Treatment method for multiple myeloma

Abstract

The present disclosure provides a method for treating multiple myeloma (e.g., refractory multiple myeloma or relapsed / refractory multiple myeloma) in an individual who has received at least two prior therapies for multiple myeloma. The method comprises administering to the individual an anti-CD38 antibody, pomalidomide, and dexamethasone. Also provided is a method for improving kidney damage in an individual with multiple myeloma.

Description

Technical Field

[0001] Cross - References to Related Applications This application claims the benefit of priority of European Patent Application Publication No. 19306554.7 filed on December 3, 2019; U.S. Provisional Patent Application No. 62 / 943,716 filed on December 4, 2019; U.S. Provisional Patent Application No. 62 / 931,014 filed on November 5, 2019; U.S. Provisional Patent Application No. 62 / 899,094 filed on September 11, 2019; U.S. Provisional Patent Application No. 62 / 861,954 filed on June 14, 2019; U.S. Provisional Patent Application No. 62 / 847,826 filed on May 14, 2019; U.S. Provisional Patent Application No. 62 / 797,876 filed on January 28, 2019, the contents of each of which are hereby incorporated by reference in their entirety.

[0002] Submission of a Sequence Listing in ASCII Text File The following submission of an ASCII text file is hereby incorporated by reference in its entirety: Computer - Readable Format (CRF) of the Sequence Listing (file name: 183952031241SEQLIST.txt, recording date: January 23, 2020, size: 11KB).

[0003] The present disclosure relates to a method of treating multiple myeloma by administering an anti - CD38 antibody in combination with pomalidomide and dexamethasone.

Background Art

[0004] Multiple myeloma (MM) is a malignant plasma cell disease characterized by clonal proliferation of plasma cells in the bone marrow (BM) and overproduction of monoclonal immunoglobulins (usually IgG or IgA type, or free urinary light chains, i.e., paraprotein, M-protein or M-component). Patients with MM may experience bone pain, fractures, fatigue, anemia, infections, hypercalcemia and kidney problems (Non-Patent Document 1). The expression of CD38 is particularly notable in MM, as more than 98% of patients are positive for this protein (Non-Patent Document 2; Non-Patent Document 3). The strong and uniform expression of CD38 on malignant clonal MM cells is in contrast to the restricted expression pattern on normal cells, suggesting that this antigen may be useful for specific targeting of tumor cells.

[0005] The current aim of MM therapy is to control the disease as effectively as possible in order to maximize quality of life and prolong survival. The disease trajectory varies from patient to patient, but relapse is inevitable, and the depth and duration of response to each treatment after relapse generally decrease. Generally, MM patients receive an average of 4 - 8 different regimens using proteasome inhibitors (e.g., bortezomib, ixazomib and carfilzomib) and immunomodulatory agents or "IMiD®" (e.g., lenalidomide and thalidomide), monoclonal antibodies (e.g., elotuzumab), histone deacetylase (HDAC) inhibitors (e.g., panobinostat) alone or in combination during their lifetime. However, when patients become resistant to these drugs, survival is limited and new treatment options are needed to treat patients after they have failed stem cell transplantation (SCT), chemotherapy, proteasome inhibitors and immunomodulatory drugs (IMiD®). Despite the dramatic improvement in patient outcomes with newer treatments, MM remains an incurable disease. Therefore, the treatment of patients who have received at least two different lines of treatment including proteasome inhibitors and immunomodulatory agents, or patients who are doubly resistant to proteasome inhibitors and IMiD®, is still an unmet medical need.

[0006] All references cited in this specification, including patent applications, patent publications, and UniProtKB / SwissProt accession numbers, are hereby incorporated by reference in their entirety as if each individual reference were specifically and individually indicated to be incorporated by reference.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Means for Solving the Problems

[0008] For use in the treatment of multiple myeloma in an individual, a heavy chain variable domain (V H ) comprising (a) CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (V LAn anti-CD38 antibody is provided that comprises, and the treatment comprises administering to the individual an anti-CD38 antibody, pomalidomide, and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg, pomalidomide is administered at a dose of 4 mg, and dexamethasone is administered at a dose of 40 mg to individuals less than 75 years of age or dexamethasone is administered at a dose of 20 mg to individuals 75 years of age or older, and the individual has received at least two prior treatments for multiple myeloma, and at least one of the at least two prior treatments for multiple myeloma is lenalidomide, and at least one of the two prior treatments is a proteasome inhibitor, and the treatment prolongs the progression-free survival (PFS) and / or overall survival (OS) of the individual.

[0009] For use in a method of restoring renal dysfunction in an individual with multiple myeloma, an anti-CD38 antibody comprising (a) a heavy chain variable domain (V H ) 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 (V L ) 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) is provided, and the method comprises administering to the individual an anti-CD38 antibody, pomalidomide, and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg, pomalidomide is administered at a dose of 4 mg, and dexamethasone is administered at a dose of 40 mg to individuals less than 75 years of age or dexamethasone is administered at a dose of 20 mg to individuals 75 years of age or older, and the individual has received at least two prior treatments for multiple myeloma, and at least one of the at least two prior treatments for multiple myeloma is lenalidomide, and at least one of the at least two prior treatments is a proteasome inhibitor.

[0010] (a) An isatuximab at a concentration of 5 - 20 mg / ml; (b) A buffer selected from the group consisting of histidine, acetate, and phosphate; (c) An excipient selected from the group consisting of sucrose and mannitol, and (d) A liquid pharmaceutical formulation containing polysorbate 80 (PS80) is also provided. In some embodiments, the isatuximab is present at a concentration of 5 mg / ml, the buffer is histidine, the histidine is at a concentration of 10 mM, the excipient is sucrose, the sucrose is at a concentration of 10% (w / v), the PS80 is present at a concentration of 0.005% (w / v), and the pharmaceutical formulation has a pH of about 6.0 or about 6.5. In some embodiments, the pH of the pharmaceutical formulation is about 6.5. In some embodiments, the isatuximab is present at a concentration of 20 mg / ml, the buffer is histidine, the histidine is at a concentration of 20 mM, the excipient is sucrose, the sucrose is present at a concentration of 10% (w / v), the PS80 is present at a concentration of 0.02% (w / v), and the pharmaceutical formulation has a pH of about 6.0. In some embodiments, the formulation is sterile.

[0011] A method of treating a human individual having multiple myeloma, the method comprising administering to the individual: (a) A heavy chain variable domain (V H ) comprising a CDR-H1 containing the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 containing the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 containing the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) A light chain variable domain (V L) An anti-CD38 antibody, pomalidomide, and dexamethasone are provided, and the treatment includes administering them, which extends the progression-free survival (PFS) of an individual. In some embodiments, the method includes administering an anti-CD38 antibody at a dose of 10 mg / kg, pomalidomide at a dose of 4 mg, and dexamethasone at a dose of 40 mg if the individual is less than 75 years old or 20 mg if the individual is 75 years old or older. In some embodiments, the individual has received at least two prior treatments for multiple myeloma. In some embodiments, at least one of the at least two prior treatments for multiple myeloma was lenalidomide. In some embodiments, at least one of the two prior treatments was a proteasome inhibitor. In some embodiments, the treatment extends the overall survival (OS) of the individual. In some embodiments, the treatment restores the individual's renal dysfunction.

[0012] A method of treating a human individual having multiple myeloma, comprising administering to the individual: (a) a heavy chain variable domain (V H ) comprising CDR-H1 containing the amino acid sequence DYWMQ (SEQ ID NO: 1), CDR-H2 containing the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and CDR-H3 containing the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (V LMethods are also provided that include administering an anti-CD38 antibody, pomalidomide, and dexamethasone, which treatment extends the overall survival (OS) of an individual. In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg / kg, pomalidomide is administered at a dose of 4 mg, and dexamethasone is administered at a dose of 40 mg if the individual is less than 75 years old or at a dose of 20 mg if the individual is 75 years old or older. In some embodiments, the individual has received at least two prior treatments for multiple myeloma. In some embodiments, at least one of the at least two prior treatments for multiple myeloma was lenalidomide. In some embodiments, at least one of the two prior treatments was a proteasome inhibitor. In some embodiments, the treatment restores the individual's renal dysfunction.

[0013] A method for improving renal impairment in a human individual with multiple myeloma, the method comprising administering to the individual (a) a heavy chain variable domain (V H ) 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 (V L ) 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), an anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg / kg, pomalidomide is administered at a dose of 4 mg, and dexamethasone is administered at a dose of 40 mg if the individual is less than 75 years old or at a dose of 20 mg if the individual is 75 years old or older.

[0014] In some embodiments of the antibodies for use herein or the methods herein, at least two prior treatments did not include treatment with an anti-CD38 antibody and / or treatment with pomalidomide. In some embodiments of the antibodies for use herein or the methods herein, the individual did not respond to at least one of the at least two prior treatments, or the individual relapsed after at least one of the at least two prior treatments, or the individual experienced disease progression during or after treatment with at least one of the two prior treatments.

[0015] In some embodiments of the antibodies for use herein or the methods herein, individuals with multiple myeloma are selected for administration with an anti-CD38 antibody, pomalidomide, and dexamethasone based on individuals with renal impairment. In some embodiments of the antibodies for use herein or the methods herein, individuals with renal impairment have an estimated glomerular filtration rate (eGFR) of less than about 60, less than about 50, or less than about 30 mL / min / 1.73m 2 prior to the start of treatment. In some embodiments of the antibodies for use herein or the methods herein, individuals with renal impairment have a creatinine clearance of less than about 60, less than about 50, or less than about 30 mL / min / 1.73m 2 prior to the start of treatment. In some embodiments of the antibodies for use herein or the methods herein, the individual has received at least two prior treatments for multiple myeloma. In some embodiments of the antibodies for use herein or the methods herein, at least one of the at least two prior treatments was lenalidomide. In some embodiments of the antibodies for use herein or the methods herein, at least one of the at least two prior treatments was a proteasome inhibitor. In some embodiments of the antibodies for use herein or the methods herein, the method prolongs the progression-free survival (PFS) of the individual. In some embodiments of the antibodies for use herein or the methods herein, the method prolongs the overall survival (OS) of the individual.

[0016] In this specification, for use in the treatment of multiple myeloma in an individual, a heavy chain variable domain (V H ) comprising (a) CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (V L ) comprising CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) are also provided, and the treatment comprises administering to the individual an anti-CD38 antibody, pomalidomide, and dexamethasone, and the treatment prolongs the progression-free survival (PFS) and / or overall survival (OS). In some embodiments of the antibody for use herein or the method herein, the anti-CD38 antibody is administered at a dose of 10 mg / kg, pomalidomide is administered at a dose of 4 mg, and dexamethasone is administered at a dose of 40 mg if the individual is less than 75 years old or at a dose of 20 mg if the individual is 75 years or older. In some embodiments of the antibody for use herein or the method herein, the individual has received at least two prior treatments for multiple myeloma. In some embodiments of the antibody for use herein or the method herein, at least one of the at least two prior treatments for multiple myeloma was lenalidomide. In some embodiments of the antibody for use herein or the method herein, at least one of the two prior treatments was a proteasome inhibitor.

[0017] For use in the recovery of renal function impairment in an individual, a heavy chain variable domain (V H) and a light chain variable domain (V L ) comprising an anti-CD38 antibody, the treatment comprising administering to the individual an anti-CD38 antibody, pomalidomide and dexamethasone. In some embodiments of the antibodies for use herein or the methods herein, the individual has multiple myeloma. In some embodiments of the antibodies for use herein or the methods herein, the individual is selected for administration with an anti-CD38 antibody, pomalidomide and dexamethasone based on having a renal disorder. In some embodiments of the antibodies for use herein or the methods herein, the individual has an estimated glomerular filtration rate (eGFR) of less than about 60, less than about 50 or less than about 30 mL / min / 1.73 m 2 prior to the start of treatment. In some embodiments of the antibodies for use herein or the methods herein, the individual has a creatinine clearance of less than about 60, less than about 50 or less than about 30 mL / min / 1.73 m 2 prior to the start of treatment. In some embodiments of the antibodies for use herein or the methods herein, the anti-CD38 antibody is administered at a dose of 10 mg / kg, pomalidomide is administered at a dose of 4 mg, and dexamethasone is administered at a dose of 40 mg if the individual is less than 75 years old or at a dose of 20 mg if the individual is 75 years or older. In some embodiments of the antibodies for use herein or the methods herein, the individual has received at least two prior treatments for multiple myeloma. In some embodiments of the antibodies for use herein or the methods herein, at least one of the at least two prior treatments for multiple myeloma was lenalidomide. In some embodiments of the antibodies for use herein or the methods herein, at least one of the two prior treatments was a proteasome inhibitor.

[0018] In some embodiments, the antibody for use herein or the method herein extends the PFS of an individual by at least about 9 months. In some embodiments, the antibody for use herein or the method herein extends the PFS of an individual by about 11.53 months. In some embodiments, the antibody for use herein or the method herein extends the PFS of an individual by about 11.14 months. In some embodiments, the antibody for use herein or the method herein extends the PFS of an individual by at least about 4.5 months compared to an individual with multiple myeloma who received treatment with pomalidomide and dexamethasone without an anti-CD38 antibody.

[0019] In some embodiments, an individual being treated with an anti-CD38 antibody, pomalidomide, and dexamethasone, such as by the antibody for use herein or the method herein, achieves a response to treatment more rapidly than an individual with multiple myeloma who received treatment with pomalidomide and dexamethasone without an anti-CD38 antibody. In some embodiments, an individual achieves a renal response to treatment (e.g., treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone, such as by the antibody for use herein or the method herein) more rapidly than an individual with multiple myeloma who received treatment with pomalidomide and dexamethasone without an anti-CD38 antibody. In some embodiments, the renal response is a complete renal response. In some embodiments, the complete renal response persists for at least 60 days.

[0020] In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (V H ) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (V L ) comprising the amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody is isatuximab.

[0021] In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered in a first 28-day cycle, the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first 28-day cycle, pomalidomide is administered daily from days 1 to 21 of the first 28-day cycle, and dexamethasone is administered on days 1, 8, 15, and 22 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are further administered in one or more 28-day cycles after the first 28-day cycle, the anti-CD38 antibody is administered on days 1 and 15 of one or more 28-day cycles after the first 28-day cycle, pomalidomide is administered daily from days 1 to 21 of one or more 28-day cycles after the first 28-day cycle, and dexamethasone is administered on days 1, 8, 15, and 22 of one or more 28-day cycles after the first 28-day cycle. In some embodiments, pomalidomide and dexamethasone are administered before the anti-CD38 antibody on day 1 of the first 28-day cycle. In some embodiments, dexamethasone is administered before the anti-CD38 antibody on days 8, 15, and 22 of the first 28-day cycle, and the anti-CD38 antibody is administered before pomalidomide on days 8 and 15 of the first 28-day cycle. In some embodiments, pomalidomide and dexamethasone are administered before the anti-CD38 antibody on day 1 of one or more 28-day cycles after the first 28-day cycle. In some embodiments, dexamethasone is administered before the anti-CD38 antibody, and the anti-CD38 antibody is administered before pomalidomide on day 15 of one or more 28-day cycles after the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered intravenously. In some embodiments, pomalidomide is administered orally. In some embodiments, dexamethasone is administered orally. In some embodiments, dexamethasone is administered intravenously.

[0022] In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered in a first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered once weekly in the first 28-day cycle, pomalidomide is administered for 21 days in the first 28-day cycle, and dexamethasone is administered once weekly in the first 28-day cycle. In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are further administered in one or more 28-day cycles after the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered once every other week in one or more 28-day cycles after the first 28-day cycle, pomalidomide is administered for 21 days in one or more 28-day cycles after the first 28-day cycle, and dexamethasone is administered once weekly in one or more 28-day cycles after the first 28-day cycle. In some embodiments, pomalidomide and dexamethasone are administered prior to the anti-CD38 antibody in the first 28-day cycle. In some embodiments, dexamethasone is administered prior to the anti-CD38 antibody, and the anti-CD38 antibody is administered prior to pomalidomide in the first 28-day cycle. In some embodiments, pomalidomide and dexamethasone are administered prior to the anti-CD38 antibody in one or more 28-day cycles after the first 28-day cycle. In some embodiments, dexamethasone is administered prior to the anti-CD38 antibody, and the anti-CD38 antibody is administered prior to pomalidomide in one or more 28-day cycles after the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered intravenously. In some embodiments, pomalidomide is administered orally. In some embodiments, dexamethasone is administered orally. In some embodiments, dexamethasone is administered intravenously.

[0023] In some embodiments, the individual was resistant to the most recent prior treatment for multiple myeloma. In some embodiments, the most recent prior treatment was lenalidomide. In some embodiments, the most recent prior treatment was a proteasome inhibitor. In some embodiments, for use herein or by any of the methods herein, the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, and ixazomib. In some embodiments, lenalidomide and the proteasome inhibitor were administered in combination.

[0024] In some embodiments, the individual has chronic obstructive pulmonary disease (COPD). In some embodiments, the individual has asthma. In some embodiments, the individual has bronchospasm. In some embodiments, the individual has not received prior treatment with pomalidomide. In some embodiments, the individual has not received prior treatment with an anti-CD38 antibody. In some embodiments, the individual has not received prior treatment with daratumumab. In some embodiments, the individual has one or more cytogenetic abnormalities selected from the group consisting of del(17p), t(4;14), and t(14;16). In some embodiments, the individual is at least 65 years old and less than 75 years old. In some embodiments, the individual is 75 years of age or older. In some embodiments, the individual has received at least three prior treatments for multiple myeloma. In some embodiments, the individual is of East Asian descent (e.g., an individual from Japan, Korea, or Taiwan). In some embodiments, the individual is in stage III according to the International Staging System (ISS). In some embodiments, the individual is in stage III according to the Revised International Staging System (R-ISS). In some embodiments, the individual has less than 10 -4 as follows (e.g., "10 -4 " means that there is less than 1 tumor cell per 10 4 bone marrow cells in the patient bone marrow sample), less than 10 -5 as follows (e.g., "10 -5 " means that there is less than 1 tumor cell per 10 5 bone marrow cells in the patient bone marrow sample), or less than 10 -6 as follows (e.g., "10 -6 " means that there is less than 1 tumor cell per 10 6 bone marrow cells in the patient bone marrow sample) and is minimal residual disease (MRD) negative at the threshold. In some embodiments, MRD is investigated through next-generation sequencing (NGS). In some embodiments, MRD is investigated through next-generation flow cytometry (NGF). Additionally, or alternatively, in some embodiments, MRD is investigated through positron emission tomography-computed tomography (PET-CT) scan.

[0025] A kit is provided that includes an anti-CD38 antibody for use in combination with pomalidomide and dexamethasone to treat multiple myeloma in an individual with an antibody for a method or use provided herein.

[0026] A liquid pharmaceutical formulation comprising isatuximab is also provided. In some embodiments, the pharmaceutical formulations herein comprise isatuximab at a concentration of 5-20 mg / ml, a buffer selected from the group consisting of histidine, acetate and phosphate, and an excipient selected from the group consisting of sucrose and mannitol, and a non-ionic surfactant (e.g., polysorbate 20 (PS20), polysorbate 80 (PS80) or poloxamer 188), wherein the pH of the pharmaceutical formulation is from about 5.5 to about 7.4. In some embodiments, the pharmaceutical formulation comprises about 20 mM histidine, about 10% (w / v) sucrose, about 0.2% (w / v) polysorbate 80 and about 20 mg / ml isatuximab, wherein the pH of the pharmaceutical formulation is about 6.0.

[0027] This patent or application documents contain at least one colored drawing. Copies of this patent or patent application publication containing color drawings are provided by the appropriate agency upon payment of the claim and the required fee.

Brief Description of the Drawings

[0028]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6A

Figure 6B

Figure 7

DETAILED DESCRIPTION OF THE INVENTION

[0029] Definitions As used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an" and "the" include the plural forms. Thus, for example, reference to "a molecule" may optionally include combinations of two or more such molecules, and the like.

[0030] "Sustained efficacy" refers to the sustained effect on preventing or delaying the progression of a disease (e.g., multiple myeloma) and / or improving one or more efficacy criteria after discontinuation of treatment. For example, efficacy of treatment for multiple myeloma can be measured according to the criteria of Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma." Lancet Oncol. 17(8):e328 - e346, and Durie et al. (2006) "International uniform response criteria for multiple myeloma." Leukemia. 20:1467 - 1473. (See also Table A below and Table B in this specification). In some embodiments, the sustained efficacy has a duration that is at least as long as, e.g., at least 1.5×, 2.0×, 2.5×, or 3.0× the length of the treatment period.

[0031] [Table 1] [Table 2]

[0032] As used herein, the term "pharmaceutical preparation" refers to a preparation that is in a form that enables the biological activity of the active ingredient and that does not contain additional constituents that are unacceptably toxic to the subject to which the preparation is administered. Such a preparation is sterile. "Pharmaceutically acceptable" excipients (vehicles, additives) are those that can be reasonably administered to the subject mammal to provide the effective dosage of the active ingredient used.

[0033] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of a disease or cells (e.g., cancer cells) being treated in the process of clinical pathology. Desirable effects of treatment include reducing the rate of disease progression, ameliorating or alleviating the disease state, and remission or improvement of prognosis. For example, without limitation, reducing (or destroying) the proliferation of cancer cells, reducing the symptoms caused by the disease, improving the quality of life of the person suffering from the disease, reducing the dosage of other pharmaceuticals required to treat the disease, and / or extending the lifespan of the individual, when one or more symptoms associated with cancer are alleviated or eliminated, the individual is "treated" successfully.

[0034] As used herein, "retarding the progression of a disease" means delaying, preventing, slowing, retarding, stabilizing, and / or postponing the onset of a disease (such as cancer). This delay can be of various lengths of time depending on the medical history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can encompass substantial prevention in the sense that the individual does not develop the disease. For example, it is possible to retard late-stage cancers such as the occurrence of metastasis.

[0035] "Effective amount" is at least the minimal amount required to achieve a measurable improvement or prevention of a particular disorder. In the present specification, the effective amount may vary depending on factors such as the patient's disease state, age, gender and weight, as well as the ability of the antibody to elicit the desired effect in an individual. The effective amount is also one in which the therapeutically beneficial effects outweigh any toxic and detrimental effects of the treatment. For prophylactic use, beneficial or desired results include removing or reducing the risk, reducing the severity, or delaying the onset of the disease, including the biochemical, histological and / or behavioral symptoms of the disease that appear during the development of the disease, its complications and intermediate pathological phenotypes. For therapeutic use, beneficial or desired results include reducing one or more symptoms resulting from the disease, improving the quality of life of the person suffering from the disease, reducing the dosage of other pharmaceuticals required to treat the disease, for example enhancing the effect of another pharmaceutical through targeting, delaying the progression of the disease, and / or extending the survival period. In the case of cancer or a tumor, the effective amount of the drug is to reduce the number of cancer cells; reduce the tumor size; inhibit the invasion of cancer cells into peripheral organs (i.e., delay to some extent, or desirably stop); inhibit tumor metastasis (i.e., delay to some extent, desirably stop); inhibit tumor growth to some extent; and / or reduce one or more of the symptoms associated with the disorder. The effective amount can be administered in one or more doses. For the purposes of the present invention, the effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to directly or indirectly achieve a prophylactic or therapeutic treatment. As understood in the clinical setting, the 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, "effective amount" may be considered in the context of administering one or more therapeutic agents, and it is possible to consider administering a single agent in an effective amount if desired results can be achieved or are achieved in combination with one or more other agents.

[0036] As used herein, "in combination with" refers to the administration of one treatment therapy in addition to another treatment therapy. Thus, "in combination with" refers to the administration of one treatment therapy before, during, or after the administration of another treatment therapy to an individual.

[0037] "Subject" or "individual" for treatment purposes refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports or pet animals such as dogs, horses, cats, cows, etc. Preferably, the mammal is a human.

[0038] The term "antibody" as used herein is used in the broadest sense and specifically includes 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.

[0039] Human light chains are generally classified into kappa and lambda light chains, and human heavy chains are generally classified into mu, delta, gamma, alpha or epsilon, defining the isotypes of antibodies as IgM, IgD, IgG, IgA and IgE respectively. IgG has several subclasses including, without limitation, IgG1, IgG2, IgG3 and IgG4. IgM has subclasses including, without limitation, IgM1 and IgM2. IgA is similarly subdivided into subclasses including, without limitation, IgA1 and IgA2. Among full-length light and heavy chains, the variable and constant domains are generally linked by a "J" region of about 12 or more amino acids, and the heavy chain also includes a "D" region of about 10 or more amino acids. See, for example, FUNDAMENTAL IMMUNOLOGY (Paul, W. ed., Raven Press, 2nd ed., 1989), which is hereby incorporated by reference in its entirety. The variable regions of each light / heavy chain pair generally form the antigen-binding site. The variable domains of antibodies generally exhibit the same general structure of relatively conserved framework regions (FRs) linked by three hypervariable regions also called complementarity-determining regions or CDRs. The CDRs of the two chains of each pair are generally aligned by the framework regions, which allows binding to specific epitopes. From the amino terminus to the carboxyl terminus, both the variable domains of the light and heavy chains generally include, in order, the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0040] The term "CDR set" refers to a group of three CDRs present in a single variable region capable of binding to an antigen. The exact boundaries of these CDRs are defined differently by different systems. The system described by Kabat (Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (National Institutes of Health, Bethesda, Md. (1987) and (1991))) provides not only an explicit residue numbering system applicable to any variable region of an antibody, but also the exact residue boundaries that define the three CDRs. These CDRs can be referred to as Kabat CDRs.

[0041] As used herein, the term "Fc" refers to the sequence of a non-antigen-binding fragment that can be derived from digestion of an antibody or generated by other means in monomeric or multimeric form and can contain a hinge region. The original immunoglobulin source of native Fc is preferably of human origin and can be any immunoglobulin. Fc molecules are composed of monomeric polypeptides that can be linked into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and non-covalent bonds. The number of intermolecular disulfide bonds between monomeric subunits of a native Fc molecule ranges from 1 to 4 depending on the class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, IgGA2, and IgG4). One example of Fc is a disulfide-linked dimer resulting from papain digestion of IgG. The term "native Fc" as used herein is a general term for monomeric, dimeric, and multimeric forms.

[0042] As used herein, the term "overall response rate" or "ORR" refers to the proportion of patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) as investigated by the IRC using the IMWG response criteria described in Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma". Lancet Oncol. 17(8):e328 - e346 and Durie et al. (2006) "International uniform response criteria for multiple myeloma". Leukemia. 20:1467 - 1473. See also Tables A and B.

[0043] Summary Provided herein are methods or antibodies for use in treating or delaying the progression of multiple myeloma in an individual who has received at least two prior treatments for multiple myeloma. The antibodies for the methods or use provided herein comprise administering to the individual an effective amount of an anti - CD38 antibody (e.g., isatuximab), pomalidomide, and dexamethasone. In some embodiments, the treatment prolongs the progression - free survival (PFS) and / or overall survival (OS) of the individual. In some embodiments, the individual is negative for minimal residual disease (MRD) after treatment. In some embodiments, the treatment prolongs the progression - free survival (PFS) and / or overall survival (OS) of the individual as compared to a treatment comprising administering pomalidomide and dexamethasone without an anti - CD38 antibody (e.g., isatuximab). In some embodiments, the treatment improves renal function. Also provided are methods or antibodies for use in improving renal impairment in an individual having multiple myeloma.

[0044] Anti - CD38 Antibody In some embodiments, the anti-CD38 antibody binds to human CD38. In some embodiments, the anti-CD38 antibody is a human antibody, a humanized antibody or a chimeric antibody. In some embodiments, the anti-CD38 antibody comprises a heavy chain variable domain (V H ) comprising (a) CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (V L ) comprising CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and 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 (V H ) having 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 range between these values) identical to SEQ ID NO: 7. Additionally, or alternatively, in some embodiments, the anti-CD38 antibody comprises a light chain variable domain (V L ) having 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 range between these values) identical to SEQ ID NO: 8 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody comprises V H comprising SEQ ID NO: 7 and V L comprising SEQ ID NO: 8 or SEQ ID NO: 9. QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS (SEQ ID NO: 7) DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKR (SEQ ID NO: 8) DIVMAQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKR (SEQ ID NO: 9)

[0045] In some embodiments, the anti-CD38 antibody is isatuximab (CAS Registry Number: 1461640-62-9). Isatuximab, also known as hu38SB19 and SAR650984, is an anti-CD38 antibody described in WO2008 / 047242 and U.S. Patent No. 8,153,765, the entire contents of both of which are incorporated herein by reference in their entirety.

[0046] The heavy chain of isatuximab comprises the following amino acid sequence: QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG (SEQ ID NO: 10) The light chain of Isatsukimab contains the following amino acid sequence: DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 11)

[0047] Anti-CD38 antibodies can be generated using recombinant methods. For the recombinant production of antigen-specific antibodies, the nucleic acid encoding the antibody is isolated and inserted into a replicable vector for further cloning (amplification of DNA) or expression. The DNA encoding the antibody can be readily isolated and sequenced using conventional techniques (e.g., using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the antibody). Many vectors are available. Vector components generally include, without limitation, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, enhancer elements, a promoter, and a transcription termination sequence. The vector is generally transformed into a host cell suitable for the expression of the nucleic acid. In some embodiments, the host cell is a eukaryotic cell or a prokaryotic cell. In some embodiments, the eukaryotic host cell is a mammalian cell. Examples of useful mammalian host cell lines include monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK, ATCC CCL10); mouse Sertoli cells (TM4, Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1 ATCC CCL70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL2); dog kidney cells (MDCK, ATCC CCL34); buffalo rat liver cells (BRL 3A, ATCC CRL1442); human lung cells (W138, ATCC CCL75); 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 NS0 and Sp2 / 0. For a review of certain mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (ed. B.K.C. Lo, Humana Press, Totowa, N.J., 2003), pp. 255-268. Anti-CD38 antibodies produced from cells can be purified, for example, using hydroxylapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography generally being one of the preferred purification steps. In general, various methods for producing antibodies for use in research, testing, and clinical applications are established in the art, consistent with the above methods, and / or considered suitable by those skilled in the art.

[0048] Pomalidomide The chemical name of pomalidomide is 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, and pomalidomide has the following chemical structure

Chemical formula

[0049] Pomalidomide has the molecular formula C 13 H 11 N3O4 and a molecular weight of 273.24 g / mol. Pomalidomide is commercially available as POMALYST, POMALID, IMNOVID, and others.

[0050] Dexamethasone The chemical name of dexamethasone is 1-dehydro-16alpha-methyl-9alpha-fluorocortisol, and dexamethasone has the following chemical structure: [Chem.]

[0051] Dexamethasone has the molecular formula of C 22 H 29 FO5 and a molecular weight of 392.461 g / mol. Dexamethasone is commercially available as a formulation for oral and intravenous administration. Exemplary trade names of dexamethasone include, for example, DECADRON, MAXIDEX, HEXADROL, DEXACORT, DEXASONE, ORADEXON, SUPERPREDNOL, DEXALONA, and others.

[0052] Pharmaceutical Compositions and Formulations As used herein, pharmaceutical compositions and formulations are also provided that include, for example, an anti-CD38 antibody (such as isatuximab), pomalidomide, or dexamethasone for the treatment of multiple myeloma (such as refractory multiple myeloma or relapsed / refractory multiple myeloma). In some embodiments, each of the anti-CD38 antibody (e.g., isatuximab), pomalidomide, and dexamethasone is provided as a separate pharmaceutical composition. In some embodiments, the pharmaceutical compositions and formulations further include a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable excipient. Suitable excipients that include nonionic surfactants such as PS80 are described in the pharmacopoeias from the US and EP (USP and PhEu, respectively) and the 2015 Chinese Pharmacopoeia (ChP, which describes, for example, polysorbate 80 for injection).

[0053] In some embodiments, the pharmaceutical formulation provided herein comprises isatuximab at a concentration of 5 to 20 mg / ml, a buffer selected from the group consisting of histidine, acetate, and phosphate, an excipient selected from the group consisting of sucrose and mannitol, and a nonionic surfactant (such as PS20, PS80, or poloxamer 188) at 0.001% to 0.03%, wherein the pH of the pharmaceutical formulation is from about 5.5 to about 7.4. In some embodiments, the pharmaceutical formulation comprises 5 mg / ml isatuximab, 10 mM histidine or 10 mM acetate, 10% (w / v) sucrose or 5% mannitol, and 0.001, 0.005%, or 0.01% (w / v) nonionic surfactant, wherein the pH of the pharmaceutical formulation is about 6.0 or about 6.5. In some embodiments, the pharmaceutical formulation comprises 5 mg / ml isatuximab, 10 mM histidine, 10% (w / v) sucrose, and 0.005% (w / v) PS80, and the pH of the pharmaceutical formulation is about 6.0 or about 6.5. In some embodiments, the nonionic surfactant is PS80.

[0054] In some embodiments, the anti-CD38 antibody (such as isatuximab) described herein is in a pharmaceutical formulation comprising about 20 mg / mL antibody, about 20 mM histidine, about 10% (w / v) sucrose, and about 0.02% (w / v) nonionic surfactant (such as PS20, PS80, or poloxamer 188), wherein the pH of the pharmaceutical formulation is about 6.0. In some embodiments, the anti-CD38 antibody (such as isatuximab) described herein is in a pharmaceutical 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 nonionic surfactant. In some embodiments, the nonionic surfactant is PS80.

[0055] In some embodiments, the pharmaceutical formulation comprises water for injection (WFI) such as sterile water for injection (SWFI). In some embodiments, the pharmaceutical formulation is sterile. In some embodiments, a single use of the formulation comprises 5 ml of the pharmaceutical formulation (i.e., 100 mg of the anti-CD38 antibody). In some embodiments, 5 ml of the single-use pharmaceutical formulation is provided, for example, in a Type I 6 mL colorless transparent glass vial with an elastomeric closure. In some embodiments, the fill volume of the vial is established to ensure removal of 5 mL. In some embodiments, the fill volume is 5.4 mL. In some embodiments, a single use of the formulation comprises 25 ml of the pharmaceutical formulation (i.e., 500 mg of the anti-CD38 antibody). In some embodiments, 25 ml of the single-use pharmaceutical formulation is provided, for example, in a 30 mL colorless transparent glass vial with an elastomeric closure. In some embodiments, the fill volume of the vial is established to ensure removal of 25 mL. In some embodiments, the pharmaceutical formulations are stable for at least about 6, 12, 18, 24, 30 or 36 months at a temperature between about 2°C and about 8°C, protected from light, including any range between those values. In some embodiments, the pharmaceutical formulation is diluted with 0.9% sodium chloride or 5% dextrose for injection. In some embodiments, the diluted injection solution is stable for up to about 6, 12, 18, 24, 30, 36, 42 or 48 hours at a temperature between about 2°C and about 8°C, including any range between those values. In some embodiments, the diluted injection solution is stable for an additional 8 hours at room temperature (e.g., including the injection time) after storage between about 2°C and about 8°C. In some embodiments, the diluted injection solution is stable in the presence of light. In some embodiments, the bag into which the injection solution to be diluted is diluted is made of polyolefin (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) and di(2-ethylhexyl) phthalate (DEHP) or ethylene-vinyl acetate (EVA). In some embodiments, the tubing used for injection is made of PE, PVC (with or without DEHP), polybutadiene (PBD) or polyurethane (PU) and an in-line filter (polyethersulfone (PES), polysulfone or nylon).

[0056] Pharmaceutical formulations of pomalidomide and dexamethasone are commercially available. For example, pomalidomide is known by various product names (described elsewhere in this specification) including POMALYST®. Dexamethasone is known by various product names (described elsewhere in this specification) including DECADRON, MAXIDEX, and HEXADROL. In some embodiments, pomalidomide and / or dexamethasone are provided in separate containers. In some embodiments, pomalidomide and / or dexamethasone are each used and / or prepared for administration to an individual as described in the prescribing information available for commercially available products.

[0057] Methods of treatment and antibodies for use in treatment Described herein are methods and antibodies for use in the treatment of multiple myeloma (e.g., relapsed multiple myeloma or relapsed / refractory multiple myeloma) in an individual (e.g., a human individual) or for delaying the progression thereof, the methods and antibodies comprising administering to the individual an anti-CD38 antibody (e.g., (a) a heavy chain variable domain (V H ) comprising CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (V LA method and an antibody are provided that comprise administering an effective amount of an anti-CD38 antibody (including the anti-CD38 antibody), pomalidomide, and dexamethasone, wherein the individual has received at least two prior treatments (e.g., lenalidomide and proteasome inhibitors) for multiple myeloma. In some embodiments, the administration of the anti-CD38 antibody, pomalidomide, and dexamethasone described herein results in durable responses in the individual. In some embodiments, the administration of the anti-CD38 antibody, pomalidomide, and dexamethasone described herein prolongs the progression-free survival (PFS) of the individual. In some embodiments, the administration of the anti-CD38 antibody, pomalidomide, and dexamethasone described herein prolongs the overall survival (OS) of the individual. In some embodiments, the administration of the anti-CD38 antibody, pomalidomide, and dexamethasone described herein results in lower minimal residual disease (MRD). In some embodiments, the individual is MRD negative after the administration of the anti-CD38 antibody, pomalidomide, and dexamethasone described herein. In some embodiments, the individual exhibits renal dysfunction prior to the administration of the anti-CD38 antibody, pomalidomide, and dexamethasone described herein. In some embodiments, the administration of the anti-CD38 antibody, pomalidomide, and dexamethasone described herein improves renal function in the individual. In some embodiments, the individual is an adult, e.g., at least 18 years old.

[0058] As used herein, a method or antibody for use in improving renal impairment in an individual (e.g., a human individual) with multiple myeloma, the method or antibody comprising administering to the individual: (a) a heavy chain variable domain (V H ) 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 (V LA method or antibody is provided that comprises administering an effective amount of an anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, an individual with multiple myeloma is selected for administration with an anti-CD38 antibody, pomalidomide, and dexamethasone based on having renal impairment. In some embodiments, an individual with multiple myeloma and renal impairment has a poor prognosis. In some embodiments, the individual is an adult, e.g., at least 18 years old. In some embodiments, if an individual has an estimated glomerular filtration rate (eGFR) of less than about 90 mL / min / 1.73m 2 prior to the start of treatment, that individual has renal impairment. In some embodiments, if an individual has an estimated glomerular filtration rate (eGFR) from about 60 mL / min / 1.73m 2 to less than about 90 mL / min / 1.73m 2 prior to the start of treatment, that individual has renal impairment. In some embodiments, an individual with an eGFR from about 60 mL / min / 1.73m 2 to less than about 90 mL / min / 1.73m 2 has mild renal impairment. In some embodiments, if an individual has an estimated glomerular filtration rate (eGFR) from about 30 mL / min / 1.73m 2 to less than about 60 mL / min / 1.73m 2 prior to the start of treatment, that individual has renal impairment. In some embodiments, an individual with an eGFR from about 30 mL / min / 1.73m 2 to less than about 60 mL / min / 1.73m 2 (e.g., less than about 30, less than about 50, or less than about 60 mL / min / 1.73m 2 ) has moderate renal impairment. In some embodiments, if an individual has an estimated glomerular filtration rate (eGFR) of less than about 30 mL / min / 1.73m 2 prior to the start of treatment, that individual has renal impairment. In some embodiments, an individual with an eGFR of less than about 30 mL / min / 1.73m 2 has severe renal impairment. In some embodiments, if an individual has an estimated glomerular filtration rate (eGFR) of less than about 90 mL / min / 1.73m 2If an individual has a creatinine clearance below, the individual has kidney impairment. In some embodiments, prior to the start of treatment, an individual has from about 60 mL / min / 1.73m 2 to about 90 mL / min / 1.73m 2 If an individual has a creatinine clearance below, the individual has kidney impairment. In some embodiments, prior to the start of treatment, from about 60 mL / min / 1.73m 2 to about 90 mL / min / 1.73m 2 An individual having a creatinine clearance below has mild kidney impairment. In some embodiments, prior to the start of treatment, an individual has from about 30 mL / min / 1.73m 2 to about 60 mL / min / 1.73m 2 If an individual has a creatinine clearance below, the individual has kidney impairment. In some embodiments, prior to the start of treatment, from about 30 mL / min / 1.73m 2 to about 60 mL / min / 1.73m 2 An individual having a creatinine clearance below (e.g., less than about 50 or less than about 60 mL / min / 1.73m 2 less than) has moderate kidney impairment. In some embodiments, prior to the start of treatment, an individual has a creatinine clearance below about 30 mL / min / 1.73m 2 If an individual has a creatinine clearance below, the individual has kidney impairment. In some embodiments, prior to the start of treatment, an individual has a creatinine clearance below about 30 mL / min / 1.73m 2 An individual having a creatinine clearance below has severe kidney impairment. In some embodiments, after the start of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone, the individual achieves renal response. In some embodiments, after the start of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone, the individual achieves complete renal response. In some embodiments, complete renal response is from <50 mL / min / 1.73m 2 prior to the start of treatment to ≧60 mL / min / 1.73m 2Characterized as an improvement in baseline eGFR or creatinine clearance to. In some embodiments, after initiation of treatment, the individual achieves sustained renal response. Sustained renal response is also known as "permanent renal response". In some embodiments, sustained renal response (or "permanent renal response") is <50 mL / min / 1.73 m prior to initiation of treatment 2 to ≥60 mL / min / 1.73 m 2Characterized as an improvement in baseline eGFR or creatinine clearance that persists for at least about 60 days. In some embodiments, the time to first renal response in an individual treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is shorter than the time to first renal response in an individual treated with pomalidomide and dexamethasone. In some embodiments, "time to first renal response" refers to the time between the first administration date of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone and the date of the first sign of renal response. In some embodiments, the time to complete renal response in an individual treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is any one of about 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, or 16 weeks from the start of treatment, and any range between these values is also included. In some embodiments, the time to complete renal response in an individual treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is shorter by any one of about 1, 1.5, 2, 2.5, 3, 3.5, 3.6, 3.7, 3.8, 3.9, or 4 weeks, and any range between these values is also included, than the time to complete renal response in an individual treated with pomalidomide and dexamethasone without an anti-CD38 antibody. In some embodiments, the time to sustained complete renal response (also known as "permanent complete renal response") in an individual treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is any one of about 1, 1.5, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3 weeks from the start of treatment, and any range between these values is also included. In some embodiments, the time to complete renal response in an individual treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is shorter by any one of about 1, 1.5, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3 weeks, and any range between these values is also included, than the time to complete renal response in an individual treated with pomalidomide and dexamethasone without an anti-CD38 antibody.

[0059] In some embodiments, treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone for the methods or uses provided herein prevents or delays end-stage renal disease (ESRD) in an individual. In some embodiments, an individual receiving treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone has a lower probability of developing ESRD than an individual receiving treatment with pomalidomide and dexamethasone without an anti-CD38 antibody. In some embodiments, ESRD in an individual receiving treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone for the methods or uses provided herein is delayed by at least about 1, 2, 3, or 4 weeks; at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 42, or 48 months; or longer than 48 months (e.g., by about 4.5, 5, 5.5, or 6 years) compared to an individual receiving treatment with pomalidomide and dexamethasone without an anti-CD38 antibody, and any range between these values is also included.

[0060] In some embodiments, the antibody for the methods or uses provided herein extends the progression-free survival (PFS) of an individual. In some embodiments, the antibody for the methods or uses provided herein extends the overall survival (OS) of an individual. In some embodiments, an individual is negative for minimal residual disease (MRD) after treatment (e.g., treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone). In some embodiments, an individual has received at least two prior treatments (or prior treatment lines) for multiple myeloma (e.g., lenalidomide and proteasome inhibitors, etc.).

[0061] In some embodiments, the individual had progressive disease during the most recent prior treatment (or treatment line), e.g., the treatment (or treatment line) immediately prior to the initiation of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual demonstrated progression (PD) within 60 days from the end of the most recent prior treatment (or treatment line) for multiple myeloma, e.g., the treatment (or treatment line) immediately prior to the initiation of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, progression (PD) is defined by the International Myeloma Working Group criteria (see, e.g., Kumar et al. (2016) “International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma”. Lancet Oncol. 17(8):e328-e346; Durie et al. (2006) “International uniform response criteria for multiple myeloma”. Leukemia. 20:1467-1473; and see Tables A and B herein). In some embodiments, a treatment line is a planned sequential treatment including ≥1 complete cycle of a single agent or combination of two or more agents, or stem cell transplantation. In some embodiments, if a new treatment line is initiated after discontinuation of a prior treatment line, a given treatment is considered a new treatment line. In some embodiments, if a treatment regimen is discontinued for any reason and a different treatment regimen is initiated, the treatment is considered a new treatment line. In some embodiments, if all drugs in a given regimen are stopped, the treatment regimen is considered discontinued. In some embodiments, if only some, but not all, of the drugs in a regimen are discontinued, the regimen is not considered discontinued. In some embodiments, the reasons for discontinuation, addition, substitution, or SCT (stem cell transplantation) do not affect how the line is counted. In some embodiments, if there is an unplanned addition or substitution of one or more drugs to an existing regimen, a given treatment is considered a new treatment line.In some embodiments, for individuals receiving more than one SCT, except for planned tandem SCTs at a predetermined interval (such as three months), each SCT (autologous or allogeneic) can be considered a new treatment line regardless of whether the pre-treatment regimens used are the same or different. In some embodiments, planned tandem SCTs are considered one line. In some embodiments, planned induction and / or consolidation, maintenance by any SCT (front-line, relapse, autologous or allogeneic) are considered one line of treatment.

[0062] In some embodiments, multiple myeloma is difficult to treat. In some embodiments, an individual has refractory multiple myeloma. In some embodiments, an individual with refractory multiple myeloma was resistant to all prior treatments (or prior treatment lines), but achieved at least minimal response (MR) to one prior treatment (or treatment line). In some embodiments, minimal response (MR) is defined by the International Myeloma Working Group criteria (see, e.g., Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma". Lancet Oncol. 17(8):e328-e346; Durie et al. (2006) "International uniform response criteria for multiple myeloma". Leukemia. 20:1467-1473; and Tables A and B herein). In some embodiments, an individual with refractory multiple myeloma is an individual who was non-responsive to prior treatment (or prior treatment line). In some embodiments, "non-responsive" to a treatment (or treatment line) for multiple myeloma means that the individual was unable to achieve at least minimal response (MR) to the treatment (or treatment line) for multiple myeloma. In some embodiments, "non-responsive" to a treatment (or treatment line) for multiple myeloma means that the individual exhibited progressive disease during the treatment (or treatment line) for multiple myeloma. In some embodiments, an individual with refractory multiple myeloma is an individual who showed progression within 60 days of the end of the last treatment for multiple myeloma.

[0063] In some embodiments, the individual has failed previous treatment for multiple myeloma (e.g., treatment with lenalidomide and / or a proteasome inhibitor). In some embodiments, to “fail” previous treatment means that during treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor) or within 60 days after the end of treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor), the individual exhibits disease progression (e.g., according to the criteria in Tables A and B). In some embodiments, to “fail” previous treatment for multiple myeloma means that the individual had a partial response (PR) or a better response (e.g., according to the criteria in Tables A and B) to treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor), but exhibited disease progression within 6 months after discontinuation of treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor). In some embodiments, to “fail” previous treatment for multiple myeloma means that the individual develops toxicity / intolerance after at least 2 consecutive cycles of a treatment regimen (e.g., a treatment regimen containing lenalidomide and / or a proteasome inhibitor (such as bortezomib, carfilzomib, ixazomib, marizomib, oprozomib, etc.)). In some embodiments, intolerance to a proteasome-containing regimen means that the individual (e.g., an individual who did not have peripheral neuropathy prior to the start of the regimen) develops peripheral neuropathy or neuropathic pain during or after treatment with the proteasome-containing regimen. In some embodiments, intolerance to a lenalidomide-containing regimen means that the individual develops severe rash during or after treatment with the lenalidomide-containing regimen.

[0064] In some embodiments, the individual has relapsed / refractory multiple myeloma. In some embodiments, the individual has measurable disease according to one or more of the following criteria: serum M protein ≥ 0.5 g / dL measured using serum protein immunoelectrophoresis, and / or urinary M protein ≥ 200 mg / 24 hours measured using urinary protein immunoelectrophoresis, and / or serum free light chain (FLC) (i.e., FLC assay ≥ 10 mg / dL (≥ 100 mg / L), and abnormal serum FLC ratio (< 0.26 or > 1.65). In some embodiments, an individual with relapsed / refractory multiple myeloma is an individual who has relapsed from at least one prior treatment (or treatment line) for multiple myeloma and was resistant to the most recent treatment (or treatment line) for multiple myeloma. In some embodiments, an individual with relapsed / refractory multiple myeloma is an individual who has relapsed from at least one prior treatment (or treatment line) for multiple myeloma and was resistant to the most recent treatment (or treatment line) for multiple myeloma and was resistant to one or more prior treatments (or treatment lines) before the most recent treatment (or treatment line) for multiple myeloma. In some embodiments, an individual with relapsed or refractory multiple myeloma is an individual who has shown progression within 60 days from the end of the most recent treatment (or treatment line).

[0065] In some embodiments, the individual was resistant to the most recent prior treatment (or treatment line).

[0066] In some embodiments, the individual has relapsed / refractory multiple myeloma (RRMM) with measurable disease (e.g., serum M protein ≥ 0.5 g / dL measured using serum protein immunoelectrophoresis, and / or urinary M protein ≥ 200 mg / 24 hours measured using urinary protein immunoelectrophoresis), has received at least two prior treatments including lenalidomide and a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, marizomib, oprozomib, etc.), and was resistant to the last treatment line (i.e., the most recent treatment line). In some embodiments, the individual has sufficient kidney, liver, and bone marrow function.

[0067] In some embodiments, the individual has a poor prognosis. In some embodiments of the antibodies for the methods or uses provided herein, the individual has received at least 1, at least 2, at least 3, at least 4 prior treatments (or prior treatment lines) or more than 4 prior treatments (or prior treatment lines) for multiple myeloma, for example, any one of at least 5, 6, 7, 8, 9, 10 or 11 prior treatments (or prior treatment lines).

[0068] In some embodiments, the individual has received at least one prior treatment (or prior treatment line) with lenalidomide. In some embodiments, the lenalidomide prior treatment (or lenalidomide prior treatment line) included at least 2 consecutive cycles of lenalidomide. In some embodiments, the individual failed the lenalidomide prior treatment (or was non-responsive to the lenalidomide prior treatment line). In some embodiments, an individual who failed the lenalidomide prior treatment (or lenalidomide prior treatment line) did not achieve at least minimal response (MR) during treatment (or treatment line) with lenalidomide. In some embodiments, an individual who failed the lenalidomide prior treatment (or lenalidomide prior treatment line) demonstrated progression (PD) during treatment (or treatment line) with lenalidomide. As referred to elsewhere herein, in some embodiments, "minimal response" and "progression" are investigated according to the criteria of Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma". Lancet Oncol. 17(8):e328-e346 and Durie et al. (2006) "International uniform response criteria for multiple myeloma". Leukemia. 20:1467-1473 (see also Tables A and B herein). In some embodiments, the previous lenalidomide was administered during the 1st, 2nd, 3rd, 4th, 5th, 6th and / or subsequent treatment (or treatment line) for multiple myeloma (i.e., before treatment with an anti-CD38 antibody, pomalidomide and dexamethasone with the antibody for the methods or uses provided herein). In some embodiments, the individual was resistant to lenalidomide. In some embodiments, the previous lenalidomide was administered to the individual as a single agent. In some embodiments, the previous lenalidomide was administered to the individual in combination with at least one additional agent.

[0069] In some embodiments, the individual has received at least one prior treatment (or at least one prior treatment line) with a proteasome inhibitor (PI). In some embodiments, the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, ixazomib, marizomib, and oprozomib. In some embodiments, the prior treatment (or prior treatment line) with the proteasome inhibitor included at least 2 consecutive cycles of the proteasome inhibitor. In some embodiments, the individual has failed a proteasome inhibitor prior treatment (or proteasome inhibitor prior treatment line) (e.g., was non-responsive). In some embodiments, an individual who has failed a prior treatment (or treatment line) with a proteasome inhibitor did not achieve at least minimal response (MR) during treatment (or treatment line) with the proteasome inhibitor. In some embodiments, an individual who has failed a prior treatment (or prior treatment line) with a proteasome inhibitor demonstrated progression (PD) during treatment (or prior treatment line) with the proteasome inhibitor. In some embodiments, the proteasome inhibitor prior treatment was administered during the 1st, 2nd, 3rd, 4th, 5th, 6th, and / or subsequent treatment (or treatment line) for multiple myeloma (i.e., prior to treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone by the method or use provided herein). In some embodiments, the individual was resistant to a proteasome inhibitor (e.g., one or more proteasome inhibitors). In some embodiments, the proteasome inhibitor prior treatment (or proteasome inhibitor prior treatment line) was administered to the individual as a single agent. In some embodiments, the proteasome inhibitor prior treatment (or proteasome inhibitor prior treatment line) was administered to the individual in combination with at least one additional agent.

[0070] In some embodiments, lenalidomide and a proteasome inhibitor were co-administered to an individual. In some embodiments, the individual had previously achieved partial response (PR) or better to lenalidomide and / or a proteasome inhibitor (e.g., given alone or in combination), but demonstrated progression (PD) within 6 months from the end of treatment with lenalidomide and / or a proteasome inhibitor (or end of treatment line).

[0071] In some embodiments, the individual is of East Asian descent. In some embodiments, the individual of East Asian descent is an individual from Japan, South Korea, or Taiwan.

[0072] In some embodiments, the individual has chronic obstructive pulmonary disease (COPD). In some embodiments, the individual is diagnosed with COPD prior to initiation of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual develops and / or is diagnosed with COPD after initiation of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone.

[0073] In some embodiments, the individual has asthma. In some embodiments, the individual is diagnosed with asthma prior to initiation of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual develops and / or is diagnosed with asthma after initiation of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone.

[0074] In some embodiments, the individual has (e.g., experiences) bronchospasm. In some embodiments, the individual has experienced bronchospasm prior to initiation of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual develops bronchospasm after initiation of treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone.

[0075] In some embodiments, the myeloma cells of an individual undergoing treatment with an antibody for a method or use provided herein have a CD38 receptor density of about 13,000 to about 340,000 receptors / cancer cell. In some embodiments, an individual undergoing treatment with an antibody for a method or use provided herein is heterozygous with respect to the F158V single nucleotide polymorphism in the FCGR3A gene. In some embodiments, an individual undergoing treatment with an antibody for a method or use provided herein is homozygous with respect to the F158V single nucleotide polymorphism in the FCGR3A gene. In some embodiments, an individual undergoing treatment with an antibody for a method or use provided herein does not have the F158V single nucleotide polymorphism in the FCGR3A gene.

[0076] In some embodiments, the individual does not have primary refractory multiple myeloma. In some embodiments, an individual with primary refractory multiple myeloma is an individual who has not achieved at least minimal response (MR) with any treatment (or line of treatment) during the course of the disease. In some embodiments, the individual has only a disease with measurable free light chain (FLC). In some embodiments, the individual has not received prior treatment with an anti-CD38 antibody. In some embodiments, the individual has received prior treatment with an anti-CD38 antibody, such as daratumumab. In some embodiments, the individual has not received prior treatment (or prior line of treatment) with isatuximab. In some embodiments, the individual did not show progression (PD) during prior treatment (or prior line of treatment) with an anti-CD38 antibody. In some embodiments, the individual did not show PD within 60 days from the end of treatment (or line of treatment) with an anti-CD38 antibody. In some embodiments, the individual has not received prior treatment (or prior line of treatment) with pomalidomide. In some embodiments, the individual has received prior treatment (or prior line of treatment) with pomalidomide. In some embodiments, the individual has not received a prior allogeneic hematopoietic stem cell transplant.

[0077] In some embodiments, the treatment comprises administering an anti-CD38 antibody at a dose of 10 mg / kg, pomalidomide at a dose of 4 mg, and dexamethasone at a dose of 40 mg (i.e., if the individual is less than 75 years old) or 20 mg (i.e., if the individual is 75 years or older). In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered intravenously. In some embodiments, pomalidomide is administered orally. In some embodiments, dexamethasone is administered intravenously or orally.

[0078] In some embodiments, the treatment comprises administering an anti-CD38 antibody, pomalidomide, and dexamethasone to the individual in 28-day cycles. In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle (i.e., cycle 1), pomalidomide is administered at a dose of 4 mg daily from day 1 to day 21 of the first 28-day cycle (i.e., cycle 1), and dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of the first 28-day cycle (i.e., cycle 1) if the individual is less than 75 years old, or at a dose of 20 mg on days 1, 8, 15, and 22 of the first 28-day cycle (i.e., cycle 1) if the individual is 75 years or older. In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered sequentially on days 1, 8, and 15 of the first 28-day cycle (i.e., cycle 1). In some embodiments, pomalidomide and dexamethasone are administered prior to the anti-CD38 antibody on day 1 of the first 28-day cycle (i.e., cycle 1). In some embodiments, dexamethasone is administered prior to the anti-CD38 antibody, and the anti-CD38 antibody is administered prior to pomalidomide on days 8 and 15 of the first 28-day cycle (i.e., cycle 1).

[0079] In some embodiments, the treatment comprises administering an anti-CD38 antibody, pomalidomide, and dexamethasone in one or more 28-day cycles after the first 28-day cycle (i.e., the first cycle). In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg / kg on days 1 and 15 of each cycle after the first cycle (e.g., cycles 2, 3, 4, etc.), pomalidomide is administered at a dose of 4 mg daily on days 1 to 21 of each cycle after the first cycle (e.g., cycles 2, 3, 4, etc.), and dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle after the first cycle (e.g., cycles 2, 3, 4, etc.) if the individual is less than 75 years old, or at a dose of 20 mg on days 1, 8, 15, and 22 of each cycle after the first cycle (e.g., cycles 2, 3, 4, etc.) if the individual is 75 years or older. In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered sequentially on days 1 and 15 of each cycle after the first cycle (e.g., cycles 2, 3, 4, etc.). In some embodiments, pomalidomide and dexamethasone are administered prior to the anti-CD38 antibody on day 1 of each 28-day cycle after the first cycle (e.g., cycles 2, 3, 4, etc.). In some embodiments, dexamethasone is administered prior to the anti-CD38 antibody, and the anti-CD38 antibody is administered prior to pomalidomide on day 15 of each 28-day cycle after the first cycle (e.g., cycles 2, 3, 4, etc.).

[0080] In some embodiments, the treatment comprises administering an anti-CD38 antibody, pomalidomide, and dexamethasone to an individual in 28-day cycles. In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg / kg once a week for the first 28-day cycle (i.e., the first cycle), pomalidomide is administered at a dose of 4 mg for 21 days during the first 28-day cycle (i.e., the first cycle), and dexamethasone is administered at a dose of 40 mg once a week for the first 28-day cycle (i.e., the first cycle) if the individual is less than 75 years old or at a dose of 20 mg once a week for the first 28-day cycle (i.e., the first cycle) if the individual is 75 years old or older. In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered sequentially during the first 28-day cycle (i.e., the first cycle). In some embodiments, pomalidomide and dexamethasone are administered before the anti-CD38 antibody during the first 28-day cycle (i.e., the first cycle). In some embodiments, dexamethasone is administered before the anti-CD38 antibody, and the anti-CD38 antibody is administered before pomalidomide on days 8 and 15 of the first 28-day cycle (i.e., the first cycle).

[0081] In some embodiments, the treatment comprises administering an anti-CD38 antibody, pomalidomide, and dexamethasone in one or more 28-day cycles after the first 28-day cycle (i.e., the first cycle). In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg / kg once every other week in each 28-day cycle (e.g., the second, third, fourth cycles, etc.) after the first cycle, pomalidomide is administered for 21 days in each 28-day cycle (e.g., the second, third, fourth cycles, etc.) after the first cycle, and dexamethasone is administered at a dose of 40 mg once a week in each 28-day cycle (e.g., the second, third, fourth cycles, etc.) after the first cycle if the individual is less than 75 years old, or at a dose of 20 mg once a week in each 28-day cycle (e.g., the second, third, fourth cycles, etc.) after the first cycle if the individual is 75 years or older. In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered sequentially in each cycle (e.g., the second, third, fourth cycles, etc.) after the first cycle. In some embodiments, pomalidomide and dexamethasone are administered before the anti-CD38 antibody in each 28-day cycle (e.g., the second, third, fourth cycles, etc.) after the first cycle. In some embodiments, dexamethasone is administered before the anti-CD38 antibody, and the anti-CD38 antibody is administered before pomalidomide in each 28-day cycle (e.g., the second, third, fourth cycles, etc.) after the first cycle.

[0082] In some embodiments, the PFS of an individual is measured as the time from the start of treatment to the first occurrence of progression (PD). In some embodiments, PD is investigated according to the criteria of Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma". Lancet Oncol. 17(8):e328-e346 and Durie et al. (2006) "International uniform response criteria for multiple myeloma". Leukemia. 20:1467-1473 (see also Tables A and B). In some embodiments, PFS is measured as the time from the start of treatment to the time of death. In some embodiments, the methods and uses provided herein result in an improvement (e.g., an extension) of at least about 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15 months or more than 15 months in the progression-free survival (PFS) of an individual (any range between these values is also included). In some embodiments, the treatment increases the progression-free survival (PFS) of an individual by at least about 11.53 months. In some embodiments, the treatment increases (e.g., extends) the progression-free survival (PFS) of an individual by at least about 11.14 months. In some embodiments, the treatment increases (e.g., extends) the PFS of an individual by at least about any one of 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5 months or more than 11.5 months compared to an individual having multiple myeloma (e.g., refractory multiple myeloma or relapsed / refractory multiple myeloma) who received treatment with pomalidomide and dexamethasone without an anti-CD38 antibody (any range between these values is also included).In some embodiments, the treatment increases (e.g., extends) the PFS of an individual by at least about 5 months as compared to an individual having multiple myeloma (e.g., refractory multiple myeloma or relapsed / refractory multiple myeloma) who received treatment with pomalidomide and dexamethasone without an anti-CD38 antibody. In some embodiments, the treatment increases (e.g., extends) the PFS of an individual by at least about 4.5 months as compared to an individual having multiple myeloma (e.g., refractory multiple myeloma or relapsed / refractory multiple myeloma) who received treatment with pomalidomide and dexamethasone without an anti-CD38 antibody.

[0083] In some embodiments, overall survival (OS) is measured as the time from the start of treatment to death. In some embodiments, the treatment increases (e.g., extends) the OS of an individual as compared to an individual having multiple myeloma (e.g., refractory multiple myeloma or relapsed / refractory multiple myeloma) who received treatment with pomalidomide and dexamethasone without an anti-CD38 antibody.

[0084] In some embodiments, the period to first response in an individual being treated with an anti-CD38 antibody, pomalidomide, and dexamethasone, by an antibody for the methods or uses provided herein, is shorter than the period to first response in an individual being treated with pomalidomide and dexamethasone. In some embodiments, treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone, by an antibody for the methods or uses provided herein, decreases the period to first response in an individual as compared to the period to first response in an individual being treated with pomalidomide and dexamethasone. In some embodiments, the "period to first response" refers to the time between the first date of administration and the date of the first sign of response according to the criteria described in Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma". Lancet Oncol. 17(8):e328-e346 and Durie et al. (2006) "International uniform response criteria for multiple myeloma". Leukemia. 20:1467-1473 (see also Tables A and B).

[0085] In some embodiments, the individual is negative for minimal residual disease (MRD) or "MRD negative" after treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the MRD status is measured by next-generation flow cytometry (NGF). In some embodiments, MRD negativity (or, "flow MRD negative") as measured by NGF refers to the absence of phenotypically abnormal clonal plasma cells (e.g., multiple myeloma cells) in the bone marrow aspirate, using (for example, the EUROFLOW™ high-throughput flow cytometry standard operating procedure for MRD detection in multiple myeloma (see Flores-Montero et al. (2017) Leukemia. 31:2094-2103), or an equivalent method), and the minimum sensitivity is, for example, 10 4 one in 10 -4 nucleated cells (10 5 )、one in 10 -5 nucleated cells (10 6 )、one in 10 -6 nucleated cells (10 7 )、or one in 10 -7 nucleated cells (10 -4 ). In some embodiments, the individual is MRD negative by NGF at a threshold of 10 -5 、10 -6 after treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone.

[0086] In some embodiments, the MRD status is measured by next-generation sequencing (NGS). In some embodiments, MRD negativity (or, "sequencing MRD negative") as measured by NGS refers to the absence of clonal plasma cells (e.g., multiple myeloma cells) in the bone marrow aspirate; the presence of a clone is defined by at least two identical sequencing read data obtained after DNA sequencing of the bone marrow aspirate, using (for example, the LYMPHOSIGHT® high-throughput sequencing platform or an equivalent method), and the minimum sensitivity is, for example, 10 4 one in 10 -4 nucleated cells (10 5 )、one in 10 -5)、10 6 One out of 10 -6 or higher. In some embodiments, the minimum sensitivity is one out of 10 6 nucleated cells (or, one out of 10 -6 ). In some embodiments, the individual is negative for MRD by NGS at a threshold of 10 -4 , 10 -5 or 10 -6 after treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone.

[0087] In some embodiments, the individual is negative in both imaging and MRD (or, "imaging + MRD negative"). In some embodiments, imaging + MRD negative means (a) being MRD negative when detected by NGF or being MRD negative when detected by NGS, and (b) disappearance of any region with increased tracer uptake found at baseline or previous positron emission tomography (PET) / computed tomography (Ct), or a decrease to less than the maximum standardized uptake value of the mediastinal blood pool, or a decrease to less than that of the surrounding normal tissue. In some embodiments, the individual is "persistently MRD negative". In some embodiments, persistently MRD negative refers to an individual confirmed to be imaging + MRD negative at two time points after the start of treatment, where the time points are more than one year apart. In some embodiments, as described herein, minimal residual disease (MRD) is investigated through NGF or NGS using bone marrow samples collected from individuals treated with isatuximab, pomalidomide, and dexamethasone. In some embodiments, the individuals investigated for MRD as described herein have achieved complete response after treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual is negative in both imaging and MRD by NGS or NGF at a threshold of 10 -4 , 10 -5 or 10 -6 after treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone.

[0088] In some embodiments, the individual is less than 65 years old. In some embodiments, the 1-year overall survival rate of individuals less than 65 years old treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 67.1%, 67.2%, 67.3%, 67.4%, 67.5%, 67.6%, 67.7%, 67.8%, 67.9%, or 68%, and any range between these values is also included. In some embodiments, the PFS of individuals less than 65 years old treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 9, 9.5, 10, 10.5, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.53, 11.6, 11.7, 11.8, 11.9, or 12 months, and any range between these values is also included. In some embodiments, the PFS of individuals less than 65 years old treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7 months longer than the PFS of individuals less than 65 years old treated with pomalidomide and dexamethasone without an anti-CD38 antibody, and any range between these values is also included. In some embodiments, the PFS is calculated as described elsewhere herein.

[0089] In some embodiments, the individual is at least 65 years old and less than 75 years old. In some embodiments, the one-year overall survival rate of individuals at least 65 years old and less than 75 years old who are being treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 74.1%, 74.2%, 74.3%, 74.4%, 74.5%, 74.6%, 74.7%, 74.8%, 74.9%, or 75%, including any range between these values. In some embodiments, the PFS of individuals at least 65 years old and less than 75 years old who are being treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 9.5, 10, 10.5, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.57, 11.6, 11.7, 11.8, 11.9, or 12 months, including any range between these values. In some embodiments, the PFS of individuals at least 65 years old and less than 75 years old who are being treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 1, 1.5, 2, 2.5, 2.6, 2.7, 2.8, 2.9, 2.99, or 3 months longer than the PFS of individuals at least 65 years old and less than 75 years old who are being treated with pomalidomide and dexamethasone without an anti-CD38 antibody, including any range between these values. In some embodiments, PFS is calculated as described elsewhere herein.

[0090] In some embodiments, the individual is 75 years of age or older. In some embodiments, the one-year overall survival rate of individuals 75 years of age or older treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 73.1%, 73.2%, 73.3%, 73.4%, 73.5%, 73.6%, 73.7%, 73.8%, 73.9%, or 74%, and any range between these values is also included. In some embodiments, the one-year overall survival rate of individuals 75 years of age or older treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is higher than the one-year overall survival rate of individuals 75 years of age or older treated with pomalidomide and dexamethasone without an anti-CD38 antibody. In some embodiments, the one-year overall survival rate of individuals 75 years of age or older treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 21, 22, 23, 24, 25, 26, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, or 27 percentage points higher than the one-year overall survival rate of individuals 75 years of age or older treated with pomalidomide and dexamethasone without an anti-CD38 antibody. In some embodiments, the PFS of individuals 75 years of age or older treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 9.5, 10, 10.5, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, or 12 months, and any range between these values is also included. In some embodiments, the PFS of individuals 75 years of age or older treated with an anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7 months longer than the PFS of individuals 75 years of age or older treated with pomalidomide and dexamethasone without an anti-CD38 antibody, and any range between these values is also included. In some embodiments, the PFS is calculated as described elsewhere in this specification.

[0091] In some embodiments, the individual is female (e.g., a pregnant-capable female of childbearing age). In some embodiments, if the patient is female and capable of pregnancy, the patient can use an effective method of contraception during treatment with the anti-CD38 antibody and for 5 months after the last administration of the anti-CD38 antibody. In some embodiments, the individual has a liver disorder such as mild liver impairment. In some embodiments, an individual has mild liver impairment if the individual's total bilirubin is between about 1 times and about 1.5 times the normal upper limit (ULN). In some embodiments, an individual has mild liver impairment if the individual's aspartate aminotransferase (AST) level is higher than the normal upper limit (ULN). In some embodiments, the individual has received at least 3 (e.g., 4, 5, 6, 7, 8, etc.) prior treatments (or lines of prior treatment) for multiple myeloma. In some embodiments, the individual has a creatinine clearance of less than about 60, less than about 50, or less than about 30 ml / min / 1.73m prior to the start of treatment 2Has a glomerular filtration rate (creatinine clearance) below. In some embodiments, the individual is stage II or stage III according to the International Staging System (ISS) for multiple myeloma. In some embodiments, stage II according to the ISS for multiple myeloma is defined as a serum beta-2 microglobulin level between about 3.5 and about 5.5 mg / L or higher. In some embodiments, stage II according to the ISS for multiple myeloma is defined as a serum albumin level of less than about 3.5 g / dL. In some embodiments, stage III according to the ISS for multiple myeloma is defined as a serum beta-2 microglobulin level higher than about 5.5 mg / L. In some embodiments, the individual is stage III according to the Revised International Staging System (R-ISS) for multiple myeloma. In some embodiments, stage III according to the R-ISS for multiple myeloma is defined by (a) a serum beta-2 microglobulin level higher than about 5.5 mg / L, and (b) high-risk cytogenetic abnormalities detected by interphase fluorescence in situ hybridization (iFISH), or (c) a serum lactate dehydrogenase (LDH) level higher than the upper limit of normal. In some embodiments, the individual has high-risk cytogenetic abnormalities (CA). In some embodiments, the high-risk cytogenetic abnormalities are one or more of del(17p), t(4;14), and / or t(14;16).

[0092] Manufactured product or kit In another embodiment of the invention, a manufactured product or kit comprising an anti-CD38 antibody (such as isatuximab) is provided. In some embodiments, the manufactured product or kit further comprises pomalidomide and / or dexamethasone. In some embodiments, the manufactured product or kit further comprises a package insert containing instructions for using an anti-CD38 antibody (such as isatuximab) in combination with pomalidomide and dexamethasone to treat multiple myeloma (e.g., refractory multiple myeloma or relapsed refractory multiple myeloma) or delay its progression in an individual who has received at least two prior treatments for multiple myeloma. In some embodiments, the kit comprises isatuximab, pomalidomide, and dexamethasone.

[0093] This specification is considered to be sufficient for those skilled in the art to practice the present invention. In addition to what is shown and described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description and are 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.

Examples

[0094] The present disclosure will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the invention. The examples and embodiments described herein are for illustrative purposes only, and it is contemplated that various modifications or changes thereto will be suggested to those skilled in the art, and these are also understood to be included within the spirit and scope of the present application and the appended claims.

[0095] Example 1: A Phase III randomized open-label multi-center collaborative study comparing isatuximab (SAR650984) in combination with pomalidomide and low-dose dexamethasone with pomalidomide and low-dose dexamethasone in patients with refractory or relapsed / refractory multiple myeloma This example describes a Phase III multi-center collaborative multinational randomized open-label parallel-group two-arm study evaluating the efficacy of the combination of isatuximab with pomalidomide and low-dose dexamethasone compared to pomalidomide and low-dose dexamethasone for the treatment of patients with refractory or relapsed / refractory multiple myeloma who have received at least two lines of prior therapy (e.g., two or more lines of prior therapy) for multiple myeloma, including lenalidomide and proteasome inhibitors (e.g., bortezomib, carfilzomib, or ixazomib) administered alone or in combination, and who showed disease progression within 60 days after the completion of the last therapy (e.g., were resistant to the last therapy).

[0096] I. Study Objectives A. Primary Objectives The primary objective (i.e., primary endpoint) of this study was to demonstrate the benefit of the addition of isatuximab to pomalidomide and low-dose dexamethasone (i.e., the "IPd group") compared to pomalidomide and low-dose dexamethasone (i.e., the "Pd group") in patients with refractory or relapsed / refractory multiple myeloma in terms of an extension of PFS. PFS was defined as the time from the date of randomization to the earlier of the date on which progressive disease (PD) was first recorded by an independent efficacy assessment committee (IRC) or the date of death from any cause.

[0097] PD (as described in the IMWG diagnostic criteria, 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 Kumar et al. (2006) ”International uniform response criteria for multiple myeloma. Leukemia. 20: 1467-1473) was defined as meeting any one of the following for patients with measurable amounts of serum and / or urinary M protein (see also Tables A and B): · An increase in the serum M component of ≥25% from the nadir on two consecutive assessments (absolute increase must be ≥0.5 g / dL); if the starting concentration of the M component is ≥5 g / dL, an increase in the serum M component of ≥1 g / dL on two consecutive assessments is sufficient as a definition of relapse, and / or · An increase in the urinary M component of ≥25% from the nadir on two consecutive assessments (absolute increase must be ≥200 mg / 24 h), and / or · Is there a definite onset of a new bone lesion or soft tissue extramedullary disease, or if there are >1 lesions, has the sum of the orthogonal diameters of existing soft tissue extramedullary disease lesions increased by ≥50% from the lowest point, or has the longest diameter of a previous soft tissue extramedullary disease disorder with a short axis >1 cm increased by ≥50%? (Pathological fractures or bone collapses were not necessarily evidence of progression.)

[0098] B. Primary and secondary objectives The primary and secondary objectives of this study (i.e., the primary and secondary evaluation items or the primary and secondary efficacy evaluation items) were to (1) evaluate the overall response rate (ORR) in each group according to the International Myeloma Working Group (IMWG) criteria (described in Kumar et al. (2016) ”International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol. 17(8): e328-e346 and Durie et al. (2006) ”International uniform response criteria for multiple myeloma. Leukemia. 20: 1467-1473); and (2) compare the overall survival (OS) between the IPd group and the Pd group.

[0099] ORR was defined as the proportion of patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) according to the assessment of an independent response assessment committee using the IMWG response criteria. See Tables A and B below. Radiated plasmacytomas were not suitable for response assessment; however, they had to be monitored for progression assessment. For a patient to achieve a very good partial response by other criteria, the sum of the perpendicular diameters (SPD) of soft tissue plasmacytomas had to decrease by >90% compared to baseline.

[0100]

Table 3

Table 4

[0101] Patients remained in the last confirmed response category until progression or improvement to a higher response status was confirmed; patients could not move to a lower response category. The percentage reduction for calculating response was relative to the baseline value (cycle 1, day 1). The percentage increase for calculating progression was relative to the lower of either the lowest response value or the baseline value; there was no requirement to identify the lowest value. The lowest value confirmed prior to suspicion of progression was used as the baseline for calculating progression; if serum and / or urine spikes were considered too low to quantify, this value could be designated as zero as the baseline for recording subsequent progression. Patients were considered to have progression if they met the progression criteria by variables that were not measurable at baseline; however, for patients with measurable serum or urine M-spike at baseline, progression could not be defined by an increase in serum FLC alone.

[0102] Patients with serum and urine M protein lower than the eligibility level of the efficacy test performed on day 1 of cycle 1 (e.g., patients with only diseases measurable for FLC by IMWG or patients with no biologically measurable diseases) could only have one of two possible complete responses: non-PD or PD only. In such cases, PD could be diagnosed based on the following parameters: · For patients with only measurable FLC: M protein and plasmacytoma according to the IMWG criteria described in the table above, · For patients with non-measurable diseases: M protein and plasmacytoma, or an increase of >10% in the percentage of bone marrow plasma cell involvement.

[0103] Overall survival (OS) was defined as the time from randomization to death from any cause.

[0104] C. Other secondary objectives Other secondary objectives (the “secondary endpoints”) of this study were as follows: (1) to evaluate time to progression (TTP) in each group; (2) to evaluate progression-free survival (PFS) in the high-risk cytogenetic population defined as patients with del(17p), t(4;14), or t(14;16) in each group; (3) to evaluate duration of response (DOR) in each group; (4) to evaluate safety in both treatment groups; (5) to determine the pharmacokinetic profile of the combination of isatuximab and pomalidomide; (6) to evaluate the immunogenicity of isatuximab; (7) to conduct disease-specific and general health-related quality of life (HRQL), disease- and treatment-related symptoms, health state utility, and assessment of health state utility.

[0105] Time to progression (TTP) was defined as the time from randomization to the date on which progression (as determined by the independent efficacy review committee) was first documented. The same definition of progression as for the PFS endpoint (see above) was used.

[0106] PFS in the high-risk cytogenetic population was defined as the time from randomization to the earlier of the date on which progressive disease (as determined by the independent efficacy review committee) was first documented or the date of death from any cause in the subgroup of patients with high-risk cytogenetic changes including del(17p), t(4;14), or t(14;16) as assessed by fluorescence in situ hybridization (FISH).

[0107] Duration of response (DOR) was defined as the time from the date of the first response as determined by the independent review committee (IRC) to the earlier of the date of the first progressive disease as determined by the IRC or the date of death. DOR was determined only for patients who achieved a response of PR or better.

[0108] Safety assessments were conducted throughout the study on adverse events (TEAE) / serious adverse events (SAE) that occurred or worsened (as determined by the study physician's findings) during treatment, laboratory parameters, vital signs (blood pressure, heart rate, and body temperature), weight, ECOG performance status, and physical examination. TEAE were defined as adverse events that occurred or worsened (as determined by the study physician's findings) or became serious during the TEAE period (i.e., the time from the first administration of study treatment to up to 30 days after the last administration of study treatment). Adverse events and laboratory parameters were graded using NCI-CTCAE v4.03, which is available at ctep.cancer.gov / reporting / ctc.html.

[0109] Blood samples were collected from all patients who were treated to assess the pharmacokinetic profile of isatuximab using a population pharmacokinetic approach.

[0110] The presence of anti-drug antibodies (ADA, i.e., anti-isatuximab antibodies) in patients in the IPd group was assessed throughout the study.

[0111] The European Organization for Research and Treatment of Cancer's 30-item Quality of Life Questionnaire (EORTC QLQ-C30), the EORTC's 20-item Myeloma Module (MY20), and the European Quality of Life Group's 5-item, 5-level scale (EQ-5D-5L) assessments were designated for self-completion by all patients (IPD group and Pd group). All patient-reported outcomes (PRO) were reported by patients at the facility at the end of the treatment visit (EOT; 30 [±5] days after the last study treatment administration), and 60 days (±5 days) after the last study treatment administration, before the patients discussed their health / disease status and before the administration of study treatment or other study-related procedures during treatment.

[0112] D. Exploratory Objectives The exploratory objectives of this study were: (1) to explore the relationship between immunogenetic determinants and efficacy evaluation items; (2) to explore the pharmacokinetic (PK) and pharmacodynamic (PD) relationships; and (3) to explore the minimal residual disease (MRD) rates in both treatment groups.

[0113] For consented patients, blood samples were collected on Day 1 of Cycle 1. This sample was used to determine whether there was a relationship between genetic markers and (a) treatment with isatuximab, (b) how the body processes isatuximab, and / or (c) the potential for side effects of isatuximab. The sample was transferred to another location. DNA was extracted from each sample and stored until further analysis.

[0114] Blood samples were collected on Day 1 of Cycle 1 or exploratory biomarker analysis (which was not part of the essential part of the study and was not conducted under a separate pharmacogenetic consent) was performed. Leukocyte DNA was extracted from each blood sample and analyzed for immunogenetic determinants (e.g., FcγR polymorphisms, human leukocyte antigen (HLA), and killer cell inhibitory receptor (KIR) genotypes) and correlated with parameters of clinical response, including, for example, ORR, DOR, PFS, and OS.

[0115] Additional serum samples were collected to evaluate the potential interference of isatuximab on M protein assessment in immunoelectrophoresis and immunofixation analysis. These samples were collected from patients in the IPd group at all time points when M protein analysis was performed.

[0116] When possible, pharmacokinetic and pharmacodynamic estimations were investigated as prognostic factors for clinical outcomes, including safety and efficacy evaluation items.

[0117] Assessment of minimal residual disease (MRD) was performed by next-generation sequencing (NGS) using the CLONOSEQ® NGS platform on bone marrow samples obtained only from patients who achieved CR. MRD status was classified as outlined in Table B below. Bone marrow aspirates were collected at baseline / screening and at CR confirmation. If a patient demonstrated CR but was determined to be MRD positive, another bone marrow sample was collected 3 months (3 cycles) later to confirm subsequent negativity. In certain cases, when a patient remained MRD positive and was still being treated, a third sample was collected 3 months later. No more than 3 on-treatment bone marrow samples were obtained per patient.

[0118]

Table 5

[0119] Each of the above-mentioned efficacy assessments was chosen for use in this study, is well established and relevant in the hematology-oncology setting.

[0120] II. Study Design After confirming the eligibility criteria (further details are provided below), patients were randomly assigned in a 1:1 ratio to one of two groups shown in Table C below using a two-way automated response technology (IRT) system.

[0121]

Table 6

[0122] Randomization was stratified by age (<75 years vs. ≥75 years) and number of prior treatment lines (2 or 3 lines vs. more than 3 lines). A complete transplant procedure (induction, mobilization, preconditioning, transplantation, consolidation, and maintenance) was considered as 1 line. Regardless of the reason for discontinuation (progression, adverse event, or patient request), additional regimens were also considered as 1 line each. Patient treatment was continued until either progression, unacceptable adverse event (e.g., unacceptable toxicity), or patient desire. The outline of the study design is shown in Figure 1.

[0123] A. Duration of study participation per patient Each patient was considered to have participated in the study from the date of signing the informed consent until the earlier of death, withdrawal of consent, or the cutoff date. The patient's study period included a period of up to 3 weeks for screening. The duration of each treatment cycle was 28 days. Patient study treatment was continued until disease progression, unacceptable AE, patient request, or some other reason. During follow-up, for patients who discontinued study treatment due to progression (PD), survival was observed every 3 months (12 weeks) until the earlier of death or the cutoff date. Patients who discontinued study treatment before the recording of progression (PD) were observed for survival every 3 months (12 weeks) every 4 weeks until disease progression (also for patients who started additional anti-myeloma therapy without PD), and then until the earlier of death or the cutoff date.

[0124] At the time of the cutoff date for OS, if the patient was still receiving treatment and benefiting from the study treatment, the patient could continue the study treatment until disease progression, unacceptable AE, patient request, or some other reason occurred. For cycles completed after the cutoff date, collection of all new related AEs (severe or non-severe), all ongoing SAEs (related or not), and all ongoing related non-severe AEs, as well as the reason for end of treatment (EOT) was continued.

[0125] B. Decision to End Clinical Trials (All Patients) The PFS analysis (analysis of the primary endpoint) was event-driven, and the cutoff date for the PFS analysis was when 162 PFS events (either progression or death, whichever came first) occurred. The OS analysis was event-driven, and the final cutoff date was when 220 deaths occurred.

[0126] III. Patient Selection A. Selection Criteria Eligible patients were considered for inclusion if they met all of the following criteria: · Age: ≥ 18 years or the adult age of the country if the legal age > 18 years · Patients must have a diagnosis of multiple myeloma with evidence of measurable disease. · Serum M protein ≥ 0.5 g / dL measured by serum protein immunoelectrophoresis, and / or · Urinary M protein ≥ 200 mg / 24 hours measured by urinary protein immunoelectrophoresis. · Patients must have received at least two lines of prior anti-myeloma therapy, which must include at least two consecutive cycles of lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), administered either alone or in combination. (Note: Induction treatment followed by subsequent ASCT and consolidation / maintenance was considered one line of treatment.) · Patients must have experienced failure of treatment with lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), alone or in combination, as defined by any of the following (failure with lenalidomide and a proteasome inhibitor could occur on any line of therapy): - Progression occurring during or within 60 days after completion of treatment with lenalidomide and / or a proteasome inhibitor. - If the previous response to lenalidomide and / or proteasome inhibition was ≥ PR, the patient must have had no progression within 6 months after treatment discontinuation. - Patients who developed intolerable toxicity after a regimen of at least 2 consecutive cycles of lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), either alone or in combination. Intolerance is defined as follows: * For regimens containing a proteasome inhibitor: Any toxicity leading to discontinuation of the proteasome inhibitor, such as grade ≥ 2 peripheral neuropathy or grade ≥ 2 neuropathic pain. Peripheral neuropathy must be ≤ grade 1 prior to study entry (according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 available at ctep.cancer.gov / reporting / ctc.html). * For regimens containing lenalidomide: Any toxicity leading to discontinuation of lenalidomide, such as grade 3 rash; the rash must not be grade 4. Also, other non-hematologic toxicities must not be grade 4. All non-hematologic toxicities must be ≤ G1 prior to study entry. - The patient must have progressed at the end or within 60 days after the end of the previous treatment before study entry, i.e., must be resistant to the last line of treatment. This patient population includes the following two categories: * Refractory disease: Patients who were resistant to all previous treatments but should have achieved minimal response (MR) with at least 1 line of previous treatment. * Relapsed refractory disease: Patients with relapse from at least 1 line of previous treatment and resistant to the last line of treatment. The patient could have been resistant to 1 or more other lines of previous treatment. Note: The patient must have achieved more than MR with at least 1 line of previous treatment (i.e., primary refractory disease is ineligible).

[0127] B. Exclusion Criteria Screening of patients who met all of the above selection criteria was performed for the following exclusion criteria: · Primary refractory multiple myeloma defined as patients who did not achieve at least MR with any treatment during the disease course. · Only diseases with measurable free light chains. · Patients who received prior treatment with anti-CD38 monoclonal antibody (progression within 60 days at or after the end of anti-CD38 monoclonal antibody treatment, e.g., resistant to prior treatment with anti-CD38 monoclonal antibody treatment). · Prior treatment with pomalidomide. · Any anti-myeloma drug treatment including dexamethasone within 14 days before randomization. · Experience of allogeneic HSC transplantation with active graft-versus-host disease (GvHD) (GvHD of any grade and / or under immunosuppressive treatment within the last 2 months). · Any major surgical procedures within 14 days before the start of the study treatment: plasmapheresis, major surgery (vertebroplasty was not considered a major procedure), radiotherapy. · Patients who received any other investigational drug or prohibited therapy for this study within the longer of 28 days or 5 half-lives from randomization. · Eastern Cooperative Oncology Group (ECOG) performance status > 2 (as described in ecog-acrin.org / resources / ecog-performance-status and / or Oken et al. (1982) ”Toxicity and response criteria of the Eastern Cooperative Oncology Group.” Am J. Clin Oncol. 5: 649-655). · Platelets < 75,000 cells / μL when < 50% of bone marrow (BM) nucleated cells were plasma cells, and < 30,000 cells / μL when ≧ 50% of BM nucleated cells were plasma cells. Platelet transfusions within 3 days before screening visit were not tolerated. · ANC (absolute neutrophil count) < 1000 / μL (1×10 9 / L). The use of G-CSF to reach this level was not tolerated. · Creatinine clearance < 30 mL / min (Modification of Diet in Renal Disease (MDRD) equation: GFR (mL / min / 1.73 m 2 ) = 175 × (Scr) -1.154 × (age) -0.203 × (0.742 if female) × (1.212 if African American)). · Total bilirubin > 2 × ULN. · Corrected serