Methods of administering anti-CD38 antibodies to treat multiple myeloma

Abstract

The present invention relates to a method of administering an anti-CD38 antibody to treat multiple myeloma comprising administering to the individual 10 mg / kg of Isatuximab by intravenous infusion wherein the volume of 10 mg / kg of Isatuximab per infusion is 250 ml. Also provided herein are methods of treating a human individual suffering from multiple myeloma, the methods comprising administering an anti-CD38 antibody over a 28-day cycle wherein the anti-CD38 antibody is administered on day 1, day 8, day 15, and day 22 of a first 28-day cycle wherein the CD38 antibody is administered on day 1 and day 15 of each 28-day cycle following the first 28-day cycle; and wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg or 20 mg / kg.

Description

[0001] This application is a divisional application based on the invention patent application with application date of May 13, 2020, application number 202080049892.8 (international application number PCT / US2020 / 032754) and name “Method of administering anti-CD38 antibodies to treat multiple myeloma”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the priority benefit of the following patent applications: European Patent Application No. EP20305223.8, filed on March 3, 2020; U.S. Provisional Application No. 62 / 899,088, filed on September 11, 2019; U.S. Provisional Application No. 62 / 860,739, filed on June 12, 2019; and U.S. Provisional Application No. 62 / 847,825, filed on May 14, 2019, the contents of each of which are incorporated herein by reference in their entirety.

[0004] Submission of Sequence Listings as ASCII Text Files

[0005] The contents of the following submitted ASCII text file are incorporated herein by reference in their entirety: Computer Readable Form (CRF) of the Sequence Listing (File Name: 183952031742SEQLIST.TXT, Record Date: May 12, 2020, Size: 11 KB). Technical Field

[0006] The present disclosure relates to methods of treating multiple myeloma by administering anti-CD38 antibodies. Background Art

[0007] Therapeutic antibodies have improved the options for treating patients with relapsed and / or refractory multiple myeloma (RRMM). However, therapeutic antibodies are typically administered by intravenous infusion, and infusion reactions (IR) are a frequently reported side effect. Symptoms of IR (e.g., rash, hives, flushing, changes in heart rate and / or blood pressure, fever, dyspnea, and / or nausea) require timely management to avoid serious adverse events including death. Strategies for alleviating the risk of IR (or causing mild IR to subside) include slowing the infusion rate, temporarily interrupting the infusion, and / or splitting the infusion dose over two or more consecutive days. However, long and / or frequent intravenous infusions may be expensive, burdensome, and inconvenient for patients, resulting in reduced compliance with the treatment regimen. In addition, long and / or frequent IV infusions require extended hospital stays and longer observation times, thereby increasing the workload of hospital staff. There is a need in the art for a safe and effective method of administering therapeutic antibodies for the treatment of RRMM that is more convenient for patients, physicians, and other medical staff. Summary of the Invention

[0008] 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-H3 comprising the amino acid sequence 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 treating a disease or disorder, optionally wherein the disease or disorder is multiple myeloma. In some embodiments, a method of administering an anti-CD38 antibody to a human individual in need thereof is provided, 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-H3 comprising the amino acid sequence In some embodiments, the anti-CD38 antibody is administered to treat multiple myeloma. In some embodiments, the anti-CD38 antibody is isatuximab.

[0009] In some embodiments, the first intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL / hour within the first hour, and wherein the infusion rate is increased by 25 mL / hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL / hour until a volume of 250 ml is infused. In some embodiments, the first infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 12.5 mL / hour within the first 30 minutes, and wherein the infusion rate is increased by 25 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 ml is infused. In some embodiments, the method comprises administering to the individual at least a second intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml. In some embodiments, the second intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 50 mL / hour for the first 30 minutes, wherein the infusion rate is increased by 50 ml / hr for the second 30 minutes, and wherein the infusion rate is increased by 100 mL / hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL / hour until a volume of 250 ml is infused. In some embodiments, the 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 is infused. In some embodiments, the second intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 25 mL / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 ml is infused. In some embodiments, the method comprises administering to the individual at least a third intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml. In some embodiments, the third intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 200 ml / hour until a volume of 250 ml is infused. In some embodiments, the third intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 ml is infused. In some embodiments, the method comprises administering to the individual a fourth intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml.In some embodiments, the fourth intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 200 ml / hour until a volume of 250 ml is infused. In some embodiments, the fourth intravenous infusion of the anti-CD38 antibody is administered to the individual over the first 30 minutes at an infusion rate of 100 ml / hour, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 ml is infused. In some embodiments, the anti-CD38 antibody is administered over the first 28-day cycle, wherein the first intravenous infusion of the anti-CD38 antibody is administered on day 1 of the first 28-day cycle, the second intravenous infusion of the anti-CD38 antibody is administered on day 8, the third intravenous infusion of the anti-CD38 antibody is administered on day 15, and the fourth intravenous infusion of the anti-CD38 antibody is administered on day 22.

[0010] In some embodiments, the method comprises administering to the individual one or more subsequent intravenous infusions of the anti-CD38 antibody after the fourth intravenous infusion, wherein for each of the one or more subsequent intravenous infusions, the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml. In some embodiments, each of the one or more subsequent intravenous infusions of the 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 is infused. In some embodiments, each of the one or more subsequent intravenous infusions of the 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, and wherein after the first 30 minutes, the infusion rate is increased by 50 mL / hour every 30 minutes until a volume of 250 ml is infused. In some embodiments, the anti-CD38 antibody is administered 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 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.

[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 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 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-H3 comprising the amino acid sequence wherein a first intravenous infusion of the anti-CD38 antibody is administered to the subject at an infusion rate of 25 mL / hour over the first hour, and wherein after the first hour, the infusion rate is increased by 25 mL / hour every 30 minutes to a maximum infusion rate of 150 mL / hour until a volume of 250 ml is infused; wherein a second intravenous infusion of the anti-CD38 antibody is administered to the subject at an infusion rate of 50 mL / hour over the first 30 minutes, and wherein the infusion rate is increased by 5 mL / hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL / hour until a volume of 250 ml is infused. 0 ml / hr for a second 30 minutes, and wherein the infusion rate is increased by 100 mL / hr every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL / hr until a volume of 250 ml is infused; and wherein the third intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 100 ml / hr over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hr every 30 minutes after the first 30 minutes until a volume of 250 ml is infused.

[0012] In some embodiments, a method of administering an anti-CD38 antibody to a human individual in need thereof is provided, 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 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-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 6). wherein a first intravenous infusion of the anti-CD38 antibody is administered to the subject at an infusion rate of 25 mL / hour over the first hour, and wherein after the first hour, the infusion rate is increased by 25 mL / hour every 30 minutes to a maximum infusion rate of 150 mL / hour until a volume of 250 ml is infused; wherein a second intravenous infusion of the anti-CD38 antibody is administered to the subject at an infusion rate of 50 mL / hour over the first 30 minutes, and wherein the infusion rate is increased by 5 mL / hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL / hour until a volume of 250 ml is infused. 0 ml / hr for a second 30 minutes, and wherein the infusion rate is increased by 100 mL / hr every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL / hr until a volume of 250 ml is infused; and wherein the third intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 100 ml / hr over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hr every 30 minutes after the first 30 minutes until a volume of 250 ml is infused.

[0013] In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the anti-CD38 antibody is used to treat a disease or disorder, optionally wherein the disease or disorder is multiple myeloma. In some embodiments, the administration of the anti-CD38 antibody is used to treat multiple myeloma. In some embodiments, the method further comprises administering to the individual one or more subsequent intravenous infusions of the anti-CD38 antibody after the third intravenous infusion, wherein for each of the one or more subsequent intravenous infusions, the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml. In some embodiments, each of the one or more subsequent intravenous infusions of the 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 is infused.

[0014] 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 by intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg, wherein the volume of each dose of the anti-CD38 antibody is 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) 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-H3 comprising the amino acid sequence 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 treating a disease or disorder, optionally wherein 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, the method comprising administering the anti-CD38 antibody to the individual by intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg, wherein the volume of each dose of the anti-CD38 antibody is 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) 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-H3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments, the anti-CD38 antibody is administered to treat multiple myeloma. In some embodiments, the anti-CD38 antibody is isatuximab.

[0015] In some embodiments, the anti-CD38 antibody is administered in a first 28-day cycle, and the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered to the individual by intravenous infusion on day 1 of the first 28-day cycle at an infusion rate of 25 mL / hour over the first hour, and the infusion rate is increased by 25 mL / hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL / hour until a 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual by intravenous infusion on day 1 of the first 28-day cycle at an infusion rate of 12.5 mL / hour over the first 30 minutes, and the infusion rate is increased by 25 mL / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual by intravenous infusion on day 8 of the first 28-day cycle at an infusion rate of 50 mL / hour for the first 30 minutes, wherein the infusion rate is increased by 50 ml / hr for the next 30 minutes, and wherein the infusion rate is increased by 100 mL / hour every 30 minutes after the first 60 minutes to a maximum infusion rate of 200 mL / hour until a volume of 250 ml is infused. In some embodiments, the anti-CD38 antibody is administered to the individual by intravenous infusion on day 8 of the 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 dose of 250 ml of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual on day 8 of the first 28-day cycle by intravenous infusion at an infusion rate of 25 mL / hour over the first 30 minutes, and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual on day 15 of the first 28-day cycle by intravenous infusion at an infusion rate of 200 ml / hour over the first 30 minutes, and the anti-CD38 antibody is administered to the individual on day 15 of the first 28-day cycle by intravenous infusion at an infusion rate of 100 ml / hour over the first 30 minutes, and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes, until a 250 ml dose of the anti-CD38 antibody is infused.In some embodiments, the anti-CD38 antibody is administered to the individual by intravenous infusion on day 22 of the first 28-day cycle at an infusion rate of 200 ml / hour until a 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual by intravenous infusion on day 22 of the first 28-day cycle at an infusion rate of 100 ml / hour over the first 30 minutes, and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody is infused.

[0016] In some embodiments, the anti-CD38 antibody is further administered in one or more subsequent 28-day cycles, and the anti-CD38 antibody is administered at a dose of at least 10 mg / kg on day 1 and day 15 of each subsequent 28-day cycle, and the volume of each dose of the anti-CD38 antibody administered in one or more subsequent cycles is 250 ml. In some embodiments, the anti-CD38 antibody is administered to the individual by intravenous infusion at an infusion rate of 200 ml / hour on day 1 of each subsequent 28-day cycle until a 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual by intravenous infusion at an infusion rate of 100 ml / hour over the first 30 minutes on day 1 of each subsequent 28-day cycle, and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody is infused. In some embodiments, the anti-CD38 antibody is administered to the individual by 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 is infused. In some embodiments, the anti-CD38 antibody is administered to the individual by intravenous infusion on day 15 of each subsequent 28-day cycle at an infusion rate of 100 ml / hour over the first 30 minutes, and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody is infused.

[0017] In some embodiments, an anti-CD38 antibody is provided for use in a method of treating an individual in need thereof, the method comprising safely administering to the individual at least a first dose of the anti-CD38 antibody by intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml, wherein the first dose is infused over a duration of about 1.5 hours and about 6.5 hours, 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-H3 comprising the amino acid sequence 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 treating a disease or disorder, optionally wherein the disease or disorder is multiple myeloma. In some embodiments, a method of safely administering an anti-CD38 antibody to a human individual in need thereof is provided, the method comprising administering to the individual at least a first dose of the anti-CD38 antibody by intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml, wherein the first dose is infused over a duration of about 1.5 hours and about 6.5 hours, 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-H3 comprising the amino acid sequence In some embodiments, the anti-CD38 antibody is administered to treat multiple myeloma. In some embodiments, the anti-CD38 antibody is isatuximab.

[0018] In some embodiments, at least a second dose of the anti-CD38 antibody is administered to the individual by intravenous infusion, wherein the anti-CD38 antibody is administered at a dosage of at least 10 mg / kg in a volume of 250 ml, wherein the second dose is infused over a duration of about 0.5 hours and about 3.5 hours. In some embodiments, at least a third dose of the anti-CD38 antibody is administered to the individual by intravenous infusion, wherein the anti-CD38 antibody is administered at a dosage of at least 10 mg / kg in a volume of 250 ml, wherein the third dose is infused over a duration of about 0.5 hours and about 1.5 hours. In some embodiments, each dose of at least 10 mg / kg of the anti-CD38 antibody in a volume of 250 ml after the third dose is infused over a duration of about 0.5 hours and about 1.5 hours. In some embodiments of any method herein, the dosage of anti-CD38 antibody (e.g., isatuximab) is 10 mg / kg or 20 mg / kg.

[0019] In some embodiments, the administration of the anti-CD38 antibody does not result in the individual experiencing an infusion reaction (IR). In some embodiments, the administration of the anti-CD38 antibody does not result in the individual experiencing an IR of severity greater than Grade 1. In some embodiments, the administration of the anti-CD38 antibody does not result in the individual experiencing an IR of severity of Grade 2 or higher. In some embodiments, the individual has not previously received premedication with one or more of the following for the purpose of preventing or minimizing infusion reactions prior to administration of the anti-CD38 antibody by intravenous infusion: analgesics, antacids, anti-inflammatory agents, antihistamines.

[0020] In some embodiments, an intravenous (IV) bag is provided, which contains an anti-CD38 antibody (e.g., isatuximab) of a 10mg / kg dose of 250ml. In some embodiments, the 10mg / kg dose of an anti-CD38 antibody (e.g., isatuximab) is calculated based on the body weight of the patient to whom the anti-CD38 antibody is administered. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is diluted to 0.9% sodium chloride, 5% glucose, or 5% dextrose from a concentrated formulation (e.g., formulation described herein). In some embodiments, the bag contains between about 360mg and about 1600mg, between about 450mg and about 16000mg, between about 450mg and 1140mg, or between about 450mg and about 910mg, including any range between these values. In some embodiments, the intravenous bag containing a 10 mg / kg dose of anti-CD38 antibody in a 250 ml volume further comprises 0.9% sodium chloride or 5% dextrose.

[0021] In some embodiments, an anti-CD38 antibody is provided for use in a method of treating multiple myeloma in an individual, the method comprising administering to the individual the anti-CD38 antibody, pomalidomide, and dexamethasone, the anti-CD38 antibody comprising: (a) a heavy chain variable domain (VH) comprising: a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising: a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-H3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). NO:6) CDR-L3, wherein the anti-CD38 antibody is administered in a 28-day cycle; wherein the anti-CD38 antibody is administered on day 1, day 8, day 15 and day 22 of the first 28-day cycle; wherein the anti-CD38 antibody is administered on day 1 and day 15 of each 28-day cycle after the first 28-day cycle; and wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg or 20 mg / kg.

[0022] In some embodiments, a method of treating a human individual having multiple myeloma is provided, the method comprising administering to the individual an anti-CD38 antibody, pomalidomide, and dexamethasone, the anti-CD38 antibody comprising: (a) a heavy chain variable domain (VH) comprising: a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising: a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-H3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). NO:6) CDR-L3, wherein the anti-CD38 antibody is administered in a 28-day cycle; wherein the anti-CD38 antibody is administered on day 1, day 8, day 15 and day 22 of the first 28-day cycle; wherein the anti-CD38 antibody is administered on day 1 and day 15 of each 28-day cycle after the first 28-day cycle; and wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg or 20 mg / kg.

[0023] In some embodiments, the individual has at least one high-risk cytogenetic abnormality selected from the group consisting of: 17p deletion, 4(4;14) translocation, and t(14;16) translocation. In some embodiments, the individual has at least two high-risk cytogenetic abnormalities.

[0024] In some embodiments, the multiple myeloma is relapsed / refractory multiple myeloma. In some embodiments, the individual is refractory to the most recent prior therapy for multiple myeloma. In some embodiments, the individual is refractory to lenalidomide. In some embodiments, the individual's most recent prior therapy for multiple myeloma is lenalidomide. In some embodiments, the individual is refractory to a proteasome inhibitor. In some embodiments, the individual's most recent prior therapy is a proteasome inhibitor. In some embodiments, the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, marizomib, olozomib, and ixazomib. In some embodiments, the individual received prior therapy with lenalidomide and a proteasome inhibitor, and the lenalidomide was administered to the individual in combination. In some embodiments, the individual received prior therapy with lenalidomide and a proteasome inhibitor, and the lenalidomide was administered to the individual separately (e.g., each administered during a different prior line of treatment). In some embodiments, the individual has received at least two prior therapies for multiple myeloma. In some embodiments, the individual has received at least three prior therapies for multiple myeloma.

[0025] In some embodiments, the individual suffers from a respiratory disorder, a chest disorder, and / or a mediastinal disorder. In some embodiments, the respiratory disorder is chronic obstructive pulmonary disease (COPD). In some embodiments, the respiratory disorder is asthma. In some embodiments, the respiratory disorder is bronchospasm.

[0026] In some embodiments, the anti-CD38 antibody is administered to the individual in combination with at least one additional agent. In some embodiments, the at least one additional agent comprises an immunomodulatory drug. In some embodiments, the immunomodulatory drug is lenalidomide or pomalidomide. In some embodiments, the at least one additional agent comprises a proteasome inhibitor. In some embodiments, the proteasome inhibitor is bortezomib, carfilzomib, marizomib, olozomib, and ixazomib. In some embodiments, the at least one additional agent comprises a corticosteroid. In some embodiments, the corticosteroid is dexamethasone.

[0027] In some embodiments, kits comprising isatuximab are provided for treating an individual with multiple myeloma according to the methods of the embodiments provided herein.

[0028] Specifically, the present invention includes but is not limited to the following:

[0029] 1. 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 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 NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6).

[0030] 2. A method of administering an anti-CD38 antibody to a human 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-H3 comprising the amino acid sequence NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6).

[0031] 3. The anti-CD38 antibody for use according to item 1 or the method according to item 2, wherein the anti-CD38 antibody is isatuximab.

[0032] 4. The anti-CD38 antibody for use according to item 1 or 3, wherein the anti-CD38 antibody is for treating a disease or disorder, optionally wherein the disease or disorder is multiple myeloma, or the method according to item 2 or 3, wherein administration of the anti-CD38 antibody is for treating multiple myeloma.

[0033] 5. An anti-CD38 antibody for use according to any one of items 1 and 3-4, or a method according to any one of items 2-4, wherein the first intravenous infusion of the anti-CD38 antibody is administered to the individual within the first hour at an infusion rate of 25 mL / hour, and wherein after the first hour the infusion rate is increased by 25 mL / hour every 30 minutes to a maximum infusion rate of 150 mL / hour until a volume of 250 ml is infused.

[0034] 6. An anti-CD38 antibody for use according to any one of items 1 and 3-4, or a method according to any one of items 2-4, wherein the first infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 12.5 mL / hour over the first 30 minutes, and wherein after the first 30 minutes the infusion rate is increased by 25 mL / hour every 30 minutes until a volume of 250 ml is infused.

[0035] 7. An anti-CD38 antibody for use according to any one of items 1 and 3-6, or a method according to any one of items 2-6, comprising administering to the individual at least a second intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml.

[0036] 8. The anti-CD38 antibody or method for use according to claim 7, wherein the second intravenous infusion of the anti-CD38 is administered to the subject at an infusion rate of 50 mL / hour over the first 30 minutes, wherein the infusion rate is increased by 50 ml / hr for the second 30 minutes, and wherein after the second 30 minutes the infusion rate is increased by 100 mL / hour every 30 minutes to a maximum infusion rate of 200 mL / hour until a volume of 250 ml is infused.

[0037] 9. The anti-CD38 antibody or method for use according to claim 7, wherein the second intravenous infusion of the anti-CD38 is administered to the subject 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 is infused.

[0038] 10. The anti-CD38 antibody or method for use according to claim 7, wherein the second intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 25 mL / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 ml is infused.

[0039] 11. The anti-CD38 antibody or method for use according to any one of items 7 to 10, comprising administering to the individual at least a third intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml.

[0040] 12. The anti-CD38 antibody or method for use according to item 11, wherein 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 is infused.

[0041] 13. An anti-CD38 antibody or method for use according to claim 11, wherein the third intravenous infusion of anti-CD38 is administered to the individual at an infusion rate of 100 ml / hour within the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 ml is infused.

[0042] 14. The anti-CD38 antibody or method for use according to any one of items 11 to 13, comprising administering to the individual a fourth intravenous infusion of the anti-CD38 antibody, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml.

[0043] 15. The anti-CD38 antibody or method for use according to item 14, wherein the fourth intravenous infusion of the anti-CD38 antibody is administered to the subject at an infusion rate of 200 ml / hour until a volume of 250 ml is infused.

[0044] 16. An anti-CD38 antibody or method for use according to claim 14, wherein the fourth intravenous infusion of the anti-CD38 antibody is administered to the individual at an infusion rate of 100 ml / hour within the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 ml is infused.

[0045] 17. An anti-CD38 antibody or method for use according to any one of items 14 to 16, wherein the anti-CD38 antibody is administered in a first 28-day cycle, wherein the first intravenous infusion of the anti-CD38 antibody is administered on day 1 of the first 28-day cycle, the second intravenous infusion of the anti-CD38 antibody is administered on day 8, the third intravenous infusion of the anti-CD38 antibody is administered on day 15, and the fourth intravenous infusion of the anti-CD38 antibody is administered on day 22.

[0046] 18. An anti-CD38 antibody or method for use according to any one of items 14-17, comprising administering to the individual one or more subsequent intravenous infusions of the anti-CD38 antibody after the fourth intravenous infusion, wherein for each of the one or more subsequent intravenous infusions, the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml.

[0047] 19. An anti-CD38 antibody or method for use according to claim 18, wherein each of the one or more subsequent intravenous infusions of the 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 is infused.

[0048] 20. An anti-CD38 antibody or method for use according to claim 18, wherein each of the one or more subsequent intravenous infusions of the anti-CD38 antibody after the fourth intravenous infusion is administered to the individual at an infusion rate of 100 ml / hour within the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 ml is infused.

[0049] 21. An anti-CD38 antibody or method for use according to any one of items 18 to 20, wherein the anti-CD38 antibody is administered 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 anti-CD38 antibody after the fourth intravenous infusion is administered on day 1 and day 15 of each of the one or more subsequent 28-day cycles after the first 28-day cycle.

[0050] 22. 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 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-H3 comprising the amino acid sequence NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6);

[0051] wherein a first intravenous infusion of the anti-CD38 antibody is administered to the subject at an infusion rate of 25 mL / hour within the first hour, and wherein after the first hour the infusion rate is increased by 25 mL / hour every 30 minutes to a maximum infusion rate of 150 mL / hour until a volume of 250 ml is infused;

[0052] wherein the second intravenous infusion of anti-CD38 is administered to the subject at an infusion rate of 50 mL / hour for the first 30 minutes, wherein the infusion rate is increased by 50 ml / hr for a second 30 minutes, and wherein the infusion rate is increased by 100 mL / hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL / hour until a volume of 250 ml is infused; and

[0053] wherein the third intravenous infusion of anti-CD38 is administered to the subject at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 ml is infused.

[0054] 23. A method of administering an anti-CD38 antibody to a human 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 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-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 6). NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6);

[0055] wherein a first intravenous infusion of the anti-CD38 antibody is administered to the subject at an infusion rate of 25 mL / hour within the first hour, and wherein after the first hour the infusion rate is increased by 25 mL / hour every 30 minutes to a maximum infusion rate of 150 mL / hour until a volume of 250 ml is infused;

[0056] wherein the second intravenous infusion of anti-CD38 is administered to the subject at an infusion rate of 50 mL / hour for the first 30 minutes, wherein the infusion rate is increased by 50 ml / hr for a second 30 minutes, and wherein the infusion rate is increased by 100 mL / hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL / hour until a volume of 250 ml is infused; and

[0057] wherein the third intravenous infusion of anti-CD38 is administered to the subject at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a volume of 250 ml is infused.

[0058] 24. The anti-CD38 antibody for use according to item 22 or the method according to item 23, wherein the anti-CD38 antibody is isatuximab.

[0059] 25. The anti-CD38 antibody for use according to item 22 or 24, wherein the anti-CD38 antibody is for treating a disease or disorder, optionally wherein the disease or disorder is multiple myeloma, or the method according to item 23 or 24, wherein administration of the anti-CD38 antibody is for treating multiple myeloma.

[0060] 26. An anti-CD38 antibody for use according to any one of items 21 and 23-25, or a method according to any one of items 22-25, further comprising administering to the individual one or more subsequent intravenous infusions of the anti-CD38 antibody after the third intravenous infusion, wherein for each of the one or more subsequent intravenous infusions, the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml.

[0061] 27. An anti-CD38 antibody or method for use according to claim 26, wherein each of the one or more subsequent intravenous infusions of the 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 is infused.

[0062] 28. An anti-CD38 antibody for use in a method of treating an individual in need thereof, the method comprising administering the anti-CD38 antibody to the individual by intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg, wherein the volume of each dose of the anti-CD38 antibody is 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) 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-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 6). NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6).

[0063] 29. A method of administering an anti-CD38 antibody to an individual in need thereof, the method comprising administering the anti-CD38 antibody to the individual by intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg, wherein the volume of each dose of the anti-CD38 antibody is 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) 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-H3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). ID NO:6).

[0064] 30. The anti-CD38 antibody for use according to item 28 or the method according to item 29, wherein the anti-CD38 antibody is isatuximab.

[0065] 31. An anti-CD38 antibody for use according to claim 28 or 30, wherein the anti-CD38 antibody is for treating a disease or disorder, optionally wherein the disease or disorder is multiple myeloma, or a method according to claim 29 or 30, wherein administration of the anti-CD38 antibody is for treating multiple myeloma.

[0066] 32. An anti-CD38 antibody for use according to any one of items 28 and 30-31, or a method according to any one of items 29-31, wherein the anti-CD38 antibody is administered in the first 28-day cycle, and wherein the anti-CD38 antibody is administered on day 1, day 8, day 15 and day 22 of the first 28-day cycle.

[0067] 33. An anti-CD38 antibody or method for use according to claim 32, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion on day 1 of the first 28-day cycle at an infusion rate of 25 mL / hour within the first hour, and wherein the infusion rate is increased by 25 mL / hour every 30 minutes after the first hour to a maximum infusion rate of 150 mL / hour until a 250 ml dose of the anti-CD38 antibody is infused.

[0068] 34. An anti-CD38 antibody or method for use according to claim 32, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion on day 1 of the first 28-day cycle at an infusion rate of 12.5 mL / hour over the first 30 minutes, and wherein the infusion rate is increased by 25 mL / hour every 30 minutes after the first 30 minutes until a 250 ml dose of the anti-CD38 antibody is infused.

[0069] 35. An anti-CD38 antibody or method for use according to any one of items 32-34, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion on day 8 of the first 28-day cycle at an infusion rate of 50 mL / hour over the first 30 minutes, wherein the infusion rate is increased by 50 ml / hr for the second 30 minutes, and wherein after the second 30 minutes the infusion rate is increased by 100 mL / hour every 30 minutes to a maximum infusion rate of 200 mL / hour until a volume of 250 ml is infused.

[0070] 36. An anti-CD38 antibody or method for use according to any one of items 32-34, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion on day 8 of the 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 dose of 250 ml of the anti-CD38 antibody is infused.

[0071] 37. An anti-CD38 antibody or method for use according to any one of items 32-34, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion on day 8 of the first 28-day cycle at an infusion rate of 25 mL / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a dose of 250 ml of the anti-CD38 antibody is infused.

[0072] 38. An anti-CD38 antibody or method for use according to any one of items 32-37, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion at an infusion rate of 200 ml / hour on day 15 of the first 28-day cycle until a 250 ml dose of the anti-CD38 antibody is infused.

[0073] 39. An anti-CD38 antibody or method for use according to any one of items 32-37, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion on day 15 of the first 28-day cycle at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a dose of 250 ml of the anti-CD38 antibody is infused.

[0074] 40. The anti-CD38 antibody or method for use according to any one of items 32-39, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion at an infusion rate of 200 ml / hour on day 22 of the first 28-day cycle until a 250 ml dose of the anti-CD38 antibody is infused.

[0075] 41. An anti-CD38 antibody or method for use according to any one of items 32-39, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion on day 22 of the first 28-day cycle at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a dose of 250 ml of the anti-CD38 antibody is infused.

[0076] 42. An anti-CD38 antibody or method for use according to any one of items 32-41, wherein the anti-CD38 antibody is further administered in one or more subsequent 28-day cycles, and wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg on day 1 and day 15 of each subsequent 28-day cycle, wherein the volume of each dose of the anti-CD38 antibody administered in the one or more subsequent cycles is 250 ml.

[0077] 43. An anti-CD38 antibody or method for use according to claim 42, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion at an infusion rate of 200 ml / hour on day 1 of each subsequent 28-day cycle until a 250 ml dose of the anti-CD38 antibody is infused.

[0078] 44. An anti-CD38 antibody or method for use according to claim 42, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion on day 1 of each subsequent 28-day cycle at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a dose of 250 ml of the anti-CD38 antibody is infused.

[0079] 45. An anti-CD38 antibody or method for use according to any one of items 42-44, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion at an infusion rate of 200 ml / hour on day 15 of each subsequent 28-day cycle until a 250 ml dose of the anti-CD38 antibody is infused.

[0080] 46. An anti-CD38 antibody or method for use according to any one of items 42-44, wherein the anti-CD38 antibody is administered to the individual by intravenous infusion on day 15 of each subsequent 28-day cycle at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until a dose of 250 ml of the anti-CD38 antibody is infused.

[0081] 47. An anti-CD38 antibody for use in a method of treating an individual in need thereof, the method comprising safely administering to the individual at least a first dose of the anti-CD38 antibody by intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml, wherein the first dose is infused over a duration of about 1.5 hours and about 6.5 hours, 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-H3 comprising the amino acid sequence NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6).

[0082] 48. A method of 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 by intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml, wherein the first dose is infused over a duration of about 1.5 hours and about 6.5 hours, 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-H3 comprising the amino acid sequence NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6).

[0083] 49. The anti-CD38 antibody for use according to item 47 or the method according to item 48, wherein the anti-CD38 antibody is isatuximab.

[0084] 50. An anti-CD38 antibody for use according to item 47 or 49, wherein the anti-CD38 antibody is for treating a disease or disorder, optionally wherein the disease or disorder is multiple myeloma, or a method according to item 48 or 49, wherein administration of the anti-CD38 antibody is for treating multiple myeloma.

[0085] 51. An anti-CD38 antibody for use according to any one of items 47 and 49-50, or a method according to any one of items 48-50, comprising administering at least a second dose of the anti-CD38 antibody to the individual by intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml, wherein the second dose is infused over a duration of approximately 0.5 and 3.5 hours.

[0086] 52. An anti-CD38 antibody for use according to any one of items 41 and 43-45, or a method according to any one of items 42-45, comprising administering at least a third dose of the anti-CD38 antibody to the individual by intravenous infusion, wherein the anti-CD38 antibody is administered at a dose of at least 10 mg / kg in a volume of 250 ml, wherein the third dose is infused over a duration of approximately 0.5 and 1.5 hours.

[0087] 53. An anti-CD38 antibody for use according to any one of items 1, 3-22, 24-28, 30-47 and 49-52, or a method according to any one of items 2-21, 23-27, 29-46 and 48-52, wherein administration of the anti-CD38 antibody does not result in the individual experiencing an infusion reaction (IR).

[0088] 54. An anti-CD38 antibody for use according to any one of items 1, 3-22, 24-28, 30-47 and 49-52, or a method according to any one of items 2-21, 23-27, 29-46 and 48-52, wherein administration of the anti-CD38 antibody does not result in the individual experiencing IR of greater than grade 1 severity.

[0089] 55. An anti-CD38 antibody for use according to any one of items 1, 3-22, 24-28, 30-47 and 49-52, or a method according to any one of items 2-21, 23-27, 29-46 and 48-52, wherein administration of the anti-CD38 antibody does not result in the individual experiencing IR of severity 2 or higher.

[0090] 56. An anti-CD38 antibody for use according to any one of items 1, 3-22, 24-28, 30-47 and 49-55, or a method according to any one of items 2-21, 23-27, 29-46 and 48-55, wherein the anti-CD38 antibody at a dose of at least 10 mg / kg in a volume of 250 ml further comprises 0.9% sodium chloride or 5% dextrose.

[0091] 57. An anti-CD38 antibody for use according to any one of items 1, 3-22, 24-28, 30-47 and 49-56, or a method according to any one of items 2-21, 23-27, 29-46 and 48-56, wherein the individual has not previously received premedication with one or more of the following for the purpose of preventing or minimizing infusion reactions prior to administration of the anti-CD38 antibody by intravenous infusion: analgesics, antacids, anti-inflammatory agents, antihistamines.

[0092] 58. An anti-CD38 antibody for use according to any one of items 1, 3-22, 24-28, 30-47 and 49-57, or a method according to any one of items 2-21, 23-27, 29-46 and 48-57, wherein the dose of anti-CD38 antibody is 10 mg / kg or 20 mg / kg.

[0093] 59. An anti-CD38 antibody for use in a method of treating multiple myeloma in an individual, the method comprising administering to the individual the anti-CD38 antibody, pomalidomide, and dexamethasone, the anti-CD38 antibody comprising: (a) a heavy chain variable domain (VH) comprising: a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising: a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6),

[0094] wherein the anti-CD38 antibody is administered in 28-day cycles;

[0095] wherein the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first 28-day cycle;

[0096] wherein the anti-CD38 antibody is administered on day 1 and day 15 of each 28-day cycle after the first 28-day cycle;

[0097] And wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg or 20 mg / kg.

[0098] 60. A method of treating a human individual having multiple myeloma, the method comprising administering to the individual an anti-CD38 antibody, pomalidomide, and dexamethasone, the anti-CD38 antibody comprising: (a) a heavy chain variable domain (VH) comprising: a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising: a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

[0099] wherein the anti-CD38 antibody is administered in 28-day cycles;

[0100] wherein the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first 28-day cycle;

[0101] wherein the anti-CD38 antibody is administered on day 1 and day 15 of each 28-day cycle after the first 28-day cycle;

[0102] And wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg or 20 mg / kg.

[0103] 61. An anti-CD38 antibody for use according to claim 59 or a method according to claim 60, wherein the individual has at least one high-risk cytogenetic abnormality selected from the group consisting of: 17p deletion, 4(4;14) translocation, and t(14;16) translocation.

[0104] 62. An anti-CD38 antibody or method for use according to claim 61, wherein the individual has at least two high-risk cytogenetic abnormalities.

[0105] 63. The anti-CD38 antibody or method for use according to any one of items 4-21, 25-27, 31-46 and 50-62, wherein the multiple myeloma is relapsed / refractory multiple myeloma.

[0106] 64. The anti-CD38 antibody for use or method according to any one of items 4-21, 25-27, 31-46 and 50-63, wherein the individual is refractory to the most recent prior therapy for multiple myeloma.

[0107] 65. The anti-CD38 antibody for use or the method according to any one of items 4-21, 25-27, 31-46 and 50-64, wherein the subject is refractory to lenalidomide.

[0108] 66. The anti-CD38 antibody or method for use according to any one of items 4-21, 25-27, 31-46 and 50-65, wherein the most recent prior therapy is lenalidomide.

[0109] 67. The anti-CD38 antibody for use or the method according to any one of items 4-21, 25-27, 31-46 and 50-66, wherein the individual is refractory to a proteasome inhibitor.

[0110] 68. The anti-CD38 antibody or method for use according to any one of items 4-21, 25-27, 31-46 and 50-67, wherein the most recent prior therapy is a proteasome inhibitor.

[0111] 69. The anti-CD38 antibody or method for use according to item 67 or 68, wherein the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, marizomib, olozomib and ixazomib.

[0112] 70. The anti-CD38 antibody for use or the method according to any one of items 64-69, wherein the lenalidomide and the proteasome inhibitor are administered in combination.

[0113] 71. An anti-CD38 antibody for use according to any one of items 1, 3-22, 24-28, 30-47 and 49-70, or a method according to any one of items 2-21, 23-27, 29-46 and 48-70, wherein the individual suffers from a respiratory disorder, a chest disorder and / or a mediastinal disorder.

[0114] 72. An anti-CD38 antibody or method for use according to claim 71, wherein the respiratory disorder is chronic obstructive pulmonary disease (COPD).

[0115] 73. An anti-CD38 antibody or method for use according to claim 71, wherein the respiratory disorder is asthma.

[0116] 74. An anti-CD38 antibody or method for use according to claim 71, wherein the respiratory disorder is bronchospasm.

[0117] 75. The anti-CD38 antibody for use or method according to any one of items 4-21, 25-27, 31-46 and 50-74, wherein the individual has received at least two prior therapies for multiple myeloma.

[0118] 76. The anti-CD38 antibody for use or method according to any one of items 4-21, 25-27, 31-46 and 50-74, wherein the individual has received at least three prior therapies for multiple myeloma.

[0119] 77. The anti-CD38 antibody for use or the method according to any one of items 4-21, 25-27, 31-46 and 50-76, wherein the anti-CD38 antibody is administered in combination with at least one additional agent.

[0120] 78. An anti-CD38 antibody or method for use according to claim 77, wherein the at least one additional agent comprises an immunomodulatory drug.

[0121] 79. An anti-CD38 antibody or method for use according to claim 78, wherein the immunomodulatory drug is lenalidomide or pomalidomide.

[0122] 80. The anti-CD38 antibody for use or method according to any one of items 4-21, 25-27, 31-46 and 50-79, wherein the at least one additional agent comprises a proteasome inhibitor.

[0123] 81. The anti-CD38 antibody for use or method according to item 80, wherein the proteasome inhibitor is bortezomib, carfilzomib, marizomib, olozomib and ixazomib.

[0124] 82. The anti-CD38 antibody for use or method according to any one of items 4-21, 25-27, 31-46 and 50-81, wherein the at least one additional agent comprises a corticosteroid.

[0125] 83. The anti-CD38 antibody or method for use according to 82, wherein the corticosteroid is dexamethasone.

[0126] 84. A kit comprising isatuximab for treating an individual with multiple myeloma according to any one of items 4-21, 25-27, 31-46, and 50-83.

[0127] 85. An intravenous infusion bag containing between about 360 mg and 1600 mg of an anti-CD38 antibody in a volume of 250 ml, wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) comprising: a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising: a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). BRIEF DESCRIPTION OF THE DRAWINGS

[0128] Figure 1 A schematic diagram of the study design for the clinical trial described in Example 1A is provided.

[0129] Figure 2 The percentage of patients who experienced Grade 2 or 3 infusion reactions (IR) in the clinical trial described in Example 1B is shown as a function of the number of infusions (isatuximab infusion rate measured as ml / h) compared to the percentage of patients who experienced Grade 2 or 3 infusion reactions (IR) in a parallel trial in which isatuximab was administered according to a standard infusion schedule (infusion rate measured as mg / h).

[0130] Figure 3 The median duration (hours) of isatuximab infusion in the clinical trial described in Example 1B is provided in comparison to the median duration (hours) of isatuximab infusion in a parallel clinical trial in which isatuximab was administered according to a standard infusion schedule.

[0131] Figure 4 A Logit Emax model is provided that best describes the relationship between isatuximab exposure and ORR in the modeling studies described in Example 2. CT4W = C trough at 4 weeks.

[0132] Figure 5 Provided are the distributions of responders and non-responders by CT4W quartiles in the modeling study described in Example 2. BOR = Best Overall Response.

[0133] Figure 6 Provided is the relationship between the predicted probability of response and CT4W from the modeling study described in Example 2. BMPC = bone marrow plasma cell percentage.

[0134] Figure 7 A disease model from the modeling study described in Example 2 was provided, which included an exposure-driven tumor growth inhibition (TGI) and a pharmacokinetic model. Serum M protein kinetics were fully described by the exposure-driven TGI model. A combined model was used to account for withdrawal.

[0135] Figure 8 Comparisons of model-predicted and observed longitudinal kinetics of serum M protein are presented for the indicated dosing regimens.

[0136] Figure 9A-9B Provides a clinical trial simulation of isatuximab monotherapy using the indicated dosing regimen. 5,000 clinical trials were simulated, each with 100 patients. Figure 9A Shown are the overall response rates (RRs) 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 real patients who were assumed to receive the same dose level for each simulation experiment. Figure 9B Shown are the percent changes in M protein at eight weeks after baseline simulated using the disease M protein model from the modeling study described in Example 2. Each clinical trial simulation was based on 122 real patients who were assumed to receive the same dose level.

[0137] Figure 10 Patient disposition is provided for Phase 1 and Phase 2 of the study described in Example 3. SD = standard deviation.

[0138] Figure 11 The pharmacokinetic profile of isatuximab (mean isatuximab concentrations) during Phase 1, Cycle 1 of the study described in Example 3 is provided.

[0139] Figure 12 A Swimmer plot of the best response and treatment duration in Phase 2 of the study described in Example 2 is provided. Patients were treated with 20 mg / kg of isatuximab every 2 weeks. 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.

[0140] Figures 13A-13B Provides progression-free survival (PFS) for patients treated with isatuximab at 20 mg / kg QW / Q2W in the study described in Example 3. Figure 13A ) and overall survival ( Figure 13B) Kaplan-Meier plot.

[0141] Figure 14 To show the relationship between CD38 receptor density and clinical response in patients receiving isatuximab at a dose of 10 mg / kg QWx4 / Q2W or 20 mg / kg QWx4 / Q2W.

[0142] Figure 15 Kaplan-Meier plot showing progression-free survival (PFS) for patients given isatuximab, pomalidomide, and dexamethasone, where isatuximab was given to the patients from a fixed infusion volume of 250 ml.

[0143] Figure 16 Shown is a Kaplan-Meier plot of overall survival (OS) for patients administered isatuximab, pomalidomide, and dexamethasone, wherein isatuximab was administered to the patients from a fixed infusion volume of 250 ml. DETAILED DESCRIPTION

[0144] 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. During or within 24 hours of intravenous infusion, IR presents various symptoms, including, for example, rash, hives, flushing, changes in heart rate and / or blood pressure, fever, dyspnea and / or nausea. The severity of IR can range from mild to life-threatening, but in all cases, timely attention and immediate response to the patient's initial symptoms are necessary. Various strategies have been adopted to alleviate and / or prevent IR, including, for example, slowing down the infusion rate, interrupting the infusion, and splitting the infusion over two or more consecutive days. However, such strategies may cause inconvenience to the patient and increase medical costs. In addition, extended hospital stays and frequent hospital visits increase the workload of hospital staff.

[0145] Provided herein are methods for treating multiple myeloma (e.g., RRMM), comprising administering an effective amount of an anti-CD38 antibody (e.g., 10 mg / kg isatuximab) to a subject via intravenous infusion, wherein the volume of each anti-CD38 antibody infusion is 250 ml. Applicants have discovered that such a fixed volume of anti-CD38 antibody (e.g., isatuximab) can be rapidly infused, thereby significantly shortening the duration of treatment without compromising patient safety.

[0146] Also provided herein are methods of treating multiple myeloma (e.g., RRMM), comprising administering to a subject 20 mg / kg of an anti-CD38 antibody (e.g., isatuximab) on each of Days 1, 8, 15, and 22 of the first 28-day cycle, and further administering to the subject 20 mg / kg of an anti-CD38 antibody (e.g., isatuximab) on each of Days 1 and 15 of each subsequent 28-day cycle after the first 28-day cycle.

[0147] definition

[0148] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a molecule" optionally includes combinations of two or more such molecules, and so forth.

[0149] As used herein, the term "about" refers to the usual error range of the corresponding value that is readily known to those skilled in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments involving the value or parameter itself. "Sustained response" refers to a sustained effect on preventing or delaying the progression of a disease (e.g., multiple myeloma) and / or improving one or more response criteria after cessation of treatment. For example, the response to treatment of multiple myeloma can be measured according to the criteria in the following literature: Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma." Lancet Oncol. 17(8): e328-e346); and Durie et al. (2006) "International uniform response criteria for multiple myeloma. Leukemia. 20: 1467-1473. (See also Table 14 herein). In some embodiments, the sustained response has a duration that is at least the same as the duration of treatment, at least 1.5X, 2.0X, 2.5X, or 3.0X the length of the duration of treatment.

[0150] The term "pharmaceutical formulation" refers to a preparation that is in such a form that the biological activity of the active ingredient is effective and that does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered. Such formulations are sterile. "Pharmaceutically acceptable" excipients (vehicles, additives) are those that can reasonably be administered to a mammal to provide an effective dose of the active ingredient employed.

[0151] As used herein, the term "treatment" refers to a clinical intervention designed to change the typical course of the disease or cell (e.g., cancer cell) being treated during the clinical pathology process. Required therapeutic effect includes reducing the rate of disease progression, improving or alleviating the disease state, and the prognosis of regression or improvement. For example, if one or more symptoms associated with cancer are alleviated or eliminated, including but not limited to reducing the proliferation of cancer cells (or destroying cancer cells), reducing the symptoms caused by the disease, improving the quality of life of those individuals with the disease, reducing the dosage of other drugs required for treating the disease, and / or prolonging the survival of the individual, the individual is successfully "treated."

[0152] As used herein, "delaying the progression of a disease" means postponing, hindering, slowing, retarding, stabilizing, and / or delaying the development of a disease (e.g., cancer). The delay can be of varying lengths of time, depending on the medical history and / or the individual being treated. It will be apparent to one skilled in the art that a sufficient or significant delay can actually encompass prevention, in that the individual will not develop the disease. For example, the development of advanced cancers, such as metastases, can be delayed.

[0153] "Effective amount" is at least the minimum amount required to achieve a measurable improvement or prevention of a specific obstacle. The effective amount herein can vary according to factors such as the patient's disease state, age, sex, and weight, and the ability of the antibody to elicit a desired response in an individual. An effective amount is also the amount in which the therapeutic beneficial effect exceeds any toxic or deleterious effects of the treatment. For preventive use, beneficial or desired results include results such as: eliminating or reducing risk, alleviating severity, or delaying the onset of a disease (including biochemical, histological, and / or behavioral symptoms of the disease, the disease, its complications, and the intermediate pathological phenotypes presented during the disease progression). For therapeutic use, beneficial or desired results include clinical results such as: reducing one or more symptoms caused by the disease, improving the quality of life of patients with the disease, reducing the dosage of other drugs required for treating the disease, such as enhancing the effect of another drug by targeting, delaying disease progression, and / or prolonging survival. In the case of cancer or tumors, an effective amount of a drug may have the following effects: reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down or desirably stop to some extent) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down and desirably stop to some extent) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with the disorder to some extent. An effective amount may be administered in one or more administrations. For the purposes of the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve a preventive or therapeutic treatment, either directly or indirectly. As understood in clinical situations, 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" may be considered in the context of administering one or more therapeutic agents, and if a single agent can achieve or achieve the desired result in combination with one or more other agents, then the single agent may be considered to be administered in an effective amount.

[0154] As used herein, "in combination with" means administering a therapeutic modality in addition to another therapeutic modality. Thus, "in combination with" means administering another therapeutic modality before, during, or after administering one therapeutic modality to a subject.

[0155] "Subject" or "individual" for purposes of treatment refers to any animal classified as a mammal, including humans, livestock and farm animals, and zoo, sport, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is a human.

[0156] The term "antibody" is used in the broadest sense herein and specifically encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired biological activity. The term "overall response rate" or "ORR" as used herein refers to the proportion of patients with strict 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 the following literature: 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.

[0157] The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that this description is not intended as a limitation on the scope of the present disclosure, but is provided as a description of exemplary embodiments.

[0158] Overview

[0159] Provided herein is a method for treating individual multiple myeloma or delaying the progress of multiple myeloma, wherein the individual has received at least two previous therapies for multiple myeloma (for example, such as lenalidomide and proteasome inhibitors). In some embodiments, the method includes administering 10mg / kg of anti-CD38 antibodies (for example, aisatuximab) to the subject by intravenous infusion, wherein each infusion of 10mg / kg of anti-CD38 antibodies (for example, aisatuximab) is in 250ml volume. In some embodiments, during or after infusion, the individual does not experience IR (or only experiences mild IR). In some embodiments, the method includes administering 20mg / kg of anti-CD38 antibodies (for example, aisatuximab) to the individual on each of the 1st day, the 8th day, the 15th day, and the 22nd day of the first 28-day cycle. In some embodiments, the method includes further administering anti-CD38 antibodies (for example, aisatuximab) to the individual in one or more subsequent 28-day cycles after the first 28-day cycle. In some embodiments, the method comprises further administering 20 mg / kg of an anti-CD38 antibody (eg, isatuximab) to the individual on each of days 1 and 15 of each subsequent 28-day cycle after the first 28-day cycle.

[0160] anti-CD38 antibody

[0161] In some embodiments, the anti-CD38 antibody binds to human CD38. In some embodiments, the anti-CD38 antibody is a human antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) 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 comprises 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). H), wherein the heavy chain variable domain comprises an amino acid sequence that is at least 90% (e.g., at least any one of 91%, 92%, 94%, 95%, 96%, 97%, 98% or 99%, including any ranges therebetween) identical to SEQ ID NO: 7. Additionally or alternatively, in some embodiments, the anti-CD38 antibody comprises a light chain variable domain (V L ), wherein the light chain variable domain comprises an amino acid sequence that is at least 90% (e.g., at least any one of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any ranges therebetween) identical to SEQ ID NO: 8 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody comprises a V domain comprising SEQ ID NO: 7. H and V containing SEQ ID NO: 8 or SEQ ID NO: 9 L .

[0162]

[0163]

[0164] In some embodiments, the anti-CD38 antibody is isatuximab (CAS Reg. No. 1461640-62-9). Isatuximab, also known as hu38SB19 and SAR650984, is an anti-CD38 antibody described in WO 2008 / 047242 and U.S. Pat. No. 8,153,765, the contents of which are incorporated herein by reference in their entirety.

[0165] The heavy chain of isatuximab contains the following amino acid sequence:

[0166]

[0167] And the light chain of isatuximab contains the following amino acid sequence:

[0168]

[0169] Anti-CD38 antibodies can be produced using recombinant methods. For the recombinant production of anti-antigen antibodies, the nucleic acid encoding the antibody is separated and inserted into a reproducible vector for further cloning (amplification of DNA) or for expression. The DNA encoding the antibody can be easily separated and sequenced using conventional procedures (for example, by using oligonucleotide probes that can be specifically bound to the genes encoding the heavy and light chains of the antibody). Many vectors are available. Vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Vectors are typically transformed into a host cell suitable for expressing nucleic acids. In some embodiments, the host cell is a eukaryotic cell or a prokaryotic cell. In some embodiments, the eukaryotic cell is a mammalian cell. Examples of useful mammalian host cell lines are monkey kidney CV1 line transformed with SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 cells or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK, ATCC CCL10); 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 N.Y. Acad. Sci. 383:44-68 (1982)); MRC 5 cells; FS4 cells; and 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 NSO and Sp2 / 0. For review of certain mammalian host cell lines suitable for antibody production, see, eg, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 255-268.Anti-CD38 antibodies produced by cells can be purified using, for example, hydroxyapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being one of the generally preferred purification steps. Generally, various methods for preparing antibodies for research, testing, and clinical applications are established in the art, consistent with the above methods, and / or deemed appropriate by those skilled in the art.

[0170] Treatment

[0171] Treatment consisting of intravenous infusion of anti-CD38 antibody from a fixed volume of 250 ml

[0172] Provided herein are methods of administering (e.g., safely administering) an anti-CD38 antibody to an individual (e.g., a human individual) in need thereof, the method comprising administering to the individual by intravenous infusion a 10 mg / kg (e.g., at least 10 mg / kg) dose of an anti-CD38 antibody (e.g., an anti-CD38 antibody comprising: (a) a heavy chain variable domain (V H ), which comprises: a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising: a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6), wherein each dose of the anti-CD38 antibody is in a volume of 250 ml. In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the individual does not experience an infusion reaction (IR) during or after administration of the anti-CD38 antibody by intravenous infusion, wherein the anti-CD38 antibody is in a volume of 250 ml. In some embodiments, the individual experiences only mild IR during or after administration of the anti-CD38 antibody by intravenous infusion, wherein the anti-CD38 antibody is in a volume of 250 ml. (Additional details regarding the characteristics of IR and mild IR are provided elsewhere herein.)

[0173] Provided herein are methods for treating or delaying progression of multiple myeloma (such as relapsed multiple myeloma or relapsed and refractory multiple myeloma) in an individual (e.g., a human individual), the method comprising administering to the individual 10 mg / kg (e.g., at least 10 mg / kg) of an anti-CD38 antibody (e.g., an anti-CD38 antibody comprising: (a) a heavy chain variable domain (VH) comprising: a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising: a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 6). 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.

[0174] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual in the first 28-day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual at a dose of 10 mg / kg (e.g., at least 10 mg / kg or 20 mg / kg) in a volume of 250 ml on each of the 1st, 8th, 15th, and 22nd days of the first 28-day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual by intravenous infusion on day 1 of the first 28-day cycle at an infusion rate of 25 mL / hour within the first hour, and after the first hour, the infusion rate is increased by 25 mL / hour every 30 minutes to a maximum infusion rate of 150 mL / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the subject by intravenous infusion on day 1 of the first 28-day cycle at an infusion rate of 12.5 mL / hour over the first 30 minutes, wherein the infusion rate is increased by 25 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 infusion of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is no more than about any of the following: 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, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2 In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is between about 3.3 and about 6.1 hours, including any range therebetween. In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of the first 28-day cycle is between about 3.2 and 5.5 hours, such as between about 3.36 and about 5.32 hours. In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) on Day 1 of the first 28-day cycle is between about 3.8 and 4.2 hours, such as about 3.94 hours.In some embodiments, the duration of the infusion includes a temporary interruption before the infusion is complete.

[0175] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual on day 8 of the first 28-day cycle by intravenous infusion at an infusion rate of 50 mL / hour over the first 30 minutes, wherein the infusion rate is increased by 50 ml / hr for the next 30 minutes, and wherein the infusion rate is increased by 100 mL / hour every 30 minutes after the first 60 minutes to a maximum infusion rate of 200 mL / hour until a volume of 250 ml is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual on day 8 of the first 28-day cycle by intravenous infusion at an infusion rate of 50 mL / hour over 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 the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the subject by intravenous infusion on day 8 of the first 28-day cycle at an infusion rate of 25 mL / hour over the first 30 minutes, and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, on day 1 of the first 28-day cycle, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) does not exceed any 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 ranges in between these values. In some embodiments, on day 8 of the first 28-day cycle, the duration of the infusion of the anti-CD38 antibody (e.g., aisatuximab) is between about 1.5 and about 3.5 hours, including any value within this range. In some embodiments, on day 8 of the first 28-day cycle, the duration of the infusion of the anti-CD38 antibody (e.g., aisatuximab) is between about 1.4 and 2.7 hours, such as between about 1.52 and about 2.6 hours. In some embodiments, on day 8 of the first 28-day cycle, the duration of the infusion of the anti-CD38 antibody (e.g., aisatuximab) is between about 1.5 and 2.0 hours, such as about 1.88 hours. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., aisatuximab) includes a temporary interruption before the completion of the infusion.

[0176] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual on day 15 of the first 28-day cycle by intravenous infusion 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, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual on day 15 of the first 28-day cycle by intravenous infusion at an infusion rate of 100 ml / hour over the first 30 minutes, and the infusion rate is increased 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, on day 15 of the first 28-day cycle, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) is no longer than about any 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 ranges in between these values. In some embodiments, on day 1 of the first 28-day cycle, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 1.2 and about 3.4 hours, including any value within this range. In some embodiments, on day 15 of the first 28-day cycle, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 2 hours, such as between about 1.03 and about 1.87 hours. In some embodiments, on day 15 of the first 28-day cycle, the duration of the infusion is between about 1 and 1.5 hours, such as about 1.27 hours. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption before the completion of the infusion.

[0177] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual on day 22 of the first 28-day cycle by intravenous infusion at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual on day 22 of the first 28-day cycle by intravenous infusion at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, on day 22 of the first 28-day cycle, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) does not exceed any 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 ranges in between these values. In some embodiments, on day 22 of the first 28-day cycle, the duration of the infusion of the anti-CD38 antibody (e.g., aisatuximab) is between about 1.1 and about 2 hours, including any value within this range. In some embodiments, on day 22 of the first 28-day cycle, the duration of the infusion of the anti-CD38 antibody (e.g., aisatuximab) is between about 1 and 2 hours, such as between about 1.18 and about 1.52 hours. In some embodiments, on day 22 of the first 28-day cycle, the duration of the infusion of the anti-CD38 antibody (e.g., aisatuximab) is between about 1 and 1.5 hours, such as about 1.27 hours. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., aisatuximab) includes a temporary interruption before the completion of the infusion.

[0178] In some embodiments, in one or more subsequent 28-day cycles (e.g., after the first 28-day cycle), the anti-CD38 antibody (e.g., isatuximab) is further administered by intravenous infusion 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 by intravenous infusion on day 1 of each subsequent 28-day cycle (e.g., after the first 28-day cycle) at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, on day 1 of each subsequent 28-day cycle (e.g., after the first 28-day cycle), the anti-CD38 antibody (e.g., isatuximab) is administered to the subject by intravenous infusion at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, on Day 1 of each subsequent 28-day cycle (e.g., after the first 28-day cycle), the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) does not exceed any 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 ranges in between these values. In some embodiments, on the 1st day of each subsequent 28-day cycle (e.g., after the first 28-day cycle), the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 1.1 and about 1.6 hours, including any value within this range. In some embodiments, on the 1st day of each subsequent 28-day cycle (e.g., after the first 28-day cycle), the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 2 hours, such as between about 1.19 and about 1.41 hours. In some embodiments, on the 1st day of each subsequent 28-day cycle (e.g., after the first 28-day cycle), the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 1.5 hours, such as about 1.27 hours. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption before the completion of the infusion.In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual by intravenous infusion on day 15 of each subsequent 28-day cycle (e.g., after the first 28-day cycle) 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, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual by intravenous infusion on day 15 of each subsequent 28-day cycle (e.g., after the first 28-day cycle) at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased 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, on day 15 of each subsequent 28-day cycle (e.g., after the first 28-day cycle), the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) does not exceed any 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 ranges in between these values. In some embodiments, on the 1st day of each subsequent 28-day cycle (e.g., after the first 28-day cycle), the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 1.2 and about 1.6 hours, including any value within this range. In some embodiments, on the 1st day of each subsequent 28-day cycle (e.g., after the first 28-day cycle), the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 2 hours, such as between about 1.2 and about 1.46 hours. In some embodiments, on the 1st day of each subsequent 28-day cycle (e.g., after the first 28-day cycle), the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 1.5 hours, such as about 1.27 hours. In some embodiments, the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption before the completion of the infusion.

[0179] In some embodiments, the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) on or after day 15 of the first 28-day cycle (e.g., including day 22 of the first 28-day cycle and days 1 and 15 of each subsequent 28-day cycle) is no more than about any 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, inclusive, including any ranges in between these values. In some embodiments, on or 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 subsequent 28-day cycle), the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 0.7 and about 3.4 hours, including any value within this range. In some embodiments, on or 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 subsequent 28-day cycle), the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 2 hours, such as between about 1.13 and about 1.53 hours. In some embodiments, on day 1 of each subsequent 28-day cycle (e.g., after the first 28-day cycle), the duration of the infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 1.5 hours, such as about 1.25 hours.

[0180] In some embodiments, after the first infusion (e.g., on day 1 of the first 28-day cycle), the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) does not exceed 0.5 hours. In some embodiments, after day 1 of the first 28-day cycle (e.g., including day 8, day 15, and day 22 of the first 28-day cycle and day 1 and day 15 of each subsequent 28-day cycle), the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) does not exceed any of the following: about 0.5 hours. In some embodiments, on or after day 8 of the first 28-day cycle (e.g., including day 15 or day 22 of the first 28-day cycle and day 1 and day 15 of each subsequent 28-day cycle), the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) does not exceed any of the following: about 0.5 hours.

[0181] Also provided herein are methods of safely administering an anti-CD38 antibody to a human individual in need thereof, the method 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 by intravenous infusion (i.e., a first intravenous infusion), wherein the anti-CD38 antibody is in a volume of 250 ml, and wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) 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-H3 comprising the amino acid sequence In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments in which the anti-CD38 antibody (e.g., isatuximab) is safely administered, the individual does not experience a Grade 3 or higher IR during or after the infusion of the anti-CD38 antibody. In some embodiments in which the anti-CD38 antibody (e.g., isatuximab) is safely administered, the individual does not experience a Grade 2 or higher IR during or after the second or subsequent infusion of the anti-CD38 antibody.

[0182] In some embodiments, the first intravenous infusion of a 10 mg / kg dose (i.e., for example, at least a 10 mg / kg dose, or a first dose of a 20 mg / kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the subject at an infusion rate of 25 mL / hour over the first hour, wherein after the first hour the infusion rate is increased by 25 mL / hour every 30 minutes to a maximum infusion rate of 150 mL / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the first intravenous infusion of a 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the subject at an infusion rate of 12.5 mL / hour for the first 30 minutes, and wherein the infusion rate is increased by 25 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the first intravenous infusion of the anti-CD38 antibody (e.g., isatuximab) at a 10 mg / kg dose is no longer than about any of: 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, In some embodiments, the duration of the first intravenous infusion of the anti-CD38 antibody (e.g., isatuximab) is between about 3.3 and about 6.1 hours, including any range therebetween. In some embodiments, the duration of the first intravenous infusion of the anti-CD38 antibody (e.g., isatuximab) at a 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) is between about 3.2 and 5.5 hours, such as between about 3.36 and about 5.32 hours. In some embodiments, the duration of the first intravenous infusion of the anti-CD38 antibody (e.g., isatuximab) at a 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) is between about 3.8 and 4.2 hours, such as about 3.94 hours.In some embodiments, the duration of the first infusion of the anti-CD38 antibody (eg, isatuximab) includes a temporary interruption prior to completion of the infusion.

[0183] In some embodiments, a second 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) of the anti-CD38 antibody (e.g., isatuximab) is administered to an individual in need thereof by intravenous infusion (i.e., a second intravenous infusion), wherein the anti-CD38 antibody is in a volume of 250 ml.

[0184] In some embodiments, the second intravenous infusion of the anti-CD38 antibody (e.g., isatuximab) at a 10 mg / kg dose (i.e., for example, a second dose of 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 subject at an infusion rate of 50 mL / hour for the first 30 minutes, wherein the infusion rate is increased by 50 ml / hr for the second 30 minutes, and wherein the infusion rate is increased by 100 mL / hour every 30 minutes after the second 30 minutes to a maximum infusion rate of 200 mL / hour until the 250 ml volume is infused. In some embodiments, the second intravenous infusion of the anti-CD38 antibody (e.g., isatuximab) at a 10 mg / kg dose (i.e., for example, a second dose of 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 subject 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 the anti-CD38 antibody (e.g., isatuximab) is 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 the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the subject at an infusion rate of 25 mL / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the second infusion of the anti-CD38 antibody (e.g., isatuximab) at a 10 mg / kg dose does not exceed any 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 ranges in between these values. In some embodiments, the duration of the second infusion of a 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) of the anti-CD38 antibody (e.g., isatuximab) is between about 1.5 and about 3.5 hours, including any values within this range.In some embodiments, the duration of the second infusion of the anti-CD38 antibody (e.g., isatuximab) at a 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) is between about 1.4 and 2.7 hours, such as between about 1.52 and about 2.6 hours. In some embodiments, the duration of the second infusion of the anti-CD38 antibody (e.g., isatuximab) at a 10 mg / kg dose (e.g., at least a 10 mg / kg dose, a 20 mg / kg dose) is approximately between about 1.5 and 2.0 hours, such as about 1.88 hours. In some embodiments, the duration of the second infusion of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption before the infusion is complete.

[0185] In some embodiments, a third 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to an individual in need thereof by intravenous infusion (i.e., a third intravenous infusion). In some embodiments, a third infusion of a 10 mg / kg dose (i.e., at least a 10 mg / kg dose, or a third dose of a 20 mg / kg dose) of the anti-CD38 antibody (e.g., isatuximab) is in a volume of 250 ml and is administered to the individual at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is 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 subject at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of the third infusion of the anti-CD38 antibody (e.g., isatuximab) at a 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) is no more than about any 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 ranges therebetween. In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) at the third 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) is between about 1.2 and about 3.4 hours, including any value within this range. In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) at the third 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) is between about 1 and 2 hours, such as between about 1.03 and about 1.87 hours. In some embodiments, the duration of infusion of the anti-CD38 antibody (e.g., isatuximab) at the third 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) is between about 1 and 1.5 hours, such as about 1.27 hours.In some embodiments, the duration of the third infusion of the anti-CD38 antibody (e.g., isatuximab) at a 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) includes a temporary interruption prior to completion of the infusion.

[0186] In some embodiments, one or more subsequent intravenous infusions of the anti-CD38 antibody (e.g., isatuximab) are administered to the individual after the third intravenous infusion, wherein each of the one or more subsequent infusions provides a 10 mg / kg dose (e.g., at least 10 mg / kg, or 20 mg / kg) (e.g., a fourth dose, a fifth dose, a sixth dose, etc.) of the anti-CD38 antibody (e.g., isatuximab) to the individual in need thereof, and wherein each of the one or more subsequent infusions of the anti-CD38 antibody is in a volume of 250 ml. The one or more subsequent infusions include, but are not limited to, for example, a fourth infusion, a fifth infusion, a sixth infusion, etc. In some embodiments, the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) are each in a volume of 250 ml and are each administered to the individual at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) are each administered to the subject at an infusion rate of 100 ml / hour over the first 30 minutes, and wherein the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the duration of each of the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) is no more than about any 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 ranges in between these values. In some embodiments, the duration of each of the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) is between about 0.7 and about 3.4 hours, such as between about 1.1 and about 1.6 hours, including any values within these values. In some embodiments, the duration of each of the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) is between about 1 and 2 hours, such as between about 1.13 and about 1.53, or between about 1.19 and about 1.41 hours, including any values within these ranges. In some embodiments, the duration of each of the one or more subsequent infusions of the anti-CD38 antibody (e.g., isatuximab) is approximately between about 1 and 1.5 hours, such as about 1.27 hours or 1.25 hours.In some embodiments, the duration of each of the one or more subsequent infusions of the anti-CD38 antibody (eg, isatuximab) includes a temporary break prior to completion of the infusion.

[0187] In some embodiments, after the first infusion (e.g., on day 1 of the first 28-day cycle), each infusion of the anti-CD38 antibody (e.g., isatuximab) provided at a dose of 10 mg / kg (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) is provided for no more than 0.5 hour. In some embodiments, 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), each infusion of the anti-CD38 antibody (e.g., isatuximab) provided at a dose of 10 mg / kg (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) is provided for no more than about 0.5 hour. In some embodiments, each infusion of a 10 mg / kg dose (e.g., at least a 10 mg / kg dose, or a 20 mg / kg dose) of the anti-CD38 antibody (e.g., isatuximab) is provided for a duration of no more than about 0.5 hours on or after day 8 of the first 28-day cycle (e.g., including day 15 or day 22 of the first 28-day cycle and days 1 and 15 of each subsequent 28-day cycle).

[0188] In some embodiments, the individual does not experience an infusion reaction (IR) during or after administration (e.g., intravenous infusion) of the anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) in a volume of 250 ml. In some embodiments, the individual does not experience an IR during or after administration of the anti-CD38 antibody (e.g., by intravenous infusion) 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 grade 3 or higher IR during or after the infusion of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual does not experience an IR during or after the second infusion of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, during or after the second infusion of the anti-CD38 antibody (e.g., isatuximab), or in subsequent infusions of the anti-CD38 antibody (e.g., isatuximab), the individual does not experience IR. IR refers to an obstacle characterized by adverse reactions to the intravenous infusion of an anti-CD38 antibody (e.g., isatuximab). IR may occur during infusion or within 24 hours of infusion (e.g., 24 hours from the start of infusion). Signs or symptoms of IR include one or more of the following: paresthesia, chest pain, cough, nasal congestion, sneezing, throat irritation, itching, syncope, flushing, chills, fever, urticaria, angioedema, rash, skin reaction, itching, maculopapular rash, tachycardia, hypotension, dyspnea, nausea, vomiting, headache, back pain, chest discomfort or non-cardiac chest pain, abdominal pain, abdominal cramps, bronchospasm, laryngospasm, wheezing, respiratory congestion, sweating and erythema. (For further details, see, e.g., Doessegger et al. (2015) Clin & Trans Immunol. 4(7):e39.) Thus, in some embodiments, the individual does not experience any one or more of these signs or symptoms.

[0189] In some embodiments, the individual receives (e.g., requires) premedication, i.e., administration of a medication for the purpose of preventing or minimizing IR prior to the infusion of the anti-CD38 antibody (e.g., isatuximab). In some embodiments, prior to the infusion of the anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) in a volume of 250 ml, the individual receives premedication with one or more of the following for the purpose of preventing or minimizing IR: an analgesic (e.g., acetaminophen or paracetamol), an H2 antagonist or antacid (e.g., ranitidine, cimetidine, omeprazole, or esomeprazole), an anti-inflammatory agent (e.g., a corticosteroid or nonsteroidal anti-inflammatory drug), and / or an antihistamine (e.g., diphenhydramine, cetirizine, promethazine, dexchlorpheniramine).

[0190] In some embodiments, the individual does not receive (e.g., requires) premedication, i.e., medications administered prior to the infusion of the anti-CD38 antibody (e.g., isatuximab) for the purpose of preventing or minimizing IR. In some embodiments, prior to the infusion of the anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) in a volume of 250 ml, the individual does not receive (e.g., requires) premedication with one or more of the following for the purpose of preventing or minimizing IR: 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, after completing the infusion of the anti-CD38 antibody (e.g., isatuximab), the individual does not receive (e.g., requires) medication (e.g., prophylactic medication) for preventing or minimizing IR. In some embodiments, after administering (e.g., intravenously infusing) the anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) in a volume of 250 ml, the individual does not experience a delayed infusion reaction. In some embodiments, the subject does not experience a delayed infusion reaction within about any of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 6.0, 9.0, 12.0, 18.0, 21.0, or 24.0 hours (including any ranges therebetween) following administration (e.g., intravenous infusion) of the anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) in a volume of 250 ml. In some embodiments, the subject does not receive (e.g., requires) a 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 did not receive (e.g., needed) a premedication or prophylactic medication, e.g., as described above, prior to 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 did not receive (e.g., needed) a premedication or prophylactic medication, e.g., as described above, prior to starting 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 did not receive (e.g., needed) a premedication or prophylactic medication, e.g., as described above, prior to the start of any infusion following 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 did not receive (e.g., needed) a premedication 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., requires) administration of a medication for the purpose of preventing or minimizing IR post-medication, i.e., after completion of infusion (e.g., within at least about any of 0.5, 1.0, 1.5, 2.0, 2.5, or 3.0 hours (including any ranges therebetween) of the infusion) of a 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) dose of the anti-CD38 antibody (e.g., isatuximab) in a volume of 250 ml. In some embodiments, the subject does not receive (e.g., requires) subsequent medication, e.g., for the purpose of preventing or minimizing IR, for at least about any of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 6.0, 9.0, 12.0, 18.0, 21.0, or 24.0 hours, including any ranges therebetween, following completion of the infusion of a 10 mg / kg dose of the anti-CD38 antibody (e.g., isatuximab) in a volume of 250 ml. In some embodiments, the subject does not receive (e.g., requires) a subsequent medication, e.g., as described above, after completion (e.g., within at least about any 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) of the first, second, third, fourth, and / or fifth infusion of a 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) dose of the anti-CD38 antibody in a volume of 250 ml. In some embodiments, the subject does not receive (e.g., requires) a subsequent medication, e.g., as described above, after completion of the first, second, third, and / or fourth infusion of a 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) dose of the anti-CD38 antibody in a volume of 250 ml (e.g., within at least about any 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., requires) a subsequent medication, e.g., as described above, after 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 is completed (e.g., within at least about any 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 subject does not receive (e.g., requires) a subsequent medication, e.g., as described above, after completion of any infusion following the third infusion of a 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) dose of the anti-CD38 antibody in a volume of 250 ml (e.g., within at least about any 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). In some embodiments, the subject does not receive (e.g., requires) subsequent medication, e.g., as described above, after any infusion of a 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) dose of the anti-CD38 antibody in a volume of 250 ml is completed (e.g., within at least about any 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 premedication or postmedication with any one or more of the following for the purpose of preventing or minimizing IR prior to infusion of the anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) in a 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).

[0191] In some embodiments, after administering the anti-CD38 antibody (such as isatuximab), the individual experiences a mild IR. In some embodiments, mild IR is no more than grade 1 or 2 IR, as defined in the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE v.4.03). NCI-CTCAE v.4.03 is publicly available online at evs(dot)nci(dot)nih(dot)gov / ftp1 / CTCAE / About(dot)html. In some embodiments, if the individual experiences a mild transient reaction (e.g., one or more of the signs / symptoms described herein, such as within 24 hours of starting infusion), where interruption of the infusion is not indicated and / or where intervention is not indicated, then IR is a grade 1 IR. In some embodiments, IR is a Grade 2 IR if the individual experiences a reaction (e.g., one or more of the signs / symptoms described herein, such as within 24 hours of starting the infusion), wherein the infusion is interrupted and / or wherein intervention is indicated, and wherein the individual responds promptly to treatment (i.e., treatment of one or more signs or symptoms of IR, such as those described herein), such as within about any of 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 hours of treatment for IR, including any ranges therebetween. In some embodiments, treatment for IR includes one or more of the following: short-term interruption of the infusion, administration of oxygen, administration of a bronchodilator, administration of a corticosteroid, administration of a histamine blocker, and restarting the infusion at a slower rate.

[0192] In some embodiments, the individual experiences a mild IR (e.g., Grade 1 or 2 IR) during or after the first intravenous infusion of an anti-CD38 antibody (e.g., isatuximab) of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) in a fixed volume of 250 ml, e.g., during the infusion on Day 1 of the first 28-day cycle. In some embodiments, the individual does not experience an IR (or does not experience another IR) during the second or subsequent infusion of an anti-CD38 antibody (e.g., isatuximab) in a fixed volume of 250 ml. For example, in some embodiments, the individual does not experience an IR (or does not experience another IR) during the infusion of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) of the 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.

[0193] In some embodiments, after the anti-CD38 antibody is infused with a volume of 250 ml, for example, according to the methods described herein, the individual does not experience moderate or severe IR. In some embodiments, the individual does not experience IR of grade 3, grade 4, or grade 5 as defined in the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE v.4.03). In some embodiments, if the individual experiences prolonged IR signs / symptoms (as described herein) and does not react quickly to medication for IR and / or to interrupting infusion, IR is grade 3 IR. In some embodiments, if the individual experiences recurrence of IR signs / symptoms (as described herein) after initial improvement, IR is grade 3 IR. In some embodiments, if the individual needs to be hospitalized for IR signs / symptoms (as described herein), IR is grade 3 IR. In some embodiments, if signs / symptoms (as described herein) are life-threatening and / or require emergency intervention, IR is grade 4 IR. In some embodiments, if IR signs / symptoms lead to death, IR is grade 5 IR.

[0194] In some embodiments, the subject does not experience any grade of IR (e.g., Grade 1, 2, 3, 4, or 5 IR) during or after the fourth intravenous infusion of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) of the anti-CD38 antibody (e.g., isatuximab) in a fixed volume of 250 ml. Additionally or alternatively, in some embodiments, the subject does not experience any grade of IR (e.g., Grade 1, 2, 3, 4, or 5 IR) during or after any intravenous infusion of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) of the anti-CD38 antibody (e.g., isatuximab) in a fixed volume of 250 ml after the fourth intravenous infusion. In some embodiments, the subject does not experience IR (or does not experience another IR) during or after the fourth infusion of the anti-CD38 antibody (e.g., isatuximab) in a fixed volume of 250 ml. For example, in some embodiments, the individual does not experience IR (or does not experience another IR) during an infusion of 10 mg / kg (e.g., at least 10 mg / kg, or 20 mg / kg) of the anti-CD38 antibody (such as isatuximab) in a fixed volume of 250 ml on day 22 of the first 28-day cycle and on any of days 1 and 15 of any subsequent 28-day cycle (i.e., after the first 28-day cycle).

[0195] In some embodiments, the dose of the anti-CD38 antibody (such as isatuximab) administered to the individual in a fixed 250 ml volume is not reduced during treatment, eg, regardless of whether the individual experiences IR.

[0196] In some embodiments, the anti-CD38 antibodies described herein (such as isatuximab) are in a formulation (pH 6.0) comprising about 20 mg / mL antibody, about 20 mM histidine, about 10% (w / v) sucrose, about 0.02% (w / v) polysorbate 80. In some embodiments, the anti-CD38 antibodies described herein (such as isatuximab) are 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 formulation (i.e., 100 mg anti-CD38 antibody). In some embodiments, the 5ml preparation of single use is provided in a type 6mL colorless transparent glass bottle of, for example, a rubber stopper. In some embodiments, the filling volume of the bottle has been determined to ensure that 5mL is taken out. In some embodiments, the filling volume is 5.4mL. In some embodiments, the single use of the preparation comprises a 25ml preparation (i.e., 500mg anti-CD38 antibodies). In some embodiments, the 25ml preparation of single use is provided in a 30mL colorless transparent glass bottle of, for example, a rubber stopper. In some embodiments, the filling volume of the bottle has been determined to ensure that 25mL is taken out. In some embodiments, at a temperature between about 2°C and about 8°C and in the absence of light, the preparation is stable for at least about 6, 12, 18, 24, 30, or 36 months, including any range between these values. In some embodiments, the preparation is diluted for infusion in 0.9% sodium chloride, 5% glucose, or 5% dextrose. In some embodiments, the diluted infusion solution is stable for up to about 6, 12, 18, 24, 30, 36, 42 or 48 hours, including any range between these values, between about 2 ° C and about 8 ° C. In some embodiments, the diluted solution for infusion is stable after storage (for example, for up to about 6, 12, 18, 24, 30, 36, 42 or 48 hours, including any range between these values) between about 2 ° C and about 8 ° C, and is stable for 8 hours (including the infusion time) at room temperature. In some embodiments, the diluted solution for infusion is stable in the presence of light. In some embodiments, the bag for storing the diluted solution for infusion is made of polyolefin (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) or ethylene vinyl acetate (EVA) with di(ethylhexyl) phthalate (DEHP).In some embodiments, tubing used for infusion is made of PE, PVC (with or without DEHP), polybutadiene (PBD), or polyurethane (PU), with an in-line filter (polyethersulfone (PES), polysulfone, or nylon).

[0197] For administration to patients, dilute an appropriate volume of isatuximab in 0.9% sodium chloride solution, 5% glucose, or 5% dextrose in an infusion bag. Storage in the infusion bag does not require protection from light. Store the investigational medicinal product at +2°C to +8°C.

[0198] In some embodiments, an intravenous (IV) bag is provided 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). In some embodiments, the 10 mg / kg dose of an anti-CD38 antibody (e.g., isatuximab) is calculated based on the body weight of the patient to whom the anti-CD38 antibody is administered. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is diluted to 0.9% sodium chloride, 5% glucose, or 5% dextrose from a concentrated formulation (e.g., a formulation described herein). In some embodiments, the bag contains between about 360 mg and about 1600 mg, between about 450 mg and about 16000 mg, between about 450 mg and 1140 mg, or between about 450 mg and about 910 mg, including any range between these values.

[0199] Treatment consists of administering an anti-CD38 antibody at a dose of 10 mg / kg or 20 mg / kg

[0200] Also provided herein are methods of treating multiple myeloma (such as relapsed multiple myeloma or relapsed and refractory multiple myeloma) or delaying progression of multiple myeloma in an individual (e.g., a human individual), the method comprising administering to the individual an anti-CD38 antibody (e.g., an anti-CD38 antibody comprising: (a) a heavy chain variable domain (VH) comprising: a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising: a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 6). NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6) and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:5) and wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg on day 1, day 8, day 15 and day 22 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered by intravenous infusion in one or more subsequent 28-day cycles after the first 28-day cycle, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg on day 1 and day 15 of each of one or more subsequent 28-day cycles after the first 28-day cycle. In some embodiments, the treatment results in a reduction in serum M protein from baseline of at least about any one of the following: 40%, 45%, 50%, 55%, 60%, 65% or greater than 65%. In some embodiments, the treatment results in a reduction in serum M protein from baseline of at least about 52%. In some embodiments, serum M protein levels decrease after about two treatment cycles. In some embodiments, the anti-CD38 antibody comprises: a heavy chain variable region (V H ) and a light chain variable region (V L In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the anti-CD38 antibody is not administered in combination with a second drug (ie, the anti-CD38 antibody is administered as a monotherapy).

[0201] Also provided herein are methods of treating multiple myeloma (such as relapsed multiple myeloma or relapsed and refractory multiple myeloma) or delaying progression of multiple myeloma in an individual (e.g., a human individual), the method comprising administering to the individual an anti-CD38 antibody (e.g., an anti-CD38 antibody comprising: (a) a heavy chain variable domain (VH) comprising: a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising: a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 6). NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6) and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:5) and wherein the anti-CD38 antibody is administered at a dose of 20 mg / kg on day 1, day 8, day 15 and day 22 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered by intravenous infusion in one or more subsequent 28-day cycles after the first 28-day cycle, wherein the anti-CD38 antibody is administered at a dose of 20 mg / kg on day 1 and day 15 of each of one or more subsequent 28-day cycles after the first 28-day cycle. In some embodiments, the treatment results in a reduction in serum M protein from baseline of at least about any one of the following: 40%, 45%, 50%, 55%, 60%, 65% or greater than 65%. In some embodiments, the treatment results in a reduction in serum M protein from baseline of at least about 52%. In some embodiments, serum M protein levels decrease after about two treatment cycles. In some embodiments, the anti-CD38 antibody comprises: a heavy chain variable region (V H ) and a light chain variable region (V L In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the anti-CD38 antibody is not administered in combination with a second drug (ie, the anti-CD38 antibody is administered as a monotherapy).

[0202] 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., 7, 8, 9, 10, 11, or 12 prior therapies). In some embodiments, the prior therapy for multiple myeloma is an immunomodulatory drug (e.g., lenalidomide, pomalidomide, and / or thalidomide). In some embodiments, the individual is refractory to immunomodulatory drugs. In some embodiments, the prior therapy for multiple myeloma is a proteasome inhibitor (e.g., bortezomib, carfilzomib, and / or ixazomib). In some embodiments, the individual is refractory to proteasome inhibitors. In some embodiments, the individual receives prior therapy with an immunomodulatory drug and a proteasome inhibitor. In some embodiments, the immunomodulatory drug and the proteasome inhibitor are administered in combination. In some embodiments, the immunomodulatory drug and the proteasome inhibitor are administered during separate therapies (e.g., separate treatment regimens). In some embodiments, the individual is refractory to immunomodulatory drugs and proteasome inhibitors.

[0203] In some embodiments, the individual has at least one high-risk cytogenetic abnormality (e.g., before starting 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.

[0204] Other characteristics of individuals receiving treatment containing anti-CD38 antibodies

[0205] In some embodiments, the individual exhibited progressive disease during the most recent prior therapy (or line of treatment) (e.g., the therapy (or line of treatment) immediately prior to initiating a treatment described herein that included administration of the anti-CD38 antibody (e.g., isatuximab)). In some embodiments, the individual exhibited progressive disease (PD) within 60 days of the end of the most recent prior therapy (or line of treatment) for multiple myeloma (e.g., the therapy (or line of treatment) immediately prior to initiating a treatment described herein that included administration of the anti-CD38 antibody (e.g., isatuximab)). In some embodiments, progressive disease (PD) is defined according to 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, a line of treatment is ≥1 complete cycle of a single agent, or a combination of two or more agents, or a planned continuous therapy that includes a stem cell transplant. In some embodiments, a given treatment is considered a new line of treatment if any one of the following three conditions is met:

[0206] 1. Starting a new line of treatment after a previous line has been discontinued. If a treatment regimen is discontinued for any reason and a different regimen is started, the different regimen may be considered a new line of treatment. For example, if all drugs in a regimen have been discontinued, then the given regimen is considered to have been discontinued. For example, if some but not all drugs in a regimen have been discontinued, then the regimen is considered to have not been discontinued. In some embodiments, the reason for discontinuation, addition, substitution, or SCT does not affect how treatment lines are counted. Reasons for changes may include, for example, the end of planned therapy, toxicity, progression, lack of response, or inadequate response.

[0207] 2. Unplanned addition or substitution of one or more drugs in an existing regimen. The unplanned addition of a new drug or switch to a different drug (or drug combination) for any reason can be considered a new line of treatment.

[0208] 3. Stem cell transplantation (SCT): In patients who have undergone >1 SCT, except in the case of planned tandem SCT with a predetermined interval (such as 3 months), each SCT (autologous or allogeneic) can be considered a new line of treatment, regardless of whether the conditioning regimen used is the same or different. Generally, planned tandem SCT is considered 1 line of treatment. Generally, planned induction and / or consolidation, maintenance with any SCT (frontline, relapse, autologous or allogeneic) is considered 1 line of treatment.

[0209] In some embodiments, multiple myeloma is difficult to treat. In some embodiments, the individual suffers from refractory multiple myeloma. In some embodiments, the individual with refractory multiple myeloma is an individual who is refractory to all previous therapies (or previous treatment lines), but has a minimal response (MR) to at least one previous therapy (or treatment line). In some embodiments, minimal response (MR) is based on 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 multiplemyeloma.Leukemia.20:1467-1473; and Table 14 herein). In some embodiments, the individual with refractory multiple myeloma is an individual who has not responded to a previous therapy (or a previous treatment line). In some embodiments, being "unresponsive" to a therapy (or treatment line) for multiple myeloma means that the individual has failed to produce a minimal response (MR) to the therapy (or treatment line) for multiple myeloma. In some embodiments, being "unresponsive" to a therapy (or treatment line) for multiple myeloma means that the individual has shown progressive disease during the therapy (or treatment line) for multiple myeloma. In some embodiments, the individual with refractory multiple myeloma is an individual who has shown progressive disease within 60 days from the end of the last therapy for multiple myeloma.

[0210] In some embodiments, the individual did not respond to prior treatment for multiple myeloma (e.g., lenalidomide and / or a proteasome inhibitor). In some embodiments, prior treatment “did not respond” means that the individual showed disease progression (e.g., according to the criteria in Table A) during or within 60 days of the end of treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor). In some embodiments, prior treatment for multiple myeloma “did not respond” means that the individual showed a partial response (PR) or better to treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor) (e.g., according to the criteria in Table A), but exhibited disease progression within 6 months of discontinuing treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor). In some embodiments, "failure" to prior treatment for multiple myeloma means that the individual developed toxicity / intolerance after a minimum of 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 means the development of peripheral neuropathy or neuropathic pain in an individual (e.g., an individual who did not have peripheral neuropathy prior to starting the regimen). In some embodiments, intolerance to a lenalidomide-containing regimen means the development of a severe rash in an individual.

[0211] 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 treatment line) for multiple myeloma and is refractory to the most recent therapy (or treatment line) 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 treatment line) for multiple myeloma and is refractory to the most recent therapy (or treatment line) for multiple myeloma and is refractory to one or more therapies (or treatment lines) prior to the most recent therapy (or treatment line) for multiple myeloma. In some embodiments, the individual with relapsed or refractory multiple myeloma is an individual who shows progressive disease within 60 days after the end of the most recent therapy (or treatment line).

[0212] In some embodiments, the individual is refractory to a recent prior therapy (or line of treatment).

[0213] In some embodiments, the individual has relapsed / refractory multiple myeloma (RRMM) with measurable disease (e.g., serum M-protein ≥ 0.5 g / dL as measured by serum protein immunoelectrophoresis; and / or urine M-protein ≥ 200 mg / 24 hours as measured by urine protein immunoelectrophoresis; and / or serum free light chains (FLC) (i.e., FLC assay ≥ 10 mg / dl (≥ 100 mg / L) and abnormal serum FLC ratio (< 0.26 or > 1.65)), the individual has received at least 2 prior therapies including lenalidomide and a proteasome inhibitor (e.g., bortezomib, carfilzomib, or ixazomib), and is refractory to the last line of treatment (i.e., most recent line of treatment). In some embodiments, the individual has adequate renal, hepatic, and bone marrow function.

[0214] In some embodiments, the individual has a poor prognosis. In some embodiments of the methods and uses provided herein, the individual has received at least one, at least two, at least three, at least four prior therapies (or treatment lines), or more than four prior therapies (or treatment lines), e.g., at least any one of 5, 6, 7, 8, 9, 10, or 11 prior therapies (or treatment lines), for multiple myeloma.

[0215] In some embodiments, the individual has experienced at least one previous therapy (or treatment line) using lenalidomide. In some embodiments, the previous lenalidomide therapy (or treatment line) includes at least two consecutive cycles of lenalidomide. In some embodiments, the previous lenalidomide therapy (or treatment line) is ineffective for the individual (e.g., no response). In some embodiments, the individual for whom the previous lenalidomide therapy (or treatment line) is ineffective does not produce at least a minimal response (MR) during the therapy (or treatment line) using lenalidomide. In some embodiments, the individual for whom the previous lenalidomide therapy (or treatment line) is ineffective shows progressive disease (PD) during the therapy (or treatment line) using lenalidomide. As described elsewhere herein, in some embodiments, “minimal response” and “progressive disease” are assessed according to the criteria in Kumar et al. (2016) “International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol. 17(8): e328-e346; and Durie et al. (2006) “International uniform response criteria for multiple myeloma.Leukemia.20:1467-1473 (see also Table 14 herein). In some embodiments, prior lenalidomide therapy is administered during the first, second, third, fourth, fifth, sixth, and / or subsequent therapy (or treatment line) for multiple myeloma (i.e., prior to treatment described herein including administration of an anti-CD38 antibody (e.g., isatuximab)). In some embodiments, the individual is refractory to lenalidomide. In some embodiments, lenalidomide is previously administered to the individual as a single agent. In some embodiments, lenalidomide is previously administered to the individual in combination with at least one additional agent.

[0216] In some embodiments, the individual has undergone at least one prior therapy (or at least one prior treatment line) 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 therapy (or treatment line) with a proteasome inhibitor includes at least two consecutive cycles of a proteasome inhibitor. In some embodiments, the prior proteasome inhibitor therapy (or prior treatment line) was ineffective (e.g., no response) for the individual. In some embodiments, the individual for whom the prior therapy (or treatment line) with a proteasome inhibitor was ineffective did not produce at least a minimal response (MR) during the therapy (or treatment line) with a proteasome inhibitor. In some embodiments, the individual for whom the prior therapy (or treatment line) with a proteasome inhibitor was ineffective showed progressive disease (PD) during the therapy (or treatment line) with a proteasome inhibitor. In some embodiments, the prior proteasome inhibitor therapy was administered during the first, second, third, fourth, fifth, sixth, and / or subsequent therapy (or treatment line) for multiple myeloma (i.e., prior to the treatment described herein including administration of an anti-CD38 antibody (e.g., isatuximab)). In some embodiments, the individual is refractory to a proteasome inhibitor (e.g., such as one or more proteasome inhibitors). In some embodiments, the individual was previously administered a proteasome inhibitor therapy as a single agent. In some embodiments, the individual was previously administered a proteasome inhibitor therapy in combination with at least one additional agent.

[0217] In some embodiments, the individual has received at least two prior therapies (or treatment lines) comprising lenalidomide (as described elsewhere herein) and a proteasome inhibitor (as described elsewhere herein). In some embodiments, the individual also shows disease progression while the most recent prior therapy is ongoing or after the most recent prior therapy is completed (e.g., before treatment as described herein including administration of an anti-CD38 antibody (e.g., isatuximab)). In some embodiments, lenalidomide and a proteasome inhibitor are administered to the individual in combination. In some embodiments, the individual previously had a partial response (PR) or greater response to lenalidomide and / or a proteasome inhibitor (administered alone or in combination), but showed progressive disease (PD) within 6 months of the completion of the therapy (or treatment line) using lenalidomide and / or a proteasome inhibitor.

[0218] In some embodiments, the individual has received prior therapy (or at least one prior line of treatment) with pomalidomide.

[0219] In some embodiments, the individual suffers from respiratory disorders, chest disorders and / or mediastinal disorders. In some embodiments, the individual suffers from chronic obstructive pulmonary disease (COPD). In some embodiments, before starting treatment described herein including administering the anti-CD38 antibody (e.g., aisatuximab), the individual is diagnosed with COPD. In some embodiments, after starting treatment described herein including administering the anti-CD38 antibody (e.g., aisatuximab), the individual develops and / or is diagnosed with COPD. In some embodiments, the individual suffers from asthma. In some embodiments, before starting treatment described herein including administering the anti-CD38 antibody (e.g., aisatuximab), the individual is diagnosed with asthma. In some embodiments, after starting treatment described herein including administering the anti-CD38 antibody (e.g., aisatuximab), the individual develops and / or is diagnosed with asthma. In some embodiments, the individual suffers from (e.g., experiences) bronchospasm. In some embodiments, the individual experiences bronchospasm prior to initiating a treatment described herein comprising administering the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual develops bronchospasm after initiating a treatment described herein comprising administering the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual suffers from one or more of the following: bronchial hypersensitivity, cough, dyspnea, dyspnea at rest, dyspnea on exertion, emphysema, hypoxia, pulmonary infiltrates, oropharyngeal pain, pleural effusion, pleural pain, pulmonary embolism, pulmonary hypertension, allergic rhinitis, and rhinorrhea. In some embodiments, prior to initiating a treatment described herein comprising administering the anti-CD38 antibody (e.g., isatuximab), the individual experienced one or more of the following: bronchial hypersensitivity, cough, dyspnea, dyspnea at rest, dyspnea on exertion, emphysema, hypoxia, pulmonary infiltrates, oropharyngeal pain, pleural effusion, pleural pain, pulmonary embolism, pulmonary hypertension, allergic rhinitis, and rhinorrhea. In some embodiments, after initiating a treatment described herein comprising administering the anti-CD38 antibody (e.g., isatuximab), the individual developed one or more of the following: bronchial hypersensitivity, cough, dyspnea, dyspnea at rest, dyspnea on exertion, emphysema, hypoxia, pulmonary infiltrates, oropharyngeal pain, pleural effusion, pleural pain, pulmonary embolism, pulmonary hypertension, allergic rhinitis, and rhinorrhea.

[0220] In some embodiments, the individual does not suffer from primary refractory multiple myeloma. In some embodiments, the individual suffering from primary refractory multiple myeloma is an individual who has never produced at least a minimal response (MR) to any therapy (or treatment line) during the course of the disease. In some embodiments, the individual does not suffer from a disease in which only free light chains (FLC) are measurable. In some embodiments, the individual has not received a previous treatment with an anti-CD38 antibody. In some embodiments, the individual has not received a previous treatment with isatuximab (or a previous treatment line). In some embodiments, during the previous treatment with an anti-CD38 antibody (or a previous treatment line), the individual did not show progressive disease (PD). In some embodiments, within 60 days after the end of the treatment with an anti-CD38 antibody (or treatment line), the individual did not show PD. In some embodiments, the individual has not received a previous treatment with pomalidomide (or a previous treatment line). In some embodiments, the individual has not received a previous allogeneic hematopoietic stem cell transplant.

[0221] In some embodiments, the individual is less than 65 years old. In some embodiments, the individual is between 65 years old and less than 75 years old. In some embodiments, the individual is 75 years old or older. In some embodiments, the individual is female (e.g., a female of childbearing age with fertility). In some embodiments, the individual has an Eastern Cooperative Oncology Group (ECOG) performance status score of no greater than 0, no greater than 1, or no greater than 2. In some embodiments, the individual is in stage I, stage II, or stage III according to the International Staging System (ISS) for multiple myeloma.

[0222] Single-agent and combination therapy

[0223] In some embodiments, the treatment methods described herein comprise administering an anti-CD38 antibody (e.g., isatuximab) as a single agent (e.g., as a 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 can be a small molecule drug or a biologic, such as an antibody.

[0224] In some embodiments, the at least one additional agent comprises an immunomodulatory drug In some embodiments, the drug is administered in conjunction with an anti-CD38 antibody (e.g., isatuximab). is thalidomide, lenalidomide and / or pomalidomide. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) and the immunomodulatory drug are further administered in combination with a corticosteroid (e.g., 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), the immunomodulatory drug (e.g., lenalidomide) and the corticosteroid (e.g., dexamethasone) are further administered in combination with an anticoagulant (e.g., aspirin, warfarin or heparin).

[0225] In some embodiments, the at least one additional agent comprises a proteasome inhibitor. In some embodiments, the proteasome inhibitor administered in conjunction with the anti-CD38 antibody (e.g., isatuximab) is bortezomib, carfilzomib, ixazomib citrate, marizomib, and / or olozomib. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) and the proteasome inhibitor are further administered in conjunction with a corticosteroid (e.g., dexamethasone or prednisone). In some embodiments, the anti-CD38 antibody (e.g., isatuximab) and the proteasome inhibitor are administered in conjunction with (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 the 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, melphalanflufenamide, melphalan hydrochloride, thiotepa, trioxalic acid). In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered in combination with bortezomib, lenalidomide and dexamethasone.

[0226] Additionally or alternatively, in some embodiments, the 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, the at least one additional agent comprises an anthracycline, such as, but not limited to, daunorubicin, doxorubicin hydrochloride, idarubicin, liposomal doxorubicin hydrochloride, mitoxantrone, pegylated liposomal doxorubicin, or pegylated liposomal doxorubicin hydrochloride. Additionally or alternatively, in some embodiments, the 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.

[0227] Products or kits

[0228] In another embodiment of the present invention, an article or kit comprising an anti-CD38 antibody (such as isatuximab) is provided. In some embodiments, the article or kit further comprises a package insert comprising instructions for treating multiple myeloma (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma) or delaying the progression of multiple myeloma using an anti-CD38 antibody (e.g., isatuximab) in individuals who have received at least two prior therapies for multiple myeloma (e.g., including lenalidomide and a proteasome inhibitor). In some embodiments, the article or kit further comprises a package insert or label comprising instructions for administering one or more 10 mg / kg doses of an anti-CD38 antibody (such as isatuximab) according to the methods described herein, wherein each dose is in a volume of 250 ml. In some embodiments, the article or kit further comprises a package insert or label comprising instructions for administering 20 mg / kg of an anti-CD38 antibody (such as isatuximab).

[0229] The description is to be considered 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 hereby incorporated by reference in their entirety for all purposes.

[0230] Example 1A: Preliminary results from a phase 1b study evaluating the feasibility and safety of a short-duration, fixed-volume infusion of esatuximab in combination with pomalidomide and dexamethasone in patients with relapsed and / or refractory multiple myeloma.

[0231] This example describes a multicenter, open-label, non-comparative Phase 1b study evaluating simplified infusion administration 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 previously been exposed to proteasome inhibitors and immunomodulatory drugs and were relapsed / refractory to the most recent therapy.

[0232] I. Research Objectives

[0233] The primary objective of the study was to evaluate the feasibility of isatuximab (I) given from a fixed infusion volume in combination with pomalidomide and dexamethasone (Pd), as assessed by the occurrence of grade ≥3 infusion reactions (IR).

[0234] The secondary objectives of the study were: (1) to evaluate the infusion duration of isatuximab given in combination with Pd at a fixed infusion volume; (2) to evaluate the safety profile of Pd given in combination 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 isatuximab with Pd in terms of overall response rate (ORR, i.e., CR+VGPR+PR) and clinical benefit rate (CBR, i.e., CR+VGPR+PR+MR) based on the International Myeloma Working Group (IMWG) response criteria and duration of response in RRMM patients (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.).

[0235] The exploratory objectives of this study were: (1) to investigate multiple myeloma molecular subtypes (as defined by cytogenetics) and clinical responses; (2) to investigate the relationship between immunogenetic determinants, immunophenotype, and parameters of clinical response; (3) to assess minimal residual disease (MRD) in patients who achieved a complete response (CR) and correlate with clinical outcomes (see Table 14); and (4) to investigate the potential interference of isatuximab with M-protein assessment in immunoelectrophoresis and immunofixation assays.

[0236] II. Study Population

[0237] A. Inclusion Criteria

[0238] Eligible patients were considered for inclusion in the study if they met all of the following criteria:

[0239] - Patients have been previously diagnosed with multiple myeloma (MM) based on standard criteria and require treatment because MM has relapsed after a response according to IMWG criteria.

[0240] ●Patients have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and have shown disease progression on or after completion of the last therapy.

[0241] The patient has measurable disease defined as at least one of the following:

[0242] ○ Serum M protein ≥ 0.5 g / dL (≥ 5 g / L).

[0243] ○ Urine M protein ≥ 200 mg / 24 hours.

[0244] ○ Serum free light chain (sFLC) measurement: This involves an FLC measurement ≥10 mg / dL (≥100 mg / L) and an abnormal serum FLC ratio (<0.26 or >1.65).

[0245] All patients enrolled in the trial were enrolled and adhered to the POMALYST REMS TM All requirements for the program (www(dot)pomalystrems(dot)com).

[0246] B. Exclusion criteria

[0247] Patients meeting any of the following criteria were ineligible for the study:

[0248] Male or female patients are under 18 years old.

[0249] ● Patients diagnosed with or treated for another malignancy within 3 years prior to enrollment, with the exception of completely resected basal cell carcinoma or squamous cell carcinoma of the skin (malignancy in situ) or low-risk prostate cancer following curative therapy.

[0250] ●Patients with an Eastern Cooperative Oncology Group (ECOG) performance status score greater than 2 or a life expectancy of less than or equal to three months.

[0251] Clinical laboratory exclusion criteria: Patients were excluded if the screening laboratory results were as follows:

[0252] Absolute neutrophil count (ANC) < 1000 cells / μl (1.0x10 9 / L). Growth factors cannot be used within the previous 7 days.

[0253] ○ Aspartate aminotransferase (AST / SGOT) or alanine aminotransferase (ALT / SGPT) ≥ 2.5x upper limit of normal (ULN).

[0254] ○ Platelet count < 50 000 cells / μl (50 x 10 9 / L).

[0255] Total bilirubin >1.5x ULN.

[0256] ○ Creatinine clearance (CrCl) calculated according to the MDRD equation using <30 mL / min:

[0257] ■Glomerular filtration rate (mL / min / 1.73m 2 ) = 175 x (Scr) - 1.154 x (age) - 0.203 x (0.742 if female) x (1.212 if African American), where Scr is serum creatine (in mg / dL) and age is in years.

[0258] o Serum calcium levels above the ULN range (corrected for albumin). Treatment of hypercalcemia is permitted and patients are enrolled in the study if the hypercalcemia is normalized with standard therapy.

[0259] • Initially refractory or intolerant to prior therapy with any anti-CD38 monoclonal antibody (MoAb), or with disease progression during anti-CD38 MoAb given as last therapy (after achieving a response ≥ MR).

[0260] ●Received any study drug within 14 days or 5 half-lives of the study drug, whichever is longer.

[0261] ●Previous anticancer therapy within 14 days.

[0262] Any adverse reaction > Grade 1 that did not resolve from previous treatment according to NCI CTC AE v.4.03. The presence of alopecia or painless peripheral neuropathy ≤ Grade 2 was allowed.

[0263] ●Prior allogeneic stem cell transplant for active graft-versus-host disease (GVHD) or ongoing immunosuppressive therapy in the last 2 months before trial enrollment.

[0264] Daily corticosteroids as needed (equivalent to 10 mg / day of prednisone for more than seven consecutive days, unless the patient is taking inhaled corticosteroids and is receiving treatment / replacement therapy for adrenal insufficiency).

[0265] ●The patient is known to be human immunodeficiency virus (HIV) positive, hepatitis B surface antigen positive, or have active hepatitis C infection.

[0266] - Any clinically significant, uncontrolled medical condition that, in the opinion of the Investigator, would pose an excessive risk to the patient or could interfere with compliance or interpretation of the study results.

[0267] ●For the previous History of erythema multiforme or severe allergic reaction.

[0268] Yes History of allergy or intolerance to dexamethasone, sucrose, histidine (as base and hydrochloride), and polysorbate 80, or any component of study therapy, that is inappropriate for premedication with steroids and H2 blockers or would contraindicate further treatment with these agents.

[0269] Hypersensitivity to boron and / or mannitol (i.e., in cases where the investigational medicinal product (IMP) and / or non-investigational medicinal product (NIMP) contains boron and / or mannitol).

[0270] ●Inability to tolerate thromboprophylactic drugs.

[0271] III. Research Design

[0272] A. Primary Endpoint

[0273] The primary endpoint of the 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.

[0274] B. Secondary endpoints

[0275] The study's secondary endpoints are:

[0276] i. Duration of infusion time

[0277] The duration of infusion was measured from the start of isatuximab infusion to the end of isatuximab infusion, without considering temporary stops / interruptions.

[0278] ii. Safety and immunogenicity

[0279] Safety was assessed by collecting 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 ECOGPs. Patients were assessed for the presence of human anti-drug antibodies (ADA) to isatuximab. An adverse event was defined as any untoward medical occurrence in a patient administered a drug product that did not necessarily have a causal relationship to the study treatment.

[0280] iii. Efficacy

[0281] Efficacy was assessed according to the updated IMWG response criteria (see 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 evaluate the percentage of patients with an objective response (overall response rate), the clinical benefit response rate (CBR) using the IMWG-defined response criteria, and the duration of response.

[0282] C. Exploratory endpoints

[0283] Bone marrow and / or blood samples are analyzed for genomic analysis and multiple myeloma molecular subtypes (using cytogenetics), and bone marrow is analyzed for the level of CD38 mRNA. These markers are associated with clinical response. In addition, blood samples are subjected to cytogenetics analysis for immunogenetic determinants (such as Fc polymorphism, human leukocyte antigen (HLA) and killer immunoglobulin-like receptors (KIR) etc.) associated with clinical response. The correlation of the immune phenotype (such as B cells, T cells and natural killer (NK) cell subsets) in peripheral blood with the parameters of clinical response is also assessed. Finally, MRD is assessed by sequencing in CR patients and is associated with clinical outcome.

[0284] D. Statistical methods

[0285] The reported incidence of grade ≥3 IR determined the sample size. For a total of approximately 40 patients, if the lower bound of the 95% CI was >5.5%; that is, if ≥6 patients had grade ≥3 IR, the fixed infusion volume of isatuximab would not be considered feasible.

[0286] Statistical evaluation of all analyses was descriptive and based on all patients treated who completed at least 6 isatuximab infusions or terminated study treatment early (decisive end 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 was analyzed using the Clopper-Pearson method with 95% confidence intervals.

[0287] E. Duration of Study Participation

[0288] The study duration for individual patients includes a screening phase for inclusion of up to 21 days. The treatment phase continues until disease progression, unacceptable AEs, or other reasons for discontinuation. Patients are tracked for a minimum of 30 days after the last use of an investigational medicinal product / non-investigational medicinal product (IMP / NIMP), or for more than 30 days in the case of unresolved IMP / NIMP-related adverse events (AEs). For all patients, any adverse events related to the study treatment that were occurring at the time of study treatment discontinuation and all serious adverse events (SAEs) (regardless of their causal relationship with the study treatment) are tracked during the follow-up phase until they resolve or stabilize. The primary analysis deadline occurs when the last patient recruited completes six infusions. The final analysis deadline is 10 months after the date of the first dose of the last patient recruited.

[0289] After 10 cycles, no samples were collected for ADA analysis. If the last ADA sample was positive or inconclusive, additional ADA sampling was performed after 3 months. Even if the 3-month sample was positive, no further ADA sampling was performed.

[0290] F. Fixed Volume Infusion Schedule

[0291] like Figure 1As shown in , isatuximab is administered intravenously (IV) at a selected dose of 10 mg / kg from a fixed volume of 250 mL with an infusion rate expressed in ml / h in a one-step process. Fixed volumes are administered on days 1, 8, 15, and 22 of the first 28-day cycle. During each subsequent 28-day cycle, fixed volumes are administered on days 1 and 15. Patient weight is measured before each cycle to allow calculation of the isatuximab dose. Pomalidomide is administered orally on days 1-21 of each 28-day cycle. Dexamethasone is administered orally or intravenously on days 1, 8, 15, and 22 of each 28-day cycle. When dexamethasone is co-administered as part of a premedication, it is administered orally or intravenously before administering isatuximab. As described in more detail below, all patients receive pre-treatment prophylaxis for allergic reactions.

[0292] Grade 3 or higher IR was assessed during the first six isatuximab infusions. Patients experiencing a Grade 3 IR were permanently discontinued from study treatment and given appropriate supportive care. After the sixth infusion, patients continued study treatment until disease progression, unacceptable toxicity, or other reasons for discontinuation. As described in more detail below, if the patient met the criteria for starting a new cycle of therapy, the patient began an additional cycle.

[0293] G. Fixed volume infusion rate

[0294] First infusion: The first infusion is started at an infusion rate of 25 mL / hour. In the absence of IR after 1 hour of infusion, the infusion rate is 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 is restarted at half the initial infusion rate (12.5 mL / hour) until the IR improves to ≤ Grade 1. If symptoms do not recur after 30 minutes, the infusion rate is increased by 25 mL / hour increments every 30 minutes until the entire volume is infused.

[0295] Second infusion: The second infusion is started at a rate of 50 mL / hour. In the absence of Grade 2 IR after 30 minutes of infusion, the rate is increased by 100 mL / hour for 30 minutes, then to 200 mL / hour for 30 minutes, and then to 300 mL / hour until the full volume is infused. In the event of Grade 2 IR during the second infusion, the infusion is restarted at half the initial infusion rate (25 mL / hour) when the IR improves to ≤ Grade 1. If symptoms do not recur after 30 minutes, the infusion rate is increased by 50 mL / hour increments every 30 minutes until the full volume is infused.

[0296] Third and subsequent infusions: The third and subsequent infusions were started at a fixed infusion rate of 200 mL / hour until the full volume was infused. In the event of a Grade 2 IR during the third infusion, the infusion was restarted at half the infusion rate (100 mL / hour) until the IR improved to ≤ Grade 1. If symptoms did not recur after 30 minutes, the infusion rate was increased by 50 mL / hour increments every 30 minutes until the full volume was infused.

[0297] H. Investigational Medicinal Products (IMPs)

[0298] i. Isaatuximab

[0299] Isatuximab is an anti-CD38 antibody comprising a heavy chain containing the sequence of SEQ ID NO: 10 and a light chain containing the sequence of SEQ ID NO: 11. Isatuximab is supplied as a sterile, pyrogen-free, injectable, colorless concentrate in 30 mL glass vials fitted with rubber stoppers. Each vial contains 20 mg / mL (500 mg / 25 mL) of Isatuximab in 20 mM histidine, 10% (w / v) sucrose, 0.02% (w / v) polysorbate 80, pH 6.0 buffer. A white to off-white precipitate is permitted in the vial. Each vial contains a nominal amount of 500 mg of Isatuximab.

[0300] Isarituximab 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. During subsequent cycles, Isarituximab was administered on Days 1 and 15. Patient weight was measured before each cycle to allow calculation of the Isarituximab dose.

[0301] For administration to patients, dilute an appropriate volume of isatuximab in a 0.9% sodium chloride solution in an infusion bag. Storage in the infusion bag does not require protection from light. Store the investigational medicinal product at +2°C to +8°C.

[0302] ii. Pomalidomide

[0303] According to the pomalidomide prescribing information (available at www(dot)accessdata.fda(dot)gov / drugsatfda_docs / label / 2013 / 204026lbl(dot)pdf), pomalidomide capsules are administered orally at a dose of 4 mg on days 1-21 of each 28-day cycle.

[0304] iii. Dexamethasone

[0305] Dexamethasone (40 mg for patients younger than 75 years; 20 mg for patients 75 years or older) was administered orally (PO) or by IV infusion on Days 1, 8, 15, and 22 of each 28-day cycle.

[0306] I. Non-Investigational Medicinal Product (NIMP) – Premedication for the Prevention of Infusion Reactions (IR)

[0307] Patients routinely receive premedication prior to the isatuximab infusion to reduce the risk and severity of IR typically observed with monoclonal antibodies. Recommended premedications are: diphenhydramine, 25-50 mg, IV (or equivalent route, the intravenous route is preferred for at least the first four infusions); ranitidine, 50 mg, IV (or equivalent route); and acetaminophen, 650-1000 mg, PO 15-30 minutes (but not longer than 60 minutes) prior to the isatuximab infusion. Once the premedication regimen is completed, the isatuximab infusion is started.

[0308] In addition, 40 mg of dexamethasone (or 20 mg in patients ≥75 years of age) was administered PO or IV as part of the premedication before the administration of isatuximab. Because dexamethasone was also administered as an IMP on days 1, 8, 15, and 22 of each 28-day cycle during the days of isatuximab infusion, dexamethasone was administered only once before the isatuximab infusion, and a single administration was used for both premedication and study treatment. The order of administering premedication is provided below:

[0309] When administering dexamethasone PO, use the following sequence:

[0310] Dexamethasone 40 mg orally (or 20 mg orally for patients ≥75 years).

[0311] Acetaminophen (paracetamol) 650 mg to 1000 mg orally.

[0312] Ranitidine 50 mg IV (or equivalent).

[0313] Diphenhydramine 25 mg to 50 mg IV (or equivalent).

[0314] When giving IV dexamethasone, use the following sequence:

[0315] Acetaminophen (paracetamol) 650 mg to 1000 mg orally.

[0316] Ranitidine 50 mg IV (or equivalent).

[0317] Diphenhydramine 25 mg to 50 mg IV (or equivalent).

[0318] Dexamethasone 40 mg IV (or 20 mg IV for patients ≥75 years).

[0319] For patients who could not tolerate dexamethasone during study treatment or if dexamethasone was discontinued prematurely, methylprednisolone 100 mg IV was given only as premedication. However, both drugs were not used simultaneously for premedication purposes.

[0320] J. Dose Delays, Omissions, and / or Modifications

[0321] i. Isaatuximab

[0322] Dose reductions were not approved for isatuximab. If a dose reduction of isatuximab occurred, the patient was withdrawn from study treatment unless a clear benefit from therapy was observed.

[0323] If toxicity occurs during a cycle and does not recover by the scheduled infusion day, the patient will skip the dose of isatuximab. In such cases, the infusion can be delayed for up to 3 days. Otherwise, the infusion is skipped and the patient receives the next isatuximab infusion after recovery from the toxicity. Each patient is allowed to skip no more than two consecutive isatuximab infusions.

[0324] Stopping and changing the infusion rate of isatuximab in response to IR is permitted as follows:

[0325] Grade 1 IR: No infusion interruption or intervention is indicated for patients experiencing a Grade 1 IR. However, if discontinuation of the infusion is deemed necessary, the IR is classified as a Grade 2.

[0326] Grade 2 IR: For patients experiencing Grade 2 IR, infusion interruptions and additional premedication are indicated as needed. Once Grade 2 IR improves to ≤ Grade 1, restart the infusion at half the initial infusion rate under close monitoring and supportive care as needed. If symptoms do not recur after 30 minutes, increase the infusion rate as follows:

[0327] During the first infusion, increase the dose by 25 mL / hour every 30 minutes until the entire volume is infused.

[0328] During the second infusion, increase the dose by 50 mL / hour every 30 minutes until the entire volume is infused.

[0329] During the third and subsequent infusions, increase by 50 mL / hour every 30 minutes until the entire volume is infused.

[0330] Grade 3 or 4 IR: Permanently discontinue isatuximab treatment in patients with Grade 3 or 4 IR and administer appropriate therapy.

[0331] ii. Pomalidomide

[0332] If toxicity occurs and does not recover on the scheduled infusion / administration day, omit one or several doses of pomalidomide within the cycle. For the first dose reduction, adjust the pomalidomide dose from the starting dose of 4 mg to 3 mg, for the second dose reduction to 2 mg, and for the third dose reduction to 1 mg. No more than three dose reductions of pomalidomide are allowed per patient. Once reduced, the dose should never be increased again. If a strong inhibitor of CYP1A2 is co-administered in the presence of a strong inhibitor of CYP3A4 and an inhibitor of P-glycoprotein, reduce the pomalidomide dose by 50%. If pomalidomide is permanently discontinued prematurely, continue to administer isatuximab until disease progression or unacceptable toxicity occurs, or the patient refuses further treatment.

[0333] iii. Dexamethasone

[0334] If toxicity occurs and does not recover on the planned infusion / administration day, omit one or several doses of dexamethasone during the cycle. For patients younger than 75 years of age, adjust the starting dose of dexamethasone from 40 mg to 20 mg for the first dose reduction, and to 12 mg for the second dose, to 8 mg for the third dose, and discontinue dexamethasone if further reductions are required. For patients 75 years of age or older, adjust the starting dose of dexamethasone from 20 mg to 12 mg for the first dose reduction, to 8 mg for the second dose, to 4 mg for the third dose, and discontinue dexamethasone if further reductions are required. Once reduced, the dose should never be increased again. If dexamethasone is permanently discontinued prematurely, continue to administer isatuximab until disease progression or unacceptable toxicity occurs, or the patient refuses further treatment.

[0335] K. Combination therapy

[0336] Administer standard prophylactic medications with antihistamines and antipyretics without post-infusion corticosteroid prophylaxis. Reconsider premedication after 4 infusions. Anticoagulant prophylaxis is indicated after evaluating each patient's underlying risk factors. All patients receive standard (e.g., prophylactic) antithrombotic therapy (unless contraindicated) unless there is an excessive bleeding risk.

[0337] L. The beginning of a new cycle

[0338] A cycle of study treatment was initiated if the following criteria were met:

[0339] ANC ≥ 1,000 / mm 3 G-CSF use was permitted during all cycles and on the same day as treatment administration.

[0340] Platelet count ≥50,000 / mm 3 Platelet transfusions were permitted during all cycles and were allowed on the same day as treatment administration.

[0341] Any IMP-related AE has resolved to less than Grade 1 severity or baseline.

[0342] Patients were re-evaluated weekly if the above criteria were not met on scheduled cycle day 1. Patients who did not meet the above criteria within 14 days of scheduled cycle day 1 were discontinued from study treatment.

[0343] IV. Results

[0344] A. Patient characteristics

[0345] Results include all patients who completed at least 6 infusions of isatuximab (2 cycles) or discontinued study treatment prematurely (definitive end of treatment). 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 discontinued treatment prematurely (Table 1).

[0346] As shown in Table 1, among the 10 patients (29.4%) who discontinued treatment prematurely, the reasons for definitive study treatment discontinuation were: disease progression (7 patients) and AEs (3 patients). One patient prematurely discontinued pomalidomide treatment, and no patient prematurely discontinued dexamethasone treatment.

[0347] Table 1: Number of patients and reasons for treatment discontinuation for all treated patients.

[0348]

[0349] Table 2 provides a summary of the demographic characteristics of the 34 patients treated. The median age was 64 years (range 46 to 85 years), and the majority of patients were <65 years (55.9%). There were 18 female patients and 16 male patients. Most patients were Caucasian (88.2%) and not Hispanic or Latin American (85.3%). All patients had an ECOGPS of 0 or 1, with only one patient (2.9%) having an ECOGPS of 2. At the time of entry into the study, the patient's weight ranged from 40 kg to 121 kg, with a median of 89.1 kg.

[0350] Table 2: Demographic characteristics of all treated patients.

[0351]

[0352] Table 2: Demographic characteristics of all treated patients.

[0353]

[0354] As shown in Table 3, when entering the study, the International Staging System (ISS) criteria for 15 (44.1%), 10 (29.4%) and 5 (14.7%) patients were respectively I stage, II stage and III stage. The ISS staging of 4 patients (11.8%) was unknown. Most patients (67.6%) had measurable serum M protein. The patient had a median of 12.6% (within the range of 0% to 96.0%) bone marrow plasma cells, and 47.1% of the patients had 20% to 50% bone marrow plasma cells. Most patients (67.6%) had bone lesions when baseline, and 10 (29.4%) patients had plasmacytomas present when baseline.

[0355] Table 3: Disease characteristics of all treated patients at study entry.

[0356]

[0357] Table 3: Disease characteristics of all treated patients at study entry.

[0358]

[0359] The most frequently reported conditions 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%) reported drug allergies in their medical history. Table 4 provides a summary of relevant respiratory history, which included asthma in 5 patients (14.7%), bronchial hyperresponsiveness in 1 patient (2.9%), and chronic obstructive pulmonary disease in 2 patients (5.9%).

[0360] Table 4: Summary of relevant respiratory history by system organ class and preferred term in all treated patients.

[0361]

[0362] As shown in Table 5, all patients had received immunomodulatory agents in previous lines of treatment. These included lenalidomide, pomalidomide, or thalidomide; proteasome inhibitors (PIs), including bortezomib, carfilzomib, ixazomib citrate, marizomib, or olozomib; and corticosteroids, including dexamethasone or prednisone. Twenty-nine patients (85.3%) received an alkylating agent (bendamustine, carmustine, cyclophosphamide, melphalan, or melphalanflufenamide) in their previous line of treatment. Fourteen (41.2%) and seven (20.6%) had previously received pomalidomide and carfilzomib, respectively. Before study entry, five (14.7%) and seven (20.6%) patients had received daratumumab (anti-CD38 monoclonal antibody) and elotuzumab (anti-SLAM7 monoclonal antibody), respectively.

[0363] Table 5: Prior anticancer treatment in all treated patients.

[0364]

[0365] Table 5: Prior anticancer treatment in all treated patients.

[0366]

[0367] B. Extent of exposure to isatuximab

[0368] Overall, the median number of isatuximab infusion cycles was 3.5 (min-max: 1 to 9), with 17 (50.0%) patients having initiated at least 4 cycles (minimum 9 infusions). The overall median duration of exposure was 13.4 weeks (min-max: 1 to 37). The median relative dose intensity (RDI) of isatuximab was 94.80% (69.8% to 112.9%) (Table 6). The median relative dose intensity of pomalidomide and dexamethasone was 84.7% and 87.5%, respectively.

[0369] Table 6: Overall exposure in all treated patients.

[0370]

[0371] Table 6: Overall exposure in all treated patients.

[0372]

[0373] C. Dose Modification and Discontinuation

[0374] As shown in Table 7, delays in the isatuximab infusion (within a cycle, excluding the first infusion of a cycle) occurred in 1 (3.0%) patient. Dose omissions occurred in 12 (35.3%) patients, and 16 of 146 (11.0%) cycles had one dose omission.

[0375] Seventeen (50.0%) patients had at least one infusion interruption, and overall, 17 of 317 (5.4%) infusions were temporarily interrupted before completion. All infusion interruptions occurred only during the first infusion (Table 7). The median time from the start of the infusion to the first interruption was 85 minutes (min-max: 46 to 145 minutes), with the majority of interruptions occurring between 61 and 90 minutes (6 interruptions) (Table 7). There were no dose reductions of isatuximab.

[0376] Table 7: Isaituximab dose modifications.

[0377]

[0378] Table 7: Isaituximab dose modifications.

[0379]

[0380] As shown in Table 8, of the seventeen patients with isatuximab infusion interruptions, 15 interruptions were due to treatment-emergent adverse events (TEAEs). There were no TEAEs ≥ Grade 3. The remaining two (5.9%) patients with infusion interruptions experienced food intolerance (G1 nausea and G1 vomiting) or technical issues, and their infusion interruptions were not related to IR. In both cases, the infusion was briefly interrupted but continued without reducing the infusion rate after restart and until completed as planned. Table 8: Treatment summary of emergency adverse events leading to isatuximab dose interruptions by major system organ class (SOC) and preferred term (PT) presented by all grades and ≥ Grade 3.

[0381]

[0382] Treatment-emergent adverse events (TEAEs)

[0383] As shown in Table 9, the median durations for the first and second infusions were 3.94 hours (min-max: 3.3 to 6.1 hours) and 1.88 hours (min-max: 1.5 to 3.5 hours), respectively. The median duration for each of the third, fourth, fifth, and sixth infusions was 1.27 hours. The median duration for the third and subsequent infusions administered at a fixed infusion rate of 200 mL / hour was 1.25 hours (min-max: 0.7 to 3.4 hours).

[0384] Table 9: Duration of infusion of isatuximab in all treated patients.

[0385]

[0386] Table 9: Duration of infusion of isatuximab in all treated patients.

[0387]

[0388] E. Infusion reactions

[0389] i. Infusion Reactions in All Treated Patients

[0390] Despite the short duration of infusion using fixed volumes, no grade 3 IR was reported and all IRs were grade 2. There were no treatment discontinuations due to IR. As shown in Table 10, IR was reported in 16 / 34 (47.1%) patients and in 16 / 317 (5.0%) infusions. All patients who experienced IR had only one episode of IR, and it occurred only during their first infusion of isatuximab. All episodes of IR occurred during the same day of isatuximab infusion, and all IRs recovered on the same day. IR that occurred in >2 patients was dyspnea and cough (n=6 each) and chills (n=3)

[0391] Table 10: Description of infusion reactions (general terminology as reported by the investigator).

[0392]

[0393] Table 10: Description of infusion reactions (general terminology as reported by the investigator).

[0394]

[0395] Table 10: Description of infusion reactions (general terminology as reported by the investigator).

[0396]

[0397] ii. Infusion reactions leading to interruption of the isatuximab infusion

[0398] Fifteen of the 16 patients with IR had their aisatuximab infusion interrupted. In the remaining patients who experienced grade 2 IR and grade 3 hypoxia (symptoms of IR), aisatuximab infusion was not interrupted, and hypoxia was managed by supplemental oxygen. The 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%). Most of the symptoms associated with IR were reported as grade 1 or 2, with the exception of grade 3 hypoxia and grade 3 dyspnea (each with 1 patient, 2.9%) (Table 11).

[0399] Table 11: Summary of infusion reactions (including symptoms as reported by the investigator) by primary SOC and PT presenting by all grades and grade ≥3.

[0400]

[0401] Table 11: Summary of infusion reactions (including symptoms as reported by the investigator) by primary SOC and PT presenting by all grades and grade ≥3.

[0402]

[0403] IR was managed by dose interruption and / or use of medication consisting of: H1 / H2 blockers, and / or paracetamol, and / or montelukast, and / or steroids. H1 / H2 blockers and steroids were each used in 9 / 16 patients (56.3%), paracetamol was used in 3 / 16 patients (18.8%), and montelukast was used in 1 / 16 patients (6.3%) (Table 12).

[0404] Table 12: List of IR and symptoms as reported by the investigator and subsequent medications.

[0405]

[0406] Table 12: List of IR and symptoms as reported by the investigator and subsequent medications.

[0407]

[0408] Subjects 840-017-203 and 840-017-206 received H1 / H2 blockers and steroids as medication for infusion reactions as per the safety complement protocol.

[0409] iii. Infusion reactions in patients with relevant medical and respiratory history

[0410] Of the seven patients previously exposed to daratumumab, three experienced IR.

[0411] Acceptable IR tolerability exists in patients with a history of bronchial disorders (asthma, bronchial hyperresponsiveness, COPD).

[0412] Seven patients (20.6%) had a history of bronchospasm and obstruction (see Table 4). As shown in Table 13, five of these seven patients experienced Grade 2 IR. Most frequently, IR was managed with bronchodilators and steroids.

[0413] Table 13: List of IR and their management in patients with bronchospasm and obstruction in history.

[0414]

[0415] F. immune response

[0416] Anti-drug antibodies (ADA) to isatuximab were assessed in patient plasma throughout the study using the PandA method in a 100 μl assay volume (Sanofi, Alfortville, France).

[0417] G. effect

[0418] Efficacy was assessed according to 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 evaluate the percentage of patients with an objective response (overall response rate "ORR"), as well as the clinical benefit response rate ("CBR") using the IMWG-defined response criteria, and the duration of response (DOR).

[0419] Overall response rate: ORR was defined as the proportion of patients with a 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:

[0420] Quantitative M protein (serum and 24-hour urine).

[0421] Serum free light chain levels.

[0422] Bone marrow biopsy / aspiration (if clinically indicated).

[0423] CT / MRI scan of plasmacytoma (if clinically indicated).

[0424] Skeletal survey (if clinically indicated).

[0425] Clinical benefit response rate: CBR was defined as the proportion of patients with sCR, CR, VGPR, PR, and minimal response (MR) according to the IMWG criteria (see Table 14).

[0426] Duration of Response: DOR was evaluated as the time from the date of first response to the date of subsequent progressive disease or death (whichever occurred first). In the absence of confirmed subsequent disease progression or death before the end of the study, the DOR was calibrated to the date of the last valid assessment before the end of the study or the date of initiation of new anticancer therapy (whichever occurred first). The DOR was determined only for patients who achieved a response of ≥ PR. The DOR was not calculated for patients who did not achieve a response.

