone. Patients must consent to deferring such options and to biopsy recurrent or progressive tumors if clinically feasible.

Patients who have received less than 13 cycles of treatment but meet all retreatment criteria may be eligible for retreatment.

Prior to retreatment with ceftriaxone, repeated bone marrow biopsies and aspirates must be obtained to assess FcRH5 expression status and the tumor microenvironment.

The above retreatment rules apply to both safety-introduced and expanded patients.

Patients who discontinue retreatment may continue tumor assessments and additional evaluations until disease progression, initiation of new anticancer therapy, or withdrawal from study participation, whichever occurs first. xvii. Study End and Study Duration

The end of this study is defined as the date when the last patient has the last visit (LPLV) or the date when the last patient receives the last data point required for statistical analysis or protocol-defined safety monitoring, whichever occurs later. The total duration of the study is expected to be 4 years from the screening of the first patient to the end of the study. xviii. Basis of Patient Population

In study GO39775, preliminary activity of ceftriaxone has been demonstrated in patients with R/R MM, a similar population to that selected for the study described in this example (GO42552). This study enrolled patients with a history of R/R MM who met the inclusion and exclusion criteria as described herein.

Confirmation of FcRH5 expression will not be required during the eligibility screening prior to enrollment, but will be assessed retrospectively based on the following: ● FcRH5 is a cell surface antigen whose expression is restricted to cells of the B lineage, including plasma cells. It is expressed at 100% prevalence in MM samples tested to date. ● Non-clinical studies have shown that ceftriaxone is broadly active in cytotoxicity in multiple human MM cell lines and primary human MM plasma cells with a broad range of FcRH5 expression, including cells with minimal FcRH5 expression, suggesting that even extremely low FcRH5 expression may be sufficient for clinical activity. ● Preliminary findings from Study GO39775 suggest that patients were able to achieve an objective response to treatment with ceftriaxone regardless of baseline FcRH5 expression as measured to date (CCOD March 2021). Clinical responses were observed in patients with the lowest FcRH5 expression. xix. Rationale for the dosing schedule of ceftriaxone

The primary objectives of the study described in this example were to determine the RP2D of ceftriaxone with Pd and ceftriaxone with Dd and to assess the safety and tolerability of ceftriaxone monotherapy and ceftriaxone in combination with Pd and Dd on a modified weekly schedule.

Initially, the study evaluated a modified weekly dosing and dosing schedule of single-agent ceftriaxone (ie, Arm A). The study further evaluated the combination of ceftriaxone with Pd in 28-day cycles (i.e., Arm B) (after an initial pre-phase of ceftriaxone alone), in which ceftriaxone was administered Q2W for the first 24 weeks (Cycles 1 to 6) and then Q4W thereafter (Cycle 7 onwards); and the combination of ceftriaxone with Dd (i.e., Arm C), in which ceftriaxone was administered Q3W for the first 24 weeks (excluding the ramp-up period in Cycle 1) (21-day cycles; Cycles 2 to 8) and then Q4W thereafter (28-day cycles; Cycle 9 onwards).

In Arm B and Arm C, randomization between two different dose levels of ceftriaxone in the expansion cohort was used to understand the choice of RP2D for ceftriaxone when given in combination with Pd or Dd. xx. Rationale for ceftriaxone dose in Arm A cohort

In Study GO39775, ceftriaxone is being evaluated using a Q3W dosing schedule with 21-day cycles; this schedule is difficult to align with potential combination therapy agents because combination therapy agents are given weekly in the first few cycles and less frequently in later cycles. Arm A evaluates a modified dosing schedule that may help align with the dosing schedule of potential combination therapy partners. The modified weekly schedule for ceftriaxone monotherapy in the A1S and A1E arms of this study (GO42552) was a 28-day cycle with ceftriaxone administered QW for the first 8 weeks (Cycles 1 to 2), followed by Q2W for 16 weeks (Cycles 3 to 6), and then Q4W (Cycles 7 to 13).

For escalating doses and target doses, the doses of single escalating ceftriaxone monotherapy in the A1S and A1E groups are 3.6 mg and 90 mg, respectively. These doses were selected based on clinical, safety, and PK data from the ongoing first-in-human (FIH) study GO39775 (described below). If the benefit-risk profile of the A1S and A1E groups is assessed to be favorable based on emerging data from study GO39775, a higher target dose may be selected to optimize the regimen, as further described below.

As of CCOD March 2022, data were available from 145 safety-evaluable patients treated with ceftriaxone in Study GO39775. Of the 207 patients, 111 received single escalation dosing (Arms A and C; 0.05-3.6 mg escalation dose and 0.15-252 mg target dose), 68 received double escalation dosing (Arms B and D; 0.3-7.2 mg escalation dose and 60-160 mg target dose), and 28 received single escalation dosing in the setting of tocilizumab pretreatment (Arm E; 3.6 mg escalation dose and 90 mg target dose).

Overall, 79 safety-evaluable patients have received ≥ 3.6 mg/90 mg in the single-ascending dosing regimen. In the double-ascending dosing regimen, 59 safety-evaluable patients have received doses of 1.2 mg/3.6 mg/60 mg, 0.3 mg/3.6 mg/90 mg, 0.6/3.6/90 mg, and 0.3 mg/3.6 mg/160 mg. Escalating doses (3.6 mg): ● In Study GO39775, single-ascending doses of 0.05 mg up to 3.6 mg were evaluated. Although the maximum tolerated dose (MTD) was not reached with escalating doses on Cycle 1 Day 1, the escalation dose was not escalated beyond 3.6 mg because CRS was observed in the majority of patients. ● The 3.6 mg dose was effective in limiting the frequency of overall CRS and ≥ Grade 2 CRS at higher target doses of up to 252 mg on Cycle 1 Day 8 in the single escalation regimen or up to 160 mg on Cycle 1 Day 15 in the dual escalation regimen. ● Based on exposure-safety analysis from Study GO39775, the incidence/severity of CRS events correlated with the maximum concentration ( _Cmax ) following an initial dose of ceftriaxone on Day 1 of Cycle 1 over the tested dose range of 0.05-3.6 mg, a significant class effect for the bispecific T-cell engaging antibody. Target Dose (90 mg): ● In Study GO39775, the MTD for the target dose had not been reached as of CCOD March 2022. ● No significant exposure-response (ER) relationship was observed for CRS and other non-CRS adverse events within the target dose range tested, including ≥ Grade 3 cytopenias, ≥ Grade 2 IRR, ≥ Grade 2 infections, ≥ Grade 2 rash, and any combined ≥ Grade 3 adverse events. ● Significant improvements in ORR and > VGPR rates were observed within the target dose range tested (0.15-252 mg).

To support the selection of a modified weekly schedule of 3.6 mg/90 mg for both the A1S and A1E cohorts, a previously developed population pharmacokinetic (popPK) model was implemented to predict exposure for this dosing schedule. Based on popPK model predictions (e.g., see Tables 8 and 9), the median exposure (C _max and AUC) of ceftriaxone in the first two cycles of the proposed 3.6 mg/90 mg dosing in this study was predicted to be 39% lower in C _max and similar in AUC _D0-56 compared to the exposure tested in Study GO39775 with ceftriaxone at a 3.6 mg/198 mg Q3W regimen. Given that higher C _max was tested compared to the predicted C _max at the 3.6 mg/90 mg dose in this modified weekly schedule and that the MTD was not reached with the 3.6 mg/198 mg Q3W regimen, the risk of C _max- related adverse events is not expected to be increased at the recommended starting dose in this study. In addition, given the absence of exposure-safety relationships related to the ceftriaxone target dose exposure (e.g., AUC, C _max , and C _trough ) and CRS/non-CRS adverse events in Study GO39775, the expected safety profiles at the starting dose for the A1S and A1E groups in this study are acceptable. Target Dose: Subsequent Cohorts

If the benefit-risk profile of the 90 mg ceftriaxone dose assessed once weekly in the A1S and A1E groups is favorable, then other groups (e.g., A2S, A2E, etc.) could be opened to evaluate higher target doses of ceftriaxone compared to 90 mg. The proposed target doses above 90 mg do not exceed previously tested exposures that were eliminated in Study GO39775 using the same approach as described above for target dose selection in the A1S and A1E groups. Table 8. Comparison of Population PK Model Predicted Medians (90% CI) for PK Exposure Indicators Following Q3W Single Increment Versus Modified Weekly Schedule Single incremental dose/target dose plan AUC _D0-56 (µg/mL × day) Median 90% CI Maximum C _max ^a (µg/mL) Median 90% CI Maximum C _min ^b (µg/mL) Median 90% CI 3.6mg/90mg Q3W 176 (75.7-357.1) 16.4 (9.4-27.4) 0.8 (0.1-3.6) 3.6mg/132mg Q3W 283.1 (117.4-585.8) 24.7 (14.6-41.6) 1.7 (0.1-7) 3.6mg/160mg Q3W 357.7 (132.9-762.6) 30.2 (16.4-56.5) 2.1 (0.1-10.3) 3.6mg/198mg Q3W 439.6 (169.3-991.7) 37.4 (22.3-66.6) 3.1 (0.2-14.2) 3.6mg/90mg Modified Weekly 449.9 (176-925.7) 22.9 (11.5-45.9) 7.3 (1.2-22.1) Note: The popPK model consists of a two-compartment model with linear and Michaelis-Menten clearance. For each dosing regimen and dose level, 500 concentration-time simulations were performed using the popPK model. PopPK model parameters were estimated using PK observations as of CCOD April 2021. AUC = area under the concentration-time curve; AUC _{D0 − 56} = AUC from days 0 to 56; C _max = maximum concentration; C _min = minimum concentration; Q3W = every 3 weeks. ^a C _max is expected to occur after administration of the target dose starting on day 63 of the Q3W schedule and on day 56 of the modified weekly schedule. ^b _Cmin is expected to occur before the target dose is administered on Day 63 of Q3W and Day 56 of the modified weekly schedule. xxi. Basis of ceftriaxone dosing in Arm B (Q2W/Q4W) Initial Safety Run-in Group (B1S):

In the initial safety run-in group, the dosing of the combination of ceftriaxone and Pd was as follows: ● First escalating dose: 0.3 mg ● Second escalating dose: 3.6 mg ● Target dose (pre-phase to cycle 6): 132 mg Q2W ● Target dose (cycle 7 onwards): 132 mg Q4W Safety run-in group (B2S):

In an additional safety run-in cohort, a lower active target dose level of 0.3/3.6/90 mg (cohort B2S) in combination with Pd was evaluated to further understand the safety and tolerability profile of the treatment combination before opening the expansion cohort. Dosing of ceftriaxone in safety run-in cohort B2S was as follows: ● First escalating dose: 0.3 mg ● Second escalating dose: 3.6 mg ● Target dose (pre-stage to cycle 6): 90 mg Q2W ● Target dose (cycle 7 onwards): 90 mg Q4W

These doses were selected based on clinical, safety, and PK data from the ongoing FIH study GO39775.

The recommended dosing and scheduling of ceftriaxone in the pre-stage of 0.3/3.6/132 mg and 0.3/3.6/90 mg dual-escalation dosing schedule (Day 1, Day 8, and Day 15) to be evaluated in combination with Pd is based on comprehensive clinical and pharmacological (e.g., PopPK and E-R assessments) evidence from Study GO39775. This dual-escalation dosing schedule in the pre-stage allows for a reduction in CRS incidence and severity at the target dose. Rationale for the selection of 0.3 mg as the dose on Day 1 of Cycle 1:

The incidence of CRS observed after the 0.3 mg dose on Day 1 of Cycle 1 was low and limited to Grade 1 (e.g., no ≥ Grade 2 CRS events). The incidence of any-grade and Grade 2 CRS events and peak IL-6 levels were higher after the 0.6 mg and 1.2 mg Cycle 1 Day 1 doses compared with the 0.3 mg dose, suggesting that increasing the Cycle 1 Day 1 dose above 0.3 mg may worsen the safety profile.

Pharmacodynamic (PD) data indicated that Cycle 1 Day 1 doses below 0.3 mg were not associated with T cell activation, suggesting that these doses may be too low to reduce CRS at subsequent doses.

Subsequent overall CRS and ≥ Grade 2 CRS rates at the 3.6 mg Cycle 1 Day 8 dose following the 0.3 mg Cycle 1 Day 1 dose in the double-escalation regimen were lower than those at the 3.6 mg Cycle 1 Day 1 dose in the single-escalation regimen. Rationale for the selection of 3.6 mg as the Cycle 1 Day 8 dose:

The 3.6 mg escalation dose was effective in limiting the frequency of overall CRS and ≥ Grade 2 CRS at higher target doses of up to 252 mg on Cycle 1 Day 8 in the single-ascending regimen or up to 160 mg on Cycle 1 Day 15 in the double-ascending regimen. Target Dose in B1S Cohort: 132 mg: ● As mentioned above, as of the CCOD in March 2022, Study GO39775 had not reached the MTD at the target dose. A clear exposure-safety relationship has not been established when the target dose of ceftriaxone was escalated from 0.15 mg to 198 mg in the single-ascending and double-ascending dosing regimens. ● No significant ER relationship was observed for CRS and other non-CRS adverse events, including ≥ grade 3 cytopenias, ≥ grade 2 IRR, ≥ grade 2 infection, ≥ grade 2 rash, and any combined ≥ grade 3 adverse events, within the target dose range tested (0.15-252 mg). ● Significant improvements in ORR and ≥ VGPR rates were observed within the target dose range tested (0.15-252 mg). ● Based on PopPK model predictions (e.g., see Table 9), ○ Compared with the highest tested target dose of 0.3/3.6/252 mg ceftriaxone administered at Q3W intervals in GO39775 as monotherapy, the ceftriaxone exposure of 0.3 mg/3.6 mg/132 mg recommended at the Q2W regimen in this study is expected to be approximately 42% lower in initial mean exposure (C _avg,0-63d ), approximately 28% lower in steady-state mean exposure (C _avg,SS ), and approximately 43% lower in maximum steady-state exposure (C _max,SS ). Therefore, these predicted exposures with the proposed dosing regimen following administration of a single ascending Q3W dose of 3.6/252 mg ceftriaxone in Study GO39775 were previously eliminated from the risk. ○ The 0.3 mg/3.6 mg/132 mg Q2W regimen proposed in this study (GO42552) is predicted to result in an initial mean exposure (C _avg,0-63d ) that is approximately 7% higher, a maximum steady-state exposure (C _max,SS ) that is approximately 9% lower, and a mean steady-state exposure (C _avg,SS ) that is approximately 37% higher, compared to exposures with the 0.3/3.6/160 mg double ascending Q3W regimen of ceftriaxone previously tested in Study GO39775. Target Dose for B2S Group: 90 mg

The lower clinically active ceftriaxone target dose of 90 mg was chosen to further understand the safety and tolerability profile of this combination. ● In the Arm B safety run-in (B1S, N=8) phase, the overall safety profile appeared manageable at the tested ceftriaxone doses of 0.3/3.6/132 mg Q2W/Q4W in combination with 4 mg Pd. All 8 patients achieved an objective response. Therefore, lower active target dose levels of ceftriaxone (e.g., 90 mg) in combination with Pd (starting dose of pomalidomide at 2 mg) may be evaluated in an additional safety cohort prior to opening the expansion cohort to further understand the safety and tolerability profile of the treatment combination. ● Based on the observed objective responses, the 90 mg target dose level was considered clinically active, defined as a PR or better in Study GO39775. ● Based on PopPK model predictions (e.g., see Table 9), compared to the exposure tested with a 0.3 mg/3.6 mg/160 mg Q3W double-titration regimen of ceftriaxone in Study GO39775, the median predicted exposure of ceftriaxone with the Q2W split-titration regimen in this study would be: ○ At the 90 mg target dose: initial mean exposure (C _avg,0-63d ) was approximately 33% lower, maximum steady-state exposure (C _max,SS ) was approximately 41% lower, and mean steady-state exposure (C _avg,SS ) was approximately 20% lower. ● Based on observed efficacy, safety, tolerability, and PK data from the safety run-in cohort in Arm B of this study, two target dose levels of ceftriaxone will be selected for randomization in the expansion cohort to determine the RP2D for the combination of ceftriaxone and Pd. Alternative escalation dosing: Option to change to a split-escalation dosing schedule of 0.3 mg and 3.3 mg ● In Study GO39775, both single and dual escalation doses were effective in reducing CRS at the target dose. This reduction in CRS risk was independent of the target dose within the tested range (10.8-198 mg). ● To further optimize the dosing schedule, it is recommended that the 3.6 mg escalating dose be split into 2 doses (0.3 mg on Day 1 of Cycle 1 and 3.3 mg on Day 2, 3, or 4) to further reduce the risk of CRS at the target dose and also allow earlier delivery of treatment doses in rapidly progressing patients in this study. ● The quantitative systems pharmacology (QSP) model predicted that 0.3/3.3 mg escalations in the split-dose schedule would result in numerically lower rates of CRS of any grade and ≥ Grade 2 compared with the 3.6 mg single-escalation schedule, regardless of the date of administration of the 3.3 mg dose (e.g., Day 2, Day 3, or Day 4). Table 9. Comparison of Population PK Model-Predicted Medians (90% CI) for PK Exposure Indicators Following the Q3W Dual-Escalation Schedule, Q2W Dual-Escalation Schedule, and the Alternative Q2W Split-Escalation Schedule C _avg,D0-63 (μg/mL ● day ) C _avg,SS ^a (μg/mL) C _max,SS ^a (μg/mL) Dosage (mg) plan Median 90% CI Median 90% CI Median 90% CI Q3W Scheduling Using Double-Incremental Medication 0.3/3.6/90 Q3W Double Step 3.11 (1.32-6.64) 3.39 (1.33-7.54) 16.59 (10.28-27.04) 0.3/3.6/132 Q3W Double Step 5.12 (1.9-10.51) 6.08 (1.97-13.62) 25.64 (14.85-45.19) 0.3/3.6/160 Q3W Double Step 6.1 (2.38-13.76) 7.34 (2.42-18.86) 31.47 (17.82-56.33) 0.3/3.6/198 Q3W Double Step 8.43 (3.13-18.75) 10.49 (3.21-28.71) 40.79 (22.1-71.94) 0.3/3.6/252 Q3W Double Step 11.27 (4.06-24.78) 13.98 (4.14-37.13) 50.57 (28.28-89.1) Q2W Scheduling Using Double-Incremental Medication 0.3/3.6/60 Q2W Double Step 2.51 (0.99-4.75) 3.35 (1.12-7.3) 12.30 (6.95-19.96) 0.3/3.6/90 Q2W Double Step 4.07 (1.62-8.45) 5.90 (1.99-15.17) 18.68 (10.43-34.12) 0.3/3.6/132 Q2W Double Step 6.52 (2.35-14.09) 10.04 (2.8-26.55) 28.68 (14.82-53.54) Q2W Scheduling Using Alternative Incremental Dosing ( Split Incremental ) 0.3/3.3/60 Q2W Split 3.07 (1.21-5.69) 3.36 (1.12-7.36) 12.3 (6.95-19.99) 0.3/3.3/90 Q2W Split 4.95 (1.98-10.24) 5.91 (1.99-15.22) 18.71 (10.43-34.69) 0.3/3.3/132 Q2W Split 7.93 (2.87-17.12) 10.12 (2.81-27.15) 28.86 (14.82-54.74) NOTE: The popPK model consisted of a two-compartment model with linear and Michaelis-Menten clearance and was developed using ceftriaxone concentration data from monotherapy in GO39775 (clinical cutoff February 2022). For each dosing regimen and dose level, 500 concentration-time simulations were performed using the popPK model. ^a C _avg,D0-63 = is the average concentration expected to occur within the first 63 days of ceftriaxone dosing. Steady-state is defined as Cycle 3 and beyond. For Q3W, cycle length is 3 weeks with a dose of ceftriaxone on cycle day 1. For Q2W, the cycle length is 4 weeks with two doses of ceftriaxone on Days 1 and 15 of the cycle. ^b C _avg,SS = is the average concentration expected to occur in a cycle at steady state. Steady state is defined as Cycle 3 and beyond. For Q3W, the cycle length is 3 weeks with one dose of ceftriaxone on Day 1 of the cycle. For Q2W, the cycle length is 4 weeks with two doses of ceftriaxone on Days 1 and 15 of the cycle. ^c C _max,SS = is the maximum concentration expected to occur after administration of the target dose at steady state. Steady state is defined as Cycle 3 and beyond. For Q3W, the cycle length is 3 weeks with one dose of ceftriaxone on cycle day 1. For Q2W, the cycle length is 4 weeks with two doses of ceftriaxone on cycle days 1 and 15. xxii. Rationale for ceftriaxone dosing in arm C (Q3W/Q4W)

In the initial safety run-in cohort C1S, the dosing of the combination of ceftriaxone and Dd was as follows: ● First escalating dose: 0.3 mg ● Second escalating dose: 3.6 mg ● Target dose (cycle 1 to cycle 8): 160 mg Q3W ● Target dose (cycle 9 onwards): 160 mg Q4W

These doses were selected based on clinical and safety data from the ongoing FIH study GO39775. Target Dose for C1S: 160 mg: ● As mentioned above, as of CCOD in March 2022, Study GO39775 has not reached the MTD at the target dose. ● No significant ER relationship was observed for CRS and other non-CRS adverse events within the target dose range tested (0.15 mg-252 mg), including ≥ Grade 3 cytopenias, ≥ Grade 2 IRRs, ≥ Grade 2 infections, ≥ Grade 2 rash, any combined ≥ Grade 3 adverse events. ● Significant improvements in ORR and ≥ VGPR rates were observed across the target dose range tested (0.15 mg-252 mg). ● Based on the favorable benefit-risk profile observed in the expansion cohort (e.g., Arm D) of Study GO39775 at a dual escalation dose schedule of 0.3 mg/3.6 mg/160 mg Q3W, ceftriaxone will be administered at 0.3 mg/3.6 mg/160 mg Q3W (Cycle 1 to Cycle 8) and Q4W (Cycle 9 onwards) in combination with Dd. Target dose for subsequent dose levels (C2S, C2E, etc.) ● If the benefit-risk profile at the ceftriaxone dose evaluated in the C1S cohort is favorable, additional cohorts at lower target dose levels can be opened to evaluate lower clinically active ceftriaxone target doses to further optimize the regimen. Alternative escalation dosing: Optional change to a split escalation schedule of 0.3 mg and 3.3 mg doses ● As described above, to further optimize the dosing schedule, it is recommended to split the 3.6 mg escalation dose into 2 doses (0.3 mg on Day 1 of Cycle 1 and 3.3 mg on Day 2, 3, or 4) to further reduce the risk of CRS at the target dose and also allow for earlier delivery of treatment doses in rapidly progressing patients in this study. ● The QSP model predicts that the 0.3/3.3 mg escalation in the split-dose regimen will result in a numerically lower incidence of CRS of any grade and ≥ 2 compared with the 3.6 mg single escalation regimen, regardless of the day the 3.3 mg dose was administered (e.g., day 2, day 3, or day 4). xxiii. Rationale for Dosing and Scheduling of Pomalidomide and Dexamethasone in Arm B

In the B1S arm of this study, pomalidomide will be administered orally (PO) at a dose of 4 mg on Days 1 to 21 of each 28-day cycle, beginning on Day 1 of Cycle 1.

Due to the potential for overlapping toxicities of cytopenias, rash, and immune-mediated events, and the rate of dose modifications and reductions observed in the Arm B 1S cohort, the pomalidomide dose in B2S will begin at 2 mg PO on Days 1 through 21 of each 28-day cycle, beginning on Day 1 of Cycle 1. If tolerated without dose reductions or modifications during Cycle 1, the pomalidomide dose may be increased to 4 mg PO on Days 1 through 21 of each 28-day cycle beginning in Cycle 2. If toxicity subsequently develops, the pomalidomide dose may be reduced.

In Arm B of this study, dexamethasone will be administered once weekly at a dose of 20 mg PO on Days 1, 8, 15, and 22 of each 28-day cycle, beginning on Day 1 of Cycle 1. Oral dexamethasone will be omitted during the pre-phase and Cycle 1 and replaced with dexamethasone IV on the days of ceftriaxone administration.

Because the immunomodulatory effects of pomalidomide may enhance the incidence and severity of ceftriaxone-related CRS, pomalidomide will be initiated 21 days (for a dual-escalation schedule) or 14 days (if a split-escalation schedule is followed) after the first ceftriaxone dose, at which time the risk of ceftriaxone-induced CRS has decreased. At the investigator’s discretion, weekly dexamethasone may be eliminated from Cycle 5 to minimize dexamethasone-related toxicity. xxiv. Rationale for Dosing and Scheduling of Daratumumab and Dexamethasone in Arm C

In the C arm of this study, daratumumab SC at a dose of 1800 mg co-formulated with hyaluronidase-fihj 30,000 units will be administered subcutaneously QW for the first 9 weeks (e.g., cycles 1 to 3), Q3W from weeks 10 to 24 (e.g., cycles 4 to 8), and Q4W starting from week 25 (e.g., cycle 9).

Dexamethasone was the protocol-specified corticosteroid in the C arm of this study.

Although daratumumab SC is generally well tolerated, IRRs occur in approximately 13% of patients, most with the first dose (DARZALEX FASPRO® EUSmPC). Because no additional overlapping toxicities are expected during the initial treatment period, ceftriaxone will be administered 1 day after the first escalating dose of daratumumab and the first target treatment dose in Cycle 1, Week 2 (on Days 9, 10, and 16 of Cycle 1) to reduce the potential for acute overlapping toxicities. In the future, if the safety profile shows no significant increase in toxicity above that expected with either agent alone, sponsors may elect to amend the regimen to administer the combination therapy on the same day of Cycle 1. C. Materials and Methods i. Patients

Approximately 184 R/R MM patients will participate in this study (see Table 10 for examples). Table 10. Number of patients in each group Group Number of patients in each group Safety running-in group 6-12 Expand Group About 30 cases ii. General inclusion criteria ( all arms )

Patients must meet the following study enrollment criteria: ● Signed informed consent. ● Aged ≥18 years at the time of signing informed consent. ● Able to comply with the study protocol, as determined by the investigator. ● Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. ● Life expectancy of at least 12 weeks. ● Agree to scheduled assessments and procedures, including bone marrow biopsy and aspirate samples. ● Adverse events from previous anticancer therapy resolved to ≤ Grade 1, with the following exceptions: – Alopecia of any grade is permitted. – Peripheral sensory or motor neuropathy must have resolved to ≤ Grade 2 (for Arm B, with the following exceptions: neuropathy must have resolved to ≤ Grade 1). ● Measurable disease defined as at least one of the following: – Serum M-protein ≥0.5 g/dL (≥5 g/L). – Urine M-protein ≥200 mg/24 hr. – Serum free light chain (SFLC) analysis: affected SFLC ≥10 mg/dL (≥100 mg/L) and abnormal SFLC ratio (<0.26 or >1.65). ● Laboratory values as follows: – Liver function ○ AST and ALT ≤3 ULN. ○ Total bilirubin ≤1.5 ULN ○ Patients with a documented history of Gilbert syndrome and elevated total bilirubin with indirect bilirubin elevation are eligible (if total bilirubin ≤ 3.0 × ULN). – Hematologic function (requirement prior to first dose of ceftriaxone): ○ Platelet count ≥75,000/mm ³ without transfusion within 7 days prior to first dose. ○ ANC ≥1000/mm ³ . ○ Total hemoglobin ≥8 g/dL. (Note: Patients may receive supportive care (e.g., blood transfusions, growth colony stimulating factor (G-CSF) etc.), except for platelet transfusions to meet hematologic eligibility criteria as detailed above. – Creatinine ≤2.0 mg/dL and creatinine clearance (CrCl) ≥30 mL/min (calculated using the modified Cockcroft-Gault equation or urine collection every 24 hours). – Serum calcium (corrected for albumin) level ≤11.5 mg/dL (treatment of hypercalcemia is allowed, and patients are eligible if hypercalcemia recovers to ≤grade 1 with standard therapy). iii. Other Arm A- specific inclusion criteria ● Diagnosis of R/R MM, no specific treatment for MM iv. Other Arm B- specific inclusion criteria ● For B1S arm: R/R MM patients who have received at least two prior lines of treatment that included at least two consecutive cycles of any of the following: – A proteasome inhibitor-containing regimen and a regimen containing an IMiD, or – A regimen containing both a proteasome inhibitor and an IMiD. ● For B2S arm and other arm: R/R MM patients who have received at least 1 prior line of treatment that included at least two consecutive cycles of any of the following: – A proteasome inhibitor-containing regimen and a regimen containing an IMiD, or – A regimen containing both a proteasome inhibitor and an IMiD. ● For B2S arm and other arm: R/R MM patients who have received at least 1 prior line of treatment that included at least two consecutive cycles of any of the following: – A proteasome inhibitor-containing regimen and a regimen containing an IMiD, or – A regimen containing both a proteasome inhibitor and an IMiD. Groups and Others: Prior exposure to pomalidomide is permitted if the patient is not refractory to pomalidomide. Patients are considered refractory to pomalidomide if they did not achieve at least a PR on their most recent pomalidomide therapy or if their disease relapsed within 60 days of their last dose of pomalidomide. ● Adverse events (including peripheral neuropathy) resolved to ≤ Grade 1 from previous anticancer therapy, with the exception of alopecia of any grade being permitted. ● Agreement to comply with all requirements of the pomalidomide pregnancy prevention program. – In each country where pomalidomide is approved, a risk minimization plan is in place that includes a pregnancy prevention program. Patients using pomalidomide should follow this risk minimization plan. ● Agreement to follow all requirements of the pomalidomide pregnancy prevention program during the treatment period (including treatment interruptions) and avoid blood donation for at least 4 weeks after the last dose of pomalidomide. v. Other C- arm specific inclusion criteria ● For C1S group: R/R MM patients who have received at least 2 prior lines of treatment that included at least 2 consecutive cycles of any of the following: – A regimen containing a proteasome inhibitor and a regimen containing an IMiD, or – A regimen containing both a proteasome inhibitor and an IMiD. ● For C2S group and other groups: R/R MM patients who have received at least 1 prior line of treatment that included at least 2 consecutive cycles of any of the following: – A regimen containing a proteasome inhibitor and a regimen containing an IMiD, or – A regimen containing both a proteasome inhibitor and an IMiD. ● For the C2S group and other groups: Prior exposure to anti-CD38 therapy is allowed if the patient is not refractory to such therapy. Patients are considered refractory to anti-CD38 therapy if they did not achieve at least a PR on their most recent anti-CD38 antibody therapy or if their disease relapsed within 60 days of the last dose of anti-CD38 therapy. A 6-month CD38 antibody-free interval is required from the last dose received until the first study treatment. vi. General Exclusion Criteria ( all arms )

Patients who met any of the following criteria were excluded from the study: ● Prior treatment with ceftriaxone or other agents targeting FcRH5. ● Inability to comply with protocol-specified hospitalization and activity restrictions. ● Prior use of any monoclonal antibody, radioimmunoconjugate, or antibody-drug conjugate as anticancer therapy within 4 weeks prior to the first study treatment, with the exception of non-myeloma therapy (e.g., denosumab for hypercalcemia was permitted). ● Prior treatment with systemic immunotherapy agents, including but not limited to cytokine therapy and anti-CTLA4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, within 12 weeks or 5 half-lives of the drug (whichever is shorter) prior to the first study treatment. ● Prior treatment with CAR T-cell therapy within 12 weeks prior to first study treatment. ● Prior allogeneic CAR T-cell therapy is permitted as long as treatment was completed ≥ 12 weeks prior to first study treatment. ● Known treatment-related, immune-mediated adverse events related to prior checkpoint inhibitors as follows: – Prior PD-L1/PD-1 or CTLA-4 inhibitors: ≥ Grade 3 adverse events, excluding Grade 3 endocrinopathies managed with alternative therapies. – Grade 1-2 adverse events that do not resolve to baseline following treatment discontinuation. ● Treatment with radiation therapy within 4 weeks (systemic radiation therapy) or 14 days (local radiation therapy) prior to first study treatment. ● Treatment with any chemotherapy or other anticancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to first study treatment. ● Autologous SCT within 100 days prior to first study treatment. ● Prior allogeneic SCT. ● Circulating plasma cell count greater than 500/µL or 5% of peripheral blood leukocytes. ● Prior solid organ transplant. ● History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. – Patients with a history of autoimmune-related hypothyroidism on stable doses of thyroid replacement hormone are eligible for this study. ● History of confirmed progressive multifocal leukoencephalopathy. ● History of severe allergic or anaphylactic reaction to monoclonal antibody therapy (or recombinant antibody-related fusion proteins). ● History of known amyloidosis (e.g., positive Congo red staining or equivalent on tissue biopsy). ● Lesions near vital organs that may suddenly decompensate/worsen in the setting of a tumor flare. ● History of other malignant tumors within 2 years before screening, excluding malignant tumors with negligible risk of metastasis or death (e.g., expected 5-year OS ≥ 90%), such as ductal carcinoma in situ not requiring chemotherapy, appropriately treated cervical carcinoma in situ, non-melanoma skin cancer, low-grade localized prostate cancer not requiring treatment (Gleason score ≤ 7), or appropriately treated stage I uterine cancer. ● Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or MM involving the CNS. – Patients with a history of stroke who have not had a stroke or transient ischemic attack in the past 2 years and who do not have residual neurological deficits as determined by the investigator are permitted. – Patients with a history of epilepsy who have not had an epileptic seizure in the past 2 years and are not receiving any anti-epileptic medication are permitted. ● Severe cardiovascular disease that may limit the patient’s ability to respond adequately to a CRS event (such as, but not limited to, New York Heart Association Class III or IV heart disease, myocardial infarction in the past 6 months, uncontrolled arrhythmia, or unstable angina). – In addition, patients enrolled in Arm B must not have a history of myocardial infarction in the past 12 months. ● Known history of ≥ Grade 3 CRS or Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) with prior bispecific therapy. ● Known history of HLH or MAS. ● Symptomatic active lung disease or requiring supplemental oxygen. ● Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding nail bed fungal infection) at study enrollment, or any major infectious episode requiring IV antibiotic treatment, with the last dose of IV antibiotics given within 14 days prior to the first study treatment. ● Active symptomatic COVID-19 infection or requiring IV antiviral treatment at study enrollment, with the last dose of IV antiviral treatment given within 14 days prior to the first study treatment. Patients with active COVID-19 infection must have recovered clinically and had two negative antigen tests at least 24 hours apart before the first study treatment. – Primary prophylaxis for COVID-19 is not considered treatment for COVID-19 infection● Positive and quantifiable EBV PCR or CMV PCR before the first study treatment. ● Known or suspected chronic active EBV infection. – Guidance for the diagnosis of chronic active EBV infection is provided by Okano et al., Am J Hematol., 80:64-49, 2005. ● Recent major surgery within 4 weeks before the first study treatment. – Protocol-mandated procedures (e.g., bone marrow biopsy) are permitted. ● Positive serology or PCR test results for acute or chronic HBV infection. – Patients whose HBV infection status cannot be determined by serological test results (cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf) must be HBV negative by PCR to be eligible for study participation. ● Acute or chronic HCV infection. – HCV antibody-positive patients must have a negative HCV PCR to be eligible for study participation. ● Known history of HIV serology. ● Administered a live attenuated vaccine within 4 weeks prior to the first study treatment, or anticipates that such a live attenuated vaccine will be required during the study. – Flu vaccination can be given during the flu season (e.g., approximately October to May in the Northern Hemisphere; approximately May to October in the Southern Hemisphere). Patients must not receive a live attenuated influenza vaccine (e.g., FLUMIST®) at any time during the study treatment period. – COVID-19 vaccines may be administered according to the approved/authorized vaccine label and official/local immunization guidelines. COVID-19 vaccines must not be administered within 1 week prior to the first study treatment or during the pre-phase (Arm B) or Phase 1 (Arms A and C). – Investigators should review the vaccination status of potential study patients being considered for enrollment in this study and follow the CDC guidance for vaccination of adults with any other non-live vaccines to prevent infectious diseases prior to the study. ● Treatment with systemic immunosuppressive drugs (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to the first study treatment, except for corticosteroid therapy ≤ 10 mg/day of prednisone or equivalent. – Inhaled corticosteroids are permitted. – Mineralocorticoids are permitted for orthostatic hypotension. – Physiologic doses of corticosteroids are permitted for adrenal insufficiency. ● History of drug or alcohol abuse within 12 months prior to screening, as determined by the investigatorvii . Other Arm B- specific exclusion criteria ● Major cardiovascular disease (such as but not limited to New York Heart Association Class III or IV heart disease, myocardial infarction within the past 12 months, uncontrolled arrhythmia, or unstable angina). ● History of erythema multiforme, ≥ Grade 3 rash, blistering, or severe hypersensitivity reactions after prior treatment with immunomodulatory drugs (such as thalidomide, lenalidomide, or pomalidomide). ● Inability to tolerate thromboprophylaxis, or contraindications to thromboprophylaxis. ● GI disease that may significantly alter oral drug absorption. viii. Other C- arm specific exclusion criteria ● Known hypersensitivity to biologics produced by CHO cells or any component of the daratumumab formulation. ● Known chronic obstructive pulmonary disease (COPD) with forced expiratory volume in 1 second (FEV ₁ ) < 50% of predicted normal. – Patients suspected of having COPD require a FEV ₁ test and must be excluded if FEV ₁ < 50% of predicted normal. Patients with no history of suspected or known COPD do not require spirometry testing during the screening period. ● Known moderate or severe persistent asthma within the past 2 years, or current uncontrolled asthma of any type. – Patients with currently controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study. ix. Study treatments and other treatments relevant to the study design

