[0001] This application claims the priority benefit of European Patent Application No.

EP20305223.8, filed March 3, 2020; U.S. Provisional Application No.62/899,088, filed September 11, 2019; U.S. Provisional Application No.62/860,739 filed June 12, 2019; and U.S. Provisional Application No.62/847,825, filed May 14, 2019, the contents of each of which are incorporated herein by reference in their entirety.

SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

[0002] The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name:

183952031741SEQLIST.TXT, date recorded: May 12, 2020, size: 11 KB).

FIELD OF THE INVENTION

[0003] The present disclosure relates to methods of treating multiple myeloma by administering an anti-CD38 antibody.

BACKGROUND

[0004] Therapeutic antibodies have improved the options for treating patients with relapsed and/or refractory multiple myeloma (RRMM). However, therapeutic antibodies are typically administered via intravenous infusion, and infusion reactions (IRs) are a commonly reported side effect. Symptoms of IR (e.g., rash, urticarial, flushing, changes in heart rate and/or blood pressure, fever, dyspnea, and/or nausea) require prompt management to avoid severe adverse events, including fatality. Strategies for mitigating the risk of IRs (or resolving mild IRs) include slowing the infusion rate, temporarily interrupting the infusion, and/or splitting the infusion dose over two or more consecutive days. However, lengthy and/or frequent intravenous infusions can be costly, burdensome, and inconvenient for patients, leading to reduced compliance with the treatment regimen. Moreover, lengthy and/or frequent IV infusions require extended hospital stays and longer observation times, thus increasing the workloads of hospital employees. What is needed in the art are safe and effective methods of administering therapeutic antibody for the treatment of RRMM that are also more convenient for patients, physicians, and other medical staff.

BRIEF SUMMARY

[0005] In some embodiments, provided is an anti-CD38 antibody for use in a method of treating a an individual in need thereof, the method comprising administering to the individual at least a first intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the dose of the anti-CD38 antibody is in a volume of 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments the anti-CD38 antibody (e.g., the administration of the anti-CD38 antibody) is for the treatment of a disease or disorder, optionally wherein the disease or disorder is multiple myeloma. In some embodiments, provided is a method of administering an anti-CD38 antibody to a human individual in need thereof, comprising administering to the individual at least a first intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the dose of the anti-CD38 antibody is in a volume of 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence

TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments, the administration of the anti-CD38 antibody is for the treatment of multiple myeloma. In some embodiments, the anti-CD38 antibody is isatuximab.

[0006] In some embodiments, the first intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL/hour for a first hour, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL/hour until the 250 ml volume is infused. In some embodiments, the first infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 12.5 mL/hour for a first 30 minutes, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused. In some embodiments, the method comprises administering to the individual at least a second intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml. In some embodiments, the second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 50 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 50 ml/hr for a second 30 minutes, and wherein the infusion rate is increased by 100 mL/hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL/hour

until the 250 ml volume is infused. In some embodiments, the second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 50 mL/hour for a first 30 minutes, 100 mL/hour for a second 30 minutes, 200 mL for the third 30 minutes, and 300 mL/hour after the third 30 minutes until the 250 ml volume is infused. In some embodiments, the second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 25 mL/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused. In some embodiments, the method comprises administering to the individual at least a third intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml. In some embodiments, the third intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 200 ml/hour until the 250 ml volume is infused. In some

embodiments, the third intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused. In some embodiments, the method comprises administering to the individual a fourth intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml. In some embodiments, the fourth intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 200 ml/hour until the 250 ml volume infused. In some embodiments, the fourth intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused. In some embodiments, the anti-CD38 antibody is administered in a first 28-day cycle, wherein the first intravenous infusion of the anti-CD38 antibody is administered on Day 1, the second intravenous infusion of the anti-CD38 antibody is administered on Day 8, the third intravenous infusion of the anti-CD38 antibody is administered on Day 15, and the fourth intravenous infusion of the anti-CD38 antibody is administered on Day 22 the first 28-day cycle.

[0007] In some embodiments, the method comprises administering to the individual one or more subsequent intravenous infusions of the anti-CD38 antibody following the fourth intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml for each of the one or more subsequent intravenous infusions. In some embodiments, each of the one or more subsequent intravenous infusions of the anti-CD38 antibody following the fourth intravenous infusion is administered to the individual at an infusion rate of 200 ml/hour until the 250 ml volume infused. In some embodiments, each of the one or more subsequent intravenous infusions of the anti-CD38 antibody following the fourth intravenous infusion is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused. In some

embodiments, the anti-CD38 antibody is administered in one or more subsequent 28-day cycles following the first 28-day cycle, wherein each of the one or more subsequent intravenous infusions of the anti-CD38 antibody following the fourth intravenous infusion is administered on Days 1 and 15 of each of the one or more subsequent 28-day cycles following the first 28-day cycle.

[0008] In some embodiments, provided is an anti-CD38 antibody for use in a method of treating a an individual in need thereof, the method comprising administering to the individual at least three intravenous infusions of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the dose of the anti-CD38 antibody is in a volume of 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6); wherein the first intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL/hour for a first hour, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL/hour until the 250 ml volume is infused; wherein the second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 50 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 50 ml/hr a second 30 minutes, and wherein the infusion rate is increased by 100 mL/hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL/hour until the 250 ml volume is infused; and wherein the third intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused.

[0009] In some embodiments, provided is a method of administering an anti-CD38 antibody to a human individual in need thereof, comprising administering to the individual at least three intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the dose of the anti-CD38 antibody is in a volume of 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6); wherein the first intravenous

infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL/hour for a first hour, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL/hour until the 250 ml volume is infused; wherein the second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 50 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 50 ml/hr a second 30 minutes, and wherein the infusion rate is increased by 100 mL/hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL/hour until the 250 ml volume is infused; and wherein the third intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused.

[0010] In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the anti-CD38 antibody is for the treatment of a disease or disorder, optionally wherein the disease or disorder is multiple myeloma. IN some embodiments, the administration of the anti-CD38 antibody is for the treatment of multiple myeloma. In some embodiments, the method further comprises administering to the individual one or more subsequent intravenous infusions of the anti-CD38 antibody following the third intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml for each of the one or more subsequent intravenous infusions. In some embodiments, each of the one or more subsequent intravenous infusions of the anti-CD38 antibody following the third intravenous infusion is administered to the individual at an infusion rate of 200 ml/hour until the 250 ml volume infused.

[0011] In some embodiments, provided is an anti-CD38 antibody for use in a method of treating an individual in need thereof, the method comprising administering the anti-CD38 antibody to the individual via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the volume of each dose of the anti-CD38 antibody is 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments the anti-CD38 antibody (e.g., the administration of the anti-CD38 antibody) is for the treatment of a disease or disorder, optionally wherein the disease or disorder is multiple myeloma. In some embodiments, provided is method of administering an anti-CD38 antibody to an individual in need thereof, comprising administering the anti-CD38 antibody to the individual via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the volume of each dose of the anti-CD38 antibody is 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence

DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence

TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments, the administration of the anti-CD38 antibody is for the treatment of multiple myeloma. In some embodiments, the anti-CD38 antibody is isatuximab.

[0012] In some embodiments, the anti-CD38 antibody is administered in a first 28-day cycle, and the anti-CD38 antibody is administered on Days 1, 8, 15, and 22 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 1 of the first 28 day cycle) at an infusion rate of 25 mL/hour for a first hour, and the infusion rate is increased by 25 mL/hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL/hour until the 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 1 of the first 28-day cycle) at an infusion rate of 12.5 mL/hour for a first 30 minutes, and the infusion rate is increased by 25 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 8 of the first 28 day cycle at an infusion rate of 50 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 50 ml/hr for the next 30 minutes, and wherein the infusion rate is increased by 100 mL/hour every 30 minutes after the first 60 minutes to a maximum infusion rate of 200 mL/hour until the 250 ml volume is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 8 of the first 28 day cycle at an infusion rate of 50 mL/hour for a first 30 minutes, 100 mL/hour for a second 30 minutes, 200 mL for the third 30 minutes, and 300 mL/hour after the third 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 8 of the first 28 day cycle at an infusion rate of 25 mL/hour for a first 30 minutes, and the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 15 of the first 28 -day cycle at an infusion rate of 200 ml/hour until the 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 15 of the first 28 day cycle at an infusion rate of 100 ml/hour for a first 30 minutes, and the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 22 of the first 28-day cycle at an infusion rate of 200 ml/hour until the 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 22 of the first 28 day cycle at an infusion rate of 100 ml/hour for a first 30 minutes, and the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused.

[0013] In some embodiments, the anti-CD38 antibody is further administered in one or more subsequent 28-day cycles, and the anti-CD38 antibody is administered at a dose of at least 10 mg/kg on Days 1 and 15 of each subsequent 28-day cycle, the volume of each dose of the anti-CD38 antibody administered in the one or more subsequent cycles is 250 ml. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 1 of each subsequent 28-day cycle at an infusion rate of 200 ml/hour until the 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 1 of each subsequent 28-day cycle at an infusion rate of 100 ml/hour for a first 30 minutes, and the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 15 of each subsequent 28-day cycle at an infusion rate of 200 ml/hour until the 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 15 of each subsequent 28-day cycle at an infusion rate of 100 ml/hour for a first 30 minutes, and the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused.

[0014] In some embodiments, provided is an anti-CD38 antibody for use in a method of treating an individual in need thereof, the method comprising safely administering to the individual at least a first dose of the anti-CD38 antibody via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml, wherein the first dose is infused over a duration of about 1.5 and about 6.5 hours, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence

TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments the anti-CD38 antibody (e.g., the administration of the anti-CD38 antibody) is for the treatment of a disease or disorder, optionally wherein the disease or disorder is multiple myeloma. In some embodiments, provided is a method of safely administering an anti-CD38 antibody to a human individual in need thereof, comprising administering to the individual at least a first dose of the anti-CD38 antibody via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml, wherein the first dose is infused over a duration of about 1.5 and about 6.5 hours, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence

KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments, the administration of the anti-CD38 antibody is for the treatment of multiple myeloma. In some embodiments, the anti-CD38 antibody is isatuximab.

[0015] In some embodiments, at least a second dose of the anti-CD38 antibody is administered to the individual via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml, wherein the second dose is infused over a duration of about 0.5 and about 3.5 hours. In some embodiments, at least a third dose of the anti-CD38 antibody is administered to the individual via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml, wherein the third dose is infused over a duration of about 0.5 and about 1.5 hours. In some embodiments each dose of at least 10 mg/kg anti-CD38 antibody in a volume of 250 ml following the third dose is infused over a duration between about 0.5 hours and about 1.5 hours. In some embodiments of any of the methods herein, the dose of anti-CD38 antibody (e.g., isatuximab) is 10 mg/kg or 20 mg/kg

[0016] In some embodiments, the administration of the anti-CD38 antibody does not result in the individual experiencing an infusion reaction (IR). In some embodiments, the administration of the anti-CD38 antibody does not result in the individual experiencing an IR greater than Grade 1 in severity. In some embodiments, the administration of the anti-CD38 antibody does not result in the individual experiencing an IR of Grade 2 or greater in severity. In some embodiments, the individual does not receive premedication with one or more of an analgesic, an antacid, an anti-inflammatory agent, an antihistamine prior for the purpose of preventing or minimizing an infusion reaction prior to the administration of the anti-CD38 antibody via intravenous infusion.

[0017] In some embodiments, provided is an intravenous (IV) bag containing 250 mls of a 10 mg/kg dose of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the 10 mg/kg dose of the anti-CD38 antibody (e.g., isatuximab) is calculated based on the weight of the patient to whom the anti-CD38 antibody is to be administered. In some embodiments, the anti-CD38 antibody (e.g.,

isatuximab) is diluted from a concentrated formulation (e.g., a formulation described herein) into 0.9% sodium chloride, 5% glucose, or 5% dextrose. In some embodiments, the bag contains between about 360 mg and about 1600 mg, between about 450 mg and about 16000 mg, between about 450 mg and 1140 mg, or between about 450 mg and about 910 mg, including any range in between these values. In some embodiments, the intravenous bag containing the 10 mg/kg dose of the anti-CD38 antibody in the volume of 250 ml further comprises 0.9% sodium chloride or 5% dextrose.

[0018] In some embodiments, provided is an anti-CD38 antibody for use in a method of treating multiple myeloma an individual, comprising administering to the individual an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence

TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6), pomalidomide, and dexamethasone, wherein the anti-CD38 antibody is administered in 28-day cycles; wherein the anti-CD38 antibody is administered on Days 1, 8, 15, and 22 of a first 28-day cycle; wherein the anti-CD38 antibody is administered on Days 1 and 15 of every 28-day cycle following the first 28-day cycle; and wherein the anti-CD38 antibody is administered at a dose of 10 mg/kg or 20 mg/kg.

[0019] In some embodiments, provided is a method of treating a human individual having multiple myeloma, comprising administering to the individual an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence

TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6), pomalidomide, and dexamethasone, wherein the anti-CD38 antibody is administered in 28-day cycles; wherein the anti-CD38 antibody is administered on Days 1, 8, 15, and 22 of a first 28-day cycle; wherein the anti-CD38 antibody is administered on Days 1 and 15 of every 28-day cycle following the first 28-day cycle; and wherein the anti-CD38 antibody is administered at a dose of 10 mg/kg or 20 mg/kg.

[0020] In some embodiments, the individual has at least one high-risk cytogenetic abnormality selected from: 17p deletion, 4(4; 14) translocation, and t(14;16) translocation. In some embodiments, the individual has at least two high-risk cytogenetic abnormalities.

[0021] In some embodiments, the multiple myeloma is relapsed/refractory multiple myeloma. In some embodiments, the individual was refractory to the most recent prior therapy for multiple myeloma. In some embodiments, the individual is refractory to lenalidomide. In some embodiments, the individual’s most recent prior therapy for multiple myeloma was lenalidomide. In some embodiments, the individual is refractory to a proteasome inhibitor. In some embodiments, the individual’s most recent prior therapy was a proteasome inhibitor. In some embodiments, the proteasome inhibitor is selected from the group consisting of: bortezomib, carfilzomib, marizomib, oprozomib, and ixazomib. In some embodiments, the individual received prior therapy with lenalidomide and a proteasome inhibitor, and the lenalidomide were administered to the individual in combination. In some embodiments, the individual received prior therapy with lenalidomide and a proteasome inhibitor, and the lenalidomide were administered to the individual separately (e.g., each during a different prior line of therapy). In some embodiments, the individual has received at least two prior therapies for multiple myeloma. In some embodiments, the individual has received at least three prior therapies for multiple myeloma.

[0022] In some embodiments, the individual has a respiratory, thoracic, and/or mediastinal disorder. In some embodiments, the respiratory disorder is chronic obstructive pulmonary disorder (COPD). In some embodiments, the respiratory disorder is asthma. In some embodiments, the respiratory disorder is bronchospam.

[0023] In some embodiments, the anti-CD38 antibody is administered to the individual in conjunction with at least one additional agent. In some embodiments, the at least one additional agent comprises an immunomodulatory drug. In some embodiments, the immunomodulatory drug is lenalidomide or pomalidomide. In some embodiments, the at least one additional agent comprises a proteasome inhibitor. In some embodiments, the proteasome inhibitor is bortezomib, carfilzomib, marizomib, oprozomib, and ixazomib. In some embodiments, the at least one additional agent comprises a corticosteroid. In some embodiments, the corticosteroid is dexamethasone.

[0024] In some embodiments, provided is a kit comprising isatuximab for treating an individual having multiple myeloma according to a method of an embodiment provided herein.

DESCRIPTION OF THE FIGURES

[0025] FIG.1 provides a schematic of the study design of the clinical trial described in Example 1A.

[0026] FIG.2 shows the percentage of patients who experienced an infusion reaction (IR) of Grade 2 or Grade 3 by infusion number in the clinical trial described in Example 1B (isatuximab infusion rate measured as ml/h) as compared to the percentage of patients who experienced an

infusion reaction (IR) of Grade 2 or Grade 3 by infusion number in a parallel trial in which isatuximab was administered according to a standard infusion protocol (infusion rate measured as mg/h).

[0027] FIG.3 provides the median duration (hours) of isatuximab infusions in the clinical trial described in Example 1B as compared to the median duration (hours) of isatuximab infusion in a parallel clinical trial in which isatuximab was administered according to a standard infusion protocol.

[0028] FIG.4 provides the Logit Emax model that best described the relationship between isatuximab exposure and ORR in the modeling studies described in Example 2. CT4W = Ctrough at 4 weeks.

[0029] FIG.5 provides the distribution of responders and non-responders by CT4W quartiles in the modeling studies described in Example 2. BOR = Best overall response.

[0030] FIG.6 provides the predicted relationship between the probability of response and CT4W in the modeling studies described in Example 2. BMPC = bone marrow plasma cell percent.

[0031] FIG.7 provides a disease model, including an exposure-driven tumor growth inhibiting (TGI) and a pharmacokinetics model from the modeling studies described in Example 2. Serum-M protein kinetics were adequately described by the exposure-driven TGI model. Dropouts were accounted for using a joint model.

[0032] FIG.8 provides a comparison of model-predicted and observed longitudinal serum M-protein kinetics for the indicated dosing regimens.

[0033] FIGS.9A-9B provide clinical trial simulations of isatuximab monotherapy with the indicated dosing regimens.5000 clinical trials of 100 patients each were simulated. FIG. 9A shows simulated overall response rates (RR) using the E-R model from the modeling studies described in Example 2. The 100 patients in the clinical trial simulations were resampled from 168 actual patients, assuming they received the same dose level for each simulated trial. FIG.9B shows simulated percent changes of M-protein from at eight weeks after baseline using the Disease M-protein model from the modeling studies described in Example 2. Each clinical trial simulation was based on 122 actual patients, assuming they received the same dose level.

[0034] FIG.10 provides the patient dispositions for Phase 1 and Phase 2 of the study described in Example 3. SD = standard deviation.

[0035] FIG.11 provides the pharmacokinetic profile of isatuximab (mean isatuximab concentration) in Phase 1, cycle 1 of the study described in Example 3.

[0036] FIG.12 provides a Swimmer plot for best response and time on treatment in Phase 2 of the study described in Example 2. Patients were treated with an isatuximab dose of 20 mg/kg

QW/Q2W. AE, adverse event; CR, complete response; MR, minimal response; NE, not evaluable;

ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease;

UNCPD, unconfirmed PD; VGPR, very good partial response.

[0037] FIGS.13A-13B provide Kaplan-Meier plots of progression-free survival (FIG.13A) and overall survival (FIG.13B) of patients treated with isatuximab at 20 mg/kg QW/Q2W in the study described in Example 3.

[0038] FIG.14 shows the relationship between CD38 receptor density and clinical response in patients receiving isatuximab at a dose of 10 mg/kg QWx4/Q2W or 20 mg/kg QWx4/Q2W.

[0039] FIG.15 shows a Kaplan-Meier plot of progression-free survival (PFS) of patients administered with isatuximab, pomalidomide, and dexamethasone, where the isatuximab was administered to the patients from a fixed infusion volume of 250 ml.

[0040] FIG.16 shows a Kaplan-Meier plot of overall survival (OS) of patients administered with isatuximab, pomalidomide, and dexamethasone, where the isatuximab was administered to the patients from a fixed infusion volume of 250 ml.

DETAILED DESCRIPTION

[0041] Therapeutic antibodies for the treatment of multiple myeloma (including relapsed and/or refractory multiple myeloma“RRMM”) have the potential to cause infusion reactions (IRs) when administered intravenously. IRs present with a variety of symptoms, including, e.g., rash, urticarial, flushing, changes in heart rate and/or blood pressure, fever, dyspnea, and/or nausea, etc.) during or within 24 hours of intravenous infusion. IRs can range in severity from mild to life-threatening, but in all cases, prompt attention and an immediate response to the patient's initial symptoms are essential. Numerous strategies, e.g., including slowing infusion rate, interrupting infusion, and splitting the infusion over two or more consecutive days, have been adopted to mitigate and/or prevent IRs.

However, such strategies can inconvenience patients and increase medical costs. Further, extended hospital stays and frequent hospital visits increase the workloads of hospital staff.

[0042] Provided herein are methods of treating multiple myeloma (e.g., RRMM) that comprise administering an effective amount of an anti-CD38 antibody (e.g., 10 mg/kg isatuximab) to an individual via intravenous infusion, wherein the volume of each anti-CD38 antibody infusion is 250 ml. Applicant found that such fixed volume of anti-CD38 antibody (e.g., isatuximab) can be infused rapidly, thus significantly decreasing the duration without detriment to patient safety.

[0043] Also provided herein are methods of treating multiple myeloma (e.g., RRMM) that comprise administering 20 mg/kg of an anti-CD38 antibody (e.g., isatuximab) to an individual on each of Days 1, 8, 15, and 22 of a first 28-day cycle, and further administering 20 mg/kg of an anti- CD38 antibody (e.g., isatuximab) to the individual on each of Days 1 and 15 of every subsequent 28-day cycle following the first 28-day cycle.

Definitions

[0044] As used in this specification and the appended claims, the singular forms“a”,“an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to“a molecule” optionally includes a combination of two or more such molecules, and the like.