[0427] Table 14: Standard International Myeloma Working Group (IMWG) response criteria

[0428]

[0429]

[0430] SPD, the sum of the products of the maximum perpendicular diameters of the measured lesions

[0431] Among the 31 patients who were 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 the results of the clinical trial NCT02990338.

[0432] H. Exploratory Analysis

[0433] Clinical response was analyzed for correlation with genomic analysis, multiple myeloma molecular subtype (using cytogenetics) and bone marrow CD38 mRNA levels in bone marrow and / or blood samples. In addition, blood samples were subjected to cytogenetics analysis for immunogenetic determinants such as Fc polymorphisms, human leukocyte antigens (HLA) and killer immunoglobulin-like receptors (KIR), and correlation with clinical response was determined. Finally, peripheral blood immunophenotypes such as B cell, T cell and natural killer (NK) cell subsets were evaluated for correlation with parameters of clinical response.

[0434] in conclusion

[0435] Compared to an infusion method consisting of a weight-based volume administered in mg / h, esatuximab administered with a fixed infusion volume of 250 ml using an infusion rate measured in mL / hour had a manageable safety profile and significantly shorter infusion time. In general, the safety profile of esatuximab administered using a simplified infusion method based on a fixed volume in mL / h, including infusion reactions, was manageable and consistent with the safety profile observed for other methods of esatuximab infusion (see, e.g., clinical trial NCT02990338), in which the infusion rate was measured in mg / h.

[0436] The study met its primary endpoint and no IR of grade ≥3 was observed. All IRs were grade 2, occurred during the first aisatuximab infusion, and resolved on the same day; no delayed onset IR was reported. For the third and subsequent infusions, the median infusion time for 10 mg / kg aisatuximab given with a fixed infusion volume of 250 ml using an infusion rate in mL / h was 75 minutes. This time was significantly shorter than the infusion time for aisatuximab given in mg / h (median was 174 minutes for the third and subsequent infusions). The general safety profile of the simplified infusion of Isa is favorable and consistent with previous observations of this Isa-Pd combination.

[0437] Example 1B: Further results from a Phase 1b study evaluating the feasibility and safety of a short-duration, fixed-volume infusion of esatuximab in combination with pomalidomide and dexamethasone in patients with relapsed and / or refractory multiple myeloma.

[0438] Further results of the Phase 1b study described in Example 1A are described below. Briefly, 47 patients were treated. The baseline characteristics of the patients are shown in Table 15 below. All patients had previously received lenalidomide, and 48.9% of patients had prior pomalidomide treatment. Prior daratumumab (Dara) exposure was documented in 14.9% of patients, and prior elotuzumab exposure was documented in 19.1% of patients. At study entry, the median length of 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.

[0439] Table 15. Patient demographics and disease characteristics

[0440]

[0441]

[0442] COPD, chronic obstructive pulmonary disease; IMID, immunomodulatory drug; ISS, international staging system

[0443] system; PI, proteasome inhibitor

[0444] At data cutoff, 30 (63.8%) patients were still on treatment, and 17 (36.2%) patients had discontinued treatment. Reasons for discontinuation were disease progression (n=10), adverse events (AEs; n=4), and other reasons (n=3).

[0445] Treatment exposure

[0446] The median number of cycles was 4.0, with 45 (95.7%) patients having initiated at least 2 cycles (minimum 5 infusions) and 31 (66.0%) patients having initiated at least 4 cycles (minimum 9 infusions). The overall median duration of exposure was 18.1 weeks (range 1–45). The median relative dose intensity of isatuximab, pomalidomide, and dexamethasone was 94.1%, 84.7%, and 87.5%, respectively.

[0447] Of the 490 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. The majority of dose reductions (85.7%) occurred during Cycle 2.

[0448] Infusion reactions

[0449] There were no grade ≥3 IR or treatment discontinuations due to IR. IR of any grade was reported in 19 / 47 (40.4%) patients and 19 / 490 (3.9%) infusions. In Part 1, 48.3% of patients receiving Isa 10 mg / kg experienced IR ( Figure 2 All IRs were grade 2 in severity, occurred during the first infusion of Isa, and all IRs recovered on the same day. IRs that occurred in >2 patients were dyspnea and cough (n=6 each) and chills (n=3). IRs were managed with dose interruptions in 18 (38.3%) patients and without dose interruption in 1 patient (2.1%).

[0450] In a parallel clinical trial designed to evaluate the efficacy of isatuximab + pomalidomide + dexamethasone in patients who had received at least two prior therapies for multiple myeloma, isatuximab was administered to study participants (n=31) according to a standard regimen with the isatuximab infusion rate measured in mg / hour. Figure 2 The left side of the Figure 5 shows the number of patients who experienced IR (ie, isatuximab was administered according to the standard regimen) in a parallel clinical trial. Figure 2The right side of the Figure shows the number of patients who experienced IR when asiltuximab was administered in a fixed volume of 250 ml in the clinical studies of the present invention (i.e., as described in Section III G of Example 1A). As discussed in Example 1A, the asiltuximab infusion rate was measured in ml / h. The percentage of patients who experienced ≥ Grade 2 IR during the first infusion in the studies of the present invention was 40.4%. In contrast, the percentage of patients who experienced ≥ Grade 2 IR (i.e., when asiltuximab was administered according to the standard regimen) in the parallel studies was 48.3%. No patient experienced Grade 3 IR during the first infusion in the feasibility and safety studies of the present invention. In contrast, 3.2% of patients in the parallel studies (i.e., when asiltuximab was administered according to the standard regimen) experienced Grade 3 IR during the first infusion.

[0451] All IR experienced by patients in the present study were managed by dose interruption and, if justified, with a medication consisting of: H1 / H2 blockers, and / or paracetamol, and / or montelukast, and / or steroids, and / or bronchodilators. All episodes of IR occurred during the same day of Isa infusion (i.e., no delayed IR occurred). Post-infusion prophylaxis was not required. In the present study, 7 patients previously exposed to Dara experienced IR. In the present study, there was an acceptable tolerance to IR in patients with a history of bronchial disorders (asthma, bronchial hyperresponsiveness, COPD).

[0452] Infusion duration

[0453] Figure 2 The left side of the Figure shows the median duration of the first isatuximab infusion and the median duration of subsequent isatuximab infusions (ie, after the first infusion) in a parallel clinical trial (ie, in which participants were given isatuximab according to the standard regimen). Figure 2 The right side of the Figure shows the median duration of the first isatuximab infusion, the second isatuximab infusion, and subsequent isatuximab infusions (i.e., after the second infusion) in the present study (i.e., in which participants were administered isatuximab in a fixed volume of 250 ml as described in Section III G of Example 1A).

[0454] In the present study (which may alternatively be referred to herein as "Part B"), the median duration of isatuximab infusion was shortened from 3.70 h (222 min, range: 1.0-6.1 hours) for the first infusion to 1.85 h for the second infusion, and then further shortened to 1.25 h (75 min) for the third infusion onwards ( Figure 3The median infusion duration remained stable with subsequent infusions (1.25 h, range: 0.9-3.4 h). In a parallel study (alternatively referred to herein as "Part A"), the median infusion duration was 3.30 h for the first infusion and 2.9 h (174 min) for the second infusion onward ( Figure 3 ), i.e., where the patient was administered isatuximab according to a standard regimen (where the infusion rate was measured in mg / hr).

[0455] Treatment-emergent adverse events (TEAEs)

[0456] All patients except one patient (97.9%) experienced TEAEs, and the most common TEAEs were fatigue (55.3%), IR (40.4%), and upper respiratory tract infection (38.3%), and neutropenia (38.3%). See, for example, Table 16. Grade 3 TEAEs were observed in 31 (68.1%) patients. Non-hematological 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, of which grade 3 infections were reported in 9 (19.1%) patients. 45 (95.7%) patients experienced treatment-related TEAEs, of which 26 (55.3%) patients experienced treatment-related TEAEs of grade 3. Severe TEAEs were observed in 23 (48.9%) patients, and the severe TEAEs were treatment-related in 12 (25.5%) patients. Four patients (8.5%) discontinued due to TEAEs (2 serious infections; 1 acute myocardial infarction; 1 sudden death). Six patients died during the treatment period (≤30 days from the last dose of study drug); no deaths occurred during the post-treatment period (>30 days from the last dose of study drug). Deaths were attributed to AEs (n=3; acute myocardial infarction, sepsis, and rectal bleeding / sepsis), progressive disease (n=2), and 1 sudden death of unknown cause. All deaths were considered unrelated to treatment.

[0457] Table 16. Most Common TEAEs

[0458] TEAE*, n (%) All levels ≥ Grade 3 any 46(97.9) 32(68.1) fatigue 26(55.3) 2(4.3) Infusion reactions 19(40.4) 0 Upper respiratory tract infection 18(38.3) 2(4.3) difficulty breathing 14(29.8) 1(2.1) constipate 13(27.7) 0 diarrhea 13(27.7) 1(2.1) nausea 12(25.5) 0 cough 11(23.4) 0 joint pain 10(21.3) 3(6.4) pneumonia 7(14.9) 3(6.4) musculoskeletal pain 5(10.6) 3(6.4)

[0459] *TEAE, treatment-emergent adverse event

[0460] Hematological abnormalities (all grades) were observed in most patients: leukopenia (95.7%); neutropenia (93.5%); anemia and thrombocytopenia (82.6% for both); lymphopenia (63.0%). Neutropenia was the most common grade 3 / 4 hematological 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.

[0461] Table 17. Grade 3 / 4 Hematologic Events (n=46)

[0462] Hematological abnormalities, n (%) Level 3 Level 4 Leukopenia 25(54.3) 6(13.0) Neutropenia 17(37.0) 16(34.8) Lymphocytopenia 16(34.8) 4(8.7) Thrombocytopenia 9(19.6) 4(8.7) anemia 8(17.4) 0

[0463] in conclusion

[0464] The study met its primary endpoint and no IR of grade ≥3 was observed. All IRs were grade 2, occurred during the first aisatuximab infusion, and resolved on the same day; no delayed onset IR was reported. For the third and subsequent infusions, the median infusion time of 10 mg / kg aisatuximab given with a fixed infusion volume of 250 ml at an infusion rate in mL / h was 75 minutes. This time was significantly shorter than the infusion time of the parallel study, in which aisatuximab was given in mg / hr according to the standard administration regimen (for the third and subsequent infusions, the median was 174 minutes). The general safety profile of the simplified infusion of aisatuximab is favorable and consistent with previous observations of this combination of aisatuximab+pomalidomide+dexamethasone. The fixed infusion volume (250 ml) of aisatuximab can help monitor the fluid balance recommended for patients with renal impairment. In addition, the change from a weight-based volume dosing regimen (mg / hr) to a fixed-volume infusion regimen (ml / hr) for isatuximab infusion had limited impact on pharmacokinetic parameters, with comparable C values simulating steady-state. max (283 μg / ml vs. 284 μg / ml) and C 低谷 (119 μg / ml vs. 119 μg / ml).

[0465] Example 1C: Efficacy results from a Phase 1b study to evaluate the feasibility and safety of a short-duration, fixed-volume infusion of isatuximab in combination with pomalidomide and dexamethasone in relapsed and / or refractory multiple myeloma.

[0466] Further results from the Phase 1b study described in Examples 1A and 1B are described below. 47 patients were included in the fully treated population. At the final cutoff, 22 patients (46.8%) were still on treatment. The reasons for discontinuation of study treatment at the time of analysis were: disease progression (15 patients, 31.9%), adverse events (AEs); (5 patients, 10.6%); and other reasons (5 patients, 10.6%). One patient (2.1%) prematurely discontinued pomalidomide treatment due to an adverse event, and no patient prematurely discontinued dexamethasone treatment. See Table 17B.

[0467] Table 17B - Reasons for treatment discontinuation

[0468]

[0469] Demographics

[0470] The median age was 65 (range 45 to 85 years), with the largest proportion of patients being <65 years (23 patients, 48.9%). All patients had an ECOG PS of 0 or 1, but 2 patients (4.3%) had an ECOG PS of 2. At baseline, patient weight ranged from 40 kg to 121 kg, with a median of 90.3 kg.

[0471] Medical history

[0472] The most frequently reported conditions 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%).

[0473] Disease characteristics at study entry

[0474] At study entry, 23 (48.9%), 12 (25.5%), and 7 (14.9%) patients had International Staging System (ISS) stage I, II, and III, respectively. The ISS stage was unknown for 5 patients (10.6%). At study entry, the majority of patients (33 patients, 70.2%) had measurable serum M-protein. (The International Staging System (ISS) stage I, II, and III criteria were met for 23, 12, and 7 (14.9%) patients, respectively. The ISS stage was unknown for 5 patients (10.6%). At study entry, the majority of patients (33 patients, 70.2%) had measurable serum M-protein.

[0475] Patients had a median of 22.5% (range 0 to 100%) bone marrow plasma cells. The majority of patients (33 patients, 70.2%) had bone lesions at baseline, and 12 (25.5%) had plasmacytomas present at baseline. Ten patients (21.3%) had high-risk cytogenetic characteristics: cytogenetic abnormalities included del17p in 7 patients (14.9%), t(4;14) translocation in 3 patients (6.4%), and t(14;16) translocation in 1 patient (2.1%). Seventeen patients (36.2%) had moderate renal impairment (GFR 30 to ≤60 mL / min / 1.73 m 2 ), and one patient had severe renal impairment (GFR 15 to <30 mL / min / 1.73 m 2 ).

[0476] Previous cancer treatment

[0477] The median number of prior treatment lines was 3 (min-max: 1-8), with 1 patient (2.1%) having received 1 prior treatment line and 17 patients (36.2%) having received 2 prior treatment lines.

[0478] All patients had received IMiDs (including lenalidomide, pomalidomide or thalidomide), PI agents (including bortezomib, carfilzomib, ixazomib, marizomib or olozomib) and corticosteroids (dexamethasone or prednisone) in the previous treatment line. All patients had received lenalidomide previously. 19 patients (40.4%) were refractory to lenalidomide in the last regimen before entering the study. Most patients (39 patients, 83.0%) had received alkylating agents (bendamustine, carmustine, cyclophosphamide, melphalan or melphalanflufenamide) in the previous treatment line. Twenty-three (48.9%) and 11 (23.4%) patients had received pomalidomide and carfilzomib previously, respectively. Seven (14.9%) and nine (19.1%) patients had received daratumumab (anti-CD38 monoclonal antibody) and elotuzumab (anti-SLAM7 monoclonal antibody), respectively, prior to study entry.

[0479] effect

[0480] Overall response rate (ORR)

[0481] The ORR determined in the entire treated population (n=47) was 53.2% (95% confidence interval [CI]: 38.1% to 67.9%), including 2 patients with CR (4.3%), 11 patients with VGPR (23.4%), and 12 patients with PR (25.5%). See Table 17C. The rate of "at least VGPR" was 27.6%. The clinical benefit rate or "CBR" (MR or better) was 72.3% (95% CI: 57.4% to 84.4%), all of which were combined with 9 patients with MR (19.1%). Investigators assessed response and disease progression. The rate of "at least VGPR" was 27.6%. The clinical benefit rate or "CBR" (MR or better) was 72.3% (95% CI: 57.4% to 84.4%), all of which were combined with 9 patients with MR (19.1%). Investigators assessed response and disease progression.

[0482] Table 17C - Best Overall Response, Overall Response Rate, and Clinical Benefit Rate

[0483]

[0484]

[0485] a Estimation by the Clopper-Pearson exact method

[0486] CI: confidence interval, CR: complete response, VGPR: very good partial response, PR: partial response, MR: minimal response, SD: stable disease

[0487] Among the 7 patients previously exposed to daratumumab (see Table 17D), there was 1 PR response for an ORR of 14.3%. In addition, 2 of 7 patients (28.6%) achieved a MR, resulting in a CBR of 42.9%. The response of one patient previously exposed to daratumumab was not evaluable. The ORR for patients not previously treated with daratumumab was 60.0% (24 of 40).

[0488] Table 17D - Best Overall Response, Overall Response Rate, and Clinical Benefit Rate in Patients Received Daratumumab as Prior Therapy

[0489]

[0490] a Estimation by the Clopper-Pearson exact method

[0491] CI: confidence interval, CR: complete response, VGPR: very good partial response, PR: partial response, MR: minimal response, SD: stable disease

[0492] The ORR was: 52.2% (12 of 23) for patients who used prior pomalidomide; 56.5% (13 of 23) for patients who did not use prior pomalidomide or prior daratumumab; 54.5% (18 of 33) for patients with measurable M-protein based on serum; 33.3% (2 of 6) for patients with measurable M-protein based on urine; and 66.7% (4 of 6) for patients with measurable disease based on FLC alone.

[0493] Duration of follow-up, time to first response, and duration of response (DOR)

[0494] The median duration of follow-up was 9.9 months (range: 0 to 17.3). The median time to first response was 0.95 months (range: 0.9 to 3.4).

[0495] The duration of response (DOR) was estimated in 25 responders using the Kaplan-Meier method. All responding patients (n=21) with ongoing response at the time of DOR analysis were censored at the time of the last disease assessment. The median DOR and the 25th quantile had not yet been reached.

[0496] Progression-free survival (PFS)

[0497] At the time of analysis, 20 patients (42.6%) were reported to have had a PFS event (i.e., confirmed progressive disease (PD), worsening of symptoms, or death), and 27 patients (57.4%) were censored. The median PFS had not yet been reached; the 6-month probability of PFS was 65.0% (95% CI: 49.3% to 76.9%), and the 12-month probability was 55.7% (95% CI: 40.1% to 68.8%). Kaplan-Meier plots of PFS are provided in Figure 15 middle.

[0498] Overall survival (OS)

[0499] At the time of analysis, 12 patients (25.5%) were reported to have died. The median OS had not yet been reached. The probability of surviving 6 months was 84.5% (95% CI: 70.1% to 92.3%), and the probability of surviving 12 months was 70.6% (95% CI: 53.7% to 82.3%). Kaplan-Meier plots of OS are provided at Figure 16 middle.

[0500] Security

[0501] Exposure

[0502] Overall, the median number of cycles was 9 (range: 1 to 19), of which 31 (66.0%) patients had started at least 6 cycles and 18 (38.3%) patients had started at least 12 cycles. The overall median duration of exposure was 36.9 weeks (range 1 to 77). See Table 17E.

[0503] Table 17E - Overall Exposure

[0504]

[0505]

[0506] Infusion durations are summarized in Table 17F. The median duration for the first infusion was 3.70 hours (range 1 to 6.1 hours); the median duration for the second infusion was 1.85 hours (range 1.5 to 3.9 hours); and from the third infusion onward, the median duration was 1.25 hours (range 0.8 to 3.4 hours).

[0507] Table 17F - Infusion Duration of Isatuximab

[0508]

[0509]

[0510] a Infusion duration was defined as the time from the start of the infusion to the end of the infusion, including interruptions, if any.

[0511] Infusion reactions

[0512] Infusion reactions (IR) are summarized in Table 17G. Overall, IR of any grade was reported in 19 patients (40.4%) and in 20 episodes (2.3%) of 871 infusions. All IRs were grade 2, and no patient had a grade ≥ 3 IR. All but one patient who experienced an IR had only a single episode, and all IRs occurred only during their first infusion of isatuximab; one patient (2.1%) had two IR episodes during the first infusion. All episodes of IR occurred during the same day of the isatuximab infusion, and all IRs recovered on the same day.

[0513] IR was managed with dose interruption and / or medication consisting of any of the following: an H1 / H2 blocker, and / or acetaminophen, and / or montelukast, and / or steroids. Eighteen of the 19 patients with IR had their esatuximab infusion interrupted; in the remaining patient with grade 2 IR and grade 3 hypoxia (a symptom of IR), the infusion was not interrupted, and hypoxia was managed with oxygen administration.

[0514] Of the seven patients who had been previously exposed to daratumumab treatment, three experienced IR.

[0515] Table 17G - Description of Infusion Reactions (Common Terms as Reported by Investigator)

[0516]

[0517]

[0518]

[0519] Treatment-emergent adverse events

[0520] All patients had at least one TEAE (of any grade), 35 patients (74.5%) had grade ≥3 TEAEs (regardless of relationship to study treatment), and 27 patients (57.4%) had at least one serious TEAE (regardless of relationship to study treatment). Six patients (12.8%) experienced a TEAE leading to death during the study. No patients (10.6%) experienced a TEAE leading to definitive treatment discontinuation (i.e., discontinuation of all study treatment), and 1 patient (2.1%) experienced a TEAE leading to premature discontinuation of pomalidomide.

[0521] The most frequently reported non-hematologic TEAEs of any grade (in >20% of patients), regardless of relationship to study treatment, were fatigue (30 patients, 63.8%), infusion-related reaction (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%).

[0522] Five patients (10.6%) had TEAEs that led to definitive discontinuation of study treatment. In addition to the four patients with the aforementioned fatal events (acute myocardial infarction, sepsis, rectal bleeding and sepsis, sudden death), one patient had severe grade 3 spinal cord compression, which was considered unrelated to study treatment. One patient also electively discontinued pomalidomide (continuing treatment with isatuximab and dexamethasone) due to non-serious grade 1 events of tremor, gait disturbance, and flushing.

[0523] During the treatment period, 71.7% of patients had Grade 3 or 4 decreased neutrophil counts (37.0% and 34.8% decreases, respectively), 67.4% of patients had Grade 3 or 4 decreased leukocytes (55.2% and 15.2% decreases, respectively), and 65.2% of patients had Grade 3 or 4 decreased lymphocyte counts (54.3% and 10.9% decreases, respectively). Grade 3 anemia was reported in 21.7% of patients, and Grade 4 anemia was not reported in any patients during treatment.

[0524] in conclusion

[0525] The results of the primary safety analyses discussed in Example 1A and Example 1B have confirmed the safety and feasibility of administering esatuximab from a fixed infusion volume. This example summarizes the main findings from the efficacy analysis at the final cutoff, which was 10 months after the date of the first dose of the last enrolled patient.

[0526] A total of 47 patients were enrolled, and 22 patients (46.8%) remained on study treatment at the cutoff date.

[0527] The median number of cycles administered was 9 (range: 1-19). When the infusion was administered at a fixed infusion rate of 200 mL / hour, the median duration of the infusion was shortened from 3.70 hours during the first infusion to 1.85 hours during the second infusion, and to 1.25 hours for ≥3 infusions. Although the infusion rate increased and the infusion duration was shorter from the second infusion onward, no IR was observed after the first infusion.

[0528] Efficacy was observed in these 47 patients who received esatuximab given from a fixed infusion volume in combination with pomalidomide and dexamethasone, with an ORR of 53.2% (95% CI: 38.1% to 67.9%), and at a median duration of follow-up of 9.9 months, the median PFS and OS had not yet been reached. The 12-month probability of PFS was 55.7%, and the 12-month probability of OS was 70.6%. Among the 7 patients previously exposed to daratumumab, there was 1 PR and 2 MRs for an ORR of 14.3% and a CBR of 42.9%; the ORR in the 40 patients not previously exposed to daratumumab was 60.0%. The response was 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 and the type of measurable M protein did not show evidence of a significant difference in response rate compared to the fully treated population.

[0529] The efficacy data using fixed volume infusion are consistent with data from parallel studies comparing daratumumab in combination with pomalidomide and dexamethasone with pomalidomide and dexamethasone in patients with refractory or relapsed and refractory multiple myeloma. In the parallel studies, daratumumab was administered by infusion at a rate (mg / hr) based on the amount of protein per hour. In the present study, the ORR for patients not exposed to daratumumab was 60.0%, compared to 60.4% in the parallel studies. In the present study, the 1-year PFS rate was 55.7%, compared to 47.6% in the parallel studies. In the present study, the 1-year OS rate was 70.6%, compared to 72.% in the parallel studies. In the present study, the time to the first reaction was 0.95 months, compared to 1.94 months in the parallel studies. In the present study, the median duration of response has not yet been reached, compared to 13.27 months in the parallel studies.

[0530] Safety findings were consistent with those reported in Example 1A and Example 1B, with no Grade 3 IR and no IR after the second infusion, and no new safety signals were recorded using fixed-volume administration. The safety data were also consistent with the infusion schedule used with IPd in parallel studies. These results confirm the safety, efficacy, and feasibility of isatuximab administered by a fixed-volume infusion approach.

[0531] Example 2: Exposure-Response Analysis and Disease Modeling for Selecting the Optimal Dosing Regimen of Isartumomab as a Single Agent in Patients with Multiple Myeloma

[0532] Exposure-response (ER) analysis of tumor burden and disease modeling were performed to evaluate the relationship between isatuximab exposure and efficacy outcomes and to support dosing selection for isatuximab as a single agent in patients with relapsed / refractory multiple myeloma (RRMM).

[0533] Study Design

[0534] Isatuximab was administered intravenously to 194 RRMM patients at doses ranging from 1 mg / kg to 20 mg / kg. Isatuximab was administered as monotherapy once weekly or every 2 weeks at the selected dose. As shown in Table 18, the median age was 63 years, 94.3% of patients had ≥3 prior lines of treatment, and the median bone marrow plasma cell percentage was 27.6.

[0535] Table 18. Patient characteristics.

[0536]

[0537] Pharmacokinetic, best overall response (ORR), and serum M protein data (a subset of 122 patients) were used for ER analysis and disease modeling described in this example.

[0538] Exposure-response analysis

[0539] Logistic regression modeling was used to examine the relationship between several isatuximab exposure parameters (including C 低谷 and bone marrow plasma cell percentage) with the probability of achieving an objective response (CR, VGPR, or PR; response criteria see Table 14).

[0540] Baseline covariates were also considered in the model to reduce potential confounding effects. 低谷 It is defined as the plasma concentration of isatuximab observed immediately before treatment administration during the repeated dosing period.

[0541] Disease progression modeling

[0542] Disease progression was captured by the kinetics of serum M protein in a subset of 122 evaluable patients. A joint model was used to account for dropouts.

[0543] The tumor growth inhibition (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 dynamics of serum M protein in 122 of 194 RRMM patients who were given isatuximab monotherapy intravenously at doses of 1 mg / kg to 20 mg / kg once weekly or every two weeks. A combined model was used to account for patient withdrawals.

[0544] Test simulation

[0545] Clinical trial simulations based on both the above ER analysis and TGI modeling were then performed (5000 trial simulations, each using 100 patients) to evaluate different dosing regimens of interest using both models (ER analysis and disease progression model).

[0546] result

[0547] Logit Emax Model

[0548] The pharmacokinetic data were best described by a biexponential distribution model using parallel linear and nonlinear (target-specificity-mediated) clearance.

[0549] By Logit E max The model (AUC of the ROC curve = 0.91) best described the relationship between isatuximab exposure and ORR ( Figure 4 Table 19 provides the parameter estimates for the Logit Emax model.

[0550] Table 19. Parameter estimates for the Logit Emax model.

[0551] parameter Estimated value Standard error P-value 95% confidence limits <![CDATA[E0]]> -3.0063 0.9560 0.0019 -4.8918--1.1208 Emax 2.7205 0.9211 0.0035 0.9038-4.5372 <![CDATA[Log_EC 50 ]]> 2.6584 1.0985 0.0164 0.4919-4.8248 β -1.0480 0.4885 0.0331 -2.0114--0.0847

[0552] The model revealed that C 低谷 (CT4W) and bone marrow plasma cell (BMPC) percentage were significant predictors of overall response rate (ORR).

[0553] ORR increased with increasing CT4W and reached an ORR plateau of approximately 33% from the third quartile for CT4W ( Figure 5 ). Used to provide 90% of maximum effect (EC 90) was 128.5 μg / mL. 90 Limited additional benefit in terms of ORR is expected for CT4W.

[0554] Patients with less than 50% BMPC were more likely to respond ( Figure 6 For a given BMPC value, using a higher CT4W yields a higher probability of response to treatment.

[0555] M protein model

[0556] The serum M protein dynamics are fully described by the exposure-driven TGI model ( Figure 7 )(Claret et al., J Clin Oncol 27 (2009) 25:4103-4108; Jonsson et al., CPT Pharmacometrics Syst Pharmacol (2015) 4912:711-719). Parameter estimates for the disease of the M protein model are provided in Table 20.

[0557] Table 20. Parameter estimates for the disease M protein model.

[0558]

[0559]

[0560] like Figure 8 As shown in , the M protein model of disease adequately describes the observed time course of serum M protein levels.

[0561] Clinical trial simulation

[0562] 5,000 clinical trial simulations were performed, each with 100 patients. The model assumed that patients received the same dose level in each simulation.

[0563] like Figure 9A and Figure 9B As shown in , clinical trial simulations showed that weekly dosing with a high dose in the first cycle (loading dose phase) allowed optimization of the response due to faster achievement of effective concentrations.

[0564] The success rates for achieving a 30% ORR using several dosing regimens are provided in Table 21. Figure 9A Simulated overall response rates are presented at several dosing schedules, including a 20 mg / kg QWX4Q2W dosing schedule.

[0565] Table 21. Simulated probability of achieving a 30% ORR using the indicated dosing regimens.

[0566]

[0567] The median percentage change in M protein levels from baseline at two months for several dosing regimens is provided in Table 22. QWX4Q2W resulted in a 52% reduction in serum M protein from baseline levels after two months of treatment ( Figure 9B ).

[0568] Table 22. Simulated percent change in M protein at two months from baseline.

[0569]

[0570]

[0571] In addition, the QWX4Q2W isatuximab dosing schedule appeared to be well tolerated.

[0572] in conclusion

[0573] This example demonstrates that a model-based drug development approach has been successfully applied to support Phase II esatuximab monotherapy dosing regimen selection in RRMM patients. This approach showed that a loading dose of 20 mg / kg esatuximab administered weekly followed by every 2 weeks over only 4 weekly doses appeared sufficient to maximize tumor response and maintain efficacy in monotherapy while being well tolerated.

[0574] A dose of 20 mg / kg QW / Q2W is recommended for monotherapy.

[0575] Example 3: Phase 1 / 2 study of isatuximab monotherapy in Japanese patients with relapsed and / or refractory multiple myeloma.

[0576] This example describes a phase 1 / 2 study of isatuximab monotherapy for relapsed and / or refractory multiple myeloma (RRMM) in Japanese patients.

[0577] Research objectives

[0578] Phase 1 : To evaluate the safety and tolerability, as well as dose-limiting toxicities (DLTs), of isatuximab in Japanese patients with RRMM.

[0579] Phase 2 To evaluate the efficacy of isatuximab at the recommended dose and to determine its overall response rate (ORR; ≥partial response [PR]) in Japanese patients with RRMM.

[0580] Research group

[0581] Patients meeting the following criteria were recruited into the study:

[0582] Patients 20 years of age or older with a diagnosis of symptomatic multiple myeloma, at least three prior lines of therapy, or refractory to both PD-1 and proteasome inhibitors (PIs), have had a minimal response or better to at least one line of treatment, are refractory to recent therapy, and have measurable disease.

[0583] RRMM is 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).

[0584] Key exclusion criteria were: prior treatment with an anti-CD38 agent; a diagnosis of another malignancy within 5 years of enrollment; prior anticancer therapy within 21 days of the first drug infusion; systemic radiotherapy within 4 weeks or local radiotherapy within 1 week before the first drug infusion; abnormal laboratory values; ongoing toxicity of grade 2 or higher; a previous allogeneic stem cell transplant; or a diagnosis of Crow-Fukase syndrome, plasma cell leukemia, Waldenstrom's macroglobulinemia, or multiple myeloma of the IgM subtype.

[0585] Study Design

[0586] The study was an open-label, non-randomized, single-arm, two-phase, multicenter trial conducted in Japan. The trial consisted of 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) to enroll patients at the maximum tolerated dose determined in Phase 1.

[0587] Phase 1

[0588] The maximum tolerated dose (MTD) of isatuximab monotherapy was determined in two patient cohorts in a 3+3 design:

[0589] Group 1 : Isarituximab was administered at 10 mg / kg in 28-day cycles, once weekly (QW) in cycle 1 (ie, four weeks), and once every 2 weeks (Q2W) in subsequent four-week cycles.

[0590] Group 2 : Isarituximab was administered at 20 mg / kg in 28-day cycles, once QW in cycle 1 and once Q2W in subsequent cycles; enrollment in Cohort 1 began after completion of the DLT observation period.

[0591] The dose regimen used in Phase 1 was selected as half the highest dose (cohort 1) and the highest dose (cohort 2) used in the study, Martin TG et al., J Clin Oncol 2014;32:abstract 8532.

[0592] Phase 2

[0593] Patients received the MTD established in Phase 1. Enrollment began after completion of the DLT observation period in Cohort 2. Patients in Phase 2 included those enrolled in the Phase 1 cohort treated with the recommended dose.

[0594] Study endpoints

[0595] Primary End Point

[0596] The primary endpoints of the study were the safety and tolerability of isatuximab in Phase 1 (including DLT) and evaluation of the efficacy of isatuximab at the recommended dose, including assessment of ORR.

[0597] Secondary End Points

[0598] Secondary endpoints included:

[0599] Safety and immunogenicity (anti-drug antibodies [ADA]) of isatuximab.

[0600] ●Pharmacokinetics of isatuximab.

[0601] ● Efficacy determined using IMWG unified response criteria, ORR, clinical benefit rate (CBR), overall survival (OS), and progression-free survival (PFS).

[0602] ●Optimal response in terms of paraprotein.

[0603] • Baseline CD38 receptor density (RD) on multiple myeloma cells.

[0604] Exploratory goals

[0605] Exploratory objectives include:

[0606] Minimal residual disease (MRD) assessed in patients who achieved a complete response (CR) and its correlation with clinical outcomes.

[0607] Statistical analysis

[0608] The ORR was assessed in all patients who received at least one dose of isatuximab at the recommended dose in either 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 the true ORR was 28%.

[0609] result

[0610] Patient demographics and baseline characteristics

[0611] like Figure 10 As shown in , eight patients were enrolled in Phase 1 and 28 patients were enrolled in Phase 2. All patients had received at least two prior therapies, including and PI, and most patients were and / or PI-refractory (Table 23).

[0612] Table 23. Patient characteristics.

[0613]

[0614]

[0615]

[0616]

[0617] The number of cycles ranged from 1 to 24, the duration of exposure ranged from 2 to 96 weeks, and the cumulative dose ranged from 40.0 to 859.3 mg / kg (Table 24).

[0618] Table 24. Isarituximab Exposure.

[0619]

[0620]

[0621] Five patients in phase 1 and nine patients in phase 2 remained on treatment at the cutoff date.

[0622] Security

[0623] Dose-limiting toxicity (DLT)

[0624] One patient was excluded from the DLT-evaluable population due to an adverse event (both AEs were unrelated to isatuximab).

[0625] No DLTs occurred in any cohort in Phase 1. Therefore, the starting dose in Phase 2 was set at 20 mg / kg QW / Q2W.

[0626] Adverse events

[0627] Treatment-emergent AEs (TEAEs) in both periods are summarized by dose and grade in Table 25. The only serious drug-related TEAE was Grade ≥3 pneumonitis, which occurred in one patient treated with 10 mg / kg QW / Q2W in Period 1 and in two patients in Period 2.

[0628] Infusion-related reactions occurred in 3 patients in Phase 1 (2 events in 2 patients at 10 mg / kg and 2 events in 1 patient at 20 mg / kg) and in 12 patients in Phase 2 (13 events). All infusion-related reactions were ≤ Grade 2. When reactions occurred, they occurred with the first infusion in all patients in Phase 1 and 11 patients in Phase 2. One patient in Phase 2 experienced reactions with the first and third infusions. All infusion-related reactions resolved within 1 day, with the exception of two patients whose reactions persisted for 2 days. No patient discontinued treatment due to infusion reactions.

[0629] Clinically significant TEAEs occurring in all 36 patients in Phases 1 and 2 combined were respiratory tract infections in 19 patients, lower respiratory tract TEAEs in 8 patients, and neutropenia in 13 patients.

[0630] Table 25. Summary of safety results.

[0631]

[0632]

[0633] Immunogenicity

[0634] Anti-drug antibodies (ADA) were measured in all 36 patients. At the cutoff date, all patients in Phase 1 were negative for ADA. In Phase 2, four patients showed evidence of treatment-induced immunogenicity, with transient ADA in one patient (Cycle 1 only) and treatment-enhanced ADA in three patients. There was no relationship between trough isatuximab concentrations and immunogenicity.

[0635] Pharmacokinetics

[0636] The duration of the infusion in Cycle 1 was longer in patients receiving isatuximab at 20 mg / kg QW / Q2W (Table 26; infusion rate measured in mg / hr).

[0637] Table 26. Pharmacokinetic parameters of isatuximab in cycle 1 of Phase 1.

[0638]

[0639] like Figure 11As shown in , a 2-fold increase in dose (from 10 mg / kg to 20 mg / kg) increased isatuximab exposure by 2.3-fold.

[0640] effect

[0641] As shown in Table 27A, ORR was assessed in 33 patients who received isatuximab at 20 mg / kg QW / Q2W in Phase 1 Cohort 2 or Phase 2. ORR (≥PR) was 36.4% (95% CI: 20.4%, 54.9%; 12 / 33 patients), which significantly exceeded the null hypothesis rate of <10% (P<0.0001) based on a one-sided exact binomial test with a significance level of 0.025. CBR (≥MBR) was 54.5% (95% CI: 36.4%, 71.9%; 18 / 33 patients). Of all recruited patients, CR was achieved in 2 patients, VGPR was achieved in 5 patients, and PR was achieved in 5 patients. There did not appear to be differences in response rates based on the number of previous treatment lines or cytogenetic risk. In eight patients with cytogenetic abnormalities, responses were ≥PR in three patients and VGPR in two patients. All three patients with ≥PR had t(4,14) cytogenetic abnormalities. In other patient subgroups, patients with low ECOG, low ISS class, baseline creatinine clearance ≥60 mL / min / 1·73 m 2 Furthermore, response rates tended to be greater in patients without plasmacytomas.

[0642] Table 27A. Best overall response.

[0643]

[0644]

[0645] 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 groups in Phase 1 and 19.2 weeks in Phase 2. The median duration of response was 82.6, 48.1, and 241 weeks in the three groups, respectively.

[0646] Table 27B. Secondary Efficacy Results by Study Period and Dose

[0647]

[0648] Figure 12 The best response was shown to vary with treatment duration in Phase 2. The median time to first response was comparable in all three groups (4.9 weeks, 5.4 weeks, and 4.3 weeks, respectively).

[0649] Figure 13A A Kaplan-Meier plot of progression-free survival is provided for the 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).

[0650] Table 28. Kaplan-Meier statistics for progression-free survival.

[0651]

[0652] Figure 13B A Kaplan-Meier plot of overall survival for patients in Phase 2 of this study is provided. As shown in Table 29, the median OS was not reached. The OS probabilities at 6 months and 1 year were 1.000 and 0.781, respectively. There were two deaths in Phase 2. Both patients died during the post-treatment period, and the cause of death was unrelated to AEs associated with study treatment. One of these patients did not receive subsequent therapy, and the other patient was treated with carfilzomib and dexamethasone after discontinuation of isatuximab.

[0653] Table 29. Kaplan-Meier statistics for overall survival.

[0654]

[0655] Best response in terms of paraprotein

[0656] Approximately half of all patients had a ≥50% reduction in paraprotein, including ≥90% reductions in four patients in Phase 1 (one given 10 mg / kg QW / Q2W and three given 20 mg / kg QW / Q2W) and six patients in Phase 2. There was no clear correlation between the best percent change in paraprotein and overall response.

[0657] Minimal residual disease (MRD)

[0658] MRD was assessed 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 (at 10 -5 Patients with VGPR in the 10 mg / kg group in Phase 1 were -5 The lower one is MRD positive.

[0659] biomarkers

[0660] CD38 RD data were available for 32 patients. The following conversion formula was used to convert the CD38 receptor density (×10 3The specific molecular equivalents per cell (sMEC) were calculated as follows: sMEC = MEC (selected antibody) - MEC (negative isotype control), where MEC (molecular equivalents per cell) = 10^(log[MFI] x 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) value of 122,313.5 (71,808 to 232,958) in 14 responders and a median (range) value of 72,731.0 (26,921 to 394,910) in 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 / unconfirmed progressive disease; NE = not evaluable). When patients were divided according to the CD38 RD threshold, the ORR tended to be greater in patients with an RD above the threshold. However, some patients with lower RD values showed responses to isatuximab.

[0661] Pharmacokinetics of isatuximab

[0662] The pharmacokinetic properties of isatuximab in Cycle 1 of Phase 1 are shown in Table 30. The overall variability of exposure parameters was low to moderate, with coefficients of variation ranging from 18% to 32%. For a two-fold dose increase (from 10 to 20 mg / kg), isatuximab exposure increased 2.3-fold (based on the geometric mean ratio).

[0663] Table 30. Plasma Pharmacokinetic Parameters of Isaatuximab in Cycle 1 of Phase 1

[0664]

[0665] a n=5

[0666] QW, weekly; Q2W, every 2 weeks; C eoi , concentration at the end of infusion; C max , maximum concentration; AUC 1周 , the area under the plasma concentration versus time curve during a 1-week dosing interval; t max , reaching C max time.

[0667] in conclusion

[0668] This study confirmed that 20 mg / kg QW / Q2W is an appropriate dosing regimen for esatuximab monotherapy in Japanese patients with RRMM, consistent with the dosing regimen used in 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). esatuximab was generally well tolerated and demonstrated favorable efficacy.

[0669] This study indicates that isatuximab monotherapy may be a treatment option for patients with multiple myeloma who have received at least three prior lines of therapy, including PIs and or the patient is a PI and Double refractory. It shows a favorable safety profile and is well tolerated even in heavily treated patients and may therefore be suitable for elderly and frail patients. In patients with high-risk cytogenetics and in patients with more than six prior lines of therapy (including PI and Responses were observed in patients refractory to both sera and leukemia. Patients who are heavily pretreated often show worsening renal and bone marrow function due to the primary disease, and continuing treatment in such patients is often difficult due to safety reasons. The current findings are clinically relevant and suggest the potential for using isatuximab in these patients, for whom few alternatives may exist.

[0670] Unless explicitly indicated to the contrary, each embodiment described herein can be combined with any other one or more embodiments. Specifically, unless explicitly indicated to the contrary, any feature or embodiment indicated as preferred or advantageous can be combined with any other one or more features or one or more embodiments indicated as preferred or advantageous.

[0671] All references cited in this application are expressly incorporated herein by reference.

Claims

1. 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 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 VIQDVQV (SEQ ID NO: 6). NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6).

2. A method of administering an anti-CD38 antibody to a human individual in need thereof, 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-H3 comprising the amino acid sequence NO:5) and a CDR-L2 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO:6).

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

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

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

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

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

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

9. The anti-CD38 antibody or method for use according to claim 7, wherein the second intravenous infusion of anti-CD38 is administered to the subject 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 is infused.

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

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