The investigational medicinal products (IMPs) for this study are ceftriaxone, pomalidomide, daratumumab, dexamethasone , and tocilizumab . Protocol-specified antecedent medications are considered non-investigational medicinal products (NIMPs).

For ceftriaxone, flat dosing will be used regardless of body weight. As described herein, each patient's ceftriaxone dose will depend on their group assignment.

Ceftuzumab is administered to patients by IV infusion using a standard medical syringe and syringe pump or an appropriate IV bag. Compatibility testing has shown that Ceftuzumab is stable in the extension set. Drug product is delivered by IV infusion, and the final Ceftuzumab volume is determined by the dose.

All ceftriaxone doses were administered to well-hydrated patients. Corticosteroid premedication (preferably, dexamethasone 20 mg IV; alternatively, corticosteroid equivalents such as methylprednisolone 80 mg IV are acceptable) must be administered 1 hour (±15 minutes) before each ceftriaxone dose as follows: ● Arm A: Corticosteroid premedication: – Prior to all ceftriaxone doses in Cycle 1 and Cycle 2. – In Cycle 3 and beyond: Only if patients experienced CRS on the previous ceftriaxone dose. ● Group B: Dexamethasone should be administered: – Before all ceftriaxone doses during the pre-phase and during Cycle 1. – During Cycle 2 and beyond: Only if the patient experienced CRS on the previous ceftriaxone dose. ● Group C: Dexamethasone premedication with ceftriaxone should be administered as follows: – During Cycle 1: ■ Before the first ceftriaxone escalation dose, 20 mg dexamethasone should be administered. ■ Before the second ceftriaxone escalation dose, 20 mg dexamethasone should be administered. ■ Before the first ceftriaxone target dose, 20 mg dexamethasone should be administered. – In Cycle 2: before all ceftriaxone doses – In Cycle 3 and beyond: only if the patient experienced CRS on the previous ceftriaxone dose. – In Cycle 3 and beyond, patients may receive oral dexamethasone instead of IV dexamethasone as a required premedication for daratumumab if they no longer require corticosteroids as a premedication for ceftriaxone. – In addition to the above, dexamethasone premedication and postmedication with daratumumab should also be administered.

In addition, all ceftriaxone doses must be preceded by premedication with oral acetaminophen or acetaminophen (e.g., 500-1000 mg) and 25-50 mg diphenhydramine, unless contraindicated. Sites without access to diphenhydramine may substitute an equivalent medication based on local practice.

Initially, ceftriaxone is administered over 4 hours (±15 minutes). The infusion may be slowed or interrupted for patients who experience IRR/CRS. Patients should be hospitalized at the end of the ceftriaxone infusion. Observe patients for at least 90 minutes after each subsequent ceftriaxone infusion for fever, chills, rigors, hypotension, nausea, or other signs and symptoms of IRR. In the absence of IRR/CRS after the first target dose, the infusion duration of ceftriaxone may be shortened to 2 hours for subsequent doses. If repeated escalation doses are necessary, the next two doses (escalation and target dose) should be administered over 4 hours.

Patients who receive less than 80% of the escalating dose of ceftriaxone should have the escalating dose repeated before receiving the higher target dose (if the patient meets all dosing requirements). Dose escalations are permitted if the patient experiences an adverse event during the escalating dose period and the investigator determines that it is clinically significant and warrants repeating the escalation at the next dose. Dose escalations must be repeated for any patient who experiences ≥Grade 3 CRS after receiving an escalating dose before receiving the first target dose. Patients who experience adverse events that require interruption of treatment may need to have their doses repeated, depending on the length of the delay. If a patient is delayed more than 4 weeks from their normally scheduled dosing, repeated escalation doses may be required.

Management and guidelines for dose and schedule modifications and treatment interruptions or discontinuations are described in this article. Tables 3A and 3B detail the recommended management of CRS and IRR, respectively. xi. Pomalidomide

For the B1S arm of Arm B, pomalidomide was administered at a dose of 4 mg PO on Days 1 through 21 of each 28-day cycle, beginning on Day 1 of Cycle 1. For the B2S and subsequent safety run-in and expansion arms, pomalidomide was administered at a dose of 2 mg PO on Days 1 through 21 of each 28-day cycle, beginning on Day 1 of Cycle 1. Starting in cycle 2, pomalidomide doses can be escalated from 2 mg to 4 mg if the following parameters are met: ● ANC ≥ 1000/µl (ANC ≥ 1000/mm3) and platelets ≥ 75000 /µl (75,000/mm3)

Pomalidomide should be taken with water at approximately the same time each day with or without food. Pomalidomide should be swallowed whole, and patients should not tear, chew, or open the capsule. If a pomalidomide dose is missed and it has been ≤12 hours since the scheduled dosing time, the patient should take the missed dose as soon as they remember. If it has been >12 hours, the pomalidomide dose should not be taken. Two doses should not be taken at the same time. If a dose is missed or vomiting occurs throughout the day, the dose should not be made up, and the patient should continue taking the medication as usual at the next dose. This article provides guidance on pomalidomide dose modifications and treatment interruptions or discontinuations.

On the days that patients are expected to receive a ceftriaxone infusion, they should be instructed to take the pomalidomide dose in the clinic prior to administration of ceftriaxone and dexamethasone to allow for proper collection of the pomalidomide PK sample. Record the date and time of the pomalidomide dose on the day of the PK visit and the most recent dose within 1 day prior to the PK visit.

During each cycle, each patient will be supplied with only enough pomalidomide for that cycle. Patients will be provided with a medication diary to record oral administration of doses, including date and time. Patients are instructed to return empty bottles or unused capsules. Pomalidomide is recommended for thromboprophylaxis, and the choice of regimen should be based on an assessment of the patient's potential risk factors. xii. Daratumumab SC  

In the C arm, daratumumab SC is administered as a fixed dose of 1800 mg/30,000 U rHuPH20 by manual push into the subcutaneous tissue of the abdomen on the left/right side (alternating between individual doses) over approximately 3-5 minutes. For the 1800-mg dose, the volume of the SC solution will be 15 mL.

Premedication should be administered approximately 1 hour prior to each daratumumab infusion to reduce the risk of administration-related reactions, as follows: ● Acetaminophen or acetaminophen 650-1000 mg IV or PO. ● Diphenhydramine 25-50 mg (or equivalent) IV or PO. ● Dexamethasone 20 mg or equivalent of an intermediate- or long-acting corticosteroid.

When daratumumab and ceftriaxone are administered on the same day, daratumumab will be administered 1 hour after the completion of the ceftriaxone infusion. In these cases, the premedication of ceftriaxone will serve as the premedication of both drugs.

When ceftriaxone and daratumumab are given on consecutive days (e.g., Cycle 1 Days 1, 8, 15 with daratumumab and Cycle 1 Days 2, 9, 16 with ceftriaxone), dexamethasone is given as a premedication (IV or oral) before daratumumab and again before ceftriaxone (IV). Dexamethasone premedication with ceftriaxone serves as a postmedication with daratumumab.

For patients with a history of COPD, the use of short- and long-acting bronchodilators and inhaled corticosteroids should be considered. These additional post-medications can be discontinued after the first 3 doses of daratumumab if the patient does not experience a severe systemic IRR.

Initiate antiviral prophylaxis within 1 week of starting daratumumab to prevent reactivation of herpes zoster and continue for 3 months after treatment.

Daratumumab administration is performed in a monitored environment with immediate access to trained personnel and adequate equipment and medications to manage severe reactions that could occur.

Guidelines for the medical management of IRRs are described herein (e.g., Table 3B). Dose reductions of daratumumab are not permitted. Dose delays may be permitted. xiii. Dexamethasone

In Arm A, patients were required to receive dexamethasone (or equivalent) as premedication for all doses of ceftriaxone during Cycles 1 and 2. Beginning with Cycle 3 and thereafter, dexamethasone was required as premedication only if patients experienced CRS on the previous dose.

In Arm B, patients will receive 20 mg dexamethasone IV as premedication for all doses of ceftriaxone during the pre-phase and Cycle 1. In Cycle 2, dexamethasone will be given orally at 20 mg on Days 8 and 22. For Cycles 2 through 4, patients will receive 20 mg dexamethasone orally on Days 1, 8, 15, and 22 of each cycle. For Arm B, dexamethasone given as premedication or weekly may be discontinued at the investigator's discretion beginning in Cycle 5. Dexamethasone (20 mg once weekly) may be restarted at any time. Beginning with Cycle 2, IV dexamethasone could be substituted with oral dexamethasone on days of ceftriaxone administration; however, if a CRS event occurred during the previous ceftriaxone infusion, IV dexamethasone was substituted for oral dexamethasone.

In Arm C, patients were required to receive dexamethasone 20 mg as a premedication for all doses of daratumumab during Cycle 1 and a specific dose of dexamethasone before all doses of ceftriaxone (20 mg before each escalating dose and the first target dose). Dexamethasone given before daratumumab could be IV or PO, and dexamethasone given before ceftriaxone must be IV from Cycle 1 to Cycle 2. Dexamethasone was given as a premedication for daratumumab starting in Cycle 5 of Arm C. Dexamethasone (20 mg on Day 1) could be restarted at any time at the investigator’s discretion. xiv. Tocilizumab

Tocilizumab is administered as a rescue IMP, if necessary, to patients experiencing a CRS event. Tocilizumab is prepared, handled, and administered according to standard institutional practice. If permitted by local regulations, study sites may obtain Tocilizumab locally for emergency use. xv. Permitted Therapies

Patients using oral contraceptives, hormone replacement therapy, or other maintenance therapies should continue to use them. Because oral contraceptives are metabolized by CYP450 enzymes, transient release of cytokines during ceftriaxone treatment may cause drug-drug interactions and may exacerbate oral contraceptive-related side effects. Potential therapeutic effects on CYP enzymes are described herein.

Concomitant use of hematopoietic growth factors such as erythropoietin, granulocyte colony-stimulating factor (G-CSF) (filgrastim, pegfilgrastim), granulocyte/macrophage colony-stimulating factor (sargramostim), or thrombopoietin (oprelvekin, eltrombopag) is permitted based on instructions provided in the package insert, institutional practice, and/or published guidelines. For patients with Grade 3 or 4 neutropenia, the use of growth factor support is encouraged and should be administered according to institutional guidelines. Platelet transfusions are permitted for patients with thrombocytopenia and should be administered according to institutional guidelines.

Anti-infective prophylaxis for viral, fungal, or bacterial infections (including IV immunoglobulin replacement) is recommended for patients at high risk for infection and should be administered according to institutional practice. Prophylaxis for Pneumocystis infection must be administered concurrently with study treatment unless contraindicated. Prophylaxis for herpes zoster reactivation should be initiated concurrently with daratumumab treatment. IV Ig replacement therapy is permitted to reduce the risk of recurrent infection due to hypogammaglobulinemia, per institutional guidelines.

Treatment or prevention of SARS-CoV-2 infection is permitted when authorized or approved by local health authorities and used in accordance with institutional practice. Patients should be monitored for adverse events of ceftriaxone and COVID-19-directed therapies. If possible, COVID-19-directed therapies should not be administered on the same day as study medications to minimize the potential for adverse drug-drug interactions. Study treatments should not be administered during active infection, including SARS-CoV-2.

Patients who were already receiving bisphosphonates or denosumab (indicated for hypercalcemia or prevention of skeletal-related events) prior to study entry were allowed to continue either therapy; initiation of these therapies was permitted during screening, pre-phase, or Cycle 1. Bisphosphonates were allowed after Cycle 1 as long as there were no signs of disease progression.

Systemic corticosteroids and other immunomodulatory drugs may attenuate the potential beneficial immune effects of ceftriaxone therapy but should be administered at the discretion of the treating physician. Inhaled corticosteroids and mineralocorticoids (e.g., fluocortisol) are permitted in patients with orthostatic hypotension or adrenocortical insufficiency. Physiologic dosing for adrenocortical insufficiency is permitted. Megestrol acetate may be administered as an appetite stimulant while patients are enrolled in the study.

Influenza vaccines should only be given during influenza season. Use of killed vaccines (e.g., COVID-19 mRNA vaccines) is permitted. Further details on live attenuated vaccines are described here.

In general, investigators should manage the patient's care (including pre-existing conditions) using supportive care, except for supportive care defined as contraindicated care as clinically indicated, in accordance with local standard practice.

Treatment of severe CRS, HLH, or MAS based on published recommendations and/or institutional practice is permitted. xvi. Drugs that may cause drug reactions with eosinophilia and systemic symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been described with pomalidomide. Medications such as sulfonamides (including dapsone and trimethoprim-sulfamethoxazole), allopurinol, vancomycin, and others should be administered with caution as they may cause DRESS in patients receiving pomalidomide in Arm B. The above list of medications is not comprehensive. Investigators should review prescribing information to determine whether concomitant medications can be safely administered with study treatments including pomalidomide. xvii. Drugs that require caution due to effects on CYP enzymes

Given the expected pharmacology of ceftriaxone, the transient release of cytokines may inhibit CYP450 enzymes and cause drug-drug interactions. Based on clinical data, cytokine levels (IL-6 and IFN-γ) are highest during the first 24 hours of the first cycle. During subsequent cycles, cytokine levels decrease significantly. Patients who may be at risk for drug-drug interactions are those receiving concomitant medications that are CYP450 substrates and have a narrow therapeutic index. Such concomitant medications should be monitored for toxicity and doses adjusted accordingly.

Pomalidomide is primarily metabolized by CYP1A2 and CYP3A and is also a substrate for P-glycoprotein (P-gp). Therefore, pomalidomide plasma concentrations may be affected by smoking or concomitant medications that inhibit or induce these pathways. The use of strong CYP1A2 inhibitors should be avoided unless medically necessary. xviii. Research Evaluation

Screening and pre-treatment testing and assessments will be performed within 14 days prior to the first dose of study treatment, except that the following may be performed up to 28 days prior to the first dose of study drug, provided that no antineoplastic therapy is administered during this period: ● Positron emission tomography (PET; also known as 18F-fluorodeoxyglucose (FDG)-PET scan)/computed tomography (CT) scan, CT scan, or whole-body magnetic resonance imaging (MRI), where necessary to evaluate suspected or known extramedullary disease ● (may be omitted if a PET/CT scan or low-dose whole-body CT or whole-body MRI is performed as part of screening) Skeletal survey xix. Disease-specific assessments

Patients were assessed for disease response and progression according to the following IMWG response criteria (see Table 11A and Table 11B). Table 11A. International Myeloma Working Group Uniform Response Criteria (2016) adapted from Durie et al. Leukemia 2015; 29:2416-7 and Kumar et al. Lancet Oncol 2016; 17:e328-46. Response Subcategory Response Standards All response categories require two consecutive assessments at any time prior to starting any new therapy. sCR CR was defined as follows, plus: normal FLC ratio and absence of clonal cells in BM as detected by immunohistochemistry (κ/λ ratio ≤ 4:1 or ≥ 1:2 after counting ≥ 100 plasma cells for κ and λ patients, respectively) ^a CR No evidence of the original monoclonal protein isotype on immunofixation of serum and urine, bDisappearance ^{of any} soft histiocytoma, and ≤ 5% plasma cells in BM VGPR Serum and urine M-protein detectable by immunofixation but not by electrophoresis; or serum M-protein reduced by ≥ 90% and urine M-protein < 100 mg/24 hr ^c PR ≥ 50% reduction in serum M-protein and ≥ 90% reduction or reduction to < 200 mg/24 hr in 24-hour urine M-protein ● If serum and urine M-protein are unmeasurable, a ≥ 50% reduction in the difference between affected and unaffected FLC levels is required to replace the M-protein criterion. ● If serum and urine M-protein are unmeasurable and the serum FLC assay is also unmeasurable, a ≥ 50% reduction in plasma cells is required to replace M-protein, with the proviso that the baseline BM plasma cell percentage is ≥ 30% ● In addition to the criteria listed above, a ≥ 50% reduction ⁱⁿ the size of the soft tissue plasma cell tumor (SPD) is also required if present at baseline. MR A decrease in serum M-protein of ≥ 25% but ≤ 49% and a decrease in 24-hour urine M-protein of 50%-89% ● In addition to the above criteria, a 25%-49% decrease in the size of the soft tissue plasma membrane (SPD) ^d is also required if present at baseline. SD Does not meet criteria for MR, CR, VGPR, PR, or PD Table 11B. International Myeloma Working Group Uniform Response Criteria (2016) adapted from Durie et al. Leukemia 2015; 29:2416-7 and Kumar et al. Lancet Oncol 2016; 17:e328-46 Recurrence subcategory Relapse criteria PD ^{e , f} Any one or more of the following criteria: ● An increase of ≥ 25% from the nadir in one or more of the following: ● Serum M-protein (absolute increase must be ≥ 0.5 g/dL) ● If the nadir M component is ≥ 5 g/dL, an increase of ≥ 1 g/dL in serum M-protein ● Urine M-protein (absolute increase must be ≥ 200 mg/24 hr) ● In patients without measurable serum and urine M-protein levels: the difference between included and unincluded FLC levels (absolute increase must be > 10 mg/dL) ● For patients without measurable serum and urine M-protein levels and without measurable FLC disease: BM plasma cell percentage is not related to baseline status (absolute percentage must be ≥ 10%) ^b ● Appearance of new lesions, > 1 lesion with an SPD increase of ≥ 1% from nadir 50%, or ≥ 50% increase in the longest diameter of a previous lesion with a minor axis > 1 cm ● ≥ 50% increase in circulating plasma cells (at least 200 cells per microliter) if this is the only measure of disease Clinical relapse One or more of the following is required: ● Disease associated with a potential selected plasmacytoma proliferative disorder and/or end-organ dysfunction (CRAB features) Direct indication of increase ^{in g} . It is not used for calculation of time to progression or PFS but is included here as a context for reporting or use in clinical practice. ● Development of new soft tissue plasmacytoma or bone lesion (osteoporotic fracture does not constitute progression) ● A significant increase in the size of an existing plasmacytoma or bone lesion. A significant increase is defined as an increase of 50% (and ≥ 1 cm) as measured serially by the sum of the products of the transverse diameters of measurable lesions. ● Hypercalcemia > 11 mg/dL (2.65 mmol/L) ● Decrease in hemoglobin ≥ 2 g/dL (1.25 mmol/L) not related to therapy or other non-myeloma-related conditions ● Increase in serum creatinine of 2 mg/dL or more (177 µmol/L or more) since initiation of therapy and attributable to myeloma ● Hyperviscosity associated with serum paraproteins Relapse after CR (only used when the study endpoint is PFS) ^d Any one or more of the following: ● Reappearance of serum or urine M-protein by immunofixation or electrophoresis ● Development of ≥5% plasma cells in BM ● Development of any other signs of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia) BM = bone marrow; CR = complete response; CT = computed tomography; FLC = free light chains; M protein = monoclonal protein; MR = minimal response; MRI = magnetic resonance imaging; PD = progressive disease; PET = positron emission tomography; PFS = progression-free survival; PR = partial response; sCR = strict complete response; SD = stable disease; SPD = sum of products of diameters; VGPR = very good partial response. Note: Patients should be classified as having stable disease until they meet the criteria for any response category or develop progressive disease. Patients will remain in the last confirmed responder category until progression or improvement to a higher responder status is confirmed; patients cannot be moved to a lower responder category. ^a The appearance of different M proteins after treatment should be noted, especially in patients who have achieved a known CR, and is usually related to oligoclonal reconstitution of the immune system. These bands usually disappear over time and, in some studies, have been associated with better outcomes. In addition, the appearance of IgGk in patients receiving monoclonal antibodies should be distinguished from therapeutic antibodies. ^bIn some cases, the native M protein light chain isotype may still be detected on immunofixation, but the accompanying heavy chain component has disappeared; even if the heavy chain component is not detectable, this is not considered a CR because the lineage may have evolved to one that secretes only the light chains. Thus, if a patient has an IgAλ myeloma, to qualify as a CR, IgA should not be detectable on serum or urine immunofixation; if free λ is detected in the absence of IgA, it must be accompanied by a different heavy chain isotype (IgG, IgM, etc.). Modified from Durie et al. Leukemia; 20:1467-73 2006. Two serial assessments are required at any time before initiating any new therapy (Durie et al. Leukemia 2015;29:2416-7). ^c For patients to achieve an excellent partial response by other criteria, the sum of the largest perpendicular diameters (SPD) of the soft tissue plasmacytomas must be reduced by more than 90% from baseline. ^d Plasma cell measurements should be obtained from the CT portion of the PET/CT or MRI scan, or a dedicated CT scan if applicable. For patients with only skin invasion, the lesions should be measured with a ruler. Tumor size measurements will be determined by the SPD. Any soft tissue plasmacytoma documented at baseline must be serially monitored; otherwise, the patient will be classified as unevaluable. ePositive immunofixation alone will not be considered progression ^{in patients previously classified as having achieved CR. Criteria for recurrence of CR should be used only for calculation of disease-free survival. fIf a} value is considered to be a false result (e.g., possible laboratory error) at the discretion of the investigator, it will not be considered in determining the nadir. ^gCRAB features = elevated calcium, renal failure, anemia, lytic bone lesions.

Bone marrow biopsies and aspirates may be obtained at various time points (e.g., before starting study treatment). Patients who are rescreened after failing the initial screening do not need to undergo a repeat bone marrow biopsy and aspirate if these assessments are completed during the initial screening period.

The following myeloma-specific tests are performed at screening and at the beginning of each cycle: ● Serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE) ● SFLC ● Quantitative Ig levels. ● 24-hour urine protein electrophoresis (UPEP) is performed only if there is measurable disease in the urine at screening

Clinical response assessment in myeloma relies on SPEP and SIFE. Daratumumab administration may interfere with SPEP and SIFE assays, especially in patients with IgG-k M protein. In some cases, such as persistent VGPR or asymptomatic biochemical progression (especially after an initial response), it may be necessary to send additional serum samples to a local laboratory for confirmatory analysis. For example, a daratumumab-specific immunofixation electrophoretic reflectance assay (DIRA) has been developed to separate daratumumab signal from myeloma M protein, which improves the interpretation of response assessments per IMWG criteria (McCudden et al. Clin Chem Lab Med 2016;54:1095-104).

The following myeloma-specific tests should be performed at screening and as needed to confirm remission: ● 24-hour UPEP with urine immunofixation electrophoresis (UIFE) for quantitative M-protein and confirmation of VGPR or better if measurable disease is present at screening.

All response categories (strict complete response (sCR), CR, VGPR, PR, and minimal response (MR)) require the following confirmatory assessments: ● If preexisting extramedullary disease, a CT scan or MRI with two-dimensional measurements to confirm size reduction per IMWG criteria (e.g., MR, PR, or VGPR). ● If preexisting extramedullary disease, a PET/CT scan, CT scan, or MRI is required to confirm complete resolution (e.g., CR or sCR). ● A 24-hour UPEP/UIFE is required to confirm VGPR even if the UPEP was negative at screening. If the UPEP was positive at screening, MR/PR and VGPR are required. If testing was not performed at screening, PR and VGPR are required.

The following additional samples/assessments are required to confirm sCR or CR: ● SIFE ● SFLC ● 24-hour UPEP/UIFE is required to confirm CR/sCR even if UPEP is negative at screening. ● Bone marrow aspirate for central MRD assessment to confirm CR/sCR (recommended within 28 days of suspected CR or sCR). ● Bone marrow biopsy (sCR). ● PET-CT scan, CT scan, or MRI to confirm complete resolution if preexisting extramedullary disease.

To confirm disease progression, the following must be met: ● If progression is suspected to be due to elevated M-protein, a SPEP, UPEP, or SFLC analysis should be performed according to IMWG criteria at two consecutive assessments. ● If progression is suspected with the development of new bone lesions or sclerocytoma or an increase in the size of an existing bone lesion or sclerocytoma, a skeletal survey/CT scan/MRI should be performed and compared with baseline imaging. xx. Skeletal Survey

A skeletal survey is completed at screening and as clinically indicated. The skeletal survey may be completed up to 28 days prior to Phase Day 1 (B-arm) or C1D1 (A-arm and C-arm). Plain radiographs and CT scans are acceptable imaging modalities for the evaluation of skeletal disease. Imaging should include the skull, long bones, chest, and pelvis. If a plasmacytoma is found during the skeletal survey, two-dimensional tumor measurements should be recorded. The skeletal survey may be omitted if a PET/CT scan or low-dose whole-body CT or whole-body MRI is performed as part of screening. xxi. Extramedullary Disease

All patients with clinically suspected extramedullary disease or known extramedullary disease at screening must undergo imaging during screening to assess the presence/extent of extramedullary disease. This should be performed using PET/CT (plasmacytoma measurements should be obtained from the CT portion of the PET/CT for response assessment per IMWG criteria) or MRI scans or dedicated CT scans as appropriate. CT scan of chest, abdomen, and pelvis (preferably with IV contrast if renal function is adequate) or whole-body MRI. Patients found to have extramedullary disease should have repeat imaging every 12 weeks (± 7 days) (using the same modality as used at screening). Imaging studies should also be performed when there is clinical suspicion of disease progression (if possible, throughout the study using the same modalities as those used at screening). Ultrasound of the abdomen/liver/spleen may be substituted for CT, PET/CT, or MRI if, in the investigator’s assessment, the patient cannot safely tolerate these imaging modalities and the anatomic location of the extramedullary disease is compatible with these alternative imaging modalities. xxii. Laboratory, Biomarker, and Other Biological Specimens

Analyze samples undergoing the following laboratory tests: ● Standard of care evaluation of bone marrow biopsy and aspirate for local clinical pathology evaluation, including but not limited to multiple myeloma response assessment, fluorescent in situ hybridization (FISH; including but not limited to the following markers: 1q gain, del17, t(11:14), t(4;14), t(14;16)), percentage of abnormal plasma cells, plasma cytoplasmic kappa:lambda ratio, and immunophenotype of abnormal plasma cells. ● Myeloma-specific tests: quantitative Ig (IgA, IgG, and IgM), SPEP and SIFE, UPEP, SFLC. ● Hematology: Hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, absolute neutrophil count, and percentage or absolute differential counts (segmented neutrophil bands, lymphocytes, eosinophils, monocytes, eosinophils, and other cells). ● Coagulation: aPTT, PT, INR, and fibrinogen. ● Serum chemistry: Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, magnesium, phosphorus, LDH, and uric acid. ● Liver function tests (LFTs): Total and direct bilirubin, total protein, albumin, ALT, AST, ALP, and gamma-glutamyl transpeptidase (GGT). ● Serum beta-2 microglobulin. ● C-reactive protein (CRP). ● Serum ferritin. ● Viral serology and testing. – Hepatitis B (HBsAg, HBsAb, and HBcAb; HBV DNA by PCR if acute or chronic HBV infection cannot be excluded based on serology (cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf) – HCV antibodies; HCV RNA by PCR if patient is HCV antibody positive – HIV serology – EBV, CMV, and HHV-6 quantitative PCR ● B arm only: thyroid function tests (TSH, free T3, and free T4)

Samples undergoing the following laboratory tests will be analyzed: ● Myeloma-specific tests: SPEP and SIFE, UPEP, SFLC. ● Blood samples for: Leukocyte immunophenotyping/flow cytometry (FACS lymphocyte subsets), including but not limited to enumeration of leukocyte subsets (e.g., T cells (CD3+, CD4+, CD8+), B cells (CD19+), and NK cells [CD16+, CD56+]), and assessment of T cell functional status by flow cytometry (using markers including but not limited to CD69, CD25, Ki67). ● Blood samples for whole genome sequencing (WGS) and human leukocyte antigen (HLA) genotyping. ● Blood for peripheral biomarkers (including but not limited to IL-6 and IFN-γ). ● Serum samples for ceftriaxone ADA analysis. – Serum samples for daratumumab ADA analysis will be collected and stored for possible future analysis. ● Serum samples for ceftriaxone PK analysis. ● Plasma samples for pomalidomide PK analysis. ● Serum samples for daratumumab PK analysis. ● Analysis of bone marrow aspirates, clots, and biopsy samples may include but are not limited to: – Pharmacodynamic biomarkers, ceftriaxone pharmacokinetics, MRD status, and changes in gene expression. Samples may be processed to obtain bone marrow mononuclear cells and their derivatives (e.g., RNA and DNA). – Leukocyte immunophenotyping, including but not limited to leukocyte subset counts (e.g., T cells (CD3+, CD4+, CD8+), B cells (CD19+), and NK cells (CD16+, CD56+)), and assessment of FcRH5+ target cell depletion, T cell functional status (using markers including but not limited to CD69, CD25, Ki67).

Cytogenetic status is confirmed by FISH or other molecular-based assays in a central testing laboratory using fresh bone marrow aspirate (at baseline only). ● Bone marrow aspirate and ring biopsy with relevant pathology reports are required prior to dosing on Pre-Phase Day 1 (Arm B) or Cycle 1 Day 1 (Arms A and C), within 3 days prior to Cycle 2 Day 1 or the day prior to Cycle 2 Day 1 infusion, and when CR is suspected. In addition, bone marrow aspirates are required at 6 and 12 months after confirmed response. For bone marrow aspirate samples, refer to the central laboratory manual for the volume of aspirate to be collected. The length of the ring/core biopsy tissue sample should preferably be a minimum of 1.5 cm (≥ 2 cm is optimal). If a paraffin block or fresh tissue is not available, 15-20 unstained slides should be sent to the sponsor (see the laboratory manual for further details). A bone marrow aspirate clot sample should only be submitted if the aspirate material has accidentally clotted. Please refer to the center laboratory manual for instructions on the submission of bone marrow aspirate clots. – For patients with extramedullary disease, in the rare circumstances where a bone marrow biopsy is not feasible, tissue obtained from an extramedullary plasmacytoma is acceptable but should meet the following criteria: If an excisional biopsy is performed, a formalin-fixed paraffin mount (preferably) or a minimum of 15 serially sectioned, unstained slides is required. For core needle biopsy tissue specimens, at least three core tissue samples should be submitted for evaluation. – Tumor tissue should be of good quality based on gross tumor content and viable tumor content (sites will be notified if the quality of the submitted specimen is inadequate). Fine needle aspiration, smear, pleural effusion-derived cellular sediment, and lavage fluid samples should not be used. – Acceptable samples include core needle biopsies for deep tumor tissue or lymph nodes or excisional, incisional, drill, or forceps biopsies for skin, subcutaneous, or mucosal lesions. D. Safety Plan

Ceftriaxone is in clinical development. The safety plan for patients in this study is based on the expected mechanism of action, clinical experience with ceftriaxone in ongoing studies, and the clinical safety profiles of pomalidomide, daratumumab, dexamethasone, and tocilizumab.

Measures have been taken to ensure the safety of patients enrolled in this trial, including the use of strict inclusion and exclusion criteria and close monitoring of patients, as described herein. For example, enrollment of the first 6 patients in the safety run-in was staggered so that the first 3 patients were each given their first study treatment dose at least 7 days apart, followed by subsequent patients being given their first study treatment dose at least 3 days apart, to allow for evaluation of any serious and unexpected acute or subacute drug or infusion-related toxicities.

Administration of ceftriaxone, daratumumab, and tocilizumab was performed in a setting with available emergency medical facilities and staff trained to monitor and respond to medical emergencies. Patients were monitored for safety during the studies, including assessment of the nature, frequency, and severity of adverse events.

All patients will be closely monitored for toxicity. Patients will be assessed for clinical toxicity using the NCI CTCAE v5.0 grading scale prior to each dose, except for CRS, for which the ASTCT consensus grading scale will be used (e.g., see Table 12). Neurological toxicity (non-ICANS) is graded according to NCI-CTCAE v5.0, ICANS events are graded according to ASTCT, and symptoms of ICANS are graded according to NCI-CTCAE v5.0. All adverse events and serious adverse events were recorded during the trial and followed up for 90 days after the last dose of study treatment in Arms A and B and for 102 days after the last dose of study treatment in Arm C or until initiation of another systemic anticancer therapy, whichever occurred first. To mitigate potential unknown risks, dosing after the first cycle is limited, at least in part, to patients who do not exhibit unacceptable toxicity or have clear evidence of progressive disease. Table 12. ASTCT Consensus Grading of Cytokine Release Syndrome CRS Parameters Level 1 Level 2 Level 3 Level 4 ^Fever Temperature ≥ 38°C Temperature ≥ 38°C Temperature ≥ 38°C Temperature ≥ 38°C Accompanied by Low blood pressure without No need for vasopressors Requires vasopressor medication with or without vasopressin Requires multiple vasopressors (excluding vasopressin) and/or ^b Hypoxia without Low flow nasal ^cannula or insufflation required Requires high flow nasal ^cannulac , face mask, non-rebreather mask, or venturi mask Requires positive pressure (eg, CPAP, BiPAP, intubation, mechanical ventilation) CRS = cytokine release syndrome; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Note: Organ toxicities associated with CRS may be graded according to NCI CTCAE v5.0, but they do not affect the CRS grade. ^a Fever is defined as a body temperature ≥ 38°C not attributable to any other cause. In patients with CRS who subsequently receive antipyretic or anticytokine therapy (e.g., tocilizumab or corticosteroids), fever is no longer necessary to grade the subsequent severity of CRS. In this setting, the CRS grade is driven by hypotension and/or hypoxia. ^b The CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with a temperature of 39.5°C, hypotension requiring a vasopressor, and hypoxia requiring a low-flow nasal cannula is classified as Grade 3 CRS. ^cLow -flow nasal cannula is defined as delivering oxygen at ≤ 6 L/min. Low flow also includes insufflated oxygen delivery, which is occasionally used in pediatrics. High-flow nasal cannula is defined as delivering oxygen at > 6 L/min.

The following sections describe specific known expected or potential toxicities associated with the administration of ceftriaxone, pomalidomide, daratumumab, dexamethasone, and tocilizumab, and the measures taken in this trial to avoid or minimize such toxicities. i. Infusion-Related Reactions / Cytokine Release Syndrome

The mechanism of action of ceftriaxone is immune cell activation directed against cells expressing FcRH5; therefore, a cascade of events may occur involving IRR, target-mediated cytokine release, and/or hypersensitivity reactions with or without acute ADA. Other bispecific antibody therapies involving T-cell activation have been associated with IRR, CRS, and/or hypersensitivity reactions.

Based on nonclinical and clinical data observed to date, ceftriaxone has the potential to cause rapid increases in plasma cytokine levels and CRS clinical events. Given the expected human pharmacology of ceftriaxone, IRR may be clinically indistinguishable from the presentation of CRS, which is defined as a condition characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath (NCI CTCAE v.5.0) in which T-cell engagement with plasma cells and B cells results in T-cell activation and cytokine release. To minimize the risk of IRR and CRS, ceftriaxone will be administered over a minimum of 4 hours in the pre-phase (Arm B) or during Cycle 1 (Arms A and C) in the clinical setting, and patients will be hospitalized for all escalating doses and the first target dose.

Mild to moderate manifestations of IRR and/or CRS may include symptoms such as fever, headache, and myalgia and may be treated symptomatically with analgesics, antipyretics, and antihistamines as indicated. Severe or life-threatening manifestations of IRR and/or CRS, such as hypotension, tachycardia, dyspnea, hypoxia, or chest discomfort, should be treated aggressively with supportive and resuscitative measures as indicated, including high-dose corticosteroids, IV fluids, anticytokine therapy, intensive care unit admission, and other supportive measures as per institutional practice. Severe CRS may be associated with other clinical sequelae of disseminated intravascular coagulation, microvascular permeability syndrome, or MAS. Standards of care for severe or life-threatening CRS due to immune-based therapies have not been established; case reports and recommendations for the use of anticytokine therapy such as tocilizumab have been published (e.g., see Teachey et al., Blood, 121:5154-7, 2013; Lee et al., Blood, 124:188-195, 2014; Maude et al., New Engl J Med., 371:1507-17, 2014; and Lee et al., Biol Blood Marrow Transplant, 25:625-638, 2019).

Severe COVID-19 has been associated with CRS involving the inflammatory cytokines IL-6, IL-10, IL-2, and IFN-γ. Ceftriaxone is a bispecific agent that recruits T cells and has an established risk of causing CRS; therefore, if a patient develops severe CRS during the study, differential diagnosis using testing should be considered to exclude COVID-19 infection. ii. Hemophagocytic lymphohistiocytosis / macrophage activation syndrome

HLH/MAS is a rare condition characterized by inappropriate immune system activation, usually triggered by factors such as infections (including EBV), autoimmune diseases, and malignancies (including, rarely, MM).

Severe CRS and HLH/MAS may have overlapping manifestations and symptoms. However, unlike CRS, HLH/MAS only occurred after cycle 1 in clinical trials of ceftriaxone. In addition, not all cases of HLH/MAS reported in clinical trials of ceftriaxone were preceded by CRS. In general, patients who experienced HLH/MAS in clinical trials of ceftriaxone presented with fever, pancytopenias, elevated transaminases, and elevated ferritin levels. Investigators should maintain a high index of suspicion for HLH/MAS so that appropriate testing and management can be initiated promptly.

Guidelines for the diagnosis, monitoring, and management of HLH/MAS are outlined below. Signs and symptoms may be nonspecific and onset may be subtle at first. Once HLH/MAS is suspected, rapid assessment of organ damage should be a priority, with the goal of initiating treatment as soon as possible once a diagnosis of HLH/MAS is made.

Traditionally, the diagnosis of HLH/MAS has used the HLH-2004 criteria, which require the fulfillment of at least five of the following eight criteria: (1) fever ≥38.5°C; (2) splenomegaly; (3) peripheral blood cytopenias affecting at least two cell lines (e.g., hemoglobin <9 g/dL, platelets <100,000/μL and/or absolute neutrophil count <1000/μL); (4) fasting triglycerides >265 mg/dL and/or fibrinogen <150 mg/dL; (5) hemophagocytosis in the bone marrow, spleen, lymph nodes, or liver; (6) low or absent NK cell activity; and (7) ferritin. >500 ng/mL; (8) Soluble interleukin-2 (IL-2) receptor (soluble CD25) elevated by two standard deviations above the laboratory-specified normal range.

Due to the overlapping features of CRS and underlying hematologic malignancies, these HLH/MAS diagnostic criteria may not be optimal in the setting of T-cell redirection therapy. Although there is currently no universally accepted set of criteria for diagnosing HLH/MAS in this setting, guidelines have been proposed that include elevated ferritin (>2 × ULN or baseline, and/or rapidly rising) in the setting of a hyperinflammatory syndrome independent of CRS and ICANS. Rather than using specific laboratory cutoffs, investigators are advised to consider the above criteria in conjunction with the following constellation of signs or symptoms presented by the patient to make the diagnosis: ● Acute or unexplained elevation of ferritin, particularly if accompanied by evidence of liver damage (marked elevation of transaminases and/or bilirubin), new onset or marked worsening of cytopenias, and/or evidence of coagulopathy. ● Signs of excessive inflammation (elevated CRP, ferritin, and similar indices) associated with acute organ damage to the lungs, kidneys, nervous system, and/or other organ systems. Signs and symptoms of severe sepsis. ● Fever of unknown origin. ● CRS ≥ Grade 3 at presentation. ● Delayed CRS signs and symptoms, regardless of severity, first appeared >72 hours after ceftriaxone administration. ● CRS symptoms, regardless of severity, persisted >24 hours after initial management and appeared refractory to treatment.

In all suspected cases of HLH/MAS, further administration of ceftriaxone should be withheld. If HLH/MAS is confirmed, ceftriaxone treatment should be discontinued. Table 13 contains recommended investigation, monitoring, and treatment guidelines for suspected or confirmed cases of HLH/MAS. The investigation, monitoring, and treatment recommendations in this guideline are not mandatory. Treatment for HLH/MAS should still be individualized based on the patient's clinical condition, institutional practice, and available therapies, and determined in consultation with the study investigator and a hematologist or other expert with expertise in the treatment of HLH/MAS. Table 13. Guidelines for the Investigation and Management of Suspected Hemophagocytic Lymphohistiocytosis / Macrophage Activation Syndrome If HLH/MAS is suspected or confirmed , mandatory guidance must be provided ● For suspected cases, withhold study medication and initiate workup for HLH/MAS. ● For confirmed cases of HLH/MAS, permanently discontinue the causative study medication. ● Discuss all suspected HLH/MAS cases. ● There should be no delay in providing care for patients with suspected/confirmed HLH/MAS. Non-binding guidance: The details provided below are intended to be informative guidance only. ● Treatment for HLH/MAS should be individualized based on the patient's clinical condition, institutional practice, and available therapies, and determined in consultation with the study investigator and a hematologist or other expert with expertise in the treatment of HLH/MAS. Surveys to consider ● Complete blood count (CBC) with differential● Renal function (creatinine and urea/BUN) ● Coagulation studies (PT, aPTT, fibrinogen, D-dimer) ● LFTs (AST, ALT, ALP, GGT, total and direct bilirubin, albumin) ● LDH, serum ferritin, CRP ● Serum triglycerides● Microscopic examination + blood and urine cultures● Bone marrow aspiration ± biopsy (and lymph node biopsy if lymphadenopathy is present). ● Viral titer: quantitative PCR testing for EBV, CMV, adenovirus, SARS-CoV-2, and other suspected ^virusesa ● Echocardiogram (ECG) and chest radiography (or CT) ● Further investigations as appropriate and/or time permits: ○ Soluble CD25, NK cell function ○ DNA ^testinga ○ Other tests based on signs/symptoms of organ involvement Monitoring ● Laboratory tests should be monitored closely (e.g., CBC, LFTs, creatinine, urea/BUN, CRP, ferritin, LDH, PT/aPTT, fibrinogen, D-dimer, triglycerides). Monitoring at least twice daily is recommended until stable. ● Close vital sign and neurologic monitoring (at least every 4 hours is recommended). Consider ICU admission if rapidly worsening. ● If HLH/MAS is highly suspected and initial results are negative, consider repeat bone marrow biopsy (± lymph node biopsy if lymphadenopathy is present). manage Effective treatment of HLH/MAS often requires a multifaceted approach that includes the following: ● Supportive care , as life-threatening manifestations occur. Consider ICU support if deteriorating rapidly. ● Elimination of triggering factors (especially infection) is critical to remove the stimulus that triggers abnormal immune system activation. Broad-spectrum antimicrobial agents, antiviral agents (especially those targeting CMV, EBV, adenovirus), and/or antifungal agents should be started immediately as appropriate. ● Suppression of the inflammatory response should be started without delay. ● Options that may be considered for first-line management: ○ Dexamethasone 20 mg IV every 6-12 hours or methylprednisolone 1000 mg IV once a day for 3 or more ^{daysb , c} ○ IL-1 blockers (e.g., anakinra) in addition to corticosteroid therapy, particularly in severe/life-threatening casesb ^{, c ○} IL-6 blockers (e.g., tocilizumab) ^d ● Options that may be considered for refractory or rapidly progressive cases: ○ There is no standard of care for refractory/rapidly progressive cases. ○ Other agents that have been tested for the treatment of HLH/MAS in this setting include: ■ Switch to methylprednisolone 1000 mg IV for 3 or more days (if refractory to other corticosteroids/lower doses) ^{b , c} ■ Add an IL-1 blocker (e.g., anakinra) if not already given ^{b , c , d} ■ Other anticytokine therapy (e.g., sildenafil); other cytotoxic agents (e.g., etoposide); ^a or other immunomodulators (e.g., ruxolitinib) ^{b , d , e} ALP = alkaline phosphatase; CRS = cytokine-releasing syndrome; CMV = cytomegalovirus; CRP = C-reactive protein; CT = computed tomography; EBV = estradiol virus; GGT = gamma glutamyl transferase; HLH = hemophagocytic lymphohistiocytosis; ICANS = immune effector cell-associated neurotoxic syndrome; LDH = lactate dehydrogenase; LFT = liver function tests; MAS = macrophage activation syndrome; NK = natural killer; PCR = polymerase chain reaction. ^a DNA testing (eg, PRF1, MUNC13-4, STXBP2) may be considered as an exploratory analysis. Other virologies: Parvovirus, herpes simplex virus, varicella-zoster virus, measles virus, human herpes virus-8, influenza virus H1N1, and epizootic virus may be considered. ^b Hayden PJ, Roddie C, Bader P, et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Ann Oncol 2022;33:259-75. ^c Hines MR, Knight TE, McNerney KO, et al. Immune Effector Cell associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS). Transplant Cell Ther 2023;S2666-6367:01164-8。 ^d Abou-el-Enein M, Gauthier J. The value of CAR-T-cell immunotherapy in cancer. The EBMT/EHACAR-T cell handbook. Cham: Springer International Publishing; 2022. 231–4。 ^e Kennedy VE, Wong C, Huang CY, et al. Macrophage activation syndrome-like (MAS-L) manifestations following BCMA-directed CAR T cells in multiple myeloma. Blood Adv 2021;5:5344‑8。 iii. Dose modification and treatment interruption of ceftriaxone

Ceftriaxone will be administered only if the patient's clinical evaluation and laboratory test values are acceptable. If the planned administration coincides with a holiday when the administration of ceftriaxone is not possible, the administration should be started on the next nearest date.

All decisions regarding dosing and scheduling modifications require documented consultation between the Medical Monitor and the Investigator.

The following hematology laboratory thresholds should be met prior to administration of the first dose of ceftriaxone in Arms A and B and the first doses of daratumumab and ceftriaxone in Arm C: ● Platelet count ≥ 75,000/mm3 in the absence of transfusion within 7 days prior to the first dose ● ANC ≥ 1000/mm3 ● Total hemoglobin ≥ 8 g/dL – Supportive care, including transfusions and G-CSF, is permitted.

Prior to administration of ceftriaxone at doses exceeding the first ceftriaxone dose, the following hematology laboratory thresholds should be met: ● Platelet count ≥ 20,000/mm3 ● ANC ≥ 500/mm3 ● Hemoglobin ≥ 7 g/dL.

Supportive care, such as transfusions or G-CSF, may be provided according to institutional standard practice to meet hematologic thresholds for dosing. The following guidelines regarding dosing and schedule modifications should be followed: ● In general, patients receiving ceftriaxone who experience a Grade 4 adverse event that is not considered by the investigator to be attributable to another clearly identifiable cause should permanently discontinue all study treatment. However, for patients with asymptomatic Grade 4 adverse events with laboratory changes, ceftriaxone may be resumed once resolution is achieved to ≤ Grade 1. ● For patients who experience an IRR on the first dose of ceftriaxone or are at increased risk for recurring IRR on subsequent doses, the infusion rate should be reduced by 50% (e.g., see Table 3B). If a patient does not experience an IRR with subsequent doses, the infusion rate may be resumed back to the initial rate based on the investigator’s judgment. ● Patients who receive less than 80% of the intended escalation dose will require repeated escalations before receiving the target dose. ● In general, patients who experience Grade 3 adverse events that are not considered by the investigator to be attributable to another clearly identifiable cause (e.g., disease progression, concomitant medications, or pre-existing medical conditions) will be permitted to delay dosing for up to 2 weeks or longer to allow for recovery from toxicity. Patients may resume receiving additional ceftriaxone infusions provided that toxicity has resolved to ≤ Grade 1 (or ≥ 80% of baseline for laboratory abnormalities) within 2 weeks. – Consider reducing the dose and/or modifying the dosing schedule to a less frequent schedule for subsequent ceftriaxone infusions. Following the occurrence of Grade 3 toxicity related to study treatment, the decision to continue treatment should be made after the investigator and patient carefully evaluate and discuss the risks and benefits, including in the following circumstances: ■ If the increase in AST or ALT is > 3 × ULN (if baseline is within normal limits) or baseline (if baseline is > ULN) and total bilirubin is > 2 × ULN, and no individual laboratory value exceeds Grade 3, occurring in the setting of ≤ Grade 2 CRS lasting < 7 days, ceftriaxone can be continued without dose reduction. ■ Patients with Grade 3 anemia events that can be managed with red blood cell transfusions according to institutional practice may continue medication without dose reduction in consultation with the Medical Monitor. ■ Patients with Grade 3 or 4 thrombocytopenia or neutropenia events that can be managed with supportive care (e.g., transfusions (of platelets) or G-CSF) according to institutional practice may continue medication without dose reduction. ■ Patients with Grade 3 or 4 neutropenia or thrombocytopenia events that are considered to be attributable to illness but do not require transfusions or G-CSF may continue medication without dose reduction. – Any patient who experiences similar toxicity again at dose reduction should have further ceftriaxone treatment discontinued. ● Depending on the length of treatment delay, patients may require repeated dose escalations. For example, patients may require repeated dose escalations if their dose is delayed by more than 4 weeks from their normally scheduled dose or more than 4 weeks from their last dose before starting the retreatment phase in Arm A. Patients will require hospitalization after repeated dose escalations of ceftriaxone and the first subsequent target dose. Patients must repeat all planned safety laboratory assessments for the initial escalation; PK, ADA, and biomarker assessments for repeated escalation do not need to be repeated for patients in the safety run-in and expansion cohorts. ● Additional guidelines specific to Arm A: – Dose modifications during weekly dosing from Cycle 1 to Cycle 2 (first 7 weeks) ■ Patients who experience a grade ≥ 3 adverse event that does not meet the stopping criteria described herein may have dosing delayed or be considered for a reduction in the subsequent dose/frequency. ■ Patients who miss a scheduled weekly dose by more than 48 hours should skip that dose and continue as planned. ■ If two consecutive or non-consecutive doses are missed during the first 7 weeks, patients will automatically move to the Q2W schedule as outlined below. ■ If enrollment is stopped after safety thresholds are met during the safety run-in period, patients currently in the first 7 weeks of dosing will move to the Q2W schedule as outlined below. – Changing schedule from weekly dosing to Q2W in Cycle 1 to Cycle 2 ■ The next scheduled dose will be administered when the patient is able to resume treatment, at least 13 days after the most recent dose, as assessed by the Investigator. ■ If the most recent dose received was an escalating dose, the target dose should be administered as planned prior to moving to the Q2W schedule. ■ Subsequent doses after the next scheduled dose will be administered on Days 1 and 15 of each cycle until Cycle 7, when the schedule shifts to Q4W dosing. ● Additional Arm B-specific guidelines: – Skip the Day 15 dose of ceftriaxone if an AE occurs before Day 15 of Cycles 1 to 6 and the Day 15 dose of ceftriaxone cannot be administered within 3 days of the scheduled dose. – If an AE occurs on or after Day 15 of Cycles 1 through 6, or at any time during the cycle in Cycles 7+, and study treatment cannot be administered as planned on Day 1 of the subsequent cycle: ■ Delay study treatment on Day 1 until resolution of the AE, then restart study treatment and assessments as planned on D1 of the cycle. ● For Arms B and C – If a patient permanently stops taking one of the combination drugs, the patient may continue on the other study drug as outlined in the individual group schedule. Pomalidomide

Guidance for pomalidomide dose modifications is described in Table 14. Table 14. Pomalidomide dose modifications Maximum dose Dose level 2 Dose level 1 (starting dose) Dose Level -1 Dose Level -2 4 mg 3 mg 2 mg 1 mg Permanently disable

If toxicity cannot be managed with dose modifications or the patient cannot tolerate the lowest dose of study drug (e.g., 1 mg), the patient should discontinue combination therapy. However, if pomalidomide is permanently discontinued, the other study drug may be continued according to the specific combination schedule.

If co-administration of a strong CYP1A2 inhibitor is medically necessary, the pomalidomide dose should be reduced by 50%.

Additional guidelines specific to Arm B: ● If the AE occurs before Day 15 and resolves before D21, and pomalidomide treatment is discontinued, restart pomalidomide at the same dose level from the time of resolution of the AE for the remainder of the cycle (until D21). ● If the AE occurs before Day 15 and resolves after D21, and pomalidomide treatment is discontinued, do not start pomalidomide until the next cycle. ● If pomalidomide treatment is withheld on Day 1 of a cycle due to persistent AEs, but ceftriaxone is administered, and the AE subsequently resolves before Day 21, pomalidomide may be administered from the date of resolution of the AE to Day 21 of that cycle. If the AE resolves after day 21, pomalidomide will be restarted in subsequent cycles.

Dose modifications of daratumumab were not permitted. Adverse events associated with daratumumab may be managed with dose delays.

Daratumumab administration may be restarted if the delay is within the time frame specified in Table 15. If daratumumab administration is not started within the scheduled window of the scheduled administration date, the dose will be considered a missed dose. Administration may be resumed on the next scheduled dosing date. Missed doses will not be made up. Table 15. Daratumumab Administration Schedule Dosage ^Suspension daysa Resume medication Dosage 1-9 > 3 days Next scheduled weekly dosing date Dosage 10-14 > 10 days Next scheduled Q3W dosing date Dosage 15 + > 14 days Next scheduled Q4W dosing date aFollow this table ^only if dosing is delayed by more than 3 days.

If a dose delay occurs, PK and pharmacodynamic assessments should be performed on the actual day of study drug administration rather than on the originally planned day of administration.

Patients who require a pause of daratumumab for >28 days to resolve daratumumab-related toxicity should permanently discontinue daratumumab.

In the event of an interruption or missed dose of daratumumab, other study medications should continue to be administered according to the individual arm schedule without delay. If daratumumab is permanently discontinued, other study medications may continue according to the individual arm dosing schedule. For additional details, please refer to the local prescribing information for daratumumab. Dexamethasone

The dose of dexamethasone given as a premedication or postmedication should not be modified during the first two cycles of ceftriaxone treatment. Permanently discontinue dexamethasone (excluding premedication or postmedication) given as a protocol-specific corticosteroid in Arms B and C if intolerance level -1 is reached (e.g., see Table 16). After Cycle 2, dexamethasone may be tapered at the investigator’s discretion before complete discontinuation, based on institutional practice. Patients may continue treatment with other protocol-specified medications. Guidelines for dexamethasone dose reductions are described in Table 16. Table 16. Dexamethasone Dose Reductions Starting dose Dose Level -1 Dose Level -2 20 mg 12 mg Permanently disable

Additional guidance specific to Arm B: ● If an AE occurs on or after Day 15 of Cycles 1 to 6, or at any time during the cycle in Cycles 7+, and study treatment cannot be administered as planned on Day 1 of the subsequent cycle: – Delay study treatment (including dexamethasone) on Day 1 until the AE resolves, then restart study treatment administration and assessments as planned on D1 of the cycle. iv. Cytokine Release Syndrome, Infusion-Related Reactions, and Local Injection Site Reactions

Investigators should promptly manage IRR and/or CRS, for example, according to Tables 14 and 15. For guidance on the management of CRS, see Table 3A. For suggested guidance on the management of IRR, see Table 3B. v. Administration-related reactions and local injection site reactions associated with daratumumab

Both administration-related reactions (including severe or life-threatening reactions) and local injection site reactions may occur with SC daratumumab. The median time to administration-related reactions after SC daratumumab is approximately 3.5 hours. If an administration-related reaction occurs, SC daratumumab administration should be temporarily interrupted. Patients who experience adverse events during SC daratumumab administration may be treated with acetaminophen (acetaminophen), antihistamines, or corticosteroids as needed. For bronchospasm, urticaria, or difficulty breathing, patients may require antihistamines, oxygen, corticosteroids, or bronchodilators. For low blood pressure, patients may require IV fluids or vasopressors. SC daratumumab should be discontinued if a life-threatening administration-related reaction (which may include pulmonary or cardiac events) or allergic reaction occurs.

Local injection site reactions should be managed according to institutional standards. In addition to institutional guidelines (e.g., see Table 17), there are specific instructions for the management of administration-related reactions associated with daratumumab. Table 17. Suggested Management Guidelines for Systemic Administration-Related Reactions Associated with Daratumumab toxicity Actions taken Level 1 to 2 Interrupt SC daratumumab. SC daratumumab may be restarted at the investigator's discretion when the patient is stable. Patients must permanently discontinue SC daratumumab if they experience an event of ≥ Grade 2 laryngeal edema, or an event of ≥ Grade 2 bronchospastic spasm that is unresponsive to systemic therapy and does not resolve within 6 hours of onset. Level 3 For Grade 3 administration-related reactions (except laryngeal edema or bronchospasm), SC daratumumab administration must be discontinued and the patient must be carefully observed until the adverse event resolves or until the intensity of the event decreases to Grade 1, at which point SC daratumumab administration may be restarted at the discretion of the investigator. If the intensity of the adverse event returns to Grade 3 after restarting SC daratumumab administration, the patient must permanently discontinue SC daratumumab treatment. Level 4 For Grade 4 administration-related reactions, SC daratumumab administration must be withheld. Permanently discontinue SC daratumumab treatment in patients. Recurrent administration-related reactions If a Grade 3 administration-related reaction (or ≥ Grade 2 laryngeal edema event, or ≥ Grade 2 bronchospastic event) recurs during or within 24 hours of a subsequent SC daratumumab administration, the patient must permanently discontinue SC daratumumab treatment.

In some patients, SC administration of daratumumab in abdominal tissues has been associated with local injection site reactions (e.g., induration and erythema). Reactions generally resolve within 60 minutes (e.g., see Table 18). Table 18. Suggested Management Guidelines for Local Injection Site Reactions Associated with Daratumumab toxicity Actions taken Local injection site reactions ● Local injection site reactions should be managed according to institutional standards.

Although the above invention is described in detail by way of illustrations and examples for the sake of clear understanding, such descriptions and examples should not be interpreted as limiting the scope of the invention. The disclosures of all patents and scientific documents cited herein are expressly incorporated by reference in their entirety.

Figure 1 shows a schematic diagram of the safety lead-in and expansion cohort of the B arm described in Example 1. "Q2W" means "every two weeks". "Q4W" means "every four weeks". Figure 2 shows a schematic diagram of the safety lead-in and expansion cohort of the C arm described in Example 1. "Q3W" means "every three weeks". Figure 3 shows a schematic diagram of the single-agent ceftriaxone Arm A single-increment dosing regimen ("modified weekly" schedule) described herein (e.g., see Example 1). "QW" means "weekly". FIG4 shows a schematic diagram of the arm B double re-escalation dosing regimen of the combination of ceftriaxone, pomalidomide (P) and dexamethasone (d) using the Q2W/Q4W ceftriaxone dosing schedule described herein (e.g., see Example 1). "Pd" refers to the combination of pomalidomide and dexamethasone . FIG5 shows a schematic diagram of the arm C double re-escalation dosing regimen of the combination of ceftriaxone, daratumumab (D) and dexamethasone (d) using the Q3W/Q4W ceftriaxone dosing schedule described herein (e.g., see Example 1). "Dd" refers to the combination of daratumumab and dexamethasone. Figure 6 shows a schematic diagram of the B-arm split-incremental dosing regimen of the combination of cefuroxime and Pd using the Q2W/Q4W cefuroxime dosing schedule described herein (e.g., see Example 1). Figure 7 shows a schematic diagram of the C-arm split-incremental dosing regimen of the combination of cefuroxime and Dd using the Q3W/Q4W cefuroxime dosing schedule described herein (e.g., see Example 1).

TW202448949A_113116571_SEQL.xml

Claims (245)

A method of treating an individual with multiple myeloma (MM), the method comprising administering to the individual a bispecific antibody that binds to Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), wherein the individual does not have: (i) a history of macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH); (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic coronavirus disease 2019 (COVID-19) Infection or need for treatment with intravenous antivirals. A method for treating an individual with MM, the method comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every week (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the individual every four weeks (Q4W), Wherein the individual does not have: (i) a history of MAS or HLH; (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or a need for treatment with intravenous antiviral agents. The method of claim 2, wherein each dosing cycle is a 28-day dosing cycle. The method of claim 3, wherein the first phase comprises at least two dosing cycles. The method of claim 4, wherein the first phase comprises a first dosing cycle (C1) and a second dosing cycle (C2). The method of claim 5, wherein the first stage comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and day 22 of C1. The method of claim 5 or 6, wherein the first stage comprises administering the bispecific antibody to the individual on day 1, day 8, day 15, and day 22 of C2. The method of any one of claims 1 to 7, wherein a target dose of the bispecific antibody is administered to the subject at each administration during the first phase. The method of any one of claims 5 to 7, wherein the first stage comprises administering a first step-up dose of the bispecific antibody to the individual. The method of claim 9, wherein the first escalating dose is administered to the subject on day 1 of C1. The method of claim 10, wherein the target dose is administered to the subject on day 8, day 15, and day 22 of C1. The method of claim 11, wherein the target dose is further administered to the subject on day 1, day 8, day 15, and day 22 of C2. The method of claim 11 or 12, wherein the first incremental dose is about 4% of the target dose. The method of any one of claims 5 to 7, wherein the first stage comprises administering to the subject a first increasing dose and a second increasing dose of the bispecific antibody. The method of claim 14, wherein the first escalating dose is administered to the subject on day 1 of C1 and the second escalating dose is administered to the subject on day 8 of C1. The method of claim 15, wherein the target dose is administered to the subject on day 15 and day 22 of C1. The method of claim 16, wherein the target dose is further administered to the subject on day 1, day 8, day 15, and day 22 of C2. The method of claim 16 or 17, wherein: (a) the first incremental dose is 0.33% of the target dose; and (b) the second incremental dose is approximately 4% of the target dose. The method of any one of claims 9 to 13, wherein the first incremental dose is 3.6 mg. The method of any one of claims 14 to 18, wherein the first increasing dose is 0.3 mg and the second increasing dose is 3.6 mg. The method of any one of claims 3 to 20, wherein the second phase comprises at least two dosing cycles, at least three dosing cycles, or at least four dosing cycles. The method of claim 21, wherein the second phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4). The method of claim 22, wherein the second phase comprises administering the bispecific antibody to the individual on day 1 and day 15 of C1, C2, C3 and/or C4. The method of any one of claims 21 to 23, wherein a target dose of the bispecific antibody is administered to the subject at each administration during the second phase. The method of any one of claims 3 to 24, wherein the third phase comprises at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, or at least seven dosing cycles. The method of claim 25, wherein the third phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7). The method of claim 26, wherein the third phase comprises administering the bispecific antibody to the individual on day 1 of C1, C2, C3, C4, C5, C6 and/or C7. The method of any one of claims 25 to 27, wherein a target dose of the bispecific antibody is administered to the subject at each administration during the third phase. The method of any one of claims 8, 11 to 13, 16 to 18, 24, and 28, wherein the target dose is 90 mg. The method of any one of claims 1 to 29, wherein the bispecific antibody is administered to the individual as a monotherapy. The method of claim 30, wherein the bispecific antibody is administered intravenously to the subject. A method of treating an individual with MM, the method comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 and an immunomodulatory drug (IMiD) in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W), wherein the individual does not have: (i) a history of MAS or HLH; (ii) a positive and quantifiable EBV prior to treatment with the bispecific antibody or CMV; or (iii) active symptomatic COVID-19 infection or need for treatment with intravenous antiviral agents. The method of claim 32, wherein each dosing cycle of the first phase and the second phase is a 28-day dosing cycle. The method of claim 32 or 33, further comprising a preliminary phase preceding the first phase comprising one or more administration cycles. The method of claim 34, wherein the pre-stage comprises administering the bispecific antibody to the individual weekly (QW). The method of claim 34 or 35, wherein each dosing cycle in the preliminary phase is a 21-day dosing cycle. The method of any of claims 34 to 36, wherein the pre-phase comprises a dosing cycle (C1). The method of any one of claims 34 to 37, wherein the pre-stage comprises administering the bispecific antibody to the individual on day 1, day 8, and day 15 of C1. The method of any one of claims 34 to 38, wherein a target dose of the bispecific antibody is administered to the subject at each administration during the pre-phase. The method of any one of claims 34 to 38, wherein the preliminary stage comprises administering to the individual a first increasing dose of the bispecific antibody. The method of claim 40, wherein the first escalating dose is administered to the subject on day 1 of C1. The method of claim 40 or 41, wherein the target dose is administered to the subject on day 8 and day 15 of C1. The method of any of claims 40 to 42, wherein the first incremental dose is about 2.73% of the target dose. The method of any of claims 40 to 42, wherein the first incremental dose is about 4% of the target dose. The method of any one of claims 40 to 44, wherein the first incremental dose is 3.6 mg. The method of any one of claims 34 to 38, wherein the preliminary stage comprises administering to the subject a first increasing dose and a second increasing dose of the bispecific antibody. The method of claim 46, wherein: (a) the first incremental dose is 0.23% of the target dose; and (b) the second incremental dose is approximately 2.73% of the target dose. The method of claim 46, wherein: (a) the first incremental dose is 0.33% of the target dose; and (b) the second incremental dose is approximately 4% of the target dose. The method of claim 47 or 48, wherein the first increasing dose is 0.3 mg and the second increasing dose is 3.6 mg. The method of claim 49, wherein the first escalating dose is administered to the subject on day 1 of C1 and the second escalating dose is administered to the subject on day 8 of C1. The method of any of claims 47 to 50, wherein the target dose is administered to the subject on day 15 of C1. The method of claim 34, wherein each dosing cycle in the preliminary phase is a 14-day dosing cycle. The method of claim 52, wherein the pre-stage comprises a dosing cycle (C1). The method of claim 52 or 53, wherein the pre-phase comprises administering the bispecific antibody to the individual on: (a) Day 1, Day 2, and Day 8 of C1; (b) Day 1, Day 3, and Day 8 of C1; or (c) Day 1, Day 4, and Day 8 of C1. The method of claim 54, wherein if the individual has an adverse reaction to the bispecific antibody, the bispecific antibody is administered to the individual on days 1, 3, and 8 of C1 or on days 1, 4, and 9 of C1. The method of any one of claims 52 to 55, wherein the preliminary stage comprises administering to the subject a first increasing dose and a second increasing dose of the bispecific antibody. The method of claim 56, wherein: (a) the first incremental dose is an amount of 0.23% of the target dose; and (b) the second incremental dose is an amount of approximately 2.5% of the target dose. The method of claim 56, wherein: (a) the first incremental dose is about 0.33% of the target dose; and (b) the second incremental dose is about 3.6% of the target dose. The method of claim 57 or 58, wherein the first increasing dose is 0.3 mg and the second increasing dose is 3.3 mg. The method of any one of claims 56 to 59, wherein the first increasing dose is administered to the subject on day 1 of C1 and the second increasing dose is administered to the subject on day 2 to day 4 of C1. The method of any of claims 57 to 60, wherein: (a) the first escalating dose is administered on day 1 of C1 and the second escalating dose is administered on day 2 of C1; (b) the first escalating dose is administered on day 1 of C1 and the second escalating dose is administered on day 3 of C1; or (c) the first escalating dose is administered on day 1 of C1 and the second escalating dose is administered on day 4 of C1. The method of any of claims 57 to 61, wherein the target dose is administered to the subject on day 8 of C1. The method of any of claims 33 to 62, wherein the first phase comprises at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, or at least six dosing cycles. The method of claim 63, wherein the first phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6). The method of claim 64, wherein the first stage comprises administering the bispecific antibody to the individual on day 1 and day 15 of C1, C2, C3, C4, C5 and/or C6. The method of claim 65, wherein a target dose of the bispecific antibody is administered to the subject at each administration during the first phase. The method of any of claims 33 to 66, wherein the second phase comprises at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, or at least seven dosing cycles. The method of claim 67, wherein the second phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7). The method of claim 67, wherein the second phase comprises administering the bispecific antibody on day 1 of C1, C2, C3, C4, C5, C6 and/or C7. The method of claim 69, wherein a target dose of the bispecific antibody is administered to the subject at each administration during the second phase. The method of any of claims 8, 11, 16, 24, 28, 39, 42, 47, 57, 66, and 70, wherein the target dose is 132 mg. The method of any of claims 8, 11, 16, 24, 28, 39, 42, 48, 58, 66, and 70, wherein the target dose is 90 mg. The method of any one of claims 33 to 72, wherein the bispecific antibody is administered intravenously to the subject. The method of any one of claims 33 to 73, wherein the IMiD is administered to the subject on day 1 to day 21 of each dosing cycle in the first phase and/or the second phase. The method of any one of claims 32 to 74, wherein the IMiD is pomalidomide. The method of claim 75, wherein pomalidomide is administered to the subject in an amount of about 2 mg to about 4 mg. The method of claim 76, wherein pomalidomide is administered to the subject in an amount of about 4 mg. The method of claim 76, wherein pomalidomide is administered to the subject in an amount of about 2 mg. The method of claim 78, wherein the first phase comprises C1, C2, C3, C4, C5, and C6, the subject has an absolute neutrophil count (ANC) greater than or equal to 1000/μl and platelets greater than or equal to 75,000 μl, and the dose of pomalidomide is increased to about 4 mg in C2 of the first phase. The method of any one of claims 71 to 79, wherein pomalidomide is administered to the subject orally. The method of any one of claims 36 to 80, further comprising administering a corticosteroid to the individual during the pre-phase, the first phase, and/or the second phase. The method of claim 81, wherein the corticosteroid is administered to the subject intravenously or orally. The method of claim 81 or 82, wherein the corticosteroid is administered to the subject QW during the pre-phase, the first phase, and/or the second phase. The method of any one of claims 81 to 83, wherein the corticosteroid is administered to the subject during the pre-phase on day 1, day 8, and day 15 of C1. The method of any of claims 81 to 84, wherein the corticosteroid is administered intravenously to the subject during the pre-period on day 1, day 8, and day 15 of C1. The method of any one of claims 81 to 85, wherein the corticosteroid is administered to the subject on day 1, day 8, day 15, and day 22 of C1, C2, C3, and/or C4 during the first phase. The method of claim 86, wherein the corticosteroid is administered to the subject: (a) intravenously on day 1 and day 15 of C1, C2, C3 and/or C4 during the first phase; and (b) orally on day 8 and day 22 of C1, C2, C3 and/or C4 during the first phase. The method of claim 81 or 82, wherein the corticosteroid is administered to the subject during the pre-phase on: (a) Day 1, Day 2, and Day 8 of C1; (b) Day 1, Day 3, and Day 8 of C1; or (c) Day 1, Day 4, and Day 8 of C1. The method of claim 88, wherein the corticosteroid is administered intravenously to the subject on day 1, day 2, and day 8 of C1 during the pre-period. The method of any one of claims 81 to 89, wherein the corticosteroid is administered to the subject on day 1, day 8, day 15, and day 22 of C1, C2, C3, and/or C4 during the first phase. The method of claim 90, wherein the corticosteroid is administered to the subject: (a) intravenously on days 1 and 15 of C1 during the first phase; and (b) orally on days 8 and 22 of C1 during the first phase. The method of any one of claims 81 to 91, wherein the corticosteroid is further administered to the subject on day 1, day 8, day 15 and/or day 22 of C1, C2, C3, C4, C5, C6, C7, C8 and/or C9 during the second phase. The method of claim 92, wherein the corticosteroid is administered to the subject: (a) intravenously or orally on day 1 of C1, C2, C3, C4, C5, C6, C7, C8 and/or C9 during the second phase; and (b) orally on day 8, day 15 and/or day 22 of C1, C2, C3, C4, C5, C6, C7, C8 and/or C9 during the second phase. The method of any one of claims 91 to 93, wherein the corticosteroid is administered intravenously to the subject prior to administering the bispecific antibody. The method of claim 94, wherein the corticosteroid is administered intravenously to the subject about 1 hour prior to administering the bispecific antibody. The method of any one of claims 81 to 95, wherein the corticosteroid is dexamethasone or methylprednisolone. The method of claim 96, wherein the corticosteroid is dexamethasone. The method of claim 96 or 97, wherein the dexamethasone is administered to the subject in an amount of about 20 mg. The method of claim 96 or 97, wherein the dexamethasone is administered to the subject in an amount of about 15 mg. The method of claim 96 or 97, wherein the dexamethasone is administered to the subject in an amount of about 4 mg. The method of claim 96, wherein the methylprazosin is administered to the subject in an amount of about 80 mg. A method for treating an individual with MM, the method comprising administering to the individual a bispecific antibody that binds to FcRH5 and CD3 and an anti-cluster of differentiation 38 (CD38) antibody in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every three weeks (Q3W); and (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W), wherein the individual does not have: (i) a history of MAS or HLH; (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or need for treatment with intravenous antiviral agents. The method of claim 102, wherein each dosing cycle in the first phase is a 21-day dosing cycle. The method of claim 102 or 103, wherein each dosing cycle in the second phase is a 28-day dosing cycle. The method of any of claims 102 to 104, further comprising a run-in phase preceding the first phase comprising one or more dosing cycles. The method of claim 105, wherein the introduction phase comprises administering the bispecific antibody to the individual weekly (QW). The method of claim 105 or 106, wherein each dosing cycle during the introduction phase is a 21-day dosing cycle. The method of any of claims 105 to 107, wherein the introduction phase comprises a dosing cycle (C1). The method of claim 108, wherein the introduction phase comprises administering the bispecific antibody to the individual on: (a) Day 2, Day 9, and Day 16 of C1; or (b) Day 3, Day 9, and Day 16 of C1. The method of claim 109, wherein if the individual has an adverse reaction to the anti-CD38 antibody, the bispecific antibody is administered to the individual on day 3, day 9, and day 16 of C1. The method of any one of claims 105 to 110, wherein a target dose of the bispecific antibody is administered to the subject at each administration during the introduction phase. The method of any one of claims 105 to 110, wherein the introduction phase comprises administering a first increasing dose of the bispecific antibody to the subject. The method of claim 112, wherein the first escalating dose is administered to the subject on day 2 of C1 or on day 3 of C1. The method of claim 112 or 113, wherein the target dose is administered to the subject on day 9 and day 16 of C1. The method of any of claims 112 to 114, wherein the first incremental dose is about 2.25% of the target dose. The method of any of claims 112 to 115, wherein the first incremental dose is 3.6 mg. The method of any one of claims 105 to 110, wherein the introduction phase comprises administering to the subject a first increasing dose and a second increasing dose of the bispecific antibody. The method of claim 117, wherein: (a) the first escalating dose is administered to the subject on day 2 of C1 or on day 3 of C1; and (b) the second escalating dose is administered to the subject on day 9 of C1. The method of claim 117 or 118, wherein: (a) the first incremental dose is about 0.19% of the target dose; and (b) the second incremental dose is about 2.25% of the target dose. The method of any of claims 117 to 119, wherein the first increasing dose is 0.3 mg and the second increasing dose is 3.6 mg. The method of claim 105, wherein the introduction phase comprises administering the bispecific antibody to the individual on: (a) Day 9, Day 10, and Day 16 of C1; (b) Day 9, Day 11, and Day 16 of C1; or (c) Day 9, Day 12, and Day 16 of C1. The method of claim 121, wherein if the individual has an adverse reaction to the bispecific antibody, the bispecific antibody is administered to the individual on days 9, 11, and 16 of C1 or on days 9, 12, and 16 of C1. The method of claim 121 or 122, wherein the introduction phase comprises administering to the subject a first increasing dose and a second increasing dose of the bispecific antibody. The method of claim 123, wherein: (a) the first incremental dose is about 0.19% of the target dose; and (b) the second incremental dose is about 2.1% of the target dose. The method of claim 123 or 124, wherein the first increasing dose is 0.3 mg and the second increasing dose is 3.3 mg. The method of any of claims 123 to 125, wherein: (a) the first increasing dose is administered to the subject on day 9 of C1; and (b) the second increasing dose is administered to the subject on day 10, day 11, or day 12 of C1. The method of any of claims 121 to 126, wherein the target dose is administered to the subject on day 16 of C1. A method as in any of claims 105 to 127, wherein the first stage comprises a first sub-stage and a second sub-stage. The method of claim 128, wherein the first subphase of the first phase comprises at least two dosing cycles. The method of claim 128 or 129, wherein the first subphase of the first phase comprises a first dosing cycle (C1) and a second dosing cycle (C2). The method of claim 130, wherein the first subphase of the first phase comprises administering the bispecific antibody on day 1 of C1 and C2. The method of any one of claims 128 to 131, wherein the target dose of the bispecific antibody is administered to the subject at each administration during the first subphase of the first phase. The method of any of claims 128 to 132, wherein the second subphase comprises at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, or at least five dosing cycles. The method of claim 133, wherein the second sub-phase of the first phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4) and a fifth dosing cycle (C5). The method of claim 134, wherein the second subphase of the first phase comprises administering the bispecific antibody on day 1 of C1, C2, C3, C4 and/or C5. The method of any of claims 133 to 135, wherein the target dose of the bispecific antibody is administered to the subject at each administration during the second subphase of the first phase. The method of any of claims 105 to 136, wherein the second phase comprises at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, or at least five dosing cycles. The method of claim 137, wherein the second phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5). The method of claim 138, wherein the second phase comprises administering the bispecific antibody on day 1 of C1, C2, C3, C4 and/or C5. The method of claim 139, wherein a target dose of the bispecific antibody is administered to the subject at each administration during the second phase. The method of any of claims 8, 11, 16, 24, 28, 111, 114, 124, 127, 132, 136, and 140, wherein the target dose is 160 mg. The method of any one of claims 102 to 141, wherein the bispecific antibody is administered intravenously to the subject. The method of any one of claims 105 to 142, wherein the anti-CD38 antibody is administered to the subject during the introduction phase. The method of claim 143, wherein the introduction phase comprises a first dosing cycle (C1) and the anti-CD38 antibody is administered to the subject during the introduction phase on day 1, day 8, and day 15 of C1. The method of any one of claims 128 to 144, wherein the anti-CD38 antibody is administered to the subject during the first subphase of the first phase. The method of claim 145, wherein the anti-CD38 antibody is administered to the subject on day 1, day 8, and day 15 of C1 and/or C2 during the first subphase of the first phase. The method of any one of claims 137 to 146, wherein the anti-CD38 antibody is administered to the subject during the second subphase of the first phase. The method of claim 147, wherein the anti-CD38 antibody is administered to the subject on day 1 of C1, C2, C3, C4 and/or C5 during the second subphase of the first phase. The method of any one of claims 137 to 148, wherein the anti-CD38 antibody is administered to the subject during the second phase. The method of claim 149, wherein the anti-CD38 antibody is administered to the subject on day 1 of C1, C2, C3, C4 and/or C5 during the second phase. The method of any one of claims 102 to 150, wherein the anti-CD38 antibody is administered to the subject subcutaneously (SC). The method of any one of claims 102 to 151, wherein the anti-CD38 antibody is daratumumab or isatuximab. The method of claim 152, wherein the anti-CD38 antibody is daratumumab. The method of claim 153, wherein the daratumumab is administered to the subject in an amount of about 1800 mg. The method of any of claims 102 to 154, further comprising administering a corticosteroid to the individual during any dosing cycle within the introduction phase, the first phase, and/or the second phase. The method of claim 155, wherein the corticosteroid is administered to the subject during the introduction phase. The method of claim 155 or 156, wherein the run-in phase comprises a first dosing cycle (C1) and the corticosteroid is administered to the subject during the run-in phase on day 1, day 2, day 8, day 9, day 15, and day 16 of C1. The method of claim 155 or 156, wherein the corticosteroid is further administered to the subject during the lead-in phase on day 3, day 10, day 11, or day 12 of C1. The method of any of claims 155 to 158, wherein the corticosteroid is administered to the subject QW during the first subphase of the first phase. The method of claim 159, wherein the corticosteroid is administered to the subject on Day 1, Day 8, and Day 15 of C1 during the first subphase of the first phase. The method of claim 159, wherein the corticosteroid is administered to the subject on day 1 of C2 during the first subphase of the first phase. The method of any of claims 155 to 161, wherein the corticosteroid is administered to the subject Q3W during the second subphase of the first phase. The method of claim 162, wherein the corticosteroid is administered to the subject on day 1 of C1, C2, C3, C4, C5 during the second subphase of the first phase. The method of any of claims 155 to 163, wherein the corticosteroid is administered to the subject Q4W during the second phase. The method of claim 164, wherein the corticosteroid is administered to the subject on day 1 of C1, C2, C3, C4 and/or C5 during the second phase. The method of any one of claims 155 to 165, wherein the corticosteroid is administered to the subject intravenously and/or orally. The method of claim 166, wherein the corticosteroid is administered to the subject: (a) intravenously or orally on Day 1, Day 8, and Day 15 of C1 during the introduction phase; (b) intravenously on Day 2, Day 9, and Day 16 of C1 during the introduction phase; (c) intravenously on Day 1 of C1 during the first subphase of the first phase; (d) intravenously or orally on Day 8 and Day 15 of C1 during the first subphase of the first phase; (e) intravenously on Day 1 of C2 during the first subphase of the first phase; intravenously or orally on day 1 of C1 during the second sub-phase of the first phase; and (f) intravenously or orally on day 1 of C1 during the second sub-phase of the first phase. The method of claim 166, wherein the corticosteroid is administered to the subject: (a) intravenously or orally on Day 1, Day 2, Day 3, Day 8, and Day 15 of C1 during the introduction phase; (b) intravenously on Day 9 and Day 16 of C1 during the introduction phase; (c) intravenously on Day 1 of C1 during the first subphase of the first phase; (d) intravenously or orally on Day 8 and Day 15 of C1 during the first subphase of the first phase; and (e) intravenously on Day 1 of C2 during the first subphase of the first phase. Intravenous or oral administration. The method of claim 167 or 168, wherein the corticosteroid is further administered intravenously or orally to the subject on day 1 of C1, C2, C3, C4 and/or C5 during the second subphase of the first phase. The method of any of claims 168 to 169, wherein the corticosteroid is further administered intravenously or orally to the subject on day 1 of C2, C3, C4 and/or C5 during the second phase. The method of any one of claims 155 to 170, wherein the corticosteroid is administered intravenously to the subject as a premedication for the bispecific antibody. The method of claim 171, wherein the corticosteroid is administered to the subject about 1 hour prior to administration of the bispecific antibody: (a) on day 2 or day 3 of C1 during the run-in phase; (b) on day 9 and day 16 of C1 during the run-in phase; and (c) on day 1 of C2 during the first subphase of the first phase. The method of claim 171, wherein the corticosteroid is administered to the subject about 1 hour prior to administration of the bispecific antibody: (a) on day 9 of C1 during the run-in phase; (b) on day 10, day 11, or day 12 of C1 during the run-in phase; (c) on day 16 of C1 during the run-in phase; and (d) on day 1 of C2 during the first subphase of the first phase. The method of any of claims 155 to 173, wherein the corticosteroid is dexamethasone or methylprednisolone. The method of any of claims 155 to 174, wherein the corticosteroid is dexamethasone. The method of claim 175, wherein the dexamethasone is administered to the subject in an amount of about 20 mg. The method of claim 175, wherein the dexamethasone is administered to the subject in an amount of about 15 mg. The method of claim 175, wherein the dexamethasone is administered to the subject in an amount of about 4 mg. The method of any one of claims 155 to 174, wherein the methylprazosin is administered to the subject in an amount of about 80 mg. A method as claimed in any one of claims 1 to 179, wherein the bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six highly variable regions (HVRs): (a) HVR-H1 comprising an amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising an amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising an amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 comprising an amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 comprising an amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3, which comprises the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). The method of any one of claims 1 to 180, wherein the bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain, the first binding domain comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b). The method of claim 181, wherein the first binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising the amino acid sequence of SEQ ID NO: 8. A method as claimed in any one of claims 1 to 182, wherein the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain, wherein the second binding domain comprises the following six HVRs: (a) HVR-H1, which comprises the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2, which comprises the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3, which comprises the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1, which comprises the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2, which comprises the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3, which comprises the amino acid sequence of KQSFILRT (SEQ ID NO: 14). The method of any one of claims 1 to 183, wherein the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain, the second binding domain comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b). The method of claim 184, wherein the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 15 and a VL domain comprising the amino acid sequence of SEQ ID NO: 16. A method as claimed in any one of claims 1 to 185, wherein the bispecific antibody comprises: an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1); and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein: (a) H1 comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38. The method of any one of claims 1 to 186, wherein the bispecific antibody comprises a mutation at an aglycosylation site. The method of claim 187, wherein the deglycosylation site mutation reduces the effector function of the bispecific antibody. The method of claim 188, wherein the deglycosylation site mutation is a substitution mutation. The method of claim 189, wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function. The method of any one of claims 1 to 190, wherein the bispecific antibody is a monoclonal antibody. The method of any one of claims 1 to 191, wherein the bispecific antibody is a humanized antibody. The method of any one of claims 1 to 192, wherein the bispecific antibody is a chimeric antibody. The method of any one of claims 1 to 184 and 187 to 193, wherein the bispecific antibody is an antibody fragment that binds to FcRH5 and CD3. The method of claim 194, wherein the antibody fragment is selected from the group consisting of: Fab, Fab'-SH, Fv, scFv and (Fab') ₂ fragments. The method of any one of claims 1 to 195, wherein the bispecific antibody is a full-length antibody. The method of any one of claims 1 to 196, wherein the bispecific antibody is an IgG antibody. The method of claim 197, wherein the IgG antibody is an _IgG1 antibody. The method of any one of claims 1 to 198, wherein the bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 ₁ ) domain, a first CH2 (CH2 ₁ ) domain, a first CH3 (CH3 ₁ ) domain, a second CH1 (CH1 ₂ ) domain, a second CH2 (CH2 ₂ ) domain and a second CH3 (CH3 ₂ ) domain. A method as claimed in claim 199, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. The method of claim 200, wherein the CH3 ₁ domain and the CH3 ₂ domain each comprise a protuberance or a cavity, and wherein the protuberance or the cavity in the CH3 ₁ domain can be positioned in the cavity or the protuberance in the CH3 ₂ domain, respectively. The method of claim 201, wherein the CH3 ₁ domain and the CH3 ₂ domain are connected at the interface between the protuberance and the cavity. A method as in any one of claims 199 to 202, wherein the CH2 ₁ domain and the CH2 ₂ domain each comprise a protuberance or a cavity, and wherein the protuberance or the cavity in the CH2 ₁ domain can be positioned in the cavity or the protuberance in the CH2 ₂ domain, respectively. The method of claim 203, wherein the CH2 ₁ domain and the CH2 ₂ domain are connected at the interface between the protuberance and the cavity. The method of claim 204, wherein the anti-FcRH5 arm comprises the protuberance and the anti-CD3 arm comprises the cavity. The method of claim 205, wherein the CH3 domain of the anti-FcRH5 arm comprises a protuberance comprising a T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm comprises a cavity comprising T366S, L368A and Y407V amino acid substitution mutations (EU numbering). The method of any one of claims 1 to 206, wherein the bispecific antibody is cevostamab. The method of any one of claims 1 to 207, wherein the bispecific antibody is administered to the subject simultaneously with one or more additional therapeutic agents. The method of claim 208, wherein the bispecific antibody is administered to the subject prior to administering one or more additional therapeutic agents. The method of claim 208, wherein the bispecific antibody is administered to the subject after administration of one or more additional therapeutic agents. The method of claim 209 or 210, wherein the one or more additional therapeutic agents comprises an effective amount of tocilizumab. The method of claim 211, wherein tocilizumab is administered to the subject by intravenous infusion. The method of claim 212, wherein: (a) the individual weighs ≥ 30 kg and tocilizumab is administered to the individual at a dose of 8 mg/kg; (b) the individual weighs < 30 kg and tocilizumab is administered to the individual at a dose of 12 mg/kg; or (c) the final dose administered does not exceed 800 mg. The method of any one of claims 211 to 213, wherein tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody. The method of any of claims 212 to 214, wherein the one or more additional therapeutic agents comprises an effective amount of a B cell maturation antigen (BCMA) directed therapy. The method of any of claims 1 to 215, wherein the individual has a cytokine release syndrome (CRS) event, and the method further comprises treating symptoms of the CRS event while withholding treatment with the bispecific antibody. The method of claim 216, wherein the method further comprises administering to the individual an effective amount of tocilizumab to treat the CRS event. The method of claim 217, wherein tocilizumab is administered intravenously to the subject in a single dose of about 8 mg/kg. The method of claim 218, wherein the CRS event does not resolve or worsens within 24 hours of treating symptoms of the CRS event, the method further comprising administering to the individual one or more additional doses of tocilizumab to manage the CRS event. The method of claim 219, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg/kg. The method of any of claims 208 to 220, wherein the one or more additional therapeutic agents comprises an effective amount of acetaminophen or paracetamol. The method of claim 221, wherein acetaminophen or pyraclostrobin is administered to the subject in an amount of between about 500 mg and about 1000 mg. The method of claim 222, wherein the acetaminophen or pyraclostrobin is administered to the subject orally. The method of any of claims 208 to 223, wherein the one or more additional therapeutic agents comprises an effective amount of diphenhydramine. The method of claim 224, wherein diphenhydramine is administered to the subject in an amount between about 25 mg and about 50 mg. The method of claim 225, wherein diphenhydramine is administered to the subject orally. The method of any one of claims 1 to 226, wherein the MM is relapsed or refractory (R/R) MM. The method of claim 227, wherein the individual has received at least three prior lines of treatment for the MM. The method of claim 228, wherein the individual has received at least four prior lines of treatment for the MM. The method of any one of claims 1 to 229, wherein the individual has been exposed to a prior therapy comprising a proteasome inhibitor, an IMiD, and/or an anti-CD38 therapy. The method of claim 230, wherein the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib. The method of claim 230, wherein the IMiD is thalidomide, lenalidomide, or pomalidomide. The method of claim 230, wherein the anti-CD38 therapeutic agent is daratumumab, MOR202, or isatuximab. The method of claim 233, wherein the anti-CD38 therapeutic agent is daratumumab. The method of any of claims 1 to 234, wherein the individual has received prior treatment comprising autologous stem cell transplant (ASCT) or CAR-T cell therapy, wherein the CAR-T cell therapy was last administered at least 12 weeks prior to initiation of the method. The method of any of claims 1 to 235, wherein the individual has: (a) an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) less than or equal to 2.5 x upper limit of normal (ULN); and/or (b) a platelet count greater than or equal to 75,000/mm ³ . A method for treating an individual with MM, the method comprising administering to the individual a monotherapy of ceftriaxone in a dosing regimen comprising: (i) a first phase comprising a first dosing cycle (C1) and a second dosing cycle (C2); (ii) a second phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); and (iii) a third phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), wherein each dosing cycle of the first phase, the second phase, and the third phase is a 28-day dosing cycle, and cefotaxime is administered to the subject as follows: A) (i) during the first phase at an escalating dose on day 1 of C1; (ii) during the first phase at a target dose on days 8, 15, and 22 of C1; (iii) during the first phase at a target dose on days 1, 8, 15, and 22 of C2; (iv) during the second phase at a target dose on days 1 and 15 of C1, C2, C3, and C4; and (v) during the third phase at a target dose on days 1, 8, 15, and 22 of C2. C1, C2, C3, C4, C5, C6 and C7 at the target dose on Day 1; or B) (i) C1 at the first escalating dose on Day 1 during the first phase and C1 at the second escalating dose on Day 8 during the first phase; (ii) C1 at the target dose on Day 15 and Day 22 during the first phase; (iii) C2 at the target dose on Day 1, Day 8, Day 15 and Day 22 during the first phase; (iv) C1, C2, C3 and C4 at the target dose on Day 1 and Day 15 during the second phase; and (v) During the third phase on Day 1 of C1, C2, C3, C4, C5, C6, and C7 at the target dose, wherein the individual does not have: (i) a history of MAS or HLH; (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or the need for treatment with intravenous antivirals. A method for treating an individual with MM, the method comprising administering ceftriaxone, pomalidomide, and dexamethasone to the individual in a dosing regimen comprising: (i) a pre-phase comprising a 21-day dosing cycle (C1); (ii) a first phase after the pre-phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6), wherein each dosing cycle of the first phase is a 28-day dosing cycle; and (iii) a second phase after the first phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6). (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), wherein each dosing cycle of the second phase is a 28-day dosing cycle, and wherein ceftriaxone is administered to the subject as follows: (i) at a first escalating dose on day 1 of C1 during the pre-phase and at a second escalating dose on day 8 of C1 during the pre-phase; (ii) at a target dose on day 15 of C1 during the pre-phase; (iii) at a target dose on days 1 and 15 of C1, C2, C3, C4, C5, and C6 during the first phase. and (iv) during the second phase at a target dose on day 1 of C1, C2, C3, C4, C5, C6, and C7; the pomalidomide is administered to the subject as follows: (i) during the first phase at a dose of about 2 to 4 mg on day 1 through day 21 of C1, C2, C3, C4, C5, C6, and C7; and (ii) during the second phase at a dose of about 2 to 4 mg on day 1 through day 21 of C1, C2, C3, C4, C5, C6, and C7; and the dexamethasone is administered to the subject as follows: (i) during the pre-phase at a dose of about 2 to 4 mg on day 1 through day 21 of C1, C2, C3, C4, C5, C6, and C7 and (ii) during the first phase on days 1, 8, 15 and 22 of C1, C2, C3 and C4, as appropriate, wherein the dexamethasone is administered to the subject as follows: (iii) during the first phase on days 1, 8, 15 and 22 of C5 and C6; and (iv) during the second phase on days 1, 8, 15 and 22 of C1, C2, C3, C4, C5, C6 and C7, wherein the subject does not have: (i) MAS or history of HLH; (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or need for treatment with intravenous antivirals. A method for treating an individual with MM, the method comprising administering ceftriaxone, pomalidomide, and dexamethasone to the individual in a dosing regimen comprising: (i) a pre-phase comprising a 14-day dosing cycle (C1); (ii) a first phase after the pre-phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6), wherein each dosing cycle of the first phase is a 28-day dosing cycle; and (iii) a second phase after the first phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), and a sixth dosing cycle (C6). (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6) and a seventh dosing cycle (C7), wherein each dosing cycle of the second phase is a 28-day dosing cycle, and wherein ceftriaxone is administered to the subject as follows: (i) at a first escalating dose on day 1 of C1 during the pre-phase and at a second escalating dose on day 2, day 3 or day 4 of C1 during the pre-phase; (ii) at a target dose on day 8 of C1 during the pre-phase; (iii) at a target dose on day 10 of C1, C2, C3, C4, C5 and C6 during the first phase; and (iv) at a target dose on day 1 of C1, C2, C3, C4, C5, C6, and C7 during the second phase; the pomalidomide is administered to the subject as follows: (i) at a dose of about 2 to 4 mg on day 1 to day 21 of C1, C2, C3, C4, C5, and C6 during the first phase; and (ii) at a dose of about 2 to 4 mg on day 1 to day 21 of C1, C2, C3, C4, C5, C6, and C7 during the second phase; and the dexamethasone is administered to the subject as follows: (i) at a dose of about 2 to 4 mg on day 1 to day 21 of C1, C2, C3, C4, C5, C6, and C7 during the first phase; (ii) during the Pre-Phase at a dose of about 20 mg on Day 2, Day 3, or Day 4 of C1; (iii) during the First Phase at a dose of about 20 mg on Day 1, Day 8, Day 15, and Day 22 of C1, C2, C3, and C4, as appropriate, wherein the dexamethasone is administered to the subject as follows: (iv) during the First Phase at a dose of about 20 mg on Day 1, Day 8, Day 15, and Day 22 of C5 and C6; and (v) during the Second Phase at a dose of about 20 mg on Day 1, Day 8, Day 15, and Day 22 of C1, C2, C3, C4, C5, C6, and C7. 1, 8, 15, and 22 at a dose of approximately 20 mg, wherein the individual does not have: (i) a history of MAS or HLH; (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or the need for treatment with intravenous antivirals. A method for treating an individual with MM, the method comprising administering to the individual ceftriaxone, daratumumab, and dexamethasone in a dosing regimen comprising: (i) an introduction phase comprising a 21-day dosing cycle (C1); (ii) a first phase following the introduction phase comprising a first sub-phase and a second sub-phase, wherein the first sub-phase comprises a first dosing cycle (C1) and a second dosing cycle (C2), and the second sub-phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), wherein each dosing cycle of the first phase is a 21-day dosing cycle; and (iii) a second phase after the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4) and a fifth dosing cycle (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, wherein the bispecific antibody is administered to the subject as follows: (i) at a first escalating dose on day 2 of C1 during the lead-in phase and at a second escalating dose on day 9 of C1 during the lead-in phase; (ii) at a target dose on day 16 of C1 during the lead-in phase; (iii) at a target dose on day 16 of C1 during each cycle during the first phase 1 day at a target dose; and (iv) during the second phase at a target dose on day 1 of each cycle; The daratumumab is administered to the subject as follows: (i) during the run-in phase at a dose of about 1800 mg on day 1, day 8, and day 15 of C1; (ii) during the first subphase of the first phase at a dose of about 1800 mg on day 1, day 8, and day 15 of C1 and C2; (iii) during the second subphase of the first phase at a dose of about 1800 mg on day 1 of C1, C2, C3, C4, and C5; and the dexamethasone is administered to the subject as follows: (i) during the run-in phase at about 20 mg on day 1, day 2, day 8, day 9, day 15, and day 16 of C1; (ii) during the first subphase of the first phase at about 20 mg on day 1, day 8, and day 15 of C1 and C2; and (iii) during the second subphase of the first phase at about 20 mg on day 1 of C1, C2, C3, C4, and C5, as appropriate, wherein the dexamethasone is administered to the subject as follows: (iv) during the second subphase at C1, C2, C3, C4, and C5 about 20 mg on day 1 of treatment, wherein the individual does not have: (i) a history of MAS or HLH; (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or the need for treatment with intravenous antivirals. A method for treating an individual with MM, the method comprising administering to the individual ceftriaxone, daratumumab, and dexamethasone in a dosing regimen comprising: (i) an introduction phase comprising a 21-day dosing cycle (C1); (ii) a first phase following the introduction phase comprising a first sub-phase and a second sub-phase, wherein the first sub-phase comprises a first dosing cycle (C1) and a second dosing cycle (C2), and the second sub-phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), wherein each dosing cycle of the first phase is a 21-day dosing cycle; and (iii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4) and a fifth dosing cycle (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, wherein the bispecific antibody is administered to the subject as follows: (i) at a first escalating dose on day 9 of C1 during the run-in phase and at a second escalating dose on day 10, day 11 or day 12 of C1 during the run-in phase; (ii) at a target dose on day 16 of C1 during the run-in phase; (iii) at a target dose on Day 1 of each cycle during the first phase; and (iv) at a target dose on Day 1 of each cycle during the second phase; The daratumumab is administered to the subject as follows: (i) at a dose of about 1800 mg on Day 1, Day 8, and Day 15 of C1 during the run-in phase; (ii) at a dose of about 1800 mg on Day 1, Day 8, and Day 15 of C1 and C2 during the first subphase of the first phase; (iii) at a dose of about 1800 mg on Day 1 of C1, C2, C3, C4, and C5 during the second subphase of the first phase and the dexamethasone is administered to the subject as follows: (i) during the run-in phase at a dose of about 20 mg on days 1, 8, 15, and 16 of C1; (ii) during the run-in phase at a dose of about 4 mg on days 2 and 3 of C1; (iii) during the run-in phase at a dose of about 15 mg on day 9 of C1; (iv) during the first subphase of the first phase at a dose of about 20 mg on days 1, 8, and 15 of C1; and (v) during the first subphase of the first phase at a dose of about 20 mg on day 1 of C2 ; (vi) during the second subphase of the first phase at a dose of about 20 mg on day 1 of C1, C2, C3, C4 and C5, as appropriate, wherein the dexamethasone is administered to the subject as follows: (vii) during the second phase at a dose of about 20 mg on day 1 of C1, C2, C3, C4 and C5, wherein the subject does not have: (i) a history of MAS or HLH; (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or the need for treatment with intravenous antivirals. A bispecific antibody that binds to FcRH5 and CD3 for use in treating an individual with MM, the treatment comprising administering to the individual the bispecific antibody that binds to Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), wherein the individual does not have: (i) a history of MAS or HLH; (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or the need for treatment with intravenous antivirals. A bispecific antibody that binds to FcRH5 and CD3 for use in treating an individual with MM, the treatment comprising administering the bispecific antibody to the individual in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every week (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the individual every four weeks (Q4W) Administering the bispecific antibody to the individual, wherein the individual does not have: (i) a history of MAS or HLH; (ii) positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or a need for treatment with an intravenous antiviral agent. A bispecific antibody that binds to FcRH5 and CD3 for use in treating an individual with MM, the treatment comprising administering the bispecific antibody and an IMiD to the individual in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every two weeks (Q2W); and (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W), wherein the individual does not have: (i) a history of MAS or HLH; (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or need for treatment with intravenous antiviral agents. A bispecific antibody that binds to FcRH5 and CD3 for use in treating an individual with MM, the treatment comprising administering the bispecific antibody and an anti-cluster of differentiation 38 (CD38) antibody to the individual in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the individual every three weeks (Q3W); and (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the individual every four weeks (Q4W), wherein the individual does not have: (i) a history of MAS or HLH; (ii) Positive and quantifiable EBV or CMV prior to treatment with the bispecific antibody; or (iii) active symptomatic COVID-19 infection or need for treatment with intravenous antiviral agents.