[0045] The term“about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to“about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. “Sustained response” refers to the sustained effect on preventing or delaying progression of a disease (e.g., multiple myeloma) and/or improving one or more response criteria after cessation of a treatment. For example, response to treatment for multiple myeloma may be measured according to the criteria in Kumar et al. (2016)“International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol.17(8): e328-e346) and Durie et al. (2006)“International uniform response criteria for multiple myeloma.

Leukemia.20: 1467-1473. (See also Table 14 herein). In some embodiments, the sustained response has a duration at least the same as the treatment duration, at least 1.5X, 2.0X, 2.5X, or 3.0X length of the treatment duration.

[0046] The term“pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be

administered. Such formulations are sterile.“Pharmaceutically acceptable” excipients (vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.

[0047] As used herein, the term“treatment” refers to clinical intervention designed to alter the typical course of the disease or cell (e.g., cancer cell) being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For example, an individual is successfully“treated” if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and/or prolonging survival of individuals.

[0048] As used herein,“delaying progression of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

[0049] An“effective amount” is at least the minimum amount required to effect a measurable improvement or prevention of a particular disorder. An 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 the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction 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, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0050] As used herein,“in conjunction with” refers to administration of one treatment modality in addition to another treatment modality. As such,“in conjunction with” refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the individual.

[0051] A“subject” or an“individual” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is human.

[0052] The term“antibody” herein is used in the broadest sense and specifically covers monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity. As used herein, the term“overall response rate” or“ORR” refers to the proportion of patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR), as assessed by the IRC using the IMWG response criteria described in Kumar et al. (2016)“International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol.17(8): e328-e346 and Durie et al. (2006)“International uniform response criteria for multiple myeloma. Leukemia.20: 1467-1473. See also Table 14.

[0053] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

Overview

[0054] Provided herein are methods for treating or delaying the progression of multiple myeloma in an individual who has received at least two prior therapies for multiple myeloma (e.g., such as lenalidomide and a proteasome inhibitor). In some embodiments, the methods comprise

administering to the individual 10 mg/kg of an anti-CD38 antibody (e.g., isatuximab) via intravenous infusion, wherein each infusion of 10 mg/kg of the anti-CD38 antibody (e.g., isatuximab) is in a 250 ml volume. In some embodiments, the individual does not experience an IR (or experiences only a mild IR) during or following the infusion. In some embodiments, the method comprises

administering 20 mg/kg of an anti-CD38 antibody (e.g., isatuximab) to the individual on each of Days 1, 8, 15, and 22 of a first 28-day cycle. In some embodiments, the method comprises further administering an anti-CD38 antibody (e.g., isatuximab) to the individual in one or more subsequent 28-day cycles following the first 28 day-cycle. In some embodiments, the method comprises further administering 20 mg/kg of an anti-CD38 antibody (e.g., isatuximab) to the individual on each of Days 1 and 15 of every subsequent 28-day cycle following the first 28-day cycle.

Anti-CD38 Antibodies

[0055] In some embodiments, the anti-CD38 antibody binds to human CD38. In some embodiments, the anti-CD38 antibody is a human antibody, a humanized antibody, or a chimeric

antibody. In some embodiments, the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments, the anti-CD38 antibody comprises a heavy chain variable domain (VH) that comprises an amino acid sequence that is at least 90% identical (e.g., at least any one of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any range between these values) to SEQ ID NO: 7. Additionally or alternatively, in some embodiments, the anti-CD38 antibody comprises a light chain variable domain (VL) that comprises an amino acid sequence that is at least 90% identical (e.g., at least any one of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any range between these values) to SEQ ID NO: 8 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody comprises a VH that comprises SEQ ID NO: 7 and a VL that comprises SEQ ID NO: 8 or SEQ ID NO: 9.

[0056] In some embodiments, the anti-CD38 antibody is isatuximab (CAS Registry Number: 1461640-62-9). Isatuximab, also known as hu38SB19 and SAR650984, is an anti-CD38 antibody described in WO 2008/047242 and US Patent No.8,153,765, the contents of both of which are incorporated by reference herein in their entirety.

[0057] The heavy chain of isatuximab comprises the amino acid sequence:

and the light chain of isatuximab comprises the amino acid sequence:

[0058] The anti-CD38 antibodies may be produced using recombinant methods. For recombinant production of an anti-antigen antibody, nucleic acid encoding the antibody is isolated and inserted into a replicable vector for further cloning (amplification of the DNA) or for expression. DNA encoding the antibody may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody). Many vectors are available. The vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. The vector is typically transformed into a host cell suitable for expression of the nucleic acid. In some embodiments, the host cell is a eukaryotic cell or a prokaryotic cell. In some embodiments, the eukaryotic host cell is a mammalian cell. Examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol.36:59 (1977)); baby hamster kidney cells (BHK, ATCC CCL 10); mouse sertoli cells (TM4, Mather, Biol. Reprod.23:243-251 (1980)); monkey kidney cells (CV1 ATCC CCL 70);

African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TRI cells (Mather et al., Annals N.Y. Acad. Sci.383:44-68 (1982)); MRC 5 cells; FS4 cells; and a human hepatoma line (Hep G2). 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 NS0 and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol.248 (B. K. C. Lo, ed., Humana Press, Totowa, N.J., 2003), pp.255-268. The anti-CD38 antibody prepared from the cells can be purified using, for example, hydroxylapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being among one of the typically preferred purification steps. In general, various methodologies for preparing antibodies for use in research, testing, and clinical applications are well-established in the art, consistent with the above-described methodologies and/or as deemed appropriate by one skilled in the art.

Methods of Treatment

Treatment Comprising Intravenous Infusion of anti-CD38 Antibody from a Fixed Volume of 250 ml

[0059] Provided herein are methods of administering (e.g., safely administering) an anti-CD38 antibody to in an individual (e.g., a human individual) in need thereof, comprising administering to the individual a dose of 10 mg/kg (e.g., at least 10 mg/kg) of an anti-CD38 antibody (e.g., an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6)) via intravenous infusion, wherein each dose of the anti-CD38 antibody is in a volume of 250 ml. In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the individual does not experience an infusion reaction (IR) during or following the administration of the anti-CD38 antibody via intravenous infusion, wherein the anti-CD38 antibody is in a volume of 250 ml.. In some embodiments, the individual experiences only mild IR during or following the administration of the anti-CD38 antibody via intravenous infusion, wherein the anti-CD38 antibody is in a volume of 250 ml.. (Further details regarding IRs and characteristics of mild IRs are provided elsewhere herein.)

[0060] Provided herein are methods for treating or delaying progression of multiple myeloma (such as relapsed multiple myeloma or relapsed and refractory multiple myeloma) in an individual (e.g., a human individual) comprising administering to the individual 10 mg/kg (e.g., at least 10 mg/kg) of an anti-CD38 antibody (e.g., an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6)) via intravenous infusion, wherein each infusion is in a volume of 250 ml. In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the dose of anti-CD38 antibody (e.g., isatuximab) is 20 mg/kg.

[0061] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual in a first 28-day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual at a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) in a volume of 250 ml on each of Days 1, 8, 15, and 22 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 1 of the first 28 day cycle at an infusion rate of 25 mL/hour for a first hour, and the infusion rate is increased by 25 mL/hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL/hour until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 1 of the first 28 day cycle at an infusion rate of 12.5 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of the first 28-day cycle is no more than any one of about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8.4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.2, 6.3, 6.4, or 6.5 hours, including any range in between these values. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of the first 28-day cycle is between about 3.3 and about 6.1 hours, including any value within in this range. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of the first 28-day cycle is between about 3.2 and 5.5 hours, such as between about 3.36 and about 5.32 hours. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of the first 28-day cycle is between about 3.8 and 4.2 hours, such as about 3.94 hours. In some embodiments, the duration of infusion includes temporary interruptions prior to completion of the infusion.

[0062] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 8 of the first 28 day cycle at an infusion rate of 50 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 50 ml/hr for the next 30 minutes, and wherein the infusion rate is increased by 100 mL/hour every 30 minutes after the first 60 minutes to a maximum infusion rate of 200 mL/hour until the 250 ml volume is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 8 of the first 28 day cycle at an infusion rate of 50 mL/hour for a first 30 minutes, 100 mL/hour for a second 30 minutes, 200 mL for the third 30 minutes, and 300 mL/hour after the third 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 8 of the first 28 day cycle at an infusion rate of 25 mL/hour for a first 30 minutes, and the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of the first 28-day cycle is no more than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range in between these values. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 8 of the first 28-day cycle is between about 1.5 and about 3.5 hours, including any value within in this range. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 8 of the first 28-day cycle is between about 1.4 and 2.7 hours, such as between about 1.52 and about 2.6 hours. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 8 of the first 28-day cycle is between about 1.5 and 2.0 hours, such as about 1.88 hours. In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) includes temporary interruptions prior to completion of the infusion.

[0063] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 15 of the first 28-day cycle at an infusion rate of 200 ml/hour until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 15 of the first 28 day cycle at an infusion rate of 100 ml/hour for a first 30 minutes, and the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 15 of the first 28-day cycle is no more than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range in between these values. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of the first 28-day cycle is between about 1.2 and about 3.4 hours, including any value within in this range. In some embodiments, the duration of the infusion the anti-CD38 antibody (e.g., isatuximab) on Day 15 of the first 28-day cycle is between about 1 and 2 hours, such as between about 1.03 and about 1.87 hours. In some embodiments, the duration of the infusion on Day 15 of the first 28-day cycle is between about 1 and 1.5 hours, such as about 1.27 hours. In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) includes temporary interruptions prior to completion of the infusion.

[0064] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 22 of the first 28-day cycle at an infusion rate of 200 ml/hour until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 22 of the first 28 day cycle at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 22 of

the first 28-day cycle is no more than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range in between these values. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 22 of the first 28-day cycle is between about 1.1 and about 2 hours, including any value within in this range. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 22 of the first 28-day cycle is between about 1 and 2 hours, such as between about 1.18 and about 1.52 hours. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 22 of the first 28-day cycle is between about 1 and 1.5 hours, such as about 1.27 hours. In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) includes temporary interruptions prior to completion of the infusion.

[0065] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is further administered via intravenous infusion in one or more subsequent 28-day cycles (e.g., following the first 28-day cycle) at a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) on each of Days 1 and 15 of each subsequent 28-day cycle, wherein the anti-CD38 antibody is in a volume of 250 ml.. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) at an infusion rate of 200 ml/hour until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 1 of each subsequent 28 day cycle (e.g., following the first 28-day cycle) at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of each subsequent 28 day cycle (e.g., following the first 28-day cycle) is no more than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range in between these values. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1.1 and about 1.6 hours, including any value within in this range. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1 and 2 hours, such as between about 1.19 and about 1.41 hours. In some

embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1 and 1.5 hours, such as about 1.27 hours. In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) includes temporary interruptions prior to completion of the infusion. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via

intravenous infusion on Day 15 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) at an infusion rate of 200 ml/hour until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on Day 15 of each subsequent 28 day cycle (e.g., following the first 28 day cycle) at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 15 of each subsequent 28 day cycle (e.g., following the first 28-day cycle) is no more than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range in between these values. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1.2 and about 1.6 hours, including any value within in this range. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1 and 2 hours, such as between about 1.2 and about 1.46 hours. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1 and 1.5 hours, such as about 1.27 hours. In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) includes temporary interruptions prior to completion of the infusion.

[0066] In some embodiments, the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) on or after Day 15 of the first 28 day cycle (e.g., including Day 22 of the first 28 day cycle and Day 1 and Day 15 of each subsequent 28-day cycle) is no more than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range in between these values. In some embodiments, the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) on or after Day 15 of the first 28-day cycle (e.g., including Day 22 of the first 28-day cycle and Day 1 and Day 15 of each subsequent 28-day cycle) is between about 0.7 and about 3.4 hours, including any value within in this range. In some embodiments, the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) on or after Day 15 of the first 28 day cycle (e.g., including Day 22 of the first 28 day cycle and Day 1 and Day 15 of each subsequent 28-day cycle) is between about 1 and 2 hours, such as between about 1.13 and about 1.53 hours. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1 and 1.5 hours, such as about 1.25 hours.

[0067] In some embodiments, the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) after the first infusion (e.g., on Day 1 of the first 28-day cycle) is no more than 0.5 hours. In some embodiments, the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) after Day 1 of the first 28 day cycle (e.g., including Days 8, 15 and 22 of the first 28 day cycle and Day 1 and Day 15 of each subsequent 28-day cycle) is no more than any one of about 0.5 hours. In some embodiments, the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) on or after Day 8 of the first 28 day cycle (e.g., including Days 15 or 22 of the first 28 day cycle and Day 1 and Day 15 of each subsequent 28-day cycle) is no more than any one of about 0.5 hours.

[0068] Also provided herein is a method of safely administering an anti-CD38 antibody to a human individual in need thereof, comprising administering at least a first 10 mg/kg dose (e.g., at least 10 mg/kg, or 20 mg/kg) of an anti-CD38 antibody via intravenous infusion (i.e., a first intravenous infusion), wherein the anti-CD38 antibody is in a volume of 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments of safely administering the anti-CD38 antibody (e.g., isatuximab), the individual does not experience grade 3 or higher IR during or after the infusion of the anti-CD38 antibody. In some embodiments of safely administering the anti-CD38 antibody (e.g., isatuximab), the individual does not experience Grade 2 or higher IR during or after the second or subsequence infusion of the anti-CD38 antibody.

[0069] In some embodiments, the first intravenous infusion of a 10 mg/kg dose (i.e., first dose of, e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the individual at an infusion rate of 25 mL/hour for a first hour, wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL/hour until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the first intravenous infusion of a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the individual at an infusion rate of 12.5 mL/hour for a first 30 minutes, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the first intravenous infusion of a 10 mg/kg dose of the anti-CD38 antibody (e.g., isatuximab) is no more than is no more than any one of about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8.4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.2, 6.3, 6.4, or 6.5 hours, including any range in between these values. In some embodiments, the duration of the first intravenous infusion of a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is between about 3.3 and about 6.1 hours, including any value within in this range. In some embodiments, the duration of the first intravenous infusion of a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is between about 3.2 and 5.5 hours, such as between about 3.36 and about 5.32 hours. In some embodiments, the duration of the first intravenous infusion of a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is between about 3.8 and 4.2 hours, such as about 3.94 hours. In some embodiments, the duration of the first infusion of the anti-CD38 antibody (e.g., isatuximab) includes temporary interruptions prior to completion of the infusion.

[0070] In some embodiments, a second 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is administered to the individual in need thereof via intravenous infusion (i.e., a second intravenous infusion), wherein the anti-CD38 antibody is in a volume of 250 ml..

[0071] In some embodiments, the second intravenous infusion of a 10 mg/kg dose (i.e., second dose of, e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the individual at an infusion rate of 50 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 50 ml/hr for a second 30 minutes, and wherein the infusion rate is increased by 100 mL/hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL/hour until the 250 ml volume is infused. In some embodiments, the second intravenous infusion of a 10 mg/kg dose (i.e., second dose of, e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the individual at an infusion rate of 50 mL/hour for a first 30 minutes, 100 mL/hour for a second 30 minutes, 200 mL for the third 30 minutes, and 300 mL/hour after the third 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the second intravenous infusion of a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the individual at an infusion rate of 25 mL/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the second infusion of a 10 mg/kg dose of the anti-CD38 antibody (e.g., isatuximab) is no more than is no more than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range in between these values. In some embodiments, the duration of the second infusion of a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g.,

isatuximab) is between about 1.5 and about 3.5 hours, including any value within in this range. In some embodiments, the duration of the second infusion of a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is between about 1.4 and 2.7 hours, such as between about 1.52 and about 2.6 hours. In some embodiments, the duration of the second infusion of a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is about between about 1.5 and 2.0 hours, such as about 1.88 hours. In some embodiments, the duration of the second infusion of the anti-CD38 antibody (e.g., isatuximab) includes temporary interruptions prior to completion of the infusion.

[0072] In some embodiments, a third 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a 250 ml volume and is administered to the individual in need thereof via intravenous infusion (i.e., a third intravenous infusion. In some embodiments, the third infusion of a 10 mg/kg dose (i.e., a third dose of, e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the individual at an infusion rate of 200 ml/hour until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the third infusion of a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some

embodiments, the duration of the third infusion of a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is no more than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range in between these values. In some embodiments, the duration of the infusion of the third 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is between about 1.2 and about 3.4 hours, including any value within in this range. In some embodiments, the duration of the infusion the third 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 2 hours, such as between about 1.03 and about 1.87 hours. In some embodiments, the duration of the infusion the third 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 1.5 hours, such as about 1.27 hours. In some embodiments, the duration of the third infusion of 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or a 20 mg/kg dose) the anti-CD38 antibody (e.g., isatuximab) includes temporary interruptions prior to completion of the infusion.

[0073] In some embodiments, one or more subsequent intravenous infusions of the anti-CD38 antibody (e.g., isatuximab) are administered to the individual following the third intravenous infusion, wherein each of the one or more subsequent infusions provides a 10 mg/kg dose (e.g., at least 10 mg/kg, or 20 mg/kg), e.g., fourth dose, fifth dose, sixth dose, etc., of the anti-CD38 antibody (e.g.,

isatuximab) to the individual in need thereof, and wherein each of the one or more subsequent infusions of the anti-CD38 antibody is in a volume of 250 ml. The one or more subsequent infusions include, but are not limited to, e.g., a fourth infusion, a fifth infusion, a sixth infusion, etc. In some embodiments, the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) are each in a volume of 250 ml and are each administered to the individual at an infusion rate of 200 ml/hour until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some

embodiments, the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) are each administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of each of the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) is no more than is no more than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range in between these values. In some embodiments, the duration of each of the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) is between about 0.7 and about 3.4 hours, such as between about 1.1 and about 1.6 hours, including any value within in these ranges. In some embodiments, the duration of each of the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 2 hours, such as between about 1.13 and about 1.53, or between about 1.19 and about 1.41 hours, including any value within these ranges. In some embodiments, the duration of each of the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) is about between about 1 and 1.5 hours, such as about 1.27 hours or 1.25 hours. In some embodiments, the duration of each of the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) includes temporary interruptions prior to completion of the infusion.

[0074] In some embodiments, the duration of each infusion that provides a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) after the first infusion (e.g., on Day 1 of the first 28-day cycle) is no more than 0.5 hours. In some

embodiments, the duration of each infusion that provides a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) after Day 1 of the first 28 day cycle (e.g., including Days 8, 15 and 22 of the first 28 day cycle and Day 1 and Day 15 of each subsequent 28-day cycle) is no more than about 0.5 hours. In some embodiments, the duration of each infusion that provides a 10 mg/kg dose (e.g., at least a 10 mg/kg dose, or 20 mg/kg dose) of the anti-CD38 antibody (e.g., isatuximab) on or after Day 8 of the first 28 day cycle (e.g., including Days 15 or 22 of the first 28 day cycle and Day 1 and Day 15 of each subsequent 28-day cycle) is no more than about 0.5 hours.

[0075] In some embodiments, the individual does not experience an infusion reaction (IR) during or following administration (e.g., intravenous infusion) of the anti-CD38 antibody (such as

isatuximab) at a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) in a 250 ml volume. In some embodiments, administration of the anti-CD38 antibody (e.g., via intravenous infusion) at a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) in a 250 ml volume does not cause the individual to experience an IR during or following administration. In some embodiments, the individual does not experience an IR of Grade 3 or higher during or following the infusion of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual does not experience IR during or following the second infusion of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual does not experience an IR during or following the second infusion of the anti-CD38 antibody (e.g., isatuximab) or in subsequent infusions of the anti-CD38 antibody (e.g., isatuximab). An IR refers to a disorder characterized by adverse reaction to the intravenous infusion of an anti-CD38 antibody (e.g., isatuximab). An IR may occur during the fusion or within 24 hours of the infusion (such as 24 hours from the time the infusion started). Signs or symptoms of an IR include one or more of the following: paresthesia, chest pain, cough, nasal congestion, sneezing, throat irritation, pruritus, syncope, flushing, chills, fever, urticarial, angioedema, rash, skin reactions, itching, maculopapular rash, tachycardia, hypotension, dyspnea, nausea, vomiting, headache, back pain, chest discomfort or non-cardiac chest pain, abdominal pain, abdominal cramps, bronchospasm, laryngospasm, wheezing, respiratory tract congestion, excessive sweating, and erythema. (See, e.g., Doessegger et al. (2015) Clin & Trans Immunol.4(7): e39 for further details.) Thus, in some embodiments, the individual does not experience any one or more of these signs or symptoms.

[0076] In some embodiments, the individual receives (e.g., requires) premedication, i.e., medication administered prior the infusion of the anti-CD38 antibody (e.g. isatuximab) for the purpose of preventing or minimizing an IR. In some embodiments, the individual receives premedication with one or more of: an analgesic (e.g., acetaminophen or paracetamol), an H2 antagonist or antacid (such as ranitidine, cimetidine, omeprazole, or esomeprazole), an anti-inflammatory agent (such as a corticosteroid or a nonsteroidal anti-inflammatory drug), and/or an antihistamine (such as diphenhydramine, cetirizine, promethazine, dexchlorpheniramine) for the purpose of preventing or minimizing an IR prior to infusion of the anti-CD38 antibody (such as isatuximab) at a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) in a 250 ml volume.

[0077] In some embodiments, the individual does not receive (e.g., require) premedication, i.e., medication administered prior the infusion of the anti-CD38 antibody (e.g. isatuximab) for the purpose of preventing or minimizing an IR. In some embodiments, the individual does not receive (e.g., require) premedication with one or more of: an analgesic (e.g., acetaminophen or paracetamol), an H2 antagonist or antacid (such as ranitidine, cimetidine, omeprazole, or esomeprazole), an anti-inflammatory agent (such as a corticosteroid or a nonsteroidal anti-inflammatory drug), and/or an antihistamine (such as diphenhydramine, cetirizine, promethazine, dexchlorpheniramine) for the purpose of preventing or minimizing an IR prior to infusion of the anti-CD38 antibody (such as isatuximab) at a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) medication (e.g., prophylactic medication) to prevent or minimize an IR following completion of the infusion of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual does not experience a delayed infusion reaction following administration (e.g., intravenous infusion) of the anti-CD38 antibody (such as isatuximab) at a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) in a 250 ml volume. In some embodiments, the individual does not experience a delayed infusion reaction within about any one of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 6.0, 9.0, 12.0, 18.0, 21.0, or 24.0 hours (including any range in between these values) following administration (e.g., intravenous infusion) of the anti-CD38 antibody (such as isatuximab) at a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) premedication or prophylactic medication, e.g., as described above, prior to the first, second, third, fourth, and/or fifth infusions in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) premedication or prophylactic medication, e.g., as described above, prior to the first, second, third, and/or fourth infusions of a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) anti-CD38 antibody in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) premedication or prophylactic medication, e.g., as described above, prior to start of the fourth infusion of a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) anti-CD38 antibody in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) premedication or prophylactic medication, e.g., as described above, prior the start of any infusion after the third infusion of a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) anti-CD38 antibody in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) premedication or prophylactic medication, e.g., as described above, prior to any infusion of a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) anti-CD38 antibody in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) post-medication, i.e., medication administered following completion of the infusion (e.g., within at least about any one of 0.5, 1.0, 1.5, 2.0, 2.5, or 3.0 hours of completion of the infusion, including any range between these values) of the anti-CD38 antibody (e.g. isatuximab) at a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) in a 250 ml volume for the purpose of preventing or minimizing an IR. In some embodiments, the individual does not receive (e.g., require) post-medication within at least about any one of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 6.0, 9.0, 12.0, 18.0, 21.0, or 24.0 hours (including any range in between these values) following the completion of an infusion of the anti-CD38 antibody (e.g. isatuximab) at a dose of 10 mg/kg in a 250 ml volume, e.g., for the purpose of preventing or minimizing an IR. In some embodiments, the individual does not receive (e.g., require) post-medication, e.g., as described above, following the completion (e.g., within at least about any one of about any one of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 6.0, 9.0, 12.0, 18.0, 21.0, or 24.0 hours of completion, including any range in between these values) of the first, second, third, fourth, and/or fifth infusions of a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) anti-CD38 antibody in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) post-

medication, e.g., as described above, following the completion (e.g., within at least about any one of about any one of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 6.0, 9.0, 12.0, 18.0, 21.0, or 24.0 hours of completion, including any range in between these values) of the first, second, third, and/or fourth infusions of a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) anti-CD38 antibody in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) post-medication, e.g., as described above, following the completion (e.g., within at least about any one of about any one of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 6.0, 9.0, 12.0, 18.0, 21.0, or 24.0 hours of completion, including any range in between these values) of the fourth infusion of a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) anti-CD38 antibody in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) post-medication, e.g., as described above, following the completion (e.g., within at least about any one about any one of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 6.0, 9.0, 12.0, 18.0, 21.0, or 24.0 hours if completion, including any range in between these values) of any infusion subsequent to the third infusion of a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) anti-CD38 antibody in a 250 ml volume. In some embodiments, the individual does not receive (e.g., require) post-medication, e.g., as described above, following the completion (e.g., within at least about any one of about any one of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 6.0, 9.0, 12.0, 18.0, 21.0, or 24.0 hours of completion, including any range in between these values) of any infusion of a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) anti-CD38 antibody in a 250 ml volume. In some embodiments the individual does not receive premedication or post-medication with any one or more of: an analgesic (e.g., acetaminophen or paracetamol), an H2 antagonist or antacid (such as ranitidine, cimetidine, omeprazole, or

esomeprazole), an anti-inflammatory agent (such as a corticosteroid or a nonsteroidal anti-inflammatory drug), and/or an antihistamine (such as diphenhydramine, cetirizine, promethazine, dexchlorpheniramine) for the purpose of preventing or minimizing an IR prior to infusion of the anti-CD38 antibody (such as isatuximab) at a dose of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) in a 250 ml volume.

[0078] In some embodiments, the individual experiences a mild IR following administration of the anti-CD38 antibody (such as isatuximab). In some embodiments, the mild IR is no more than a Grade 1 or Grade 2 IR, as defined in the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v.4.03). The NCI-CTCAE v.4.03 is publicly available online at evs(dot)nci(dot)nih(dot)gov/ftp1/CTCAE/About(dot)html. In some embodiments, the IR is a Grade 1 IR if the individual experiences a mild transient reaction (e.g., one or more of the signs/symptoms described herein, such as within 24 hours of the start of the infusion), wherein the interruption of the infusion is not indicated and/or wherein intervention is not indicated. In some embodiment, the IR is a Grade 2 IR if the individual experiences a reaction (e.g., one or more of the signs/symptoms described herein, such as within 24 hours of the start of the infusion), wherein infusion is interrupted and/or wherein intervention is indicated, and wherein the individual responds promptly to treatment (i.e., treatment of the one or more signs or symptoms of IR, such as those

described herein), such as within about any one of 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 hours of the treatment for the IR (including any range between these values). In some embodiments, the treatment for the IR comprises one or more of: short-term interruption of the infusion, administration of oxygen, administration of bronchodilators, administration of corticosteroids, administration of histamine blockers, and restarting the infusion at a slower rate

[0079] In some embodiments, the individual experiences a mild IR (e.g., a Grade 1 or Grade 2 IR) during or following the first intravenous infusion of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) of the anti-CD38 antibody (such as isatuximab) in a 250 ml fixed volume, e.g., during infusion on Day 1 of the first 28-day cycle. In some embodiments, the individual experiences no IR (or no further IR) during a second or subsequent infusion of the anti-CD38 antibody (e.g., isatuximab) in a 250 ml fixed volume. For example, in some embodiments, the individual experiences no IR (or no further IR) during infusion of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) of the anti-CD38 antibody (such as isatuximab) in a 250 ml fixed volume on any of Days 8, 15, and 22 of the first 28-day cycle and on any of Days 1 and 15 of any subsequent 28-day cycle.

[0080] In some embodiments, the individual does not experience a moderate or severe IR following infusion of an anti-CD38 antibody in a 250 ml volume, e.g., according to a method described herein. In some embodiments, the individual does not experience an IR of Grade 3, 4, or 5, as defined in the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v.4.03). In some embodiments, the IR is a Grade 3 IR if the individual experiences prolonged signs/symptoms of IR (such as described herein) and is not rapidly responsive to medication for the IR and/or to interruption of the infusion. In some embodiments, the IR is Grade 3 IR if the individual experiences recurrence of the signs/symptoms of IR (such as described herein) following initial improvement. In some embodiments, the IR is grade 3 IR is the individual requires hospitalization for the signs/symptoms of IR (such as described herein). In some embodiments, the IR is a Grade 4 IR if the signs/symptoms (such as described herein) are life threatening and/or require urgent intervention. In some embodiments, the IR is Grade 5 IR if the signs/symptoms of IR result in death.

[0081] In some embodiments, the individual does not experience an IR of any grade (e.g., Grade 1, 2, 3, 4, or 5 IR) during or following the fourth intravenous infusion of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) of the anti-CD38 antibody (such as isatuximab) in a 250 ml fixed volume. Additionally or alternatively, in some embodiments, the individual does not experience an IR of any grade (e.g., Grade 1, 2, 3, 4, or 5 IR) during or following any intravenous infusion of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) of the anti-CD38 antibody (such as isatuximab) in a 250 ml fixed volume subsequent to the fourth intravenous infusion. In some embodiments, the individual experiences no IR (or no further IR) during a fourth infusion or an infusion after the fourth infusion of the anti-CD38 antibody (e.g., isatuximab) in a 250 ml fixed volume. For example, in some embodiments, the individual experiences no IR (or no further IR) during infusion of 10 mg/kg (e.g., at least 10 mg/kg, or 20 mg/kg) of the anti-CD38 antibody (such as isatuximab) in a 250 ml fixed volume on Day 22 of the first 28-day cycle and on any of Days 1 and 15 of any subsequent 28-day cycle (i.e., after the first 28-day cycle).

[0082] In some embodiments, the dose of anti-CD38 antibody (such as isatuximab) that is in a fixed 250 ml volume and is administered to the individual is not reduced during treatment, e.g., whether or not the individual experiences an IR.

[0083] In some embodiments, an anti-CD38 antibody described herein (such as isatuximab) is in a formulation comprising about 20 mg/mL antibody, about 20 mM histidine, about 10% (w/v) sucrose, about 0.02% (w/v) polysorbate 80 at pH 6.0. In some embodiments, an anti-CD38 antibody described herein (such as isatuximab) is in a formulation comprising about 20 mg/mL antibody, about 100 mg/mL sucrose, 2.22 mg/mL histidine hydrochloride monohydrate, about 1.46 mg/ml histidine, and about 0.2 mg/ml polysorbate 80. In some embodiments, the formulation comprises water for injection (WFI), such as sterile water for injection (SWFI). In some embodiments, the formulation is sterile. In some embodiments, a single use of the formulation comprises 5 ml of the formulation (i.e., 100 mg anti-CD38 antibody). In some embodiments, the single use 5 ml formulation is provided in, e.g., a type I 6 mL colorless clear glass vial fitted with elastomeric closure. In some embodiments, the fill volume of the vial has been established to ensure removal of 5 mL. In some embodiments, the fill volume is 5.4 mL. In some embodiments, a single use of the formulation comprises 25 ml of the formulation (i.e., 500 mg anti-CD38 antibody). In some embodiments, the single use 25 ml formulation is provided in, e.g., a 30 mL colorless clear glass vial fitted with elastomeric closure. In some embodiments, the fill volume of the vial has been established to ensure removal of 25 mL. In some embodiments, the formulation is stable for at least about 6, 12, 18, 24, 30, or 36 months, including any range in between these values, at a temperature between about 2°C and about 8°C and protected from light. In some embodiments, the formulation is diluted for infusion in 0.9% sodium chloride, 5% glucose, or 5% dextrose. In some embodiments, the diluted infusion solution is stable for up to about 6, 12, 18, 24, 30, 36, 42, or 48 hours, including any range in between these values, between about 2°C and about 8°C. In some embodiments, the diluted solution for infusion is stable following storage (e.g., for up to about 6, 12, 18, 24, 30, 36, 42, or 48 hours, including any range in between these values) between about 2°C and about 8°C and for a further 8 hours (including the infusion time) at room temperature. In some embodiments, the diluted solution for infusion is stable in the presence of light. In some embodiments the bag in which the diluted solution for infusion is stored is fabricated from polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) with di(ethylhexyl)phthalate (DEHP) or ethy vinyl acetate (EVA). In some embodiments, the tubing used for infusion is fabricated from PE, PVC (with or without DEHP), polybutyldiene (PBD), or polyurethane (PU) with an in-line filter (polyethersulfone (PES), polysulfone or nylon).

[0084] For administration to patients, the appropriate volume of isatuximab is diluted in an infusion bag of 0.9% sodium chloride solution, 5% glucose, or 5% dextrose. No protection from light is required for storage in the infusion bags. The Investigational medicinal product was stored at +2°C to +8°C.

[0085] In some embodiments, provided is an intravenous (IV) bag containing 250 mls of a 10 mg/kg dose (e.g., at least 10 mg/kg, or 20 mg/kg) of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the 10 mg/kg dose of the anti-CD38 antibody (e.g., isatuximab) is calculated based on the weight of the patient to whom the anti-CD38 antibody is to be administered. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is diluted from a concentrated formulation (e.g., a formulation described herein) into 0.9% sodium chloride, 5% glucose, or 5% dextrose. In some embodiments, the bag contains between about 360 mg and about 1600 mg, between about 450 mg and about 16000 mg, between about 450 mg and 1140 mg, or between about 450 mg and about 910 mg, including any range in between these values.

Treatment Comprising Administration of 10 mg/kg or 20 mg/kg Dose of Anti-CD38 Antibody

[0086] Also provided herein are methods for treating or delaying progression of multiple myeloma (such as relapsed multiple myeloma or relapsed and refractory multiple myeloma) in an individual (e.g., a human individual) comprising administering to the individual an anti-CD38 antibody (e.g., an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6)via intravenous infusion in a first 28 day cycle, and wherein the anti-CD38 antibody is administered at a dose of 10 mg/kg on Days 1, 8, 15, and 22 of the first 28 day cycle. In some embodiments, the anti-CD38 antibody is administered via intravenous infusion in one or more subsequent 28-day cycles following the first 28-day cycle, wherein the anti-CD38 antibody is administered at a dose of 10 mg/kg on Days 1 and 15 of each of the one or more subsequent 28-day cycles following the first 28-day cycle. In some embodiments, treatment results in a reduction of serum M protein by at least about any one of 40%, 45%, 50%, 55%, 60%, 65% or more than 65% from baseline. In some embodiments, treatment results in a reduction of serum M protein by at least about 52% from baseline. In some embodiments, serum M protein level is reduced after about two cycles of treatment. In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (VH)

comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the anti-CD38 antibody is not administered in combination with a second drug (i.e., the anti-CD38 antibody is administered as monotherapy).

[0087] Also provided herein are methods for treating or delaying progression of multiple myeloma (such as relapsed multiple myeloma or relapsed and refractory multiple myeloma) in an individual (e.g., a human individual) comprising administering to the individual an anti-CD38 antibody (e.g., an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6)via intravenous infusion in a first 28 day cycle, and wherein the anti-CD38 antibody is administered at a dose of 20 mg/kg on Days 1, 8, 15, and 22 of the first 28 day cycle. In some embodiments, the anti-CD38 antibody is administered via intravenous infusion in one or more subsequent 28-day cycles following the first 28-day cycle, wherein the anti-CD38 antibody is administered at a dose of 20 mg/kg on Days 1 and 15 of each of the one or more subsequent 28-day cycles following the first 28-day cycle. In some embodiments, treatment results in a reduction of serum M protein by at least about any one of 40%, 45%, 50%, 55%, 60%, 65% or more than 65% from baseline. In some embodiments, treatment results in a reduction of serum M protein by at least about 52% from baseline. In some embodiments, serum M protein level is reduced after about two cycles of treatment. In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the anti-CD38 antibody is not administered in combination with a second drug (i.e., the anti-CD38 antibody is administered as monotherapy).

[0088] In some embodiments, the individual has received at least two, at least three, at least four, at least five, or at least six prior therapies (such as 7, 8, 9, 10, 11, or 12 prior therapies) for multiple myeloma. In some embodiments, the prior therapy for multiple myeloma was an immunomodulatory drug (e.g., lenalidomide, pomalidomide, and/or thalidomide). In some embodiments, the individual was refractory to the immunomodulatory drug. In some embodiments, the prior therapy for multiple myeloma was a proteasome inhibitor (e.g., bortezomib, carfilzomib, and/or ixazomib). In some embodiments, the individual was refractory to the proteasome inhibitor. In some embodiments, the

individual received prior therapy with an immunomodulatory drug and a proteasome inhibitor. In some embodiments, the immunomodulatory drug and the proteasome inhibitor were administered in combination. In some embodiments, the immunomodulatory drug and the proteasome inhibitor were administered during separate therapies (e.g., separate treatment regimens). In some embodiments, the individual was refractory to the immunomodulatory drug and the proteasome inhibitor.

[0089] In some embodiments, the individual has at least one high-risk cytogenetic abnormality (e.g., prior to starting treatment with the anti-CD38 antibody). In some embodiments the at least one high-risk cytogenetic abnormality is selected from the group consisting of: 17p deletion/del(17p) (TP53), t(4; 14) translocation (FGFR3/IGH), and t(14;16) translocation (IGH/MAF). In some embodiments, the individual has at least two high-risk cytogenetic abnormalities. In some embodiments, the individual has all three high-risk cytogenetic abnormalities.

Other Characteristics of Individuals Receiving Treatment Comprising an Anti-CD38 Antibody

[0090] In some embodiments, the individual demonstrated progressive disease during the most recent prior therapy (or line of therapy), e.g., the therapy (or line of therapy) just before the start of a treatment described herein comprising administration of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual demonstrated progressive disease (PD) within 60 days after the end of the most recent prior therapy (or line of therapy) for multiple myeloma, e.g., the therapy (or line of therapy) just before the start of the treatment comprising administration of the anti-CD38 antibody (e.g., isatuximab) a treatment described herein comprising administration of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, a progressive disease (PD) is defined according to

International Myeloma Working Group criteria (see, e.g., Kumar et al. (2016)“International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol. 17(8):e328-e346; Durie et al. (2006)“International uniform response criteria for multiple myeloma. Leukemia. 20: 1467-1473; and Table 14 herein). In some

embodiments, a line of therapy is ³1 complete cycle of a single agent, or of a combination of two or more agents, or a planned sequential therapy that includes stem cell transplantation. In some embodiments, a given treatment is considered a new line of therapy if any 1 of the following 3 conditions are met:

1. Start of a new line of treatment after discontinuation of a previous line. If a treatment regimen is discontinued for any reason and a different regimen is started, it can be considered a new line of therapy. For example, a regimen is considered to have been discontinued if all the drugs in that given regimen have been stopped. For example, a regimen is not considered to have been

discontinued if some of the drugs of the regimen, but not all, have been discontinued. In some embodiments, the reasons for discontinuation, addition, substitution, or SCT do not influence how lines are counted. Reasons for change may include, for example, end of planned therapy, toxicity, progression, lack of response, inadequate response.

2. The unplanned addition or substitution of 1 or more drugs in an existing regimen. Unplanned addition of a new drug or switching to a different drug (or combination of drugs) due to any reason can be considered a new line of therapy.

3. Stem cell transplantation (SCT): In patients undergoing >1 SCT, except in the case of a planned tandem SCT with a predefined interval (such as 3 months), each SCT (autologous or allogeneic) can be considered a new line of therapy regardless of whether the conditioning regimen used is the same or different. Generally, planned tandem SCT is considered 1 line. Planned induction and/or consolidation, maintenance with any SCT (frontline, relapse, autologous or allogeneic) is generally considered 1 line of therapy.

[0091] In some embodiments, the multiple myeloma is difficult to treat. In some embodiments, the individual has refractory multiple myeloma. In some embodiments, an individual with refractory multiple myeloma is one who was refractory to all prior therapies (or prior lines of therapy), but achieved at least a minimal response (MR) to one prior therapy (or line of therapy). In some embodiments, a minimal response (MR) is defined according to International Myeloma Working Group criteria (see, e.g., Kumar et al. (2016)“International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol. 17(8):e328-e346; Durie et al. (2006)“International uniform response criteria for multiple myeloma. Leukemia.20: 1467-1473; and Table 14 herein). In some embodiments, an individual with refractory multiple myeloma is one who was non-responsive to a prior therapy (or prior line of therapy). In some embodiments,“non-responsive” to a therapy (or line of therapy) for multiple myeloma means that the individual failed to achieve a minimal response (MR) to the therapy (or line of therapy) for multiple myeloma. In some embodiments“non-responsive” to a therapy (or line of therapy) for multiple myeloma means that the individual has demonstrated progressive disease during the therapy (or line of therapy) for multiple myeloma. In some embodiments, an individual with refractory multiple myeloma is one who demonstrated progressive disease within the 60 days from the end of the last therapy for multiple myeloma.

[0092] In In some embodiments, the individual has failed prior treatment (such as lenalidomide and/or a proteasome inhibitor) for multiple myeloma. In some embodiments,“failing” a prior treatment means that the individual has demonstrated disease progression (e.g. according to the criteria in Table A) while on the treatment (such as treatment with lenalidomide and/or a proteasome inhibitor) or within 60 days from end of treatment (such as treatment with lenalidomide and/or a proteasome inhibitor). In some embodiments,“failing” a prior treatment for multiple myeloma means that the individual had demonstrated a partial response (PR) or better (e.g., according to the criteria in Table A) to treatment (such as treatment with lenalidomide and/or a proteasome inhibitor), but exhibited disease progression within 6 months after discontinuing the treatment (e.g., as treatment with lenalidomide and/or a proteasome inhibitor). In some embodiments,“failing” a prior treatment

for multiple myeloma means that this individual developed toxicity / intolerance after a minimum of 2 consecutive cycles of a treatment regimen (e.g., a treatment regimen containing lenalidomide and/or a proteasome inhibitor (bortezomib, carfilzomib, ixazomib)). In some embodiments, intolerance to a proteasome-containing regimen refers to the individual (e.g., an individual who did not have peripheral neuropathy prior to starting the regimen) developing peripheral neuropathy or neuropathic pain. In some embodiments, intolerance to a lenalidomide -containing regimen refers to the individual developing a severe rash.

[0093] In some embodiments, the individual has relapsed and refractory multiple myeloma. In some embodiments, an individual with relapsed and refractory multiple myeloma is one who relapsed from at least one prior therapy (or line of therapy) for multiple myeloma and was refractory to the most recent therapy (or line of therapy) for multiple myeloma. In some embodiments, the individual with relapsed and refractory multiple myeloma is one who relapsed from at least one prior therapy (or line of therapy) for multiple myeloma, was refractory to the most recent therapy (or line of therapy) for multiple myeloma, and was refractory to one or more therapies (or lines of therapy) prior to the most recent therapy (or line of therapy) for multiple myeloma. In some embodiments, an individual with relapsed or refractory multiple myeloma is one who demonstrated progressive disease within 60 days after the end of the most recent therapy (or line of therapy).

[0094] In some embodiments, the individual was refractory to the most recent prior therapy (or line of therapy).

[0095] In some embodiments, the individual has relapsed/refractory multiple myeloma (RRMM) with measurable disease (e.g., serum M protein ³0.5 g/dL measured using serum protein

immunoelectrophoresis and/or urine M protein ³200 mg/24 hours measured using urine protein immunoelectrophoresis and/or serum free light chain (FLC) (i.e., FLC assay ³ 10 mg/dl ( ³ 100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65)) who has received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (e.g., bortezomib, carfilzomib, or ixazomib) and was refractory to the last line of therapy (i.e., most recent line of therapy). In some embodiments, the individual has adequate renal, hepatic and bone marrow function.

[0096] In some embodiments, the individual has a poor prognosis. In some embodiments of the methods and uses provided herein, the individual has received at least one, at least two, at least three, at least four prior therapies (or lines of therapy), or more than four prior therapies (or lines of therapy), e.g., at least any one of 5, 6, 7, 8, 9, 10, or 11 prior therapies (or lines of therapy) for multiple myeloma.

[0097] In some embodiments, the individual has undergone at least one prior therapy (or line of therapy) with lenalidomide. In some embodiments, the prior lenalidomide therapy (or line of therapy) comprised at least two consecutive cycles of lenalidomide. In some embodiments, the individual failed (e.g., was non-re sponsive to) a prior lenalidomide therapy (or a line of therapy). In some

embodiments, an individual who failed a prior lenalidomide therapy (or a line of therapy) did not achieve at least a minimal response (MR) during the therapy (or line of therapy) with lenalidomide. In some embodiments, an individual who failed a prior lenalidomide therapy (or a line of therapy) demonstrated progressive disease (PD) during the therapy (or line of therapy) with lenalidomide. As noted elsewhere herein, in some embodiments,“minimal response” and“progressive disease” are assessed according to the criteria in Kumar et al. (2016)“International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol.17(8): e328-e346 and Durie et al. (2006)“International uniform response criteria for multiple myeloma. Leukemia.20: 1467-1473 (see also Table 14 herein). In some embodiments, prior lenalidomide therapy was administered during the first, second, third, fourth, fifth, sixth, and/or later therapy (or line of therapy) for multiple myeloma (i.e., prior to a treatment described herein comprising administration of the anti-CD38 antibody (e.g., isatuximab)). In some embodiments, the individual was refractory to lenalidomide. In some embodiments, the prior lenalidomide was administered to the individual as a single agent. In some embodiments, the prior lenalidomide was administered to the individual in conjunction with at least one additional agent.

CLAIMS

1. An anti-CD38 antibody for use in a method of treating a an individual in need thereof, the method comprising administering to the individual at least a first intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the dose of the anti-CD38 antibody is in a volume of 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6).

2. A method of administering an anti-CD38 antibody to a human individual in need thereof, comprising administering to the individual at least a first intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the dose of the anti-CD38 antibody is in a volume of 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence

TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6).

3. The anti-CD38 antibody for use according to claim 1 or the method of claim 2 wherein the anti-CD38 antibody is isatuximab.

4. The anti-CD38 antibody for use according to claim 1 or 3 wherein the anti-CD38 antibody is for the treatment of a disease or disorder, optionally wherein the disease or disorder is multiple myeloma, or the method of claim 2 or 3, wherein the administration of the anti-CD38 antibody is for the treatment of multiple myeloma.

5. The anti-CD38 antibody for use of any one of claims 1 and 3-4 or the method of any one of claims 2-4, wherein the first intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL/hour for a first hour, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL/hour until the 250 ml volume is infused.

6. The anti-CD38 antibody for use of any one of claims 1 and 3-4 or the method of any one of claims 2-4, wherein the first infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 12.5 mL/hour for a first 30 minutes, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused.

7. The anti-CD38 antibody for use according to any one of claims 1 and 3-6, or the method of any one of claims 2-6, comprising administering to the individual at least a second intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml.

8. The anti-CD38 antibody for use or the method of claim 7, wherein the second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 50 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 50 ml/hr a second 30 minutes, and wherein the infusion rate is increased by 100 mL/hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL/hour until the 250 ml volume is infused.

9. The anti-CD38 antibody for use or the method of claim 7, wherein the second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 50 mL/hour for a first 30 minutes, 100 mL/hour for a second 30 minutes, 200 mL for the third 30 minutes, and 300 mL/hour after the third 30 minutes until the 250 ml volume is infused.

10. The anti-CD38 antibody for use or the method of claim 7, wherein the second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 25 mL/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused.

11. The anti-CD38 antibody for use or the method of any one of claims 7-10, comprising administering to the individual at least a third intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml.

12. The anti-CD38 antibody for use or the method of claim 11, wherein the third intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 200 ml/hour until the 250 ml volume is infused.

13. The anti-CD38 antibody for use or the method of claim 11, wherein the third intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused.

14. The anti-CD38 antibody for use or the method of any one of claims 11-13, comprising administering to the individual a fourth intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml.

15. The anti-CD38 antibody for use or the method of claim 14, wherein the fourth intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 200 ml/hour until the 250 ml volume infused.

16. The anti-CD38 antibody for use or the method of claim 14, wherein the fourth intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused.

17. The anti-CD38 antibody for use or the method of any one of claims 14-16, wherein the anti-CD38 antibody is administered in a first 28-day cycle, wherein the first intravenous infusion of the anti-CD38 antibody is administered on Day 1, the second intravenous infusion of the anti-CD38 antibody is administered on Day 8, the third intravenous infusion of the anti-CD38 antibody is administered on Day 15, and the fourth intravenous infusion of the anti-CD38 antibody is administered on Day 22 the first 28-day cycle.

18. The anti-CD38 antibody for use or the method of any one of claims 14-17, comprising administering to the individual one or more subsequent intravenous infusions of the anti-CD38 antibody following the fourth intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml for each of the one or more subsequent intravenous infusions.

19. The anti-CD38 antibody for use or the method of claim 18, wherein each of the one or more subsequent intravenous infusions of the anti-CD38 antibody following the fourth intravenous infusion is administered to the individual at an infusion rate of 200 ml/hour until the 250 ml volume infused.

20. The anti-CD38 antibody for use or the method of claim 18, wherein each of the one or more subsequent intravenous infusions of the anti-CD38 antibody following the fourth intravenous infusion is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused.

21. The anti-CD38 antibody for use or the method of any one of claims 18-20, wherein the anti-CD38 antibody is administered in one or more subsequent 28-day cycles following the first 28-day cycle, wherein each of the one or more subsequent intravenous infusions of the anti-CD38 antibody following the fourth intravenous infusion is administered on Days 1 and 15 of each of the one or more subsequent 28-day cycles following the first 28-day cycle.

22. An anti-CD38 antibody for use in a method of treating a an individual in need thereof, the method comprising administering to the individual at least three intravenous infusions of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the dose of the anti-CD38 antibody is in a volume of 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6);

wherein the first intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL/hour for a first hour, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL/hour until the 250 ml volume is infused;

wherein the second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 50 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 50 ml/hr a second 30 minutes, and wherein the infusion rate is increased by 100 mL/hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL/hour until the 250 ml volume is infused; and

wherein the third intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused.

23. A method of administering an anti-CD38 antibody to a human individual in need thereof, comprising administering to the individual at least three intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the dose of the anti-CD38 antibody is in a volume of 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence

TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6);

wherein the first intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL/hour for a first hour, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL/hour until the 250 ml volume is infused;

wherein the second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 50 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 50 ml/hr a second 30 minutes, and wherein the infusion rate is increased by 100 mL/hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL/hour until the 250 ml volume is infused; and

wherein the third intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml volume is infused.

24. The anti-CD38 antibody for use according to claim 22 or the method of claim 23 wherein the anti-CD38 antibody is isatuximab.

25. The anti-CD38 antibody for use according to claim 22 or 24 wherein the anti-CD38 antibody is for the treatment of a disease or disorder, optionally wherein the disease or disorder is multiple myeloma, or the method of claim 23 or 24, wherein the administration of the anti-CD38 antibody is for the treatment of multiple myeloma.

26. The anti-CD38 antibody for use according to any one of claims 21 and 23-25, or the method of any one of claims 22-25, further comprising administering to the individual one or more subsequent intravenous infusions of the anti-CD38 antibody following the third intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml for each of the one or more subsequent intravenous infusions.

27. The anti-CD38 antibody for use or the method of claim 26, wherein each of the one or more subsequent intravenous infusions of the anti-CD38 antibody following the third intravenous infusion is administered to the individual at an infusion rate of 200 ml/hour until the 250 ml volume infused.

28. An anti-CD38 antibody for use in a method of treating an individual in need thereof, the method comprising administering the anti-CD38 antibody to the individual via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the volume of each dose of the anti-CD38 antibody is 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence

TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6).

29. A method of administering an anti-CD38 antibody to an individual in need thereof, comprising administering the anti-CD38 antibody to the individual via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg, wherein the volume of each dose of the anti-CD38 antibody is 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence

TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6).

30. The anti-CD38 antibody for use according to claim 28 or the method of claim 29 wherein the anti-CD38 antibody is isatuximab.

31. The anti-CD38 antibody for use according to claim 28 or 30 wherein the anti-CD38 antibody is for the treatment of a disease or disorder, optionally wherein the disease or disorder is multiple myeloma, or the method of claim 29 or 30, wherein the administration of the anti-CD38 antibody is for the treatment of multiple myeloma.

32. The anti-CD38 antibody for use according to any one of claims 28 and 30-31, or the method of any one of claims 29-31 wherein the anti-CD38 antibody is administered in a first 28-day cycle, and wherein the anti-CD38 antibody is administered on Days 1, 8, 15, and 22 of the first 28-day cycle.

33. The anti-CD38 antibody for use or the method of claim 32, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 1 of the first 28 day cycle at an infusion rate of 25 mL/hour for a first hour, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL/hour until the 250 ml dose of the anti-CD38 antibody is infused.

34. The anti-CD38 antibody for use or the method of claim 32, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 1 of the first 28 day cycle at an infusion rate of 12.5 mL/hour for a first 30 minutes, and wherein the infusion rate is increased by 25 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused.

35. The anti-CD38 antibody for use or the method of any one of claims 32-34 wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 8 of the first 28 day cycle at an infusion rate of 50 mL/hour for a first 30 minutes, wherein the infusion rate is increased by 50 ml/hr for an second 30 minutes, and wherein the infusion rate is increased by 100 mL/hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL/hour until the 250 ml volume is infused.

36. The anti-CD38 antibody for use or the method of any one of claims 32-34, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 8 of the first 28 day cycle at an infusion rate of 50 mL/hour for a first 30 minutes, 100 mL/hour for a second 30 minutes, 200 mL for the third 30 minutes, and 300 mL/hour after the third 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused.

37. The anti-CD38 antibody for use or the method of any one of claims 32-34, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 8 of the first 28 day cycle at an infusion rate of 25 mL/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused.

38. The anti-CD38 antibody for use or the method of any one of claims 32-37, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 15 of the first 28-day cycle at an infusion rate of 200 ml/hour until the 250 ml dose of the anti-CD38 antibody is infused.

39. The anti-CD38 antibody for use or the method of any one of claims 32-37, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 15 of the first 28 day cycle at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused.

40. The anti-CD38 antibody for use or the method of any one of claims 32-39, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 22 of the first 28-day cycle at an infusion rate of 200 ml/hour until the 250 ml dose of the anti-CD38 antibody is infused.

41. The anti-CD38 antibody for use or the method of any one of claims 32-39, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 22 of the first 28 day cycle at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused.

42. The anti-CD38 antibody for use or the method of any one of claims 32-41, wherein the anti-CD38 antibody is further administered in one or more subsequent 28-day cycles, and wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg on Days 1 and 15 of each subsequent 28 day cycle, wherein the volume of each dose of the anti-CD38 antibody administered in the one or more subsequent cycles is 250 ml.

43. The anti-CD38 antibody for use or the method of claim 42, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 1 of each subsequent 28-day cycle at an infusion rate of 200 ml/hour until the 250 ml dose of the anti-CD38 antibody is infused.

44. The anti-CD38 antibody for use or the method of claim 42, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 1 of each subsequent 28-day cycle at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused.

45. The anti-CD38 antibody for use or the method of any one of claims 42-44, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 15 of each subsequent 28-day cycle at an infusion rate of 200 ml/hour until the 250 ml dose of the anti-CD38 antibody is infused.

46. The anti-CD38 antibody for use or the method of any one of claims 42-44, wherein the anti-CD38 antibody is administered to the individual via intravenous infusion on Day 15 of each subsequent 28 day cycle at an infusion rate of 100 ml/hour for a first 30 minutes, and wherein the infusion rate is increased by 50 mL/hour every 30 minutes after the first 30 minutes until the 250 ml dose of the anti-CD38 antibody is infused.

47. An anti-CD38 antibody for use in a method of treating an individual in need thereof, the method comprising safely administering to the individual at least a first dose of the anti-CD38 antibody via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml, wherein the first dose is infused over a duration of about 1.5 and about 6.5 hours, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6).

48. A method of safely administering an anti-CD38 antibody to a human individual in need thereof, comprising administering to the individual at least a first dose of the anti-CD38 antibody via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml, wherein the first dose is infused over a duration of about 1.5 and about 6.5 hours, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence

KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6).

49. The anti-CD38 antibody for use according to claim 47 or the method of claim 48, wherein the anti-CD38 antibody is isatuximab.

50. The anti-CD38 antibody for use according to claim 47 or 49, wherein the anti-CD38 antibody is for the treatment of a disease or disorder, optionally wherein the disease or disorder is multiple myeloma, or the method of claim 48 or 49, wherein the administration of the anti-CD38 antibody is for the treatment of multiple myeloma.

51. The anti-CD38 antibody for use according to any one of claims 47 and 49-50, or the method of any one of claims 48-50, comprising administering at least a second dose of the anti-CD38 antibody to the individual via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml, wherein the second dose is infused over a duration of about 0.5 and 3.5 hours.

52. The anti-CD38 antibody for use according to any one of claims 41 and 43-45, or the method of any one of claims 42-45, comprising administering at least a third dose of the anti-CD38 antibody to the individual via intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg/kg in a volume of 250 ml, wherein the third dose is infused over a duration of about 0.5 and 1.5 hours.

53. The anti-CD38 antibody for use according to any one of claims 1, 3-22, 24-28, 30-47, and 49-52, or the method of any one of claims 2-21, 23-27, 29-46, and 48-52, wherein the administration of the anti-CD38 antibody does not result in the individual experiencing an infusion reaction (IR).

54. The anti-CD38 antibody for use according to any one of claims 1, 3-22, 24-28, 30-47, and 49-52, or the method of any one of claims 2-21, 23-27, 29-46, and 48-52, wherein the administration of the anti-CD38 antibody does not result in the individual experiencing an IR greater than Grade 1 in severity.

55. The anti-CD38 antibody for use according to any one of 1, 3-22, 24-28, 30-47, and 49-52, or the method of any one of claims 2-21, 23-27, 29-46, and 48-52, wherein the administration of the anti-CD38 antibody does not result in the individual experiencing an IR of Grade 2 or greater in severity.

56. The anti-CD38 antibody for use according to any one of claims 1, 3-22, 24-28, 30-47, and 49-55, or the method of any one of claims 2-21, 23-27, 29-46, and 48-55, wherein the at least 10

mg/kg dose of the anti-CD38 antibody in the volume of 250 ml further comprises 0.9% sodium chloride or 5% dextrose.

57. The anti-CD38 antibody for use according to any one of claims 1, 3-22, 24-28, 30-47, and 49-56, or the method of any one of claims 2-21, 23-27, 29-46, and 48-56, wherein the individual does not receive premedication with one or more of an analgesic, an antacid, an anti-inflammatory agent, an antihistamine prior for the purpose of preventing or minimizing an infusion reaction prior to the administration of the anti-CD38 antibody via intravenous infusion.

58. The anti-CD38 antibody for use according to any one of claims 1, 3-22, 24-28, 30-47, and 49-57, or the method of any one of claims 2-21, 23-27, 29-46, and 48-57, wherein the dose of anti-CD38 antibody is 10 mg/kg or 20 mg/kg.

59. An anti-CD38 antibody for use in a method of treating multiple myeloma an individual, comprising administering to the individual an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6), pomalidomide, and dexamethasone,

wherein the anti-CD38 antibody is administered in 28-day cycles;

wherein the anti-CD38 antibody is administered on Days 1, 8, 15, and 22 of a first 28-day cycle;

wherein the anti-CD38 antibody is administered on Days 1 and 15 of every 28-day cycle following the first 28-day cycle;

and wherein the anti-CD38 antibody is administered at a dose of 10 mg/kg or 20 mg/kg.

60. A method of treating a human individual having multiple myeloma, comprising administering to the individual an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence

KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI

(SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6), pomalidomide, and dexamethasone,

wherein the anti-CD38 antibody is administered in 28-day cycles;

wherein the anti-CD38 antibody is administered on Days 1, 8, 15, and 22 of a first 28-day cycle;

wherein the anti-CD38 antibody is administered on Days 1 and 15 of every 28-day cycle following the first 28-day cycle;

and wherein the anti-CD38 antibody is administered at a dose of 10 mg/kg or 20 mg/kg.

61. The anti-CD38 antibody for use according to claim 59 or the method of claim 60, wherein the individual has at least one high-risk cytogenetic abnormality selected from: 17p deletion, 4(4; 14) translocation, and t(14;16) translocation.

62. The anti-CD38 antibody for use or the method of claim 61, wherein the individual has at least two high-risk cytogenetic abnormalities.

63. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-62, wherein the multiple myeloma is relapsed/refractory multiple myeloma.

64. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-63, wherein the individual was refractory to the most recent prior therapy for multiple myeloma.

65. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-64, wherein the individual is refractory to lenalidomide.

66. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-65, wherein the most recent prior therapy was lenalidomide.

67. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-66, wherein the individual is refractory to a proteasome inhibitor.

68. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-67, wherein the most recent prior therapy was a proteasome inhibitor.

69. The anti-CD38 antibody for use or the method of claim 67 or 68, wherein the proteasome inhibitor is selected from the group consisting of: bortezomib, carfilzomib, marizomib, oprozomib, and ixazomib.

70. The anti-CD38 antibody for use or the method of any one of claims 64-69, wherein the lenalidomide and the proteasome inhibitor were administered in combination.

71. The anti-CD38 antibody for use according to any one of claims 1, 3-22, 24-28, 30-47, and 49-70, or the method of any one of claims 2-21, 23-27, 29-46, and 48-70, wherein the individual has a respiratory disorder, thoracic disorder, and/or mediastinal disorder.

72. The anti-CD38 antibody for use or method of claim 71, wherein the respiratory disorder is chronic obstructive pulmonary disorder (COPD).

73. The anti-CD38 antibody for use or method of claim 71, wherein the respiratory disorder is asthma.

74. The anti-CD38 antibody for use or method of claim 71, wherein the respiratory disorder is bronchospam.

75. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-74, wherein the individual has received at least two prior therapies for multiple myeloma.

76. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-74, wherein the individual has received at least three prior therapies for multiple myeloma.

77. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-76, wherein the anti-CD38 antibody is administered in conjunction with at least one additional agent.

78. The anti-CD38 antibody for use or the method of claim 77, wherein the at least one additional agent comprises an immunomodulatory drug.

79. The anti-CD38 antibody for use or the method of claim 78, wherein the

immunomodulatory drug is lenalidomide or pomalidomide.

80. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-79, wherein the at least one additional agent comprises a proteasome inhibitor.

81. The anti-CD38 antibody for use or the method of claim 80, wherein the proteasome inhibitor is bortezomib, carfilzomib, marizomib, oprozomib, and ixazomib.

82. The anti-CD38 antibody for use or the method of any one of claims 4-21, 25-27, 31-46, and 50-81, wherein the at least one additional agent comprises a corticosteroid.

83. The anti-CD38 antibody for use or the method of 82, wherein the corticosteroid is dexamethasone.

84. A kit comprising isatuximab for treating an individual having multiple myeloma according to the method of any one of claims 4-21, 25-27, 31-46, and 50-83.

85. An intravenous bag containing between about 360 mg and 1600 mg of an anti-CD38 antibody in a volume of 250 ml, wherein the wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) that comprises: a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence

TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6).