Methods of treating multiple myeloma by administering anti-CD38 antibodies

Abstract

A method of treating a human individual with multiple myeloma is provided, comprising administering 10 mg / kg of isatuximab to the individual via intravenous infusion, wherein each infusion of the 10 mg / kg isatuximab has a volume of 250 ml. Also provided is a method of treating a human individual with multiple myeloma, comprising administering an anti-CD38 antibody in 28-day cycles, wherein the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first 28-day cycle, and the anti-CD38 antibody is administered on days 1 and 15 of every 28-day cycle after the first 28-day cycle; the anti-CD38 antibody is administered at a dose of 10 mg / kg or 20 mg / kg.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to European Patent Application EP 20305223.8, filed March 3, 2020; U.S. Provisional Patent Application No. 62 / 899,088, filed September 11, 2019; U.S. Provisional Patent Application No. 62 / 860,739, filed June 12, 2019; and U.S. Provisional Patent Application No. 62 / 847,825, filed May 14, 2019, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Submit sequence listing as an ASCII text file The contents of the following submission, an ASCII text file, are incorporated herein by reference in their entirety: Computer Readable Form (CRF) of Sequence Listing (Filename: 183952031741SEQLIST.TXT, Date Recorded: May 12, 2020, Size: 11 KB).

[0003] The present disclosure relates to methods of treating multiple myeloma by administering anti-CD38 antibodies. [Background technology]

[0004] Therapeutic antibodies have improved options for treating patients with relapsed and / or refractory multiple myeloma (RRMM). However, because therapeutic antibodies are commonly administered via intravenous infusion, infusion reactions (IR) are a commonly reported side effect. IR symptoms (e.g., rash, hives, flushing, changes in heart rate and / or blood pressure, fever, dyspnea, and / or nausea) require prompt management to avoid severe adverse events, including death. Strategies to reduce the risk of IR (or resolve mild IR) include slowing the infusion rate, temporarily interrupting the infusion, and / or dividing the infusion dose over two or more consecutive days. However, long and / or frequent intravenous infusions are costly, burdensome, and inconvenient for patients, potentially leading to decreased compliance with treatment regimens. Furthermore, long and / or frequent IV infusions require prolonged hospital stays and longer observation times, thus increasing the workload of hospital employees. There is a need in the art for safe and effective methods of administering therapeutic antibodies for the treatment of RRMM that are more convenient for patients, physicians, and other medical staff. Summary of the Invention [Means for solving the problem]

[0005] In some embodiments, an anti-CD38 antibody is provided for use in a method of treating 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) comprising 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) comprising 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 (eg, administration of the anti-CD38 antibody) is for the treatment of a disease or disorder, and optionally the disease or disorder is multiple myeloma. In some embodiments, methods are provided for administering an anti-CD38 antibody to a human individual in need thereof, the method comprising administering at least a first intravenous infusion of the anti-CD38 antibody to the individual, 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) comprising 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) comprising 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, hi some embodiments, the anti-CD38 antibody is isatuximab.

[0006] In some embodiments, a first intravenous infusion of an anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL / hour for the first hour, with the infusion rate increasing by 25 mL / hour every 30 minutes thereafter until a volume of 250 ml has been infused, up to a maximum infusion rate of 150 ml / hour. In some embodiments, a first infusion of an anti-CD38 antibody is administered to the individual at an infusion rate of 12.5 mL / hour for the first 30 minutes, with the infusion rate increasing by 25 mL / hour every 30 minutes thereafter until a volume of 250 ml has been infused. In some embodiments, the method comprises administering to the individual at least a second intravenous infusion of an 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, a second intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 50 mL / hour for the first 30 minutes, the infusion rate being increased by 50 mL / hour for the second 30 minutes, and the infusion rate being increased by 100 mL / hour every 30 minutes after the second 30 minutes until a volume of 250 mL has been infused. In some embodiments, a second intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 50 mL / hour for the first 30 minutes, 100 mL / hour for the second 30 minutes, 200 mL for the third 30 minutes, and 300 mL / hour after the third 30 minutes until a volume of 250 mL has been infused. In some embodiments, a second intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 25 mL / hour for the first 30 minutes, and the infusion rate being increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 mL has been infused. In some embodiments, the method includes administering to the individual at least a third intravenous infusion of an 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 anti-CD38 is administered to the individual at an infusion rate of 200 ml / hour until a volume of 250 ml has been infused. In some embodiments, the third intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 100 ml / hour for the first 30 minutes, with the infusion rate increased by 50 ml / hour every 30 minutes after the first 30 minutes until a volume of 250 ml has been infused.In some embodiments, the method includes administering to the individual a fourth intravenous infusion of an 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 a volume of 250 ml has been 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 the first 30 minutes, with the infusion rate increased by 50 ml / hour every 30 minutes after the first 30 minutes until a volume of 250 ml has been infused. In some embodiments, the anti-CD38 antibody is administered in a first 28-day cycle, wherein a first intravenous infusion of the anti-CD38 antibody is administered on day 1, a second intravenous infusion of the anti-CD38 antibody is administered on day 8, a third intravenous infusion of the anti-CD38 antibody is administered on day 15, and a fourth intravenous infusion of the anti-CD38 antibody is administered on day 22 of the first 28-day cycle.

[0007] In some embodiments, the method includes administering to the individual one or more subsequent intravenous infusions of an anti-CD38 antibody after 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 an anti-CD38 antibody after the fourth intravenous infusion is administered to the individual at an infusion rate of 200 ml / hour until a volume of 250 ml has been infused. In some embodiments, each of the one or more subsequent intravenous infusions of an anti-CD38 antibody after the fourth intravenous infusion is administered to the individual at an infusion rate of 100 ml / hour for the first 30 minutes, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until a volume of 250 ml has been infused. In some embodiments, the anti-CD38 antibody is administered in one or more subsequent 28-day cycles after the first 28-day cycle, and each of the one or more subsequent intravenous infusions of the anti-CD38 antibody after the fourth intravenous infusion is administered on days 1 and 15 of each of the one or more subsequent 28-day cycles after the first 28-day cycle.

[0008] In some embodiments, the present invention provides an anti-CD38 antibody for use in a method of treating 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) comprising 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 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). an anti-CD38 antibody comprising a light chain variable domain (VL); wherein a first intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL / hour for the first hour, with the infusion rate increasing by 25 mL / hour every 30 minutes thereafter until a volume of 250 mL has been infused, up to a maximum infusion rate of 150 mL / hour; a second intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 50 mL / hour for the first 30 minutes, with the infusion rate increasing by 50 mL / hour for the second 30 minutes, with the infusion rate increasing by 100 mL / hour every 30 minutes thereafter until a volume of 250 mL has been infused, up to a maximum infusion rate of 200 mL / hour; and a third intravenous infusion of the anti-CD38 is administered to the individual at an infusion rate of 100 mL / hour for the first 30 minutes, with the infusion rate increasing by 50 mL / hour every 30 minutes thereafter until a volume of 250 mL has been infused.

[0009] In some embodiments, a method of administering an anti-CD38 antibody to a human individual in need thereof comprises administering to the individual at least three intravenous infusions of an 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) comprising: (a) 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 (VH) comprising: (a) 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). a first intravenous infusion of anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL / hour for the first hour, with the infusion rate increased by 25 mL / hour every 30 minutes thereafter until a volume of 250 mL has been infused, up to a maximum infusion rate of 150 mL / hour; a second intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 50 mL / hour for the first 30 minutes, with the infusion rate increased by 50 mL / hour for the second 30 minutes, with the infusion rate increased by 100 mL / hour every 30 minutes thereafter until a volume of 250 mL has been infused, up to a maximum infusion rate of 200 mL / hour; and a third intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 100 mL / hour for the first 30 minutes, with the infusion rate increased by 50 mL / hour every 30 minutes thereafter until a volume of 250 mL has been 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 step b: administering to the individual one or more subsequent intravenous infusions of an anti-CD38 antibody after 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 an anti-CD38 antibody after the third intravenous infusion is administered to the individual at an infusion rate of 200 ml / hour until a volume of 250 ml has been infused.

[0011] In some embodiments, an anti-CD38 antibody is provided 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 each dose of the anti-CD38 antibody has a volume of 250 ml, and wherein the anti-CD38 antibody comprises: (a) a heavy chain variable domain (VH) comprising 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) comprising 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 (eg, administration of the anti-CD38 antibody) is for the treatment of a disease or disorder, and optionally the disease or disorder is multiple myeloma. In some embodiments, a method of administering an anti-CD38 antibody to an individual in need thereof is provided, 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, each dose of the anti-CD38 antibody has a volume of 250 ml, and the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) comprising 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) comprising 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, wherein 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 at an infusion rate of 25 mL / hour for the first hour on day 1 of the first 28-day cycle, with the infusion rate increasing by 25 mL / hour every 30 minutes after the first hour until a 250 ml dose of the anti-CD38 antibody has been infused, up to a maximum infusion rate of 150 mL / hour. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion at an infusion rate of 12.5 mL / hour for the first 30 minutes on day 1 of the first 28-day cycle, with the infusion rate increasing by 25 mL / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody has been infused. In some embodiments, an anti-CD38 antibody is administered to an individual via intravenous infusion on day 8 of a first 28-day cycle at an infusion rate of 50 mL / hour for the first 30 minutes, with the infusion rate increasing by 50 mL / hour for the next 30 minutes, and the infusion rate increasing by 100 mL / hour every 30 minutes after the first 60 minutes until a volume of 250 mL has been infused. In some embodiments, an anti-CD38 antibody is administered to an individual via intravenous infusion on day 8 of a first 28-day cycle at an infusion rate of 50 mL / hour for the first 30 minutes, 100 mL / hour for the second 30 minutes, 200 mL for the third 30 minutes, and 300 mL / hour after the third 30 minutes until a 250 mL dose of anti-CD38 antibody has been infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion at an infusion rate of 25 mL / hour for the first 30 minutes on day 8 of the first 28 day cycle, with the infusion rate increasing by 50 mL / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody has been infused. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion at an infusion rate of 200 mL / hour until a 250 ml dose of the anti-CD38 antibody has been infused on day 15 of the first 28 day cycle. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion at an infusion rate of 100 mL / hour for the first 30 minutes on day 15 of the first 28 day cycle, with the infusion rate increasing by 50 mL / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody has been infused.In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion at an infusion rate of 200 ml / hour until a 250 ml dose of the anti-CD38 antibody is infused on day 22 of the first 28 day cycle. In some embodiments, the anti-CD38 antibody is administered to the individual via intravenous infusion at an infusion rate of 100 ml / hour for the first 30 minutes on day 22 of the first 28 day cycle, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until a 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, 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, and wherein each dose of the anti-CD38 antibody administered in the one or more subsequent cycles has a volume of 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 a 250 ml dose of the anti-CD38 antibody has been 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 the first 30 minutes, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody has been 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 a 250 ml dose of the anti-CD38 antibody has been 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 the first 30 minutes, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody has been infused.

[0014] In some embodiments, the present invention provides 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 an 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, the first dose being infused over a duration of between about 1.5 and about 6.5 hours, the anti-CD38 antibody comprising: (a) a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1); Anti-CD38 antibodies are provided, comprising (a) a heavy chain variable domain (VH) comprising a CDR-H2 comprising PGDGDTGYAQKFQG (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) comprising 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., administration of the anti-CD38 antibody) is for the treatment of a disease or disorder, and optionally the disease or disorder is multiple myeloma. In some embodiments, methods are provided for safely administering an anti-CD38 antibody to a human individual in need thereof, the method 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, and the first dose is infused over a duration of between about 1.5 and about 6.5 hours, and the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) comprising 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) comprising 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, hi some embodiments, the anti-CD38 antibody is isatuximab.

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

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

[0017] In some embodiments, an intravenous infusion (IV) bag containing 250 ml of a 10 mg / kg dose of an anti-CD38 antibody (e.g., isatuximab) is provided. In some embodiments, the 10 mg / kg dose of the anti-CD38 antibody (e.g., isatuximab) is calculated based on the body weight of the patient to whom the anti-CD38 antibody will 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 about 360 mg to about 1600 mg, about 450 mg to about 16000 mg, about 450 mg to 1140 mg, or about 450 mg to about 910 mg, including any range between these values. In some embodiments, the intravenous infusion bag containing a 10 mg / kg dose of an anti-CD38 antibody in a volume of 250 ml further comprises 0.9% sodium chloride or 5% dextrose.

[0018] In some embodiments, there is provided an anti-CD38 antibody for use in a method of treating multiple myeloma in an individual, comprising administering to the individual (a) a heavy chain variable domain (V) comprising 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). H ), and (b) a light chain variable domain (V) comprising 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). L and administering an anti-CD38 antibody comprising: (a) a medicament for treating a rheumatoid arthritis; (b) a medicament for treating a rheumatoid arthritis; (c) a medicament for treating a rheumatoid arthritis; (d) a medicament for treating a rheumatoid arthritis; (e) a medicament for treating a rheumatoid arthritis; (f) a medicament for treating a rheumatoid arthritis; (g) a medicament for treating a rheumatoid arthritis; (g) a medicament for treating a rheumatoid arthritis; (h) a medicament for treating a rheumatoid arthritis; (i) a medicament for treating a rheumatoid arthritis; (ii) a medicament for treating a rheumatoid arthritis; (iii) a medicament for treating a rheumatoid arthritis; (iv) a medicament for treating a rheumatoid arthritis; (v) a medicament for treating a rheumatoid arthritis; (vi ...

[0019] In some embodiments, there is provided a method of treating a human individual with multiple myeloma, comprising administering to the individual (a) a heavy chain variable domain (V) comprising 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). H ), and (b) a light chain variable domain (V) comprising 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). L and administering an anti-CD38 antibody comprising: pomalidomide and dexamethasone; wherein the anti-CD38 antibody is administered in 28 day cycles; the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first 28 day cycle; the anti-CD38 antibody is administered on days 1 and 15 of all 28 day cycles after the first 28 day cycle; and 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 has been refractory to a recent prior therapy for multiple myeloma. In some embodiments, the individual is refractory to lenalidomide. In some embodiments, the individual's 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 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 has received prior therapy with lenalidomide and a proteasome inhibitor, and lenalidomide was administered concomitantly to the individual. In some embodiments, the individual has received prior therapy with lenalidomide and a proteasome inhibitor, and lenalidomide was administered to the individual separately (e.g., in different prior lines of therapy). In some embodiments, the individual has undergone at least two prior therapies for multiple myeloma, hi some embodiments, the individual has undergone 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 bronchospasm.

[0023] In some embodiments, the anti-CD38 antibody is administered to an individual in combination with at least one additional agent. In some embodiments, the at least one additional agent comprises an immunomodulatory agent. In some embodiments, the immunomodulatory agent 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, or ixazomib. In some embodiments, the at least one additional agent comprises a corticosteroid. In some embodiments, the corticosteroid is dexamethasone.

[0024] In some embodiments, a kit is provided that includes isatuximab for treating an individual with multiple myeloma according to the methods of the embodiments provided herein. [Brief explanation of the drawings]

[0025] [Figure 1] FIG. 1 is a schematic diagram of the study design for the clinical trial described in Example 1A. [Figure 2] FIG. 1 shows the percentage of patients experiencing Grade 2 or Grade 3 infusion reactions (IR) by infusion number in the clinical trial described in Example 1B (isatuximab infusion rate measured in ml / h) compared to the percentage of patients experiencing Grade 2 or Grade 3 IR by infusion number in a parallel study in which isatuximab was administered by a standard infusion protocol (infusion rate measured in mg / h). [Figure 3] FIG. 1 provides the median duration (hours) of isatuximab infusion in the clinical trial described in Example 1B compared to the median duration (hours) of isatuximab infusion in a parallel clinical trial in which isatuximab was administered by a standard infusion protocol. [Figure 4] FIG. 1 provides the logit Emax model that best describes the relationship between isatuximab exposure and ORR in the modeling study described in Example 2. CT4W = Ctrough at 4 weeks. [Figure 5] Figure 1 provides the distribution of responders and non-responders by CT4W quartiles in the modeling study described in Example 2. BOR = best overall response. [Figure 6] FIG. 1 provides the predicted relationship between response probability and CT4W in the modeling study described in Example 2. BMPC = bone marrow plasma cell percent. [Figure 7]FIG. 1 provides disease models including exposure-promoted tumor growth inhibition (TGI) and pharmacokinetic models from the modeling studies described in Example 2. Serum-M protein kinetics were well described by the exposure-promoted TGI model. Dropout was accounted for using a joint model. [Figure 8] FIG. 1 provides a comparison of model-predicted and observed longitudinal serum M-protein kinetics for the indicated dosing regimens. [Figure 9A] Figure 9 provides a clinical trial simulation of isatuximab monotherapy with the indicated dosing regimens. Five thousand clinical trials of 100 patients each were simulated. Figure 9A shows the overall response rate (RR) simulated using the ER model from the modeling study described in Example 2. The 100 patients in the clinical trial simulation were resampled from 168 actual patients, assuming they received the same dose level for each simulation trial. Figure 9B shows the simulated percent change in M-protein from baseline to week 8 using the disease M-protein model from the modeling study described in Example 2. Each clinical trial simulation was based on 122 actual patients, assuming they received the same dose level. [Figure 9B] Figure 9 provides a clinical trial simulation of isatuximab monotherapy with the indicated dosing regimens. Five thousand clinical trials of 100 patients each were simulated. Figure 9A shows the overall response rate (RR) simulated using the ER model from the modeling study described in Example 2. The 100 patients in the clinical trial simulation were resampled from 168 actual patients, assuming they received the same dose level for each simulation trial. Figure 9B shows the simulated percent change in M-protein from baseline to week 8 using the disease M-protein model from the modeling study described in Example 2. Each clinical trial simulation was based on 122 actual patients, assuming they received the same dose level. [Figure 10] Figure 1 provides patient disposition for Phase 1 and Phase 2 of the study described in Example 3. SD = standard deviation. [Figure 11] FIG. 1 provides the pharmacokinetic profile of isatuximab (mean isatuximab concentrations) in Phase 1, Cycle 1 of the study described in Example 3. [Figure 12] Figure 1 provides a swimmer plot of best response and time after 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. [Figure 13A] 13A and 13B are Kaplan-Meier plots of progression-free survival (FIG. 13A) and overall survival (FIG. 13B) for patients treated with 20 mg / kg QW / Q2W isatuximab in the study described in Example 3. [Figure 13B] 13A and 13B are Kaplan-Meier plots of progression-free survival (FIG. 13A) and overall survival (FIG. 13B) for patients treated with 20 mg / kg QW / Q2W isatuximab in the study described in Example 3. [Figure 14] FIG. 1 shows the relationship between CD38 receptor density and clinical response in patients receiving isatuximab at doses of 10 mg / kg QWx4 / Q2W or 20 mg / kg QWx4 / Q2W. [Figure 15] FIG. 1 shows a Kaplan-Meier plot of progression-free survival (PFS) for patients receiving isatuximab, pomalidomide, and dexamethasone, where isatuximab was administered to patients from a fixed infusion volume of 250 ml. [Figure 16] FIG. 1 shows a Kaplan-Meier plot of overall survival (OS) for patients receiving isatuximab, pomalidomide, and dexamethasone, where isatuximab was administered to patients from a fixed infusion volume of 250 ml. DETAILED DESCRIPTION OF THE INVENTION

[0026] Therapeutic antibodies for the treatment of multiple myeloma (including relapsed and / or refractory multiple myeloma "RRMM") have the potential to cause infusion reactions (IR) when administered intravenously. IR manifests during or within 24 hours of intravenous infusion with a variety of symptoms, including rash, hives, flushing, changes in heart rate and / or blood pressure, fever, difficulty breathing, and / or nausea. While IR can range in severity from mild to life-threatening, prompt attention to the patient's initial symptoms and immediate intervention are essential in all cases. Numerous strategies have been employed to mitigate and / or prevent IR, including slowing the infusion rate, interrupting the infusion, and splitting the infusion over two or more consecutive days. However, such strategies can be inconvenient for patients and increase healthcare costs. Furthermore, prolonged hospital stays and frequent visits increase the workload of hospital staff.

[0027] Provided herein is a method for treating multiple myeloma (e.g., RRMM) comprising 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 has discovered that such a fixed volume of anti-CD38 antibody (e.g., isatuximab) can be infused quickly, thus significantly reducing the duration without compromising patient safety.

[0028] Also provided herein are methods of treating multiple myeloma (e.g., RRMM), comprising administering to an individual 20 mg / kg of an anti-CD38 antibody (e.g., isatuximab) on each of days 1, 8, 15, and 22 of a first 28-day cycle, and further administering to the individual 20 mg / kg of an anti-CD38 antibody (e.g., isatuximab) on each of days 1 and 15 of each subsequent 28-day cycle following the first 28-day cycle.

[0029] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural unless the content clearly dictates otherwise. Thus, for example, reference to a "molecule" optionally includes a combination of two or more such molecules, and so forth.

[0030] As used herein, the term "about" refers to a normal error range for each value, which is readily apparent to one skilled in the art. Reference herein to a value or parameter with "about" includes (and describes) embodiments directed to the value or parameter itself. A "sustained response" refers to a sustained effect on preventing or slowing the progression of a disease (e.g., multiple myeloma) and / or improving one or more response criteria after cessation of treatment. For example, response to treatment for multiple myeloma can be measured by the criteria of 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 durable response has a duration at least as long as the treatment period, at least 1.5x, 2.0x, 2.5x, or 3.0x the length of the treatment period.

[0031] The term "pharmaceutical formulation" refers to a preparation that is in a form that effectively utilizes the biological activity of the active ingredient and does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered. Such formulations are sterile. A "pharmaceutically acceptable" excipient (vehicle, additive) is one that can reasonably be administered to a mammalian subject to provide an effective dose of the active ingredient employed.

[0032] As used herein, the term "treatment" refers to a clinical intervention designed to alter the general course of a disease or cells (e.g., cancer cells) being treated during clinical pathology. Desirable effects of treatment include slowing the rate of disease progression, improving or mitigating the disease state, and achieving remission or improving prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with cancer are alleviated or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancer cells, reducing symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other medications required to treat the disease, and / or prolonging the individual's life.

[0033] As used herein, "delaying disease progression" means to prolong, prevent, slow, retard, stabilize, and / or postpone the onset of a disease (such as cancer). This delay can be of varying lengths of time depending on the disease being treated and / or the individual's medical history. As will be apparent to one skilled in the art, a sufficient or significant delay can essentially encompass prevention, in that the individual does not develop the disease. For example, late-stage cancer, such as the development of metastases, can be delayed.

[0034] An "effective amount" is at least the minimum amount required to achieve measurable improvement or prevention of a particular disorder. As used herein, the effective amount may vary depending on factors such as the patient's disease state, age, sex, and weight, as well as the ability of the antibody to elicit a desired response in an individual. An effective amount is also one in which any toxic and adverse effects of treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, reducing the severity, or delaying the onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, the disease, its complications, and intermediate pathological phenotypes manifesting during the disease's development. For therapeutic use, beneficial or desired results include clinical results such as reducing one or more symptoms resulting from the disease, improving the quality of life of those suffering from the disease, reducing the dose of other pharmaceutical agents required to treat the disease, enhancing the effectiveness of another pharmaceutical agent, for example through targeting, slowing disease progression, and / or prolonging life. In the case of cancer or tumors, an effective amount of a drug can be effective in reducing the number of cancer cells; reducing tumor size; preventing (i.e., slowing to some extent, and preferably stopping) the infiltration of cancer cells into peripheral organs; preventing (i.e., slowing to some extent, and preferably stopping) tumor metastasis; preventing (i.e., slowing to some extent, and preferably stopping) tumor growth to some extent; and / or alleviating to some extent one or more symptoms associated with the disorder. An effective amount can be administered one or more times. For purposes of this invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As understood in clinical settings, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" can be considered in the context of administering one or more therapeutic agents, and can be considered to be an effective amount of a single agent when a desired result can be or is achieved in conjunction with one or more other agents.

[0035] As used herein, "in combination with" refers to the administration of one treatment therapy in addition to another treatment therapy. Thus, "in combination with" refers to the administration of one treatment therapy before, during, or after the administration of the other treatment therapy to an individual.

[0036] A "subject" or "individual" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is a human.

[0037] The term "antibody" as used herein is used in the broadest sense and specifically encompasses 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 who achieve a 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.

[0038] The following description sets forth example methods, parameters, etc. However, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of example embodiments.

[0039] overview Provided herein are methods for treating or delaying the progression of multiple myeloma in individuals who have received at least two prior therapies for multiple myeloma (e.g., lenalidomide and a proteasome inhibitor). In some embodiments, the method comprises administering 10 mg / kg of an anti-CD38 antibody (e.g., isatuximab) to the individual via intravenous infusion, with each 10 mg / kg infusion of the anti-CD38 antibody (e.g., isatuximab) having a volume of 250 ml. In some embodiments, the individual does not experience IR (or only mild IR) during or after the infusion. In some embodiments, the method comprises administering 20 mg / kg of an anti-CD38 antibody (e.g., isatuximab) to the individual on days 1, 8, 15, and 22 of a first 28-day cycle. In some embodiments, the method comprises further administering to the individual an anti-CD38 antibody (e.g., isatuximab) during one or more subsequent 28-day cycles after the first 28-day cycle. In some embodiments, the method comprises further administering to the individual 20 mg / kg of an anti-CD38 antibody (e.g., isatuximab) on each of days 1 and 15 of each subsequent 28-day cycle following the first 28-day cycle.

[0040] Anti-CD38 antibody 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 (V) comprising 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). H ), and (b) a light chain variable domain (V) comprising 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). LIn some embodiments, the anti-CD38 antibody comprises a heavy chain variable domain (V) comprising an amino acid sequence at least 90% identical (e.g., at least 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any range between these values) to SEQ ID NO:7. H Additionally, or alternatively, in some embodiments, the anti-CD38 antibody comprises a light chain variable domain (V) comprising an amino acid sequence that is at least 90% identical (e.g., at least 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. L In some embodiments, the anti-CD38 antibody comprises a V comprising SEQ ID NO: 7. H and V comprising SEQ ID NO: 8 or SEQ ID NO: 9 L Includes: QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS (SEQ ID NO: 7) DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKR (SEQ ID NO: 8) DIVMAQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKR (SEQ ID NO: 9)

[0041] 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 WO2008 / 047242 and U.S. Patent No. 8,153,765, the contents of both of which are incorporated by reference in their entireties.

[0042] The heavy chain of isatuximab comprises the following amino acid sequence: QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG (SEQ ID NO: 10) The light chain of isatuximab comprises the following amino acid sequence: DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 11)

[0043] Anti-CD38 antibodies can be produced using recombinant methods. For recombinant production of anti-antigen antibodies, nucleic acids encoding the antibody are isolated and inserted into a replicable vector for further cloning (amplification of the DNA) or expression. DNA encoding the antibody can be easily isolated and sequenced using conventional techniques (e.g., using oligonucleotide probes capable of specifically binding to genes encoding the antibody heavy and light chains). Many vectors are available. Vector components typically 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. Vectors are typically transformed into a suitable host cell for expression of the nucleic acid. In some embodiments, the host cell is a eukaryotic or prokaryotic cell. In some embodiments, the eukaryotic host cell is a mammalian cell. Examples of useful mammalian host cell lines include SV40-transformed monkey kidney CV1 (COS-7, ATCC CRL 1651); human embryonic kidney (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 hepatocytes (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human hepatocytes (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TRI cells (Mather et al., Annals NY 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 (ed. BKC Lo, Humana Press, Totowa, NJ, 2003), pp. 255-268. Anti-CD38 antibodies prepared from cells can be purified using, for example, hydroxylapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being one of the generally preferred purification steps. In general, a variety of methods for preparing antibodies for use in research, testing and clinical applications are established in the art and are consistent with the methods described above and / or as deemed suitable by those skilled in the art.

[0044] Treatment method Treatment involves intravenous infusion of anti-CD38 antibody from a fixed volume of 250 ml Provided herein is a method of administering (e.g., safely administering) an anti-CD38 antibody to an individual (e.g., a human individual) in need thereof, comprising administering to the individual via intravenous infusion an anti-CD38 antibody (e.g., a heavy chain variable domain (V) comprising: (a) 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)). H ), and (b) a light chain variable domain (V) comprising 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). LIn some embodiments, the method includes administering a 10 mg / kg (e.g., at least 10 mg / kg) dose of an anti-CD38 antibody comprising administering to an individual ...

[0045] Provided herein are methods of treating or slowing the progression of multiple myeloma (e.g., 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., a heavy chain variable domain (V) comprising: (a) 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)). H ), and (b) a light chain variable domain (V) comprising 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). L ), wherein each injection is in a volume of 250 ml. In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the dose of the anti-CD38 antibody (e.g., isatuximab) is 20 mg / kg.

[0046] In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered to an individual during a first 28-day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to an 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 an individual via intravenous infusion at an infusion rate of 25 mL / hour for the first hour on day 1 of the first 28-day cycle, with the infusion rate increased by 25 mL / hour every 30 minutes after the first hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused, up to a maximum infusion rate of 150 mL / hour. In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered to an individual via intravenous infusion at an infusion rate of 12.5 mL / hour for the first 30 minutes on day 1 of a first 28-day cycle, and the infusion rate is increased by 25 mL / hour every 30 minutes after the first 30 minutes until 250 ml of anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion period of the anti-CD38 antibody (e.g., isatuximab) on day 1 of a first 28-day cycle is 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, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15, 4.16, 4.17, 4.18, 4.19, 4.20, 4.21, 4.22, 4.23, 4.24, 4.25, 4.26, 4.27, 4.28, 4.29, 5.30, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36, 5.37, 5.38, 5.39, 5.40, 5 In some embodiments, the infusion duration 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 therein. In some embodiments, the infusion duration 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, e.g., between about 3.36 and about 5.32 hours.In some embodiments, the infusion duration 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, e.g., about 3.94 hours. In some embodiments, the infusion duration includes a temporary interruption prior to completion of the infusion.

[0047] In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered to an individual via intravenous infusion on day 8 of a first 28-day cycle at an infusion rate of 50 mL / hour for the first 30 minutes, with the infusion rate increasing by 50 mL / hour for the next 30 minutes, and the infusion rate increasing by 100 mL / hour every 30 minutes after the first 60 minutes until a volume of 250 mL has been infused. In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered to an individual via intravenous infusion on day 8 of a first 28-day cycle at an infusion rate of 50 mL / hour for the first 30 minutes, 100 mL / hour for the second 30 minutes, 200 mL for the third 30 minutes, and 300 mL / hour after the third 30 minutes until 250 mL of anti-CD38 antibody (e.g., isatuximab) has been 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 the first 30 minutes, with the infusion rate increasing by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is equal to or less 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 therebetween. In some embodiments, the infusion duration 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 this range. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 8 of the first 28-day cycle is between about 1.4 and about 2.7 hours, e.g., between about 1.52 and about 2.6 hours. In some embodiments, the infusion duration 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, e.g., about 1.88 hours.In some embodiments, the infusion period of the anti-CD38 antibody (eg, isatuximab) includes a temporary interruption prior to completion of the infusion.

[0048] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused on day 15 of the first 28 day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 100 ml / hour for the first 30 minutes on day 15 of the first 28 day cycle, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle is less than or equal to about any one of 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 therebetween. In some embodiments, the infusion duration 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 this range. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle is between about 1 and 2 hours, e.g., between about 1.03 and about 1.87 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle is between about 1 and 1.5 hours, e.g., about 1.27 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption prior to completion of the infusion.

[0049] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused on day 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 at an infusion rate of 100 ml / hour for the first 30 minutes on day 22 of the first 28-day cycle, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 22 of the first 28 day cycle is equal to or less 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 therebetween. In some embodiments, the infusion duration 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 this range. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 22 of the first 28-day cycle is between about 1 and 2 hours, e.g., between about 1.18 and about 1.52 hours. In some embodiments, the infusion duration 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, e.g., about 1.27 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption prior to completion of the infusion.

[0050] 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 at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle). In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 100 ml / hour for the first 30 minutes on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle), with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion duration 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 less than or equal to about any one of 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 therebetween. In some embodiments, the infusion duration 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 this range. In some embodiments, the infusion duration 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, e.g., between about 1.19 and about 1.41 hours.In some embodiments, the infusion duration 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, e.g., about 1.27 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption prior to completion of the infusion. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused on day 15 of each subsequent 28-day cycle (e.g., following 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 15 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) at an infusion rate of 100 ml / hour for the first 30 minutes, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion duration 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 less than or equal to about any one of 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 therebetween. In some embodiments, the infusion duration 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 this range. In some embodiments, the infusion duration 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, e.g., between about 1.2 and about 1.46 hours. In some embodiments, the infusion duration 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, e.g., about 1.27 hours.In some embodiments, the infusion period of the anti-CD38 antibody (eg, isatuximab) includes a temporary interruption prior to completion of the infusion.

[0051] In some embodiments, the duration of each infusion of an anti-CD38 antibody (e.g., isatuximab) after day 15 of the first 28 day cycle (e.g., including day 22 of the first 28 day cycle and days 1 and 15 of each 28 day cycle thereafter) is less than or equal to about any one of 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 therebetween. In some embodiments, the duration of each infusion of an anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle and thereafter (e.g., including day 22 of the first 28-day cycle and days 1 and 15 of each subsequent 28-day cycle) is between about 0.7 and about 3.4 hours, including any value within this range. In some embodiments, the duration of each infusion of an anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle and thereafter (e.g., including day 22 of the first 28-day cycle and days 1 and 15 of each subsequent 28-day cycle) is between about 1 and 2 hours, e.g., between about 1.13 and about 1.53 hours. In some embodiments, the duration of infusion of an 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, e.g., about 1.25 hours.

[0052] In some embodiments, the duration of each infusion of an anti-CD38 antibody (e.g., isatuximab) after the first infusion (e.g., day 1 of the first 28-day cycle) is 0.5 hours or less. In some embodiments, the duration of each infusion of an 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 days 1 and 15 of each subsequent 28-day cycle) is 0.5 hours or less. In some embodiments, the duration of each infusion of an anti-CD38 antibody (e.g., isatuximab) after day 8 of the first 28-day cycle (e.g., including days 15 or 22 of the first 28-day cycle and days 1 and 15 of each subsequent 28-day cycle) is 0.5 hours or less.

[0053] 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 the 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 the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) comprising 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) comprising 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, when an anti-CD38 antibody (e.g., isatuximab) is safely administered, the individual does not experience Grade 3 or higher IR during or after an infusion of the anti-CD38 antibody. In some embodiments, when an anti-CD38 antibody (e.g., isatuximab) is safely administered, the individual does not experience Grade 2 or higher IR during or after a second or subsequent infusion of the anti-CD38 antibody.

[0054] In some embodiments, a first intravenous infusion of a 10 mg / kg dose of an anti-CD38 antibody (e.g., isatuximab) (i.e., an initial dose of, for example, at least a 10 mg / kg dose or a 20 mg / kg dose) is in a volume of 250 ml and is administered to the individual at an infusion rate of 25 mL / hour for the first hour, with the infusion rate increasing by 25 mL / hour every 30 minutes after the first hour until 250 ml of anti-CD38 antibody (e.g., isatuximab) has been infused, up to a maximum infusion rate of 150 mL / hour. In some embodiments, a 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 an 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 the first 30 minutes, with the infusion rate increasing by 25 mL / hour every 30 minutes after the first 30 minutes until 250 ml of anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the duration of the first intravenous infusion of a 10 mg / kg dose of an anti-CD38 antibody (e.g., isatuximab) is 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, 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 an anti-CD38 antibody (e.g., isatuximab) is between about 3.3 and about 6.1 hours, including any value within 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 an anti-CD38 antibody (e.g., isatuximab) is between about 3.2 and 5.5 hours, e.g., 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 an anti-CD38 antibody (e.g., isatuximab) is between about 3.8 and 4.2 hours, e.g., about 3.94 hours. In some embodiments, the duration of the first infusion of an anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption before completion of the infusion.

[0055] 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 an anti-CD38 antibody (e.g., isatuximab) is administered to an 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.

[0056] In some embodiments, a second intravenous infusion of a 10 mg / kg dose of an anti-CD38 antibody (e.g., isatuximab) (i.e., a second dose of, e.g., at least a 10 mg / kg dose or a 20 mg / kg dose) is in a volume of 250 ml and is administered to the individual at an infusion rate of 50 ml / hour for the first 30 minutes, with the infusion rate increased by 50 ml / hour for the second 30 minutes, and the infusion rate increased by 100 ml / hour every 30 minutes after the second 30 minutes until a volume of 250 ml has been infused, up to a maximum infusion rate of 200 ml / hour. In some embodiments, a second intravenous infusion of a 10 mg / kg dose of an anti-CD38 antibody (e.g., isatuximab) (i.e., a second dose of, e.g., at least a 10 mg / kg dose or a 20 mg / kg dose) is in a volume of 250 ml and is administered to the individual at an infusion rate of 50 mL / hour for the first 30 minutes, 100 mL / hour for the second 30 minutes, 200 mL for the third 30 minutes, and 300 mL / hour after the third 30 minutes until 250 ml of anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, a 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 an anti-CD38 antibody (e.g., isatuximab) is administered to the individual in a volume of 250 ml at an infusion rate of 25 mL / hour for the first 30 minutes, with the infusion rate increasing by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the duration of the second infusion of a 10 mg / kg dose of anti-CD38 antibody (e.g., isatuximab) is less than or equal to about any one of 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 therebetween. 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 an anti-CD38 antibody (e.g., isatuximab) is between about 1.5 and about 3.5 hours, including any value within 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 an anti-CD38 antibody (e.g., isatuximab) is between about 1.4 and 2.7 hours, e.g., 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 an anti-CD38 antibody (e.g., isatuximab) is between about 1.5 and 2.0 hours, e.g., about 1.88 hours. In some embodiments, the duration of the second infusion of an anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption prior to completion of the infusion.

[0057] 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 an anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to an individual in need thereof via intravenous infusion (i.e., a third intravenous infusion). In some embodiments, a 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 an anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to an individual at an infusion rate of 200 ml / hour until 250 ml of anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, a third infusion of a 10 mg / kg dose (e.g., at least a 10 mg / kg dose or a 20 mg / kg dose) of an 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 the first 30 minutes, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until 250 ml of anti-CD38 antibody (e.g., isatuximab) has been 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 an anti-CD38 antibody (e.g., isatuximab) is less than or equal to about any one of 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 therebetween. 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 therein. 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 and 2 hours, e.g., between about 1.03 and about 1.87 hours.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 and 1.5 hours, e.g., about 1.27 hours. In some embodiments, the duration of the third infusion of the 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) includes a temporary interruption prior to completion of the infusion.

[0058] In some embodiments, one or more subsequent intravenous infusions of an anti-CD38 antibody (e.g., isatuximab) are administered to the individual after the third intravenous infusion, each of the one or more subsequent infusions providing the individual in need thereof with a 10 mg / kg dose (e.g., at least 10 mg / kg or 20 mg / kg) of the anti-CD38 antibody (e.g., isatuximab), e.g., a fourth dose, a fifth dose, a sixth dose, etc., 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, a fourth infusion, a fifth infusion, a sixth infusion, etc. In some embodiments, each of the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and are each administered to the individual at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, each of one or more subsequent infusions of an anti-CD38 antibody (e.g., isatuximab) is administered to the individual at an infusion rate of 100 ml / hour for the first 30 minutes, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the duration of each of the one or more subsequent infusions of anti-CD38 antibody (e.g., isatuximab) is less than or equal to about any one of 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 therebetween. In some embodiments, the duration of each of the one or more subsequent infusions of anti-CD38 antibody (e.g., isatuximab) is between about 0.7 and about 3.4 hours, e.g., between about 1.1 and about 1.6 hours, including any value within these ranges.In some embodiments, the duration of each of the one or more subsequent infusions of an anti-CD38 antibody (e.g., isatuximab) is between about 1 and 2 hours, e.g., between about 1.13 and about 1.53 hours, 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 an anti-CD38 antibody (e.g., isatuximab) is between about 1 and about 1.5 hours, e.g., about 1.27 hours or 1.25 hours. In some embodiments, the duration of each of the one or more subsequent infusions of an anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption prior to completion of the infusion.

[0059] In some embodiments, the duration of each infusion providing a 10 mg / kg dose (e.g., at least a 10 mg / kg dose or a 20 mg / kg dose) of an anti-CD38 antibody (e.g., isatuximab) after the first infusion (e.g., day 1 of the first 28-day cycle) is 0.5 hours or less. In some embodiments, the duration of each infusion providing a 10 mg / kg dose (e.g., at least a 10 mg / kg dose or a 20 mg / kg dose) of an 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 days 1 and 15 of each subsequent 28-day cycle) is about 0.5 hours or less. In some embodiments, the duration of each infusion providing a 10 mg / kg dose (e.g., at least a 10 mg / kg dose or a 20 mg / kg dose) of an anti-CD38 antibody (e.g., isatuximab) on and after day 8 of the first 28-day cycle (e.g., including days 15 and 22 of the first 28-day cycle and days 1 and 15 of each subsequent 28-day cycle) is about 0.5 hours or less.

[0060] In some embodiments, the individual does not experience an infusion reaction (IR) during or after administration (e.g., intravenous infusion) of an 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 volume of 250 ml. In some embodiments, administration (e.g., by intravenous infusion) of an anti-CD38 antibody at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml causes the individual to experience no IR during or after administration. In some embodiments, the individual does not experience grade 3 or higher IR during or after an infusion of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual does not experience an IR during or after a second infusion of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual does not experience IR during or after the second infusion of an anti-CD38 antibody (e.g., isatuximab), or during subsequent infusions of an anti-CD38 antibody (e.g., isatuximab). IR refers to a disorder characterized by an adverse reaction to intravenous infusion of an anti-CD38 antibody (e.g., isatuximab). IR can occur during the infusion or within 24 hours of the infusion (e.g., 24 hours from the start of the infusion). Signs or symptoms of IR include one or more of the following: paresthesias, chest pain, cough, nasal congestion, sneezing, throat irritation, itching, fainting, flushing, chills, fever, hives, angioedema, rash, skin reactions, itching, maculopapular rash, cardiac tachycardia, decreased blood pressure, dyspnea, nausea, vomiting, headache, back pain, chest discomfort or non-cardiac chest pain, abdominal pain, abdominal cramps, bronchospasm, laryngospasm, wheezing, respiratory congestion, excessive sweating, and erythema. (For further details, see, e.g., Doessegger et al. (2015) Clin & Trans Immunol. 4(7):e39.) Accordingly, in some embodiments, an individual does not experience any one or more of these signs or symptoms.

[0061] In some embodiments, the individual receives (e.g., requires) premedication, i.e., a medication administered prior to infusion of an anti-CD38 antibody (e.g., isatuximab) to prevent or minimize IR. In some embodiments, the individual receives premedication with one or more of the following to prevent or minimize IR prior to infusion of an 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 volume of 250 ml: an analgesic (e.g., acetaminophen or paracetamol), an H2 antagonist or antacid (e.g., ranitidine, cimetidine, omeprazole, or esomeprazole), an anti-inflammatory (e.g., a corticosteroid or nonsteroidal anti-inflammatory drug), and / or an antihistamine (e.g., diphenhydramine, cetirizine, promethazine, dexchlorpheniramine).

[0062] In some embodiments, the individual does not receive (e.g., does not require) premedication, i.e., medications administered prior to infusion of an anti-CD38 antibody (e.g., isatuximab) to prevent or minimize IR. In some embodiments, the individual does not receive (e.g., does not require) premedication with one or more of the following to prevent or minimize IR prior to infusion of an 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 volume of 250 ml: analgesics (e.g., acetaminophen or paracetamol), H2 antagonists or antacids (e.g., ranitidine, cimetidine, omeprazole, or esomeprazole), anti-inflammatory agents (e.g., corticosteroids or nonsteroidal anti-inflammatory drugs), and / or antihistamines (e.g., diphenhydramine, cetirizine, promethazine, dexchlorpheniramine). In some embodiments, the individual does not receive (e.g., does not require) a medication (e.g., a prophylactic medication) to prevent or minimize IR after completion of an infusion of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual does not experience a delayed infusion reaction after administration (e.g., intravenous infusion) of an 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 volume of 250 ml. In some embodiments, the individual does not experience a delayed infusion reaction within any one of about 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 ranges therebetween) of administration (e.g., intravenous infusion) of an 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 volume of 250 ml. In some embodiments, the individual does not receive (e.g., does not require) premedication or prophylactic medication, e.g., as described above, prior to the first, second, third, fourth, and / or fifth infusion in a volume of 250 ml.In some embodiments, the individual does not receive (e.g., does not require) premedication or prophylactic medication, e.g., as described above, before the first, second, third, and / or fourth infusion of an anti-CD38 antibody at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml. In some embodiments, the individual does not receive (e.g., does not require) premedication or prophylactic medication, e.g., as described above, before the start of the fourth infusion of an anti-CD38 antibody at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml. In some embodiments, the individual does not receive (e.g., does not require) premedication or prophylactic medication, e.g., as described above, before the start of any infusions after the third infusion of an anti-CD38 antibody at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml. In some embodiments, the individual does not receive (e.g., does not require) any pre-medication or prophylactic medication, e.g., as described above, prior to any infusion of an anti-CD38 antibody at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml. In some embodiments, the individual does not receive (e.g., does not require) a post-medication, i.e., a medication administered after completion of an infusion of an 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 volume of 250 ml to prevent or minimize IR (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 ranges therebetween). In some embodiments, the individual does not receive (e.g., does not require) a post-medication within any one of at least about 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 ranges therebetween) of completing an infusion of an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg in a volume of 250 ml, for example, to prevent or minimize IR.In some embodiments, the individual does not receive (e.g., does not require) a follow-up medication, e.g., as described above, after completion of the first, second, third, fourth, and / or fifth infusion of an anti-CD38 antibody at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml (e.g., 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 of completion, including any ranges therebetween). In some embodiments, the individual does not receive (e.g., does not require) a follow-up medication, e.g., as described above, after completion of the first, second, third, and / or fourth infusion of an anti-CD38 antibody at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml (e.g., 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 of completion, including any ranges therebetween). In some embodiments, the individual does not receive (e.g., does not require) a follow-up medication, e.g., as described above, after completion of the fourth infusion of an anti-CD38 antibody at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml (e.g., within at least any one of about 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 ranges therebetween). In some embodiments, the individual does not receive (e.g., does not require) a follow-up medication, e.g., as described above, after completion of any infusion after the third infusion of an anti-CD38 antibody at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml (e.g., 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 of completion, including any ranges therebetween).In some embodiments, the individual does not receive (e.g., does not require) a follow-up medication, e.g., as described above, after completion of any infusion of an anti-CD38 antibody at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml (e.g., 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 of completion, including any ranges therebetween). In some embodiments, the individual is not pre- or post-medicated with any one or more of the following to prevent or minimize IR prior to infusion of an 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 volume of 250 ml: analgesics (e.g., acetaminophen or paracetamol), H2 antagonists or antacids (e.g., ranitidine, cimetidine, omeprazole, or esomeprazole), anti-inflammatory agents (e.g., corticosteroids or nonsteroidal anti-inflammatory drugs), and / or antihistamines (e.g., diphenhydramine, cetirizine, promethazine, dexchlorpheniramine).

[0063] In some embodiments, an individual experiences mild IR after administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, mild IR is Grade 1 or Grade 2 or lower IR as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v.4.03). NCI-CTCAE v.4.03 is published online at evs(dot)nci(dot)nih(dot)gov / ftp1 / CTCAE / About(dot)html. In some embodiments, IR is Grade 1 IR if the individual experiences a mild, transient reaction (e.g., one or more of the signs / symptoms described herein, e.g., within 24 hours of starting the infusion), in which interruption of the infusion and / or intervention is not indicated. In some embodiments, IR is Grade 2 IR if the individual experiences a reaction (e.g., one or more of the signs / symptoms described herein, e.g., within 24 hours of starting the infusion), in which the infusion is discontinued and / or intervention is indicated, and the individual responds promptly to treatment (i.e., treatment of one or more signs or symptoms of IR, such as those described herein), e.g., within any one of about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 hours (including any ranges therebetween) of treatment for IR. In some embodiments, treatment for IR includes one or more of the following: a short interruption of the infusion, administration of oxygen, administration of a bronchodilator, administration of a corticosteroid, administration of a histamine blocker, and resuming the infusion at a slower rate.

[0064] In some embodiments, the individual experiences mild IR (e.g., Grade 1 or Grade 2 IR) during or after a first intravenous infusion of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) of an anti-CD38 antibody (e.g., isatuximab) at a fixed volume of 250 ml, e.g., during the infusion on day 1 of a first 28-day cycle. In some embodiments, the individual does not experience IR (or further IR) during a second or subsequent infusion of an anti-CD38 antibody (e.g., isatuximab) at a fixed volume of 250 ml. For example, in some embodiments, the individual does not experience IR (or further IR) during an infusion of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) of an anti-CD38 antibody (e.g., isatuximab) in a fixed volume of 250 ml 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.

[0065] In some embodiments, the individual does not experience moderate or severe IR after infusion of an anti-CD38 antibody in a volume of 250 ml, for example, according to the methods described herein. In some embodiments, the individual does not experience Grade 3, 4, or 5 IR as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v.4.03). In some embodiments, IR is Grade 3 IR if the individual experiences prolonged signs / symptoms of IR (e.g., those described herein) and does not respond promptly to discontinuation of medication and / or infusion for IR. In some embodiments, IR is Grade 3 IR if the individual experiences a recurrence of signs / symptoms of IR (e.g., those described herein) after initial improvement. In some embodiments, IR is Grade 3 IR if the individual requires hospitalization due to signs / symptoms of IR (e.g., those described herein). In some embodiments, IR is Grade 4 IR if the signs / symptoms (e.g., those described herein) are life-threatening and / or require urgent intervention. In some embodiments, IR is Grade 5 IR when signs / symptoms of IR lead to death.

[0066] In some embodiments, the individual does not experience any grade of IR (e.g., grade 1, 2, 3, 4, or 5 IR) during or after a fourth intravenous infusion of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) of an anti-CD38 antibody (e.g., isatuximab) at a fixed volume of 250 ml. Additionally, or alternatively, in some embodiments, the individual does not experience any grade of IR (e.g., grade 1, 2, 3, 4, or 5 IR) during or after any intravenous infusion subsequent to the fourth intravenous infusion of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) of an anti-CD38 antibody (e.g., isatuximab) at a fixed volume of 250 ml. In some embodiments, the individual does not experience IR (or further IR) during the fourth infusion or any infusion after the fourth infusion of an anti-CD38 antibody (e.g., isatuximab) at a fixed volume of 250 ml. For example, in some embodiments, the individual does not experience IR (or further IR) during an infusion of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) of an anti-CD38 antibody (e.g., isatuximab) in a fixed volume of 250 ml on day 22 of the first 28-day cycle and on days 1 and 15 of any subsequent 28-day cycle (i.e., after the first 28-day cycle).

[0067] In some embodiments, the dose of anti-CD38 antibody (e.g., isatuximab) administered to an individual is a fixed 250 ml volume and is not reduced during treatment, e.g., regardless of whether the individual experiences IR.

[0068] In some embodiments, the anti-CD38 antibody described herein (e.g., 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, pH 6.0. In some embodiments, the anti-CD38 antibody described herein (e.g., 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 of anti-CD38 antibody). In some embodiments, a single-use 5 ml formulation is provided, for example, in a Type I 6 ml clear glass vial fitted with an elastomeric fastener. In some embodiments, the fill volume of the vial is 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 contains 25 ml of formulation (i.e., 500 mg of anti-CD38 antibody). In some embodiments, a single-use 25 ml formulation is provided, for example, in a 30 ml clear glass vial fitted with an elastomeric fastener. In some embodiments, the fill volume of the vial is 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 at a temperature between about 2°C and about 8°C, protected from light, including any range therebetween. In some embodiments, the formulation is diluted in 0.9% sodium chloride, 5% glucose, or 5% dextrose for injection. In some embodiments, the diluted infusion solution is stable for up to about 6, 12, 18, 24, 30, 36, 42, or 48 hours at between about 2°C and about 8°C, including any ranges therebetween.In some embodiments, the diluted infusion solution is stable after storage between about 2°C and about 8°C (e.g., for up to about 6, 12, 18, 24, 30, 36, 42, or 48 hours, including any range therebetween), and for an additional 8 hours at room temperature (including the time of infusion). In some embodiments, the diluted infusion solution is stable in the presence of light. In some embodiments, the bag in which the diluted infusion solution is stored is fabricated from polyolefin (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) and di(ethylhexyl)phthalate (DEHP) or ethylene-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) and an in-line filter (polyethersulfone (PES), polysulfone, or nylon).

[0069] For patient administration, the appropriate volume of isatuximab is diluted in an infusion bag with 0.9% sodium chloride solution, 5% glucose, or 5% dextrose. No protection from light is required for storage in the infusion bag. The investigational product was stored at +2°C to +8°C.

[0070] In some embodiments, an intravenous (IV) bag containing 250 ml 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) is provided. 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 will 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 about 360 mg to about 1600 mg, about 450 mg to about 16000 mg, about 450 mg to 1140 mg, or about 450 mg to about 910 mg, including any range therebetween.

[0071] Treatment comprising administration of a 10 mg / kg or 20 mg / kg dose of anti-CD38 antibody Provided herein are methods of treating or slowing the progression of multiple myeloma (e.g., 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., a heavy chain variable domain (V) comprising: (a) 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)). H ), and (b) a light chain variable domain (V) comprising 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). L Also provided are methods comprising administering an anti-CD38 antibody comprising: (a) a medicament for treating a rheumatoid arthritis; (b) a medicament for treating a rheumatoid arthritis; (c) a medicament for treating a rheumatoid arthritis; (d) a medicament for treating a rheumatoid arthritis; (e) a medicament for treating a rheumatoid arthritis; (f) a medicament for treating a rheumatoid arthritis; (g) a medicament for treating a rheumatoid arthritis; (g) a medicament for treating a rheumatoid arthritis; (h) a medicament for treating a rheumatoid arthritis; (i) a medicament for treating a rheumatoid arthritis; (j) a medicament for treating a rheumatoid arthritis; (j) a medicament for treating a rheumatoid arthritis; (j) a medicament for treating a rheumatoid arthritis; (k ... In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (V) comprising the amino acid sequence of SEQ ID NO:7. H ) and a light chain variable region (V) comprising the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 9 LIn 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).

[0072] Provided herein are methods of treating or slowing the progression of multiple myeloma (e.g., 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., a heavy chain variable domain (V) comprising: (a) 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)). H ), and (b) a light chain variable domain (V) comprising 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). L Also provided are methods comprising administering an anti-CD38 antibody comprising: (a) a medicament for treating a rheumatoid arthritis; (b) a medicament for treating a rheumatoid arthritis; (c) a medicament for treating a rheumatoid arthritis; (d) a medicament for treating a rheumatoid arthritis; (e) a medicament for treating a rheumatoid arthritis; (f) a medicament for treating a rheumatoid arthritis; (g) a medicament for treating a rheumatoid arthritis; (h) a medicament for treating a rheumatoid arthritis; (i) a medicament for treating a rheumatoid arthritis; (j) a medicament for treating a rheumatoid arthritis; (j) a medicament for treating a rheumatoid arthritis; (j) a medicament for treating a rheumatoid arthritis; (k ... In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (V) comprising the amino acid sequence of SEQ ID NO:7. H ) and a light chain variable region (V) comprising the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 9 LIn 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).

[0073] 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 for multiple myeloma (e.g., seven, eight, nine, ten, eleven, or twelve prior therapies). In some embodiments, the prior therapy for multiple myeloma was an immunomodulatory agent (e.g., lenalidomide, pomalidomide, and / or thalidomide). In some embodiments, the individual was refractory to an immunomodulatory agent. 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 a proteasome inhibitor. In some embodiments, the individual received prior therapy with an immunomodulatory agent and a proteasome inhibitor. In some embodiments, the immunomodulatory agent and the proteasome inhibitor were administered concomitantly. In some embodiments, the immunomodulatory agent and the proteasome inhibitor were administered during separate therapies (e.g., separate treatment regimens). In some embodiments, the individual has been refractory to an immunomodulatory agent and a proteasome inhibitor.

[0074] In some embodiments, the individual has at least one high-risk cytogenetic abnormality (e.g., before initiating treatment with an 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.

[0075] Other characteristics of individuals receiving treatment involving anti-CD38 antibodies In some embodiments, the individual exhibited progressive disease during a recent prior therapy (or line of therapy), e.g., the therapy (or line of therapy) immediately preceding initiation of a treatment described herein that included administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual exhibited progressive disease (PD) within 60 days of completing a recent prior therapy (or line of therapy) for multiple myeloma, e.g., the therapy (or line of therapy) immediately preceding initiation of a treatment described herein that included administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, progressive disease (PD) is defined by the 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, the course of therapy is ≥ 1 complete cycle of a single agent or combination of two or more agents, or planned sequential therapy including stem cell transplantation. In some embodiments, a given treatment is considered a new line of therapy if any one of the following three conditions is met: 1. Initiation of a new line of treatment after discontinuation of the previous line. If a treatment regimen is discontinued for any reason and a different regimen is initiated, it can be considered a new line of therapy. For example, if all drugs in a given regimen are stopped, the regimen is considered discontinued. For example, if some but not all drugs in a regimen are discontinued, the regimen is not considered discontinued. In some embodiments, the reason for discontinuation, addition, substitution, or SCT does not affect how the line is counted. Causes for changes can include, for example, completion of planned therapy, toxicity, progression, lack of response, or inadequate response. 2. Unplanned addition or substitution of one or more drugs in an existing regimen. The unplanned addition of a new drug or switching to a different drug (or drug combination) for any reason can be considered a new line of therapy. 3. Stem cell transplantation (SCT): In patients undergoing more than one SCT, except in the case of planned tandem SCTs at specified intervals (e.g., 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 SCTs are considered 1 line. Planned induction and / or consolidation, maintenance with any SCT (first-line, relapse, autologous, or allogeneic) are generally considered 1 line of therapy.

[0076] 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 an individual who has been refractory to all prior therapies (or prior lines of therapy) but has achieved at least a minimal response (MR) to one prior therapy (or first line of therapy). In some embodiments, a minimal response (MR) is defined by the 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 an individual who was unresponsive to a previous therapy (or previous line of therapy). In some embodiments, "unresponsive" to a therapy (or line of therapy) for multiple myeloma means that the individual failed to achieve a minimal response (MR) to a therapy (or line of therapy) for multiple myeloma. In some embodiments, "unresponsive" to a therapy (or line of therapy) for multiple myeloma means that the individual showed progressive disease during a therapy (or line of therapy) for multiple myeloma. In some embodiments, an individual with refractory multiple myeloma is an individual who showed progressive disease within 60 days of completing the last therapy for multiple myeloma.

[0077] In some embodiments, an individual has failed a previous treatment for multiple myeloma (e.g., lenalidomide and / or a proteasome inhibitor). In some embodiments, "failing" a previous treatment means that the individual exhibited disease progression (e.g., according to the criteria in Table A) during the treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor) or within 60 days of completing the treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor). In some embodiments, "failing" a previous treatment for multiple myeloma means that the individual had a partial response (PR) or better response (e.g., according to the criteria in Table A) to the treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor), but exhibited disease progression within 6 months of discontinuing the treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor). In some embodiments, "failing" a previous treatment for multiple myeloma means that the individual experienced toxicity / intolerance after at least two 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 experiencing peripheral neuropathy or neuropathic pain (e.g., an individual who did not have peripheral neuropathy before starting the regimen). In some embodiments, intolerance to a lenalidomide-containing regimen refers to the individual experiencing a severe rash.

[0078] In some embodiments, the individual has relapsed and refractory multiple myeloma. In some embodiments, the individual with relapsed and refractory multiple myeloma is an individual who has relapsed from at least one previous therapy (or line of therapy) for multiple myeloma and was refractory to a most recent therapy (or line of therapy) for multiple myeloma. In some embodiments, the individual with relapsed and refractory multiple myeloma is an individual who has relapsed from at least one previous therapy (or line of therapy) for multiple myeloma, is refractory to a 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, the individual with relapsed or refractory multiple myeloma is an individual who has demonstrated progressive disease within 60 days of completing a most recent therapy (or line of therapy).

[0079] In some embodiments, the individual was refractory to the most recent previous therapy (or line of therapy).

[0080] In some embodiments, the individual has relapsed / refractory multiple myeloma (RRMM) with measurable disease (e.g., serum M protein of ≧0.5 g / dL measured using serum protein immunoelectrophoresis, and / or urinary M protein of ≧200 mg / 24 hour measured using urine protein immunoelectrophoresis, and / or serum free light chains (FLC) (i.e., FLC assay ≧10 mg / dL (≧100 mg / L), and an abnormal serum FLC ratio (<0.26 or >1.65)), has received at least two prior therapies including lenalidomide and a proteasome inhibitor (e.g., bortezomib, carfilzomib, or ixazomib), and was refractory to last-line therapy (i.e., most recent line therapy). In some embodiments, the individual has adequate renal, liver, and bone marrow function.

[0081] 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, or more than four previous therapies (or lines of therapy) for multiple myeloma, for example, at least any one of 5, 6, 7, 8, 9, 10, or 11 previous therapies (or lines of therapy).

[0082] In some embodiments, the individual has received at least one prior therapy (or line of therapy) with lenalidomide. In some embodiments, the prior lenalidomide therapy (or line of therapy) included at least two consecutive cycles of lenalidomide. In some embodiments, the individual has failed (e.g., been non-responsive to) a prior lenalidomide therapy (or line of therapy). In some embodiments, the individual who failed a prior lenalidomide therapy (or line of therapy) did not achieve at least a minimal response (MR) during the lenalidomide therapy (or line of therapy). In some embodiments, the individual who failed a prior lenalidomide therapy (or line of therapy) showed progressive disease (PD) during the lenalidomide therapy (or line of therapy). As noted elsewhere herein, in some embodiments, "minimal response" and "progressive disease" refer to 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 prior lenalidomide therapy was administered during the first, second, third, fourth, fifth, sixth, and / or subsequent therapy (or line of therapy) for multiple myeloma (i.e., before a treatment described herein that includes administration of an 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 combination with at least one additional agent.

[0083] In some embodiments, the individual has received at least one prior therapy (or at least one prior line of therapy) with a proteasome inhibitor. In some embodiments, the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, and ixazomib. In some embodiments, the prior proteasome inhibitor therapy (or line of therapy) included at least two consecutive cycles of a proteasome inhibitor. In some embodiments, the individual has failed (e.g., been non-responsive to) a prior proteasome inhibitor therapy (or prior line of therapy). In some embodiments, an individual who has failed a prior proteasome inhibitor therapy (or line of therapy) did not achieve at least a minimal response (MR) during the proteasome inhibitor therapy (or line of therapy). In some embodiments, an individual who has failed a prior proteasome inhibitor therapy (or line of therapy) exhibited progressive disease (PD) during the proteasome inhibitor therapy (or line of therapy). In some embodiments, the prior proteasome inhibitor therapy was administered during the first, second, third, fourth, fifth, sixth, and / or subsequent therapy (or line of therapy) for multiple myeloma (i.e., prior to a treatment described herein that includes administration of an anti-CD38 antibody (e.g., isatuximab)). In some embodiments, the individual was refractory to a proteasome inhibitor (e.g., one or more proteasome inhibitors). In some embodiments, the prior proteasome inhibitor therapy was administered to the individual as a single agent. In some embodiments, the prior proteasome inhibitor therapy was administered to the individual in combination with at least one additional agent.

[0084] In some embodiments, the individual has received at least two prior therapies (or lines of therapy) including lenalidomide (described elsewhere herein) and a proteasome inhibitor (described elsewhere herein). In some embodiments, the individual further exhibited disease progression during or after completion of the most recent prior therapy (e.g., prior to treatment described herein including administration of an anti-CD38 antibody (e.g., isatuximab)). In some embodiments, lenalidomide and a proteasome inhibitor were administered concomitantly to the individual. In some embodiments, the individual previously achieved a partial response (PR) or better to lenalidomide and / or a proteasome inhibitor (given alone or in combination), but exhibited progressive disease (PD) within 6 months of completing therapy (or lines of therapy) with lenalidomide and / or a proteasome inhibitor.

[0085] In some embodiments, the individual has received prior therapy (or at least one prior line of therapy) with pomalidomide.

[0086] In some embodiments, the individual has a respiratory, thoracic, and / or mediastinal disorder. In some embodiments, the individual has chronic obstructive pulmonary disorder (COPD). In some embodiments, the individual is diagnosed with COPD before the initiation of a treatment described herein comprising administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual develops and / or is diagnosed with COPD after the initiation of a treatment described herein comprising administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual has asthma. In some embodiments, the individual is diagnosed with asthma before the initiation of a treatment described herein comprising administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual develops and / or is diagnosed with asthma after the initiation of a treatment described herein comprising administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual has (e.g., experiences) bronchospasm. In some embodiments, the individual experienced bronchospasm before the initiation of a treatment described herein comprising administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual develops bronchospasm after the initiation of a treatment described herein comprising administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual has one or more of the following: bronchial hyperresponsiveness, cough, dyspnea, dyspnea at rest, dyspnea on exertion, emphysema, hypoxia, pulmonary infiltrates, oropharyngeal pain, pleural effusion, pleuritic pain, pulmonary embolism, pulmonary hypertension, allergic rhinitis, and nasal discharge. In some embodiments, the individual experienced one or more of bronchial hyperresponsiveness, cough, dyspnea, dyspnea at rest, dyspnea on exertion, emphysema, hypoxia, pulmonary infiltrates, oropharyngeal pain, pleural effusion, pleuritic pain, pulmonary embolism, pulmonary hypertension, allergic rhinitis, and nasal discharge before the initiation of a treatment described herein comprising administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual develops one or more of bronchial hyperresponsiveness, cough, dyspnea, dyspnea at rest, dyspnea on exertion, emphysema, hypoxia, pulmonary infiltrates, oropharyngeal pain, pleural effusion, pleuritic pain, pulmonary embolism, pulmonary hypertension, allergic rhinitis, and nasal discharge after initiation of treatment described herein that includes administration of an anti-CD38 antibody (e.g., isatuximab).

[0087] In some embodiments, the individual does not have primary refractory multiple myeloma. In some embodiments, an individual with primary refractory multiple myeloma is an individual who has not achieved at least a minimal response (MR) with any therapy (or line of therapy) during the course of their disease. In some embodiments, the individual does not have measurable free light chain (FLC) disease alone. In some embodiments, the individual has not received prior treatment with an anti-CD38 antibody. In some embodiments, the individual has not received prior therapy (or prior line of therapy) with isatuximab. In some embodiments, the individual has not shown progressive disease (PD) during prior therapy (or prior line of therapy) with an anti-CD38 antibody. In some embodiments, the individual has not shown PD within 60 days of completing therapy (or line of therapy) with an anti-CD38 antibody. In some embodiments, the individual has not received prior therapy (or prior line of therapy) with pomalidomide. In some embodiments, the individual has not received prior allogeneic hematopoietic stem cell transplantation.

[0088] In some embodiments, the individual is under 65 years of age. In some embodiments, the individual is between 65 and 75 years of age. In some embodiments, the individual is 75 years of age or older. In some embodiments, the individual is female (e.g., a female of childbearing age). In some embodiments, the individual has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or less, 1 or less, or 2 or less. In some embodiments, the individual is in stage I, stage II, or stage III according to the Multiple Myeloma International Stating System (ISS).

[0089] Single Agent and Combination Treatments In some embodiments, the methods of treatment described herein involve administration of an anti-CD38 antibody (e.g., isatuximab) as a single agent (e.g., as monotherapy). In some embodiments, the anti-CD38 antibody is administered in combination with at least one additional agent (e.g., two or more additional agents). The additional agent may be a small molecule drug or a biopharmaceutical, such as an antibody.

[0090] In some embodiments, the at least one additional agent comprises an immunomodulatory agent IMiD®. In some embodiments, the IMiD® administered in combination with the anti-CD38 antibody (e.g., isatuximab) is thalidomide, lenalidomide, and / or pomalidomide. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) and immunomodulatory agent are further administered in combination with a corticosteroid, such as dexamethasone or prednisone. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered in combination with lenalidomide and dexamethasone. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered in combination with pomalidomide and dexamethasone. In some embodiments, the anti-CD38 antibody (e.g., isatuximab), immunomodulatory agent (e.g., lenalidomide), and corticosteroid (e.g., dexamethasone) are further administered in combination with an anticoagulant (e.g., aspirin, warfarin, or heparin).

[0091] In some embodiments, at least one additional agent comprises a proteasome inhibitor. In some embodiments, the proteasome inhibitor administered in combination with an anti-CD38 antibody (e.g., isatuximab) is bortezomib, carfilzomib, ixazomib citrate, marizomib, and / or oprozomib. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) and proteasome inhibitor are further administered in combination with a corticosteroid, such as dexamethasone or prednisone. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) and proteasome inhibitor are further administered in combination with an IMiD® (e.g., thalidomide, lenalidomide, and / or pomalidomide). In some embodiments, the anti-CD38 antibody is administered in combination with carfilzomib, lenalidomide, and dexamethasone. In some embodiments, the anti-CD38 antibody is administered in combination with bortezomib, lenalidomide, and dexamethasone. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) and proteasome inhibitor are further administered in combination with an alkylating agent (e.g., including but not limited to, cyclophosphamide, cyclophosphamide monohydrate, bendamustine, bendamustine hydrochloride, busulfan, carmustine, lomustine, melphalan, melphalan flufenamide, melphalan hydrochloride, thiotepa, and treosulfan). In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered in combination with bortezomib, lenalidomide, and dexamethasone.

[0092] Additionally or alternatively, in some embodiments, at least one additional agent comprises a histone deacetylase inhibitor (HDAC inhibitor), such as, but not limited to, panobinostat or panobinostat lactate. Additionally or alternatively, in some embodiments, at least one additional agent comprises an anthracycline, such as, but not limited to, daunorubicin, doxorubicin, doxorubicin hydrochloride, idarubicin, liposomal doxorubicin hydrochloride, mitoxantrone, pegylated liposomal doxorubicin, or pegylated liposomal doxorubicin hydrochloride. Additionally or alternatively, in some embodiments, at least one additional agent comprises a corticosteroid, such as, but not limited to, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, methylprednisolone, prednisolone, or prednisone. Additionally or alternatively, in some embodiments, the at least one additional agent comprises a vinca alkaloid, such as, but not limited to, vincristine or vincristine sulfate.

[0093] Manufactured product or kit In another embodiment of the present invention, an article of manufacture or kit comprising an anti-CD38 antibody (e.g., isatuximab) is provided. In some embodiments, the article of manufacture or kit further comprises a package insert containing instructions for using the anti-CD38 antibody (e.g., isatuximab) to treat or delay the progression of multiple myeloma (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma) in an individual who has received at least two prior therapies for multiple myeloma (e.g., including lenalidomide and a proteasome inhibitor). In some embodiments, the article of manufacture or kit further comprises a package insert or label containing instructions for administering one or more 10 mg / kg doses of the anti-CD38 antibody (e.g., isatuximab), each dose in a volume of 250 ml, according to the methods described herein. In some embodiments, the article of manufacture or kit further comprises a package insert or label containing instructions for administering 20 mg / kg of the anti-CD38 antibody (e.g., isatuximab).

[0094] The specification is considered to be sufficient to enable one skilled in the art to practice the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

[0095] Example 1A Preliminary results from a phase 1b study evaluating the feasibility and safety of short-term fixed-volume infusion of isatuximab in combination with pomalidomide and dexamethasone for relapsed and / or refractory multiple myeloma. This example describes a multicenter, open-label, non-comparative Phase 1b study that investigated abbreviated infusion dosing of isatuximab (I) in combination with pomalidomide and dexamethasone (Pd) using a fixed infusion volume in patients with relapsed / refractory multiple myeloma (RRMM) who had been previously exposed to proteasome inhibitors and immunomodulatory agents and who were relapsed / refractory to most current therapies.

[0096] I. Test Objectives The primary objective of this study was to evaluate the feasibility of isatuximab (I) administered from a fixed infusion volume in combination with pomalidomide and dexamethasone (Pd), as investigated by the occurrence of grade ≥3 infusion reactions (IR).

[0097] The secondary objectives of this study were as follows: (1) to evaluate the infusion duration for the administration of isatuximab in combination with Pd at a fixed infusion volume; (2) to evaluate the safety profile of the combination of Pd with isatuximab at a fixed volume; (3) to evaluate the immunogenicity of isatuximab in combination with Pd; and (4) to describe the efficacy of the combination of Pd and isatuximab in terms of overall response rate (ORR, i.e., CR+VGPR+PR) and clinical benefit rate (CBR, i.e., CR+VGPR+PR+mR) and duration of response based on the International Myeloma Working Group (IMWG) response criteria in patients with RRMM (see Table 14) (Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346 and Durie et al. (2006) "International uniform response criteria for multiple myeloma". Leukemia. 20:1467-1473).

[0098] The research objectives of this study were: (1) to investigate multiple myeloma molecular subtypes (defined by cytogenetics) and clinical response; (2) to investigate the relationship between immunogenetic determinants, immunophenotype, and clinical response parameters; (3) to investigate minimal residual disease (MRD) patients who achieved complete response (CR) and correlate with clinical outcome (see Table 14); and (4) to investigate potential isatuximab interference with M protein studies in immunoelectrophoresis and immunofixation assays.

[0099] II. Study Population A. Inclusion criteria Eligible patients were considered for inclusion in the study if they met all of the following criteria: The patient had previously been diagnosed with multiple myeloma (MM) according to standard criteria, but required treatment because the MM had relapsed after a response according to IMWG criteria. Patients had received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and had disease progression during or after completion of the last therapy. Patients had measurable disease defined as at least one of the following: o Serum M protein ≥ 0.5 g / dL (≥ 5 g / L). o ≥ 200 mg / 24-hour urinary M protein. Serum free light chain (sFLC) assay: included FLC assay ≥ 10 mg / dL (≥ 100 mg / L) and abnormal serum FLC ratio (< 0.26 or > 1.65). All patients enrolled in this trial were enrolled in and met all requirements of the POMALYST REMS™ program (www.pomalystrems.com).

[0100] B. Exclusion criteria Patients who met any of the following criteria were ineligible for this study: Male or female patients under the age of 18. Patients who have been diagnosed with or treated for another malignancy within 3 years prior to enrollment, except for basal or squamous cell carcinoma of the skin after curative therapy, in-situ malignancies, or complete resection of low-risk prostate cancer. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status score of greater than 2 or a life expectancy of 3 months or less. Clinical laboratory exclusion criteria: Patients were excluded if the screening test results were: Absolute neutrophil count (ANC) <1000 cells / μl (1.0x10 9 / L). Growth factors had not been used within the previous 7 days. Aspartate aminotransferase (AST / SGOT) or alanine aminotransferase (ALT / SGPT) ≥ 2.5 × upper limit of normal (ULN). - No platelet transfusion in the previous 7 days, platelet count <50,000 cells / μl (50x10 9 / L). o Total bilirubin >1.5xULN. Calculated creatinine clearance (CrCl) using the MDRD formula <30 mL / min: Glomerular filtration rate (mL / min / 1.73m 2 ) = 175 × (Scr) − 1.154 × (Age) − 0.203 × (0.742 for women) × (1.212 for African Americans), where Scr is serum creatine in mg / dL and Age is age. Serum calcium (corrected for albumin) levels above the ULN range. Patients were allowed to enroll in the study if treatment for hypercalcemia was tolerated and hypercalcemia returned to normal with standard treatment. Initially refractory or intolerant to prior therapy with any anti-CD38 monoclonal antibody (MoAb) or had disease progression while on an anti-CD38 MoAb administered as last therapy (after achieving a response of ≥ MR). -Received any investigational drug within 14 days or 5 half-lives of an investigational drug, whichever is longer. Previous anti-cancer therapy within 14 days. Any unresolved Grade >1 adverse reaction from prior treatment per NCI CTC AE v.4.03. Peripheral neuropathy Grade ≤2 without the presence of alopecia or pain was allowed. · Previous allogeneic stem cell transplant with active graft-versus-host disease (GVHD) in the last 2 months prior to study enrollment or on immunosuppressive therapy. Daily corticosteroids are required (equivalent to 10 mg / day of prednisone for more than 7 consecutive days except in patients being treated for inhaled corticosteroids and adrenal insufficiency / replacement therapy). Patients were known to be human immunodeficiency virus (HIV) positive, hepatitis B surface antigen positive, or had active hepatitis C infection. Any clinically significant uncontrolled medical condition that, in the opinion of the investigator, may have placed the patient at undue risk or interfered with compliance or interpretation of the study results. History of erythema multiforme or previous severe hypersensitivity to an IMiD®. History of hypersensitivity or intolerance to IMiD®, dexamethasone, sucrose, histidine (as base and hydrochloride salt), and polysorbate 80, or any of the components of the study therapy that would be incompatible with premedication with steroids and H2-blockers or would prohibit further treatment with these agents. Hypersensitivity to boron and / or mannitol (i.e., when the investigational medicinal product (IMP) and / or non-investigational medicinal product (NIMP) contain boron and / or mannitol) -Inability to tolerate thromboprophylaxis.

[0101] III. Test Plan A. Primary Endpoint The primary endpoint of this study was the incidence of grade ≥3 IR reported during the first six infusions of isatuximab from a fixed infusion volume in combination with Pd.

[0102] B. Secondary Endpoints The secondary endpoints of this study were:

[0103] i. Infusion period The duration of infusion was measured from the start of isatuximab infusion to the end of isatuximab infusion, regardless of temporary cessation / interruption.

[0104] ii. Safety and immunogenicity Safety was investigated through collection of treatment-emergent adverse events (TEAEs) and changes in laboratory parameters (hematology, biochemistry, and urinalysis), vital signs (heart rate, blood pressure, and weight), ECG, physical examination, and ECOG PS. Patients were investigated for the presence of human anti-drug antibodies (ADA) to isatuximab. An adverse event was defined as any untoward medical occurrence occurring in a patient receiving the drug and not necessarily causally related to the study treatment.

[0105] iii.Validity Efficacy was investigated using the updated IMWG response criteria (see, e.g., Kumar S. et al., Lancet Oncol. 2016; 17(8) e328-e46; Durie et al. (2006) "International uniform response criteria for multiple myeloma". Leukemia. 20:1467-1473; and Table 14 herein) to assess objective response (overall response rate), percentage of patients with clinical beneficial response (CBR), and duration of response using response criteria defined by the IMWG.

[0106] C. Investigational Endpoints Bone marrow and / or blood samples were analyzed for genomic profiling, and multiple myeloma molecular subtypes (using cytogenetics) and bone marrow were analyzed for CD38 mRNA levels. These markers were correlated with clinical response. Furthermore, cytogenetic analysis was performed on blood samples for immune gene determinants associated with clinical response (e.g., Fc polymorphisms, human leukocyte antigens (HLA), and killer immunoglobulin-like receptors (KIRs)). Correlations between immune phenotypes in peripheral blood (e.g., B cell, T cell, and natural killer (NK) cell subsets) and clinical response parameters were also investigated. Finally, MRD by sequencing was investigated in patients with CR and correlated with clinical outcome.

[0107] D. Statistical methods The reported incidence of grade ≥3 IR determined the sample size: if there were approximately 40 patients in total and the lower limit of the 95% CI was >5.5%, i.e., ≥6 patients had grade ≥3 IR, a fixed infusion dose of isatuximab would not be considered feasible.

[0108] Statistical evaluation for all analyses was descriptive and performed based on all treated patients who completed at least six isatuximab infusions or terminated study treatment early (due to definitive termination of treatment). Continuous data were summarized using the number, mean, standard deviation, median, minimum, and maximum values ​​of available data. Categorical and ordinal data were summarized using the number and percentage of patients. The number (percentage) of patients with grade ≥ 3 IR within the first six isatuximab infusions among patients evaluable for IR surveillance was analyzed with 95% confidence intervals using the Clopper-Pearson method.

[0109] E. Study Participation Period The study period for each patient included a screening period for enrollment of up to 21 days. Treatment continued until disease progression, unacceptable AE, or other reason for discontinuation. Patients were followed for a minimum of 30 days from the last use of investigational / non-investigational medication (IMP / NIMP), or for more than 30 days in the case of an unresolved IMP / NIMP-related adverse event (AE). For all patients, any study treatment-related adverse events and all ongoing serious adverse events (SAEs) at the time of study treatment discontinuation (regardless of their causal relationship to study treatment) were followed during the follow-up period until resolution or stabilization. The cutoff date for the primary analysis was the date on which the last enrolled patient completed six infusions. The cutoff date for the final analysis was 10 months after the date of the last enrolled patient's first dose.

[0110] No samples were collected for ADA analysis after 10 cycles. If the last ADA sample was positive or inconclusive, additional ADA sampling was performed after 3 months. No further ADA sampling was performed even if the 3-month sample was positive.

[0111] F. Fixed Volume Infusion Schedule As shown in Figure 1, isatuximab was administered intravenously (IV) in a single step at a selected dose of 10 mg / kg from a 250 mL fixed volume, with the infusion rate expressed in ml / hour. The fixed volume was administered on days 1, 8, 15, and 22 of the first 28-day cycle. During each subsequent 28-day cycle, the fixed volume was administered on days 1 and 15. Patients were weighed before each cycle to allow for calculation of the isatuximab dose. Pomalidomide was administered orally on days 1–21 of all 28-day cycles. Dexamethasone was administered orally or intravenously on days 1, 8, 15, and 22 of all 28-day cycles. When dexamethasone was coadministered as part of premedication, it was administered orally or intravenously before the administration of isatuximab. All patients received pretreatment prophylaxis for hypersensitivity reactions, as described in further detail below.

[0112] During the first six isatuximab infusions, IR of grade 3 or greater was investigated. Patients who experienced a grade ≥ 3 IR were permanently discontinued from study treatment and administered appropriate supportive care. After the sixth infusion, patients continued study treatment until disease progression, unacceptable toxicity, or other reason for discontinuation. If patients met the criteria for initiating a new cycle of therapy, as described in more detail below, they began an additional cycle.

[0113] G. Fixed volume injection rate First infusion: The initial infusion was initiated at a 25 mL / hour infusion rate. In the absence of IR 1 hour after infusion, the infusion rate was increased by 25 mL / hour increments every 30 minutes to a maximum infusion rate of 150 mL / hour. In the event of grade 2 IR during the first infusion, the infusion was resumed at half the initial infusion rate (12.5 mL / hour) after improvement of the IR to grade ≤1. If symptoms did not recur after 30 minutes, the infusion rate was increased by 25 mL / hour increments every 30 minutes until the total volume was infused.

[0114] Second infusion: The second infusion was initiated at a rate of 50 mL / hour. In the absence of grade 2 IR after 30 minutes of infusion, the rate was increased to 100 mL / hour for 30 minutes, then 200 mL / hour for 30 minutes, then 300 mL / hour until the total volume was infused. In the event of grade 2 IR during the second infusion, the infusion was resumed at half the initial infusion rate (25 mL / hour) upon improvement of the IR to grade ≤1. If symptoms did not recur after 30 minutes, the infusion rate was increased in 50 mL / hour increments every 30 minutes until the total volume was infused.

[0115] Third and subsequent infusions: The third and subsequent infusions were initiated at a fixed infusion rate of 200 mL / h until the total volume was infused. In the event of grade 2 IR during the third infusion, the infusion was resumed at half the infusion rate (100 mL / h) when the IR improved to grade ≤1. If symptoms did not recur after 30 minutes, the infusion rate was increased by 50 mL / h increments every 30 minutes until the total volume was infused.

[0116] H. Investigational Medicinal Products (IMPs) i. Isatuximab Isatuximab is an anti-CD38 antibody containing a heavy chain comprising the sequence of SEQ ID NO: 10 and a light chain comprising the sequence of SEQ ID NO: 11. Isatuximab was provided as a sterile, non-pyrogenic, colorless concentrate for injection in a 30 mL glass vial fitted with an elastomeric fastener. Each vial contained 20 mg / mL (500 mg / 25 mL) isatuximab in 20 mM histidine, 10% (w / v) sucrose, 0.02% (w / v) polysorbate 80, pH 6.0 buffer. Vials with white to off-white particulates were tolerated. Each vial contained a nominal content of 500 mg isatuximab.

[0117] Isatuximab was administered at a selected dose of 10 mg / kg IV (from a fixed volume of 250 mL) on days 1, 8, 15, and 22 of the first 28-day cycle. Thereafter, isatuximab was administered on days 1 and 15. Patients were weighed before each cycle to allow calculation of the isatuximab dose.

[0118] For patient administration, the appropriate volume of isatuximab was diluted in an infusion bag with 0.9% sodium chloride solution. No protection from light was required for storage in the infusion bag. The investigational product was stored at +2°C to +8°C.

[0119] ii. Pomalidomide Pomalidomide capsules were administered orally at a dose of 4 mg on days 1 to 21 of each 28-day cycle according to the pomalidomide prescribing information (available at the website: www.accessdata.fda.gov / drugsatfda_docs / label / 2013 / 204026lbl.pdf).

[0120] iii. Dexamethasone Dexamethasone (40 mg for patients under 75 years of age; 20 mg for patients over 75 years of age) was administered orally (PO) or by IV infusion on days 1, 8, 15, and 22 of each 28-day cycle.

[0121] I. Non-Investigational Medicinal Products (NIMPs) - Premedication for Prevention of Infusion Reactions (IR) To reduce the risk and severity of IR, which is commonly observed with monoclonal antibodies, patients typically received premedication before isatuximab infusion. Recommended premedication medications were as follows: diphenhydramine, 25–50 mg, administered IV (or equivalent intravenous route preferred for at least the first four infusions); ranitidine, 50 mg, administered IV (or equivalent route); and acetaminophen, 650–1000 mg, administered PO 15–30 minutes (but no more than 60 minutes) before isatuximab infusion. Once the premedication regimen was completed, the isatuximab infusion was initiated.

[0122] Additionally, dexamethasone 40 mg (or 20 mg for patients ≥ 75 years old) was administered as part of a PO or IV premedication regimen prior to administration of isatuximab. Because dexamethasone was also an IMP administered on days 1, 8, 15, and 22 of each 28-day cycle, during isatuximab infusion days, dexamethasone was administered only once prior to the isatuximab infusion, and a single dose was used for both premedication and study treatment. The order of administration of premedication is provided below:

[0123] When dexamethasone was administered PO, the following sequence was used: ·Dexamethasone 40 mg PO (or 20 mg PO for patients ≥ 75 years of age). · Acetaminophen (paracetamol) 650mg to 1000mg PO. · Ranitidine 50 mg IV (or equivalent). ·Diphenhydramine 25mg to 50mg IV (or equivalent).

[0124] When dexamethasone was administered IV, the following sequence was used: · Acetaminophen (paracetamol) 650mg to 1000mg PO. · Ranitidine 50 mg IV (or equivalent). ·Diphenhydramine 25mg to 50mg IV (or equivalent). ·Dexamethasone 40 mg IV (or 20 mg IV for patients ≥ 75 years old).

[0125] For patients who could not tolerate dexamethasone during study treatment or in whom dexamethasone was discontinued prematurely, methylprednisolone 100 mg IV was administered as premedication only, but both drugs were not used simultaneously for premedication purposes.

[0126] J. Dose Delays, Omissions, and / or Modifications i. Isatuximab For isatuximab, dose reductions were not authorized. If a dose reduction of isatuximab occurred, the patient was discontinued from study treatment unless a clear benefit from therapy was observed.

[0127] If toxicity occurred during a cycle and did not resolve on the scheduled infusion date, the patient had their isatuximab dose omitted. In such cases, the infusion could be delayed for up to 3 days. Otherwise, the infusion was omitted, and the patient received the next isatuximab infusion after the toxicity resolved. No more than two consecutive isatuximab infusions were allowed to be omitted per patient.

[0128] Isatuximab infusion rates were allowed to be stopped and changed in response to IR as follows:

[0129] Grade 1 IR: No infusion interruption or intervention was indicated for patients experiencing grade 1 IR. However, if the infusion was stopped as deemed necessary, the IR was classified as grade 2.

[0130] Grade 2 IR: Infusion interruption and additional premedication were indicated as needed for patients experiencing grade 2 IR. If grade 2 IR improved to grade ≤1, the infusion was resumed at half the original infusion rate under close monitoring and supportive care as needed. If symptoms had not recurred after 30 minutes, the infusion rate was increased as follows: · 25mL / hour increments every 30 minutes during the initial infusion until the total volume is infused. · 50mL / hour increments every 30 minutes until the total volume is infused during the second infusion. During the third and subsequent infusions, in 50 mL / hour increments every 30 minutes until the total volume is infused.

[0131] Grade 3 or 4 IR: Patients with grade 3 or 4 IR had isatuximab treatment permanently discontinued and were administered appropriate therapy.

[0132] ii. Pomalidomide If toxicity occurred and did not resolve on the scheduled infusion / administration day, one or several doses of pomalidomide were omitted within the cycle. The pomalidomide dose was adjusted from a starting dose of 4 mg to 3 mg for the first dose reduction, 2 mg for the second dose reduction, and 1 mg for the third dose reduction. No more than three dose reductions of pomalidomide were permitted per patient. Once reduced, the dose was never re-escalated. When a strong CYP1A2 inhibitor was coadministered in the presence of a strong CYP3A4 inhibitor and an inhibitor of P-glycoprotein, the pomalidomide dose was reduced by 50%. If pomalidomide was permanently discontinued early, isatuximab was continued until disease progression, unacceptable toxicity, or the patient's refusal to undergo further treatment.

[0133] iii. Dexamethasone If toxicity occurred and did not resolve on the scheduled infusion / administration day, one or more doses of dexamethasone were omitted within the cycle. For patients younger than 75 years, the starting dose of 40 mg dexamethasone was adjusted to 20 mg for the first dose reduction, 12 mg for the second dose reduction, and 8 mg for the third dose reduction; if further dose reductions were required, dexamethasone was discontinued. For patients 75 years or older, the starting dose of 20 mg dexamethasone was adjusted to 12 mg for the first dose reduction, 8 mg for the second dose reduction, and 4 mg for the third dose reduction; if further dose reductions were required, dexamethasone was discontinued. Once reduced, the dose was never re-escalated. If dexamethasone was discontinued early and permanently, isatuximab was continued until disease progression, unacceptable toxicity, or the patient's refusal to undergo further treatment.

[0134] K. Simultaneous therapy Standard prophylactic medication with antihistamines and antipyretics without post-infusion corticosteroid prophylaxis was given. Premedication was reconsidered after four infusions. Anticoagulant prophylaxis was required after review of each patient's underlying risk factors. Unless there was excessive risk of bleeding, all patients received standard (e.g., prophylactic) antithrombotic treatment unless contraindicated.

[0135] L. Starting a new cycle A cycle of study treatment was initiated if the following criteria were met: ANC≧1,000 / mm 3 G-CSF use was permitted during all cycles and was permitted on the same day as treatment administration. ·Platelet count ≧50,000 / mm 3 Platelet transfusions were permitted during all cycles and were allowed on the same day as treatment administration. Any IMP-related AEs were less than Grade 1 in severity or reduced to baseline.

[0136] Patients were re-evaluated weekly if the above criteria were not met on Day 1 of the scheduled cycle. Patients who did not meet the above criteria within 14 days of Day 1 of the scheduled cycle were discontinued from study treatment.

[0137] IV.Results A. Patient characteristics All patients who completed at least six isatuximab infusions (two cycles) or who terminated study treatment early (due to definitive termination of treatment) were included in the results. Thus, a total of 34 patients were included, of whom 24 (70.6%) were still on treatment at the end of the study and 10 (29.4%) had terminated treatment early (Table 1).

[0138] As shown in Table 1, the reasons for definitive study treatment discontinuation in the 10 (29.4%) patients who terminated treatment early were as follows: disease progression (7 patients) and AEs (3 patients). One patient discontinued pomalidomide treatment early, and no patients discontinued dexamethasone treatment early.

[0139] [Table 1]

[0140] Table 2 provides a summary of the demographic characteristics of the 34 treated patients. The median age was 64 years (range 46 to 85 years), with most patients <65 years of age (55.9%). There were 18 female and 16 male patients. Most patients were white (88.2%) and not Hispanic or Latino (85.3%). All patients had an ECOG PS of 0 or 1, except for one patient (2.9%) who had an ECOG PS of 2. At study entry, patients weighed between 40 kg and 121 kg, with a median of 89.1 kg.

[0141] [Table 2-1] [Table 2-2]

[0142] As shown in Table 3, at study entry, 15 (44.1%), 10 (29.4%), and 5 (14.7%) patients had International Staging System (ISS) stage I, II, and III disease, respectively. The ISS stage of four patients (11.8%) was unknown. Most patients (67.6%) had measurable serum M protein. Patients had a median of 12.6% (range, 0% to 96.0%) plasma cells in the bone marrow, with 47.1% of patients having 20% ​​to 50% bone marrow plasma cells. Most patients (67.6%) had bone lesions at baseline, and 10 (29.4%) patients had plasmacytoma at baseline.

[0143] [Table 3]

[0144] The most common conditions reported in the medical history were: hypertension (18 patients, 52.9%), peripheral sensory neuropathy (17 patients, 50.0%), back pain (16 patients, 47.1%), and gastroesophageal reflux disease (10 patients, 29.4%). Three patients (8.8%) had drug hypersensitivity reported in their medical history. Table 4 provides a summary of relevant respiratory history, which included asthma in five patients (14.7%), bronchial hyperreactivity in one patient (2.9%), and chronic obstructive pulmonary disease in two patients (5.9%).

[0145] [Table 4]

[0146] As shown in Table 5, all patients had received prior lines of immunomodulatory agents (IMiD®), including lenalidomide, pomalidomide, or thalidomide; proteasome inhibitors (PIs), including bortezomib, carfilzomib, ixazomib citrate, marizomib, or oprozomib; and corticosteroids, including dexamethasone or prednisone. Twenty-nine patients (85.3%) had received prior lines of alkylating agents (bendamustine, carmustine, cyclophosphamide, melphalan, or melphalan-flufenamide). Fourteen (41.2%) and seven (20.6%) had received prior pomalidomide and carfilzomib, respectively. Prior to study entry, five (14.7%) and seven (20.6%) patients had received daratumumab (anti-CD38 monoclonal antibody) and elotuzumab (anti-SLAM7 monoclonal antibody), respectively.

[0147] [Table 5]

[0148] B. Extent of Isatuximab Exposure Overall, the median number of isatuximab infusion cycles was 3.5 (min-max: 1-9), with 17 (50.0%) patients initiating at least 4 cycles (minimum 9 infusions). The overall median duration of exposure was 13.4 weeks (min-max: 1-37). The median relative dose intensity (RDI) of isatuximab was 94.80% (69.8%-112.9%) (Table 6). The median relative dose intensities of pomalidomide and dexamethasone were 84.7% and 87.5%, respectively.

[0149] [Table 6-1] [Table 6-2]

[0150] C. Dose Modification and Discontinuation As shown in Table 7, a delay in an isatuximab infusion (within a cycle, excluding the first infusion of a cycle) occurred in one patient (3.0%). Omission of a dose occurred in 12 patients (35.3%), with 16 of 146 cycles (11.0%) having one dose omission.

[0151] Seventeen patients (50.0%) had at least one infusion interruption, and overall, 17 of 317 infusions (5.4%) were temporarily interrupted before completion. All infusion interruptions occurred exclusively during the first infusion (Table 7). The median time from the start of the infusion to the first interruption was 85 minutes (minimum-maximum: 46-145 minutes), with most interruptions occurring between 61 and 90 minutes (six interruptions) (Table 7). There were no isatuximab dose reductions.

[0152] [Table 7-1] [Table 7-2]

[0153] As shown in Table 8, of the 17 patients who had an isatuximab infusion interruption, 15 were interrupted due to a treatment-emergent adverse event (TEAE). There were no grade ≥3 TEAEs. The remaining two patients (5.9%) who had an infusion interruption experienced food intolerance (G1 nausea and G1 vomiting) or technical problems, and their interruption was not related to IR. In both cases, the infusion was interrupted shortly thereafter but continued as scheduled without a reduction in the infusion rate after resumption and until completion.

[0154] [Table 8]

[0155] Treatment-emergent adverse events (TEAEs) As shown in Table 9, the median durations of the first and second infusions were 3.94 hours (min-max: 3.3-6.1 hours) and 1.88 hours (min-max: 1.5-3.5 hours), respectively. The third, fourth, fifth, and sixth infusions each had a median duration of 1.27 hours. The median duration of the third and subsequent infusions, administered at a fixed infusion rate of 200 mL / hour, was 1.25 hours (min-max: 0.7-3.4 hours).

[0156] [Table 9-1] [Table 9-2]

[0157] E. Infusion Reaction i. Infusion reactions in all treated patients Despite the short infusion period using a fixed volume, no grade ≥3 IRs were reported, and all IRs were grade 2. There were no treatment discontinuations due to IRs. As shown in Table 10, IRs were reported in 16 of 34 (47.1%) patients and in 16 of 317 (5.0%) infusions. All patients who experienced IRs had only one episode of IR and only during their first isatuximab infusion. The onset of all IRs occurred on the same day of isatuximab infusion, and all IRs resolved within the same day. IRs that occurred in >2 patients were dyspnea and cough (n=6 each) and chills (n=3).

[0158] [Table 10-1] [Table 10-2] [Table 10-3]

[0159] ii. Infusion reactions leading to interruption of isatuximab infusion In 15 of the 16 patients with IR, the isatuximab infusion was interrupted. In the remaining patients who experienced grade 2 IR and grade 3 hypoxia (symptoms of IR), the isatuximab infusion was not interrupted, and the hypoxia was managed with supplemental oxygen administration. Symptoms of IR occurring in >1 patient were cough (6 patients, 17.6%), dyspnea (5 patients, 14.7%), nasal congestion (2 patients, 5.9%), and chills (2 patients, 5.9%). With the exception of grade 3 hypoxia and grade 3 dyspnea (1 patient, 2.9% each), most of the symptoms associated with IR were reported as grade 1 or 2 (Table 11).

[0160] [Table 11]

[0161] IR was managed by dose interruption and / or use of medications consisting of H1 / H2 blockers, and / or paracetamol, and / or montelukast, and / or steroids. H1 / H2 blockers and steroids were each used in 9 of 16 patients (56.3%), paracetamol in 3 of 16 patients (18.8%), and montelukast in 1 of 16 patients (6.3%) (Table 12).

[0162] [Table 12-1] [Table 12-2]

[0163] iii. Infusion reactions in patients with relevant medical and respiratory history Of the seven patients with prior exposure to daratumumab, three experienced IR.

[0164] In patients with a history of bronchial disorders (asthma, bronchial hyperresponsiveness, COPD), IR was tolerable.

[0165] Seven patients (20.6%) had a history of bronchospasm and obstruction (see Table 4). Five of these seven patients experienced grade 2 IR, as shown in Table 13. Most frequently, the IR was managed with bronchodilators and steroids.

[0166] [Table 13]

[0167] F. Immune Response Anti-drug antibodies (ADA) against isatuximab have been investigated in patient plasma using the PandA method (Sanofi, Alfortville, France) in an assay volume of 100 μl throughout the study.

[0168] G. Effectiveness Efficacy was investigated using the updated IMWG response criteria (Kumar S. et al., Lancet Oncol. 2016; 17(8) e328-e46 and Durie et al. (2006) "International uniform response criteria for multiple myeloma". Leukemia. 20:1467-1473) to assess objective response (overall response rate "ORR"), percentage of patients with clinical beneficial response ("CBR"), and duration of response (DOR) using response criteria defined by the IMWG.

[0169] Overall Response Rate: ORR was defined as the proportion of patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) using the updated IMWG response criteria (see Table 14). Response assessments were performed monthly and included the following: · M protein quantification (serum and 24-hour urine). · Serum free light chain levels. · Bone marrow biopsy / aspiration (if clinically indicated). · CT / MRI scan for plasmacytoma (if clinically indicated). · Skeletal survey (if clinically indicated).

[0170] Clinical Beneficial Response: CBR was defined as the proportion of patients with sCR, CR, VGPR, PR, and minimal response (MR) according to IMWG criteria (see Table 14).

[0171] Duration of response: DOR was assessed as the time from the date of first response to subsequent PD or death, whichever occurred first. If no subsequent disease progression or death was confirmed before the end of the study, DOR was censored at the date of the last valid survey performed before the end of the study or the start of new anticancer treatment, whichever occurred first. DOR was determined only for patients who achieved a response of ≥PR. DOR was not calculated for patients who did not achieve a response.

[0172] [Table 14-1] [Table 14-2]

[0173] Among 31 patients evaluable for efficacy, the ORR was 64.5% and the median PFS was 17.58 months (95% CI: 6.538 to not reached). The efficacy results were consistent with those of clinical trial NCT02990338.

[0174] H. Research and Analysis We will analyze the correlation between clinical response and genomic profiling, multiple myeloma molecular subtype (using cytogenetics), and bone marrow CD38 mRNA levels in bone marrow and / or blood samples. Furthermore, we will perform cytogenetic analysis on blood samples for immune gene determinants (e.g., Fc polymorphism, human leukocyte antigen (HLA) and killer immunoglobulin-like receptor (KIR)), to determine their correlation with clinical response. Finally, we will investigate the correlation between immune phenotypes (e.g., B cell, T cell, and natural killer (NK) cell subsets) in peripheral blood and parameters of clinical response.

[0175] conclusion Isatuximab administered at a fixed infusion volume of 250 ml at an infusion rate measured in mL / hour had a manageable safety profile and a significantly shorter infusion time compared with infusion methods consisting of a weight-based volume administered in mg / hour. In general, the safety profile (including infusion reactions) of isatuximab administered by the simplified infusion method based on a fixed volume in mL / hour was manageable and consistent with the safety profile observed with other methods of isatuximab infusion where the infusion rate was measured in mg / hour (see, e.g., clinical trial NCT02990338).

[0176] The study met its primary endpoint, with no grade ≥3 IRs observed. All IRs were grade 2, occurred during the first isatuximab infusion, and resolved the same day; no delayed-onset IRs were reported. The median infusion time for isatuximab 10 mg / kg administered at a fixed infusion volume of 250 mL at an infusion rate of 1 mL / hour for the third and subsequent infusions was 75 minutes. This is significantly shorter than the infusion time for isatuximab administered at 1 mg / hour (median 174 minutes for the third and subsequent infusions). The general safety profile of the abbreviated infusion of Isa was favorable and consistent with previous observations of this Isa-Pd combination.

[0177] Example 1B Further results from a phase 1b study evaluating the feasibility and safety of short-term fixed-volume isatuximab infusion in combination with pomalidomide and dexamethasone for relapsed and / or refractory multiple myeloma. Further results from the Phase 1b trial described in Example 1A are provided below. Briefly, 47 patients were treated. Patient baseline characteristics are shown in Table 15 below. All patients had previously received lenalidomide, and 48.9% had previous pomalidomide treatment. Previous daratumumab (Dara) exposure was recorded in 14.9% of patients, and previous elotuzumab exposure was recorded in 19.1%. At study entry, the median time from initial diagnosis was approximately 6.2 years (range 1.1-22.7 years). 41 patients (87.2%) were refractory to their last regimen.

[0178] [Table 15]

[0179] At data cutoff, 30 (63.8%) patients continued treatment, and 17 (36.2%) discontinued treatment. Reasons for discontinuation included disease progression (n=10), adverse events (AEs; n=4), and other (n=3).

[0180] Treatment exposure The median number of cycles was 4.0, with 45 (95.7%) patients starting at least 2 cycles (minimum 5 infusions) and 31 (66.0%) starting at least 4 cycles (minimum 9 infusions). The overall median duration of exposure was 18.1 weeks (range 1-45). The median relative dose intensities of isatuximab, pomalidomide, and dexamethasone were 94.1%, 84.7%, and 87.5%, respectively.

[0181] Of the 490 total Isa infusions, 22 (4.5%) were interrupted and restarted. Twenty (90.9%) interruptions occurred during the first infusion. Twenty-five patients (53.2%) had ≥1 pomalidomide dose omission; 21 patients (44.7%) had ≥1 dose reduction. Most dose reductions (85.7%) occurred during the second cycle.

[0182] infusion reaction There were no grade ≥3 IRs or treatment discontinuations due to IRs. IRs of any grade were reported in 19 of 47 (40.4%) patients and 19 of 490 (3.9%) infusions. In Part 1, 48.3% of patients receiving Isa 10 mg / kg experienced IRs (Figure 2). All IRs were grade 2 in severity, all occurred during the first Isa infusion, and all resolved within the same day. IRs occurring in >2 patients were dyspnea and cough (n = 6 each) and chills (n = 3). IRs were managed with dose interruption in 18 (38.3%) patients and not interrupted in 1 patient (2.1%).

[0183] In a parallel clinical trial designed to investigate the efficacy of isatuximab plus pomalidomide plus dexamethasone in patients with multiple myeloma who had received at least two prior therapies, isatuximab was administered to study participants (n=31) via standard protocol, with the isatuximab infusion rate measured in mg / hour. The left side of Figure 2 shows the number of patients from the parallel clinical trial who experienced IR (i.e., those who received isatuximab via standard protocol). The right side of Figure 2 shows the number of patients in this clinical trial who experienced IR when administered isatuximab at a fixed volume of 250 ml (i.e., those described in Section IIIG of Example 1A). As discussed in Example 1A, the isatuximab infusion rate was measured in ml / hour. The percentage of patients who experienced grade ≥ 2 IR during the first infusion in this study was 40.4%. In contrast, the percentage of patients in the parallel study who experienced a grade ≥ 2 IR (i.e., when administered isatuximab by standard protocol) was 48.3%. No patients in the feasibility and safety study experienced a grade 3 IR during the first infusion. In contrast, 3.2% of patients in the parallel study (i.e., those administered isatuximab by standard protocol) experienced a grade 3 IR during the first infusion.

[0184] All IR experienced by patients in this study was managed by dose interruption and, if justified, the use of medications consisting of H1 / H2 blockers, and / or paracetamol, and / or montelukast, and / or steroids, and / or bronchodilators. The onset of all IR occurred on the same day of Isa infusion (i.e., no delayed IR occurred). Post-infusion prophylaxis was not required. Of the seven patients in this study with previous exposure to Dara, three experienced IR. In patients in this study with a history of bronchial disorders (asthma, bronchial hyperresponsiveness, COPD), IR was tolerable.

[0185] Infusion period The left side of Figure 2 shows the median duration of the first isatuximab infusion and the median duration of subsequent isatuximab infusions (i.e., following the first infusion) from a parallel clinical trial, i.e., a trial in which participants received isatuximab by standard protocol. The right side of Figure 2 shows the median duration of the first isatuximab infusion, the second isatuximab infusion, and subsequent isatuximab infusions (i.e., following the second infusion) from the present study described in Section IIIG of Example 1A, i.e., a study in which participants received isatuximab at a fixed volume of 250 ml.

[0186] In this study (alternatively referred to herein as "Part B"), the median duration of isatuximab infusion decreased from 3.70 hours (222 minutes, range: 1.0-6.1 hours) for the first infusion to 1.85 hours for the second infusion, and then further decreased to 1.25 hours (75 minutes) for the third infusion and beyond (right side of Figure 3). The median infusion duration remained stable during subsequent infusions (1.25 hours, range: 0.9-3.4 hours). In the parallel study (alternatively referred to herein as "Part A"), in which patients received isatuximab via the standard protocol (infusion rate measured in mg / hour), the median infusion duration was 3.30 hours for the first infusion and 2.9 hours (174 minutes) for the second infusion (left side of Figure 3).

[0187] Treatment-emergent adverse events (TEAEs) All but one patient (97.9%) experienced a TEAE, with fatigue (55.3%), IR (40.4%), and upper respiratory tract infection (38.3%) and neutropenia (38.3%) being the most common. See Table 16 for an example. Grade ≥3 TEAEs were observed in 31 (68.1%) patients. Non-hematologic TEAEs observed in >2 patients included arthralgia, pneumonia, and musculoskeletal pain (n=3 each). Infections of any grade were reported in 34 (72.3%) patients, and grade ≥3 infections were reported in 9 (19.1%) patients. Treatment-related TEAEs were experienced by 45 (95.7%) patients, with 26 (55.3%) experiencing grade ≥3 treatment-related TEAEs. Serious TEAEs were observed in 23 (48.9%) patients, and they were treatment-related in 12 (25.5%) patients. Four (8.5%) patients discontinued due to TEAEs (two severe infections; one acute myocardial infarction; one sudden death). Six patients died during the treatment period (within 30 days of the last dose of study drug); no deaths occurred during the posttreatment period (>30 days after the last dose of study drug). Deaths were attributed to AEs (n=3; acute myocardial infarction, sepsis, and rectal bleeding / sepsis), progressive illness (n=2), and one sudden death was due to unknown causes. None of the deaths were considered treatment-related.

[0188] [Table 16]

[0189] Hematologic abnormalities (all grades) were observed in the majority of patients: leukopenia (95.7%); neutropenia (93.5%); anemia and thrombocytopenia (both 82.6%); and lymphopenia (63.0%). Neutropenia was the most common grade 3 / 4 hematologic adverse event, with 17 patients experiencing grade 3 and 16 patients experiencing grade 4 (see Table 17). Grade 4 neutropenia was observed in 34.8% of patients, and grade 4 thrombocytopenia was observed in 8.7% of patients. Twenty patients (42.6%) received granulocyte colony-stimulating factor.

[0190] [Table 17]

[0191] conclusion The study met its primary endpoint, with no grade ≥3 IRs observed. All IRs were grade 2, occurred during the first isatuximab infusion, and resolved the same day; no delayed-onset IRs were reported. The median infusion time for isatuximab 10 mg / kg administered at a fixed infusion volume of 250 mL at an infusion rate of 1 mL / hour for the third and subsequent infusions was 75 minutes. This is significantly shorter than the infusion time from a parallel study in which isatuximab was administered at 1 mg / hour by the standard administration protocol (median 174 minutes for the third and subsequent infusions). The general safety profile of the abbreviated isatuximab infusion was favorable and consistent with previous observations of this combination of isatuximab, pomalidomide, and dexamethasone. The fixed infusion volume of isatuximab (250 mL) can aid in monitoring fluid balance, as recommended for patients with renal impairment. Furthermore, changing from a weight-based volume administration method (mg / hr) to a fixed volume infusion method (ml / hr) for isatuximab infusion resulted in comparable steady-state simulation C max (283 μg / ml vs. 284 μg / ml) and C trough (119 μg / ml vs. 119 μg / ml), so the effect on pharmacokinetic parameters was limited.

[0192] Example 1C Efficacy results from a phase 1b study evaluating the feasibility and safety of short-term fixed-volume isatuximab infusion in combination with pomalidomide and dexamethasone for relapsed and / or refractory multiple myeloma. Further results from the Phase 1b study described in Examples 1A and 1B are provided below. 47 patients were included in the overall treatment population. At the final cutoff, 22 patients (46.8%) were still on treatment. Reasons for discontinuation of study treatment at the time of analysis were as follows: disease progression (15 patients, 31.9%), adverse events (AEs); (5 patients, 10.6%), and other reasons (5 patients, 10.6%). One patient (2.1%) discontinued pomalidomide treatment early due to an adverse event, and no patients discontinued dexamethasone treatment early. See Table 17B.

[0193] [Table 18]

[0194] demographics The median age was 65 years (range 45 to 85 years), with the greatest proportion of patients <65 years (23 patients, 48.9%). All patients had an ECOG PS of 0 or 1, except for two patients (4.3%) who had an ECOG PS of 2. At baseline, patients weighed between 40 kg and 121 kg, with a median of 90.3 kg.

[0195] Medical history The most common conditions reported in the medical history consisted of the following: peripheral sensory neuropathy (27 patients, 57.4%); hypertension (25 patients, 53.2%); back pain (18 patients, 38.3%); and gastroesophageal reflux disease (15 patients, 31.9%). Relevant respiratory history included asthma in 8 patients (17.0%) and chronic obstructive pulmonary disease in 2 patients (4.3%).

[0196] Disease characteristics at study entry At study entry, 23 (48.9%), 12 (25.5%), and 7 (14.9%) patients had International Staging System (ISS) stage I, II, and III disease, respectively. Five patients (10.6%) had an unknown ISS stage. Most patients (33 patients, 70.2%) had measurable serum M protein at study entry.

[0197] Patients had a median of 22.5% (range 0%-100%) plasma cells in their bone marrow. Most patients (33 patients, 70.2%) had bone lesions at baseline, and 12 (25.5%) patients had plasmacytomas at baseline. Ten patients (21.3%) had high-risk cytogenetic features: cytogenetic abnormalities included del17p in seven patients (14.9%), t(4;14) translocation in three patients (6.4%), and t(14;16) translocation in one patient (2.1%). Seventeen patients (36.2%) had moderate renal impairment (GFR 30 to ≤60 mL / min / 1.73 m). 2 ) entered the study, and one patient had severe renal impairment (GFR 15 to <30 mL / min / 1.73 m 2 ) and entered the exam.

[0198] Previous anti-cancer treatment The median number of prior lines of treatment was 3 (lowest to highest: 1–8), with 1 patient (2.1%) receiving 1 prior line of treatment and 17 patients (36.2%) receiving 2 prior lines of treatment.

[0199] All patients had received an IMiD (including lenalidomide, pomalidomide, or thalidomide), a PI (including bortezomib, carfilzomib, ixazomib, marizomib, or oprozomib), and a corticosteroid (dexamethasone or prednisone) in a previous line of treatment. All patients had received previous lenalidomide. Nineteen patients (40.4%) were refractory to lenalidomide in their last regimen before study entry. Most patients (39 patients, 83.0%) had received a previous alkylating agent (bendamustine, carmustine, cyclophosphamide, melphalan, or melphalan-flufenamide). Twenty-three (48.9%) and 11 (23.4%) patients had received previous pomalidomide and carfilzomib, respectively. Prior to study entry, 7 (14.9%) and 9 (19.1%) patients had received daratumumab (anti-CD38 monoclonal antibody) and elotuzumab (anti-SLAM7 monoclonal antibody), respectively.

[0200] Effectiveness Overall response rate (ORR) The ORR determined in the entire treated population (n=47) was 53.2% (95% confidence interval [CI]: 38.1%-67.9%), including 2 patients (4.3%) with a CR, 11 patients (23.4%) with a VGPR, and 12 patients (25.5%) with a PR. See Table 17C. The "at least VGPR" rate was 27.6%. The clinical benefit rate or "CBR" (MR or better) was 72.3% (95% CI: 57.4%-84.4%), including 9 patients (19.1%) with all of the above plus MR. Response and disease progression were monitored by investigators.

[0201] [Table 19]

[0202] Among the seven patients with prior exposure to daratumumab treatment (see Table 17D), there was one response of PR for an ORR of 14.3%. Additionally, two of the seven patients (28.6%) achieved MR, resulting in a CBR of 42.9%. One patient with prior exposure to daratumumab was not evaluable for response. The ORR for patients without prior daratumumab was 60.0% (24 of 40).

[0203] [Table 20]

[0204] ORR was 52.2% (12 of 23) for patients with prior pomalidomide, 56.5% (13 of 23) for patients with neither prior pomalidomide nor prior daratumumab, 54.5% (18 of 33) for patients with measurable serum M protein, 33.3% (2 of 6) for patients with measurable urine M protein, and 66.7% (4 of 6) for patients with measurable disease by FLC alone.

[0205] Duration of follow-up, time to first response and duration of response (DOR) The median follow-up period was 9.9 months (range: 0-17.3). The median time to first response was 0.95 months (range: 0.9-3.4).

[0206] Duration of response (DOR) was assessed using the Kaplan-Meier method in 25 responders. All responding patients with ongoing responses in DOR analysis were censored at the time of last disease follow-up (N=21). Median and 25th quartile DOR were not reached.

[0207] Progression-free survival (PFS) At the time of analysis, 20 patients (42.6%) were reported to have had a PFS event (i.e., confirmed progressive disease (PD), symptomatic worsening, or death), and 27 patients (57.4%) were censored. Median PFS was not reached; the 6-month PFS probability was 65.0% (95% CI: 49.3%-76.9%), and the 12-month probability was 55.7% (95% CI: 40.1%-68.8%). A Kaplan-Meier plot of PFS is provided in Figure 15.

[0208] Overall survival (OS) At the time of analysis, 12 patients (25.5%) were reported dead. Median OS was not reached. The 6-month survival probability was 84.5% (95% CI: 70.1%-92.3%), and the 12-month survival probability was 70.6% (95% CI: 53.7%-82.3%). A Kaplan-Meier plot of OS is provided in Figure 16.

[0209] safety Degree of exposure Overall, the median number of cycles was 9 (range: 1-19), with 31 (66.0%) patients initiating at least 6 cycles and 18 (38.3%) patients initiating at least 12 cycles. The overall median duration of exposure was 36.9 weeks (range 1-77). See Table 17E.

[0210] [Table 21]

[0211] Infusion durations are summarized in Table 17F. The median duration of the first infusion was 3.70 hours (range 1-6.1 hours); the median duration of the second infusion was 1.85 hours (range 1.5-3.9 hours); and for the third and subsequent infusions, the median duration was 1.25 hours (range 0.8-3.4 hours).

[0212] [Table 22]

[0213] infusion reaction Infusion reactions (IR) are summarized in Table 17G. Overall, IR of any grade was reported in 19 patients (40.4%), with 20 episodes (2.3%) in 871 infusions. All IRs were grade 2, and no patient had an IR of grade ≥ 3. All but one patient who experienced an IR had only a single episode, and all occurred only during the first infusion of isatuximab; one patient (2.1%) had two IR episodes during the first infusion. The onset of all IRs occurred on the same day of isatuximab infusion, and all IRs resolved within the same day.

[0214] IR was managed by interruption of administration and / or use of medications consisting of H1 / H2 blockers, paracetamol, montelukast, and / or steroids. Isatuximab infusion was interrupted in 18 of 19 patients with IR; in the remaining patients with grade 2 IR and grade 3 hypoxia (symptoms of IR), the infusion was not interrupted and hypoxia was managed with supplemental oxygen.

[0215] Among the seven patients with prior exposure to daratumumab treatment, three experienced IR.

[0216] [Table 23-1] [Table 23-2]

[0217] Adverse events occurring during treatment All patients had at least one TEAE (any grade), 35 patients (74.5%) had a grade ≥ 3 TEAE regardless of study treatment, and 27 patients (57.4%) had at least one serious TEAE regardless of study treatment. Six patients (12.8%) experienced a TEAE that led to death during the study. Five patients (10.6%) experienced a TEAE that led to definitive treatment discontinuation (i.e., discontinuation of all study treatment), and one patient (2.1%) experienced a TEAE that led to early discontinuation of pomalidomide.

[0218] The most frequently reported non-hematologic TEAEs of any grade regardless of study treatment (in >20% of patients) were fatigue (30 patients, 63.8%), infusion-related reactions (19 patients, 40.4%), upper respiratory tract infection (19 patients, 40.4%), cough (19 patients, 40.4%), diarrhea (16 patients, 34.0%), nausea (16 patients, 34.0%), dyspnea (16 patients, 34.0%), insomnia (15 patients, 31.9%), back pain (14 patients, 29.8%), constipation (14 patients, 29.8%), arthralgia (13 patients, 27.7%), peripheral sensory neuropathy (10 patients, 21.3%), and pneumonia (10 patients, 21.3%). The most frequently reported grade ≥3 non-hematologic TEAEs (in >5% of patients) were pneumonia (5 patients, 10.6%), arthralgia (3 patients, 6.4%), upper respiratory tract infection (3 patients, 6.4%), and musculoskeletal pain (3 patients, 6.4%).

[0219] Five (10.6%) patients had TEAEs that led to definitive discontinuation of study treatment. In addition to the four patients with fatal events mentioned above (acute myocardial infarction, sepsis, rectal bleeding and sepsis, sudden death), there was one patient with serious grade 3 spinal cord compression that was considered unrelated to study treatment. There was also one patient who electively discontinued pomalidomide (treatment with isatuximab and dexamethasone was continued) due to a non-serious grade 1 event of tremor, gait disturbance, and flushing.

[0220] During the treatment period, 71.7% of patients had grade 3 or 4 neutropenia (37.0% and 34.8%, respectively), 67.4% of patients had grade 3 or 4 leukopenia (55.2% and 15.2%, respectively), and 65.2% of patients had grade 3 or 4 lymphopenia (54.3% and 10.9%, respectively). Grade 3 anemia was reported in 21.7% of patients, and grade 4 anemia was not reported in any of the patients during treatment.

[0221] conclusion Results from the primary safety analysis discussed in Examples 1A and 1B confirmed the safety and feasibility of administering isatuximab from a fixed infusion volume. This Example summarizes key findings from the efficacy analysis at the final cutoff, 10 months after the first dose date of the last enrolled patient.

[0222] A total of 47 patients were enrolled, with 22 patients (46.8%) still receiving study treatment at the cut-off date.

[0223] The median number of cycles administered was 9 (range: 1-19). When infusions were administered at a fixed infusion rate of 200 mL / h, the median infusion duration decreased from 3.70 hours during the first infusion to 1.85 hours during the second infusion and to 1.25 hours for ≥3 infusions. Despite the increased infusion rate and shorter infusion duration from the second infusion onwards, no IR was observed after the first infusion.

[0224] Efficacy was observed in these 47 patients who received isatuximab administered via a fixed infusion in combination with pomalidomide and dexamethasone, with an ORR of 53.2% (95% CI: 38.1%-67.9%), and median progression-free survival (PFS) and overall survival (OS) had not yet been reached at a median follow-up of 9.9 months. The 12-month probability of PFS was 55.7%, and the 12-month probability of OS was 70.6%. Among the seven patients with prior exposure to daratumumab, there was one partial response and two moderate response (MR), with an ORR of 14.3% and a CBR of 42.9%; in the 40 patients without prior exposure to daratumumab, the ORR was 60.0%. Responses were durable, and the median duration of response had not yet been reached. Other ORR subgroup analyses based on prior exposure to pomalidomide and other treatments, as well as the type of measurable M-protein, showed no evidence of a major difference in response rate compared with the overall treated population.

[0225] The efficacy data with fixed-volume infusion were consistent with data from a parallel study comparing isatuximab in combination with pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with refractory or relapsed and refractory multiple myeloma. In the parallel study, isatuximab was administered by infusion at a rate based on the amount of protein per hour (mg / hour). In this study, the ORR in patients without exposure to daratumumab was 60.0% compared with 60.4% in the parallel study. In this study, the 1-year PFS rate was 55.7% compared with 47.6% in the parallel study. In this study, the 1-year OS rate was 70.6% compared with 72% in the parallel study. In this study, the time to first response was 0.95 months compared with 1.94 months in the parallel study. The median duration of response was not reached in this study, compared with 13.27 months in the parallel study.

[0226] Safety findings were consistent with those reported in Examples 1A and 1B, with no grade ≥ 3 IR, no IR after the second infusion, and no new safety signals noted with fixed-dose administration. Safety data were also consistent with the infusion schedule used with IPd in ​​a parallel study. These results confirm the safety, efficacy, and feasibility of isatuximab administered by the fixed-dose infusion method.

[0227] [Example 2] Exposure-Response Analysis and Disease Modeling for Selection of Optimal Dosing Regimen for Single-Agent Isatuximab in Patients with Multiple Myeloma Exposure-response (ER) analysis of tumor burden and disease modeling were performed to assess the relationship between isatuximab exposure and efficacy outcomes and to support dosing regimen selection for isatuximab as a single agent in patients with relapsed / refractory multiple myeloma (RRMM).

[0228] Test Plan One hundred ninety-four patients with RRMM received isatuximab intravenously at doses ranging from 1 mg / kg to 20 mg / kg. Isatuximab was administered as monotherapy at the selected dose, either weekly or every other week. As shown in Table 18, the median age was 63 years, 94.3% of patients had received ≥3 prior lines of treatment, and the median percent bone marrow plasma cells was 27.6.

[0229] [Table 24]

[0230] Pharmacokinetic, best overall response (ORR) and serum M protein data (a subset of 122 patients) were used for the ER analysis and disease modeling described in this example.

[0231] Exposure-response analysis C troughLogistic regression modeling was used to examine the association between several isatuximab exposure parameters, including CR, VGPR, or PR; and percent bone marrow plasma cells, and the probability of achieving an objective response (CR, VGPR, or PR; see Table 14 for response criteria).

[0232] To reduce potential confounding effects, baseline covariates were also considered in the model. trough was defined as the plasma concentration of isatuximab observed immediately prior to treatment administration during repeated dosing.

[0233] Disease progression modeling Disease progression was captured in a subset of 122 evaluable patients with serum M protein kinetics. Dropout was accounted for using a joint model.

[0234] The tumor growth arrest (TGI) model (Claret et al., J Clin Oncol 27 (2009) 25:4103-4108; Jonsson et al., CPT Pharmacometrics Syst Pharmacol 2015 4 (12):711-719) was applied to the longitudinal kinetics of serum M protein in 122 of 194 RRMM patients receiving isatuximab monotherapy at doses ranging from 1 mg / kg to 20 mg / kg administered intravenously once weekly or every other week. Dropout was accounted for using a joint model.

[0235] Clinical trial simulation To evaluate different dosing regimens of interest using both models (ER analysis and disease progression model), we next performed clinical trial simulations based on the above ER analysis and TGI modeling (5000 trial simulations with 100 patients each).

[0236] result Logit Emax model The pharmacokinetic data were best described by a biexponential distribution model with parallel linear and nonlinear (target-specific mediated) clearance.

[0237] The relationship between isatuximab exposure and ORR was measured using logit E max The logit Emax model was best described by the model (AUC of the ROC curve = 0.91) (Figure 4). Table 19 provides the parameter estimates for the logit Emax model.

[0238] [Table 25]

[0239] C after 4 weeks trough The model revealed that (CT4W) and percent bone marrow plasma cells (BMPC) were significant predictors of overall response rate (ORR).

[0240] The ORR increased with increasing CT4W, and a plateau of approximately 33% ORR was reached at CT4W from the third quartile (Figure 5). 90 The CT4W value providing EC was 128.5 μg / mL. 90 Limited additional benefits in ORR are expected at higher CT4W.

[0241] Patients with a BMPC below 50% were more likely to respond (Figure 6). For a given BMPC value, a higher probability of response to treatment was obtained with a higher CT4W.

[0242] M protein model Serum M protein kinetics was well described by the exposure-promoted TGI model (Figure 7) (Claret et al., J Clin Oncol 27(2009)25:4103-4108; Jonsson et al., CPT Pharmacometrics Syst Pharmacol (2015)4(12):711-719). Parameter estimates for the M protein model of disease are provided in Table 20.

[0243] [Table 26]

[0244] As shown in Figure 8, the disease M protein model well described the observed time course of serum M protein levels.

[0245] Clinical trial simulation Five thousand simulated clinical trials of 100 patients each were run. The model assumed that patients received the same dose level in each simulated trial.

[0246] As shown in Figures 9A and 9B, clinical trial simulations revealed that weekly dosing with a higher dose in the first cycle (loading dose period) allows for optimization of response because effective concentrations are reached more quickly.

[0247] The probability of success in reaching a 30% ORR for several dosing regimens is provided in Table 21. Figure 9A provides the overall response rates simulated for several dosing regimens, including the 20 mg / kg QWX4Q2W dosing regimen.

[0248] [Table 27]

[0249] The median percent change in M ​​protein levels after 2 months compared to baseline is provided for several dosing regimens in Table 22. QWX4Q2W led to a 52% reduction in serum M protein from baseline levels after 2 months of treatment (Figure 9B).

[0250] [Table 28]

[0251] Furthermore, the QWX4Q2W isatuximab dosing regimen appears to be well tolerated.

[0252] conclusion This example demonstrates that a model-based drug development approach was successfully applied to support the selection of a phase II isatuximab monotherapy dosing regimen in patients with RRMM. This approach showed that a weekly loading dose of 20 mg / kg isatuximab for only four weekly doses, followed by dosing every two weeks, appeared to be sufficient to maximize tumor response and sustain monotherapy efficacy while remaining well tolerated.

[0253] The recommended dose of 20 mg / kg QW / Q2W applies to monotherapy.

[0254] [Example 3] A phase 1 / 2 study of isatuximab monotherapy for relapsed and / or refractory multiple myeloma in Japanese patients. This example describes a phase 1 / 2 study of isatuximab monotherapy for relapsed and / or refractory multiple myeloma (RRMM) in Japanese patients.

[0255] Test Purpose Phase 1: To evaluate the safety and tolerability of isatuximab, and dose-limiting toxicities (DLTs) in Japanese patients with RRMM.

[0256] Phase 2: To evaluate the efficacy of isatuximab at the recommended dose in Japanese patients with RRMM and determine its overall response rate (ORR; ≥ partial response [PR]).

[0257] Study population Patients who met the following criteria were enrolled in the study: Patients ≥ 20 years of age with a diagnosis of symptomatic multiple myeloma, who have had at least three prior lines of therapy or are refractory to both an IMiD® and a proteasome inhibitor (PI), with better than a minimal response to at least one line, who are refractory to most recent therapy, and who have measurable disease. RRMM was diagnosed according to the International Myeloma Working Group criteria (Palumbo A et al., J Clin Oncol 2014;32:587-600) and staged according to the International Staging System (Greipp PR et al., J Clin Oncol 2005;23:3112-20).

[0258] Key exclusion criteria were: previous treatment with an anti-CD38 agent; diagnosis of another malignancy within 5 years of enrollment; previous anticancer therapy within 21 days of the first drug infusion; total body radiation therapy within 4 weeks or local radiation therapy within 1 week before the first drug infusion; abnormal laboratory values; ongoing toxicity of grade ≥ 2; previous allogeneic stem cell transplant; or a diagnosis of Crow-Fukase syndrome, plasma cell leukemia, Waldenström macroglobulinemia, or multiple myeloma of the IgM subtype.

[0259] Test Plan This study was an open-label, non-randomized, single-arm, two-phase, multicenter trial conducted in Japan. The trial included a dose-escalation phase (Phase 1) to determine the maximum tolerated dose based on dose-limiting toxicity (DLT), followed by a confirmatory phase (Phase 2) in which patients at the maximum tolerated dose determined in Phase 1 were enrolled.

[0260] Phase 1 The maximum tolerated dose (MTD) of isatuximab monotherapy was determined in two cohorts of patients in a 3+3 design: Cohort 1: Isatuximab was administered at 10 mg / kg weekly (QW) in 28-day cycles for the first cycle (i.e., 4 weeks) and every other week (Q2W) for subsequent 4-week cycles. Cohort 2: Isatuximab was administered in 28-day cycles at 20 mg / kg QW in cycle 1 and Q2W in subsequent cycles; enrollment began in Cohort 1 after completion of the DLT observation period.

[0261] The dosing regimens used in phase 1 were selected as half the highest dose (cohort 1) and half the highest dose (cohort 2) used in the trial Martin TG et al., J Clin Oncol 2014;32:Abstract 8532.

[0262] Phase 2 Patients received the MTD established in Phase 1. Enrollment began in Cohort 2 after completion of the DLT observation period. Phase 2 patients included those enrolled in the Phase 1 cohort who were treated at the recommended dose.

[0263] Study endpoints Primary endpoint The primary endpoints of this study were to evaluate the safety and tolerability of isatuximab in phase 1, including DLTs, and the efficacy of isatuximab at the recommended dose, including an investigation of ORR.

[0264] Secondary endpoints Secondary endpoints included: · Safety and immunogenicity (anti-drug antibodies [ADA]) of isatuximab. · Pharmacokinetics of isatuximab. Efficacy determined using IMWG uniform response criteria, ORR, clinical benefit rate (CBR), overall survival (OS), and progression-free survival (PFS). · Best response with paraproteins. Baseline CD38 receptor density (RD) on multiple myeloma cells.

[0265] Survey purpose The research objectives included: Minimal residual disease (MRD) investigated in patients who achieved a complete response (CR) and its association with clinical outcome.

[0266] statistical analysis ORR was investigated in all patients who received at least one dose of isatuximab at the recommended dose in phase 1 or phase 2. The null hypothesis that the true response rate was <10% was tested using a one-sided exact binomial test with a significance level of 0.025, assuming a true ORR of 28%.

[0267] result Patient demographics and baseline characteristics As shown in Figure 10, 8 patients were enrolled in Phase 1 and 28 patients were enrolled in Phase 2. All patients had received at least two prior therapies, including an IMiD® and a PI, and the majority were refractory to an IMiD® and / or a PI (Table 23).

[0268] [Table 29-1] [Table 29-2] [Table 29-3]

[0269] The number of cycles ranged from 1 to 24, the exposure duration ranged from 2 to 96 weeks, and the cumulative dose ranged from 40.0 to 859.3 mg / kg (Table 24).

[0270] [Table 30]

[0271] Five patients in phase 1 and nine patients in phase 2 were still on treatment at the cut-off date.

[0272] safety Dose-limiting toxicity (DLT) One patient was excluded from the DLT evaluation population due to adverse events (both AEs were unrelated to isatuximab).

[0273] No DLTs occurred in any cohort in Phase 1. Therefore, the starting dose for Phase 2 was set at 20 mg / kg QW / Q2W.

[0274] Adverse events Treatment-emergent AEs (TEAEs) in both phases are summarized by dose and grade in Table 25. The only serious drug-related TEAE was grade ≥3 pneumonia, which occurred in one patient treated with 10 mg / kg QW / Q2W in phase 1 and in two patients in phase 2.

[0275] Infusion-related reactions occurred in three phase 1 patients (two events in two patients at 10 mg / kg and two events in one patient at 20 mg / kg) and 12 patients in phase 2 (13 events). All infusion-related reactions were grade ≤2. When a reaction occurred, it occurred during the first infusion in all patients in phase 1 and in 11 patients in phase 2. One patient in phase 2 experienced a reaction during the first and third infusions. All infusion-related reactions resolved within 1 day, except for two patients who had reactions that persisted for 2 days. No patients discontinued treatment due to an infusion reaction.

[0276] Clinically significant TEAEs occurring in all 36 patients combined in Phases 1 and 2 were respiratory infections in 19 patients, lower respiratory tract TEAEs in 8 patients, and neutropenia in 13 patients.

[0277] [Table 31]

[0278] immunogenicity Antidrug antibodies (ADA) were measured in all 36 patients. At the cutoff date, all patients in phase 1 were ADA-negative. In phase 2, four patients showed evidence of treatment-induced immunogenicity, with transient ADA in one patient (first cycle only) and treatment-enhanced ADA in three patients. There was no relationship between tracheosatuximab concentration and immunogenicity.

[0279] Pharmacokinetics The duration of infusion during cycle 1 was longer in patients receiving isatuximab at 20 mg / kg QW / Q2W (Table 26; infusion rates measured in mg / hour).

[0280] [Table 32]

[0281] As shown in Figure 11, a two-fold increase in dose (from 10 mg / kg to 20 mg / kg) increased isatuximab exposure by 2.3-fold.

[0282] Effectiveness As shown in Table 27A, ORR was investigated in 33 patients who received isatuximab at 20 mg / kg QW / Q2W in phase 1 cohort 2 or phase 2. The ORR (≥PR) was 36.4% (95% CI: 20.4%, 54.9%; 12 of 33 patients), significantly exceeding the null hypothesis of a rate of <10% based on a one-sided exact binomial test with a significance level of 0.025 (P<0.0001). The CBR (≥MBR) was 54.5% (95% CI: 36.4%, 71.9%; 18 of 33 patients). Among all enrolled patients, CR was achieved in 2 patients, VGPR in 5 patients, and PR in 5 patients. There did not appear to be any difference in response rates according to the number of previous lines or cytogenetic risk. Among the eight patients with cytogenetic abnormalities, responses were ≥PR in three patients and VGPR in two patients. All three patients with ≥PR had the t(4,14) cytogenetic abnormality. In other subgroups of patients, response rates tended to be higher in patients with low ECOG, low ISS grade, baseline creatinine clearance of ≥60 mL / min / 1.73 m2, and absence of plasmacytoma at screening.

[0283] [Table 33]

[0284] Patients were followed for 4.1 to 90.1 weeks from the start of isatuximab therapy (Table 27B), with median follow-up of 84.6 and 52.0 weeks in the 10 and 20 mg / kg QW / Q2W arms in phase 1 and 19.2 weeks in phase 2. Median duration of response in the three arms was 82.6, 48.1, and 241 weeks, respectively.

[0285] [Table 34]

[0286] Figure 12 shows best response to treatment as a function of time in Phase 2. The median time to first response was similar in all three groups (4.9, 5.4, and 4.3 weeks, respectively).

[0287] Figure 13A provides a Kaplan-Meier plot of progression-free survival for 28 patients in phase 2 of this study. As shown in Table 28, the median PFS was approximately 4.7 months (95% CI: 3.75 to not reached).

[0288] [Table 35]

[0289] Figure 13B provides a Kaplan-Meier plot of overall survival for patients in phase 2 of this study. As shown in Table 29, median OS was not reached. The 6-month and 1-year OS probabilities were 1.000 and 0.781, respectively. There were two deaths in phase 2. Both patients died in the post-treatment period, and the cause of death was not related to AEs from study treatment. One of these patients received no subsequent therapy, and the other was treated with carfilzomib and dexamethasone after isatuximab discontinuation.

[0290] [Table 36]

[0291] Best response with paraproteins Approximately half of all patients had a ≥50% reduction in paraprotein, with ≥90% reduction in four patients in phase 1 (one at 10 mg / kg QW / Q2W and three at 20 mg / kg QW / Q2W) and six patients in phase 2. There was no clear correlation between best percent change in paraprotein and overall response.

[0292] Minimum residual disease (MRD) MRD was investigated in three patients. Of the two patients who achieved CR, one patient in the 20 mg / kg group in Phase 1 was MRD-negative, and one patient in Phase 2 was MRD-positive (10 -5 In the 10 mg / kg group in phase 1, 10 patients had VGPR. -5 The patient was MRD positive.

[0293] Biomarkers CD38 RD data were available for 32 patients. CD38 receptor density (×10 3 The CD38RD (per cell) was calculated in (sMEC)-specific molecular equivalents per cell using the conversion formula: sMEC = MEC (selected antibody) - MEC (negative isotype control), where MEC (molecular equivalents per cell) = 10^(log[MFI] × a + b), where a and b are the slope and y-intercept of the calibration curve equation, respectively. CD38RD was slightly higher in responders than in non-responders, with a median (range) of 122,313 5 (71,808-232,958) among 14 responders and 72,731 0 (26,921-394,910) among 18 non-responders. See Figure 14 (CR = complete response; VGPR = very good partial response; PR = partial response; MR = minimal response; SD = stable disease; PD / UNCPD = progressive disease / undetermined progressive disease; NE = not evaluable). When patients were divided by CD38 RD threshold, ORR tended to be higher in patients with RD above the threshold, but some patients with lower RD values ​​showed a response to isatuximab.

[0294] Pharmacokinetics of isatuximab The pharmacokinetic properties of isatuximab from Cycle 1 of Phase 1 are shown in Table 30. Overall variability in exposure parameters was low to moderate, with coefficients of variability ranging from 18% to 32%. With a two-fold dose increase (from 10 to 20 mg / kg), isatuximab exposure increased 2.3-fold (based on geometric mean ratios).

[0295] [Table 37]

[0296] conclusion This study confirmed that 20 mg / kg QW / Q2W is an appropriate dosing regimen for isatuximab monotherapy for Japanese patients with RRMM, consistent with previous phase 1 / 2 monotherapy studies conducted in other countries (Martin TG et al., (2014) J Clin Oncol 32: Abstract 8532; Martin T et al., (2017) Blood 129: 3294-303). Isatuximab was generally well tolerated and demonstrated good efficacy.

[0297] This study indicates that isatuximab monotherapy may be a treatment option for multiple myeloma patients who have received at least three prior lines of therapy, including a PI and an IMiD®, or who are dually refractory to a PI and an IMiD®. It demonstrated a favorable safety profile and was well tolerated, even among patients treated with large doses, and thus may be suitable for elderly and frail patients. Responses were observed in patients with high-risk cytogenetics and in patients who had received more than six prior lines, including those refractory to both a PI and an IMiD®. Heavily pretreated patients frequently exhibit worsening renal and bone marrow function due to their primary disease, and continuing treatment in such patients for safety reasons is often difficult. These findings are clinically important and suggest the potential use of isatuximab in these patients for whom few alternatives are available.

[0298] Each embodiment described herein may be combined with any other one or more embodiments unless expressly indicated to the contrary. In particular, any configuration or embodiment indicated as being preferred or advantageous may be combined with any other configuration or embodiments indicated as being preferred or advantageous, unless expressly indicated to the contrary.

[0299] All references cited in this application are expressly incorporated herein by reference.

Claims

1. 1. Use of an anti-CD38 antibody in the manufacture of a medicament for treating an individual in need thereof, wherein the medicament is formulated for administration by at least a first intravenous infusion and a second intravenous infusion of the medicament, the medicament being formulated to provide the anti-CD38 antibody at a dose of at least 10 mg / kg, the medicament being formulated in a volume of 250 mL; The first intravenous infusion of the agent is (a) administered at an infusion rate of 25 mL / hour for the first hour, with the infusion rate increased by 25 mL / hour every 30 minutes after the first hour until a volume of 250 mL has been infused, up to a maximum infusion rate of 150 mL / hour; or (b) formulated to be administered at an infusion rate of 12.5 mL / hour for the first 30 minutes, with the infusion rate increasing by 25 mL / hour every 30 minutes thereafter until a volume of 250 mL has been infused; The second intravenous infusion of the drug (i) administered at an infusion rate of 50 mL / hour for the first 30 minutes, the infusion rate being increased by 50 mL / hour for the second 30 minutes, the infusion rate being increased by 100 mL / hour every 30 minutes after the second 30 minutes until a volume of 250 mL has been infused, up to a maximum infusion rate of 200 mL / hour; or (ii) administered at an infusion rate of 50 mL / hour for the first 30 minutes, 100 mL / hour for the second 30 minutes, 200 mL / hour for the third 30 minutes, and 300 mL / hour after the third 30 minutes until a volume of 250 mL has been infused; or (iii) formulated to be administered at an infusion rate of 25 mL / hour for the first 30 minutes, with the infusion rate increasing by 50 mL / hour every 30 minutes thereafter until a volume of 250 mL has been infused; and The above-mentioned use, wherein the anti-CD38 antibody is isatuximab.

2. 2. The use of claim 1, wherein the agent is formulated for administration by at least a third intravenous infusion of an anti-CD38 antibody, the agent is formulated to provide the anti-CD38 antibody at a dose of at least 10 mg / kg, and the agent is formulated in a volume of 250 mL.

3. A third intravenous infusion of the agent is formulated to be administered at an infusion rate of 200 mL / hour until a volume of 250 mL has been infused; or A third intravenous infusion of the agent is formulated to be administered at an infusion rate of 100 mL / hour for the first 30 minutes, with the infusion rate increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 mL has been infused.

3. The use according to claim 2.

4. 4. The use of claim 2 or 3, wherein the medicament is formulated for administration by a fourth intravenous infusion of anti-CD38 antibody, the medicament is formulated to provide the anti-CD38 antibody at a dose of at least 10 mg / kg, and the medicament is formulated in a volume of 250 mL.

5. said fourth intravenous infusion of agent is formulated to be administered at an infusion rate of 200 mL / hour until a volume of 250 mL has been infused; or the fourth intravenous infusion of agent is formulated to be administered at an infusion rate of 100 mL / hour for the first 30 minutes, with the infusion rate being increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 mL has been infused; 5. The use according to claim 4.

6. 6. The use of claim 4 or 5, wherein the agent is formulated for administration in a first 28-day cycle, wherein a first intravenous infusion of the agent is formulated for administration on day 1, a second intravenous infusion of the agent is formulated for administration on day 8, the third intravenous infusion of the agent is formulated for administration on day 15, and the fourth intravenous infusion of the agent is formulated for administration on day 22 of the first 28-day cycle.

7. the agent is formulated for administration by one or more subsequent intravenous infusions after the fourth intravenous infusion; the medicament is formulated to provide an anti-CD38 antibody at a dose of at least 10 mg / kg; and The agent is formulated in a volume of 250 mL for each of the one or more subsequent intravenous infusions. Use according to any one of claims 4 to 6.

8. each of the one or more subsequent intravenous infusions of the agent after the fourth intravenous infusion is formulated to be administered at an infusion rate of 200 mL / hour until a volume of 250 mL has been infused; or each of the one or more subsequent intravenous infusions of agent after the fourth intravenous infusion is formulated to be administered at an infusion rate of 100 mL / hour for the first 30 minutes, with the infusion rate being increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 mL has been infused; 8. The use according to claim 7.

9. the agent is formulated for administration in one or more subsequent 28-day cycles after the first 28-day cycle; wherein each of the one or more subsequent intravenous infusions of the agent after the fourth intravenous infusion is formulated for administration on days 1 and 15 of one or more subsequent 28-day cycles after the first 28-day cycle; Use according to claim 7 or 8.

10. 1. Use of an anti-CD38 antibody in the manufacture of a medicament for treating an individual in need thereof, comprising: the agent is formulated for administration by at least three intravenous infusions; the medicament is formulated to provide the anti-CD38 antibody at a dose of at least 10 mg / kg; The drug is formulated in a volume of 250 mL, the anti-CD38 antibody is isatuximab; a first intravenous infusion of the agent formulated to be administered at an infusion rate of 25 mL / hour for the first hour, with the infusion rate being increased by 25 mL / hour every 30 minutes after the first hour until a volume of 250 mL has been infused, up to a maximum infusion rate of 150 mL / hour; a second intravenous infusion of the agent formulated to be administered at an infusion rate of 50 mL / hour for the first 30 minutes, the infusion rate being increased by 50 mL / hour for the second 30 minutes, the infusion rate being increased by 100 mL / hour every 30 minutes after the second 30 minutes until a volume of 250 mL has been infused, up to a maximum infusion rate of 200 mL / hour; and A third intravenous infusion of the agent is formulated to be administered at an infusion rate of 100 mL / hour for the first 30 minutes, with the infusion rate being increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 mL has been infused. The above use.

11. the agent is formulated for administration by one or more subsequent intravenous infusions after the third intravenous infusion; the medicament is formulated to provide an anti-CD38 antibody at a dose of at least 10 mg / kg in each of the one or more subsequent intravenous infusions; the agent is formulated in a volume of 250 mL for each of the one or more subsequent intravenous infusions; and the agent is formulated to be administered at an infusion rate of 200 mL / hour to a volume of 250 mL in each of the one or more subsequent intravenous infusions; The use according to claim 10.

12. 1. Use of an anti-CD38 antibody in the manufacture of a medicament formulated for safe administration by intravenous infusion to a human individual in need thereof, comprising: the medicament is formulated to provide the anti-CD38 antibody at a dose of at least 10 mg / kg; The drug is formulated in a volume of 250 mL, the agent is formulated for administration in at least a first dose and a second dose; the first dose of the agent is formulated for administration over a period of 1.5 to 6.5 hours; the second dose of the agent is formulated to be administered over a period of 0.5 to 3.5 hours; and The anti-CD38 antibody is isatuximab. The above use.

13. the agent is formulated to provide an anti-CD38 antibody at a dose of at least 10 mg / kg in a volume of 250 mL; the medicament is formulated for administration of at least a third dose, and the third dose of the agent is formulated to be administered over a period of 0.5 to 1.5 hours; 13. The use according to claim 12.

14. The individual is: (a) not experiencing an infusion reaction (IR) after administration of the drug; (b) does not experience an IR of greater than Grade 1 severity after administration of the drug, or (c) not experiencing IR of greater than grade 2 severity after administration of the drug; Use according to any one of claims 1 to 13.

15. The use according to any one of claims 1 to 14, wherein the medicament further comprises 0.9% sodium chloride or 5% glucose.

16. 16. The use of any one of claims 1 to 15, wherein the individual is not previously pre-medicated with one or more of analgesics, antacids, anti-inflammatory agents, and / or antihistamines for the purpose of preventing or minimizing infusion reactions prior to administration of the medicament.

17. The use of any one of claims 1 to 16, wherein the medicament is formulated to provide anti-CD38 antibody at a dose of 10 mg / kg or 20 mg / kg in a volume of up to 250 mL.

18. The use according to any one of claims 1 to 17, wherein the medicament is used in the treatment of multiple myeloma.

19. 19. The use according to any one of claims 1 to 18, wherein the individual has at least one high-risk cytogenetic abnormality or at least two high-risk cytogenetic abnormalities selected from the group consisting of 17p deletion, 4(4;14) translocation and t(14;16) translocation.

20. 20. The use according to claim 18 or 19, wherein the multiple myeloma is relapsed / refractory multiple myeloma.

21. 21. The use of claim 20, wherein the individual was refractory to the most recent prior therapy for multiple myeloma.

22. 22. The use of claim 20 or 21, wherein the individual is refractory to lenalidomide.

23. The use of any one of claims 20 to 22, wherein the most recent previous therapy was lenalidomide.

24. The use according to any one of claims 20 to 23, wherein the individual is refractory to proteasome inhibitors.

25. The use according to any one of claims 20 to 22 and 24, wherein the most recent previous therapy was a proteasome inhibitor.

26. 26. The use according to claim 24 or 25, wherein the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, marizomib, oprozomib and ixazomib.

27. The use according to any one of claims 22 to 26, wherein lenalidomide and a proteasome inhibitor are administered in combination.

28. The use according to any one of claims 1 to 27, wherein the individual has a respiratory disorder, a thoracic disorder, and / or a mediastinal disorder.

29. 29. The use of claim 28, wherein the respiratory disorder is chronic obstructive pulmonary disorder (COPD), asthma, or bronchospasm.

30. The use of any one of claims 20 to 29, wherein the individual has undergone at least two prior therapies for multiple myeloma, or at least three prior therapies for multiple myeloma.

31. The use of any one of claims 1 to 30, wherein the medicament is formulated for administration in combination with at least one additional medicament.

32. 32. The use of claim 31 , wherein the at least one additional agent comprises an immunomodulatory agent, a proteasome inhibitor, and / or a corticosteroid.

33. 33. The use of claim 32, wherein the immunomodulatory agent is lenalidomide or pomalidomide.

34. 33. The use of claim 32, wherein the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, marizomib, oprozomib, and ixazomib.

35. 33. The use of claim 32, wherein the corticosteroid is dexamethasone.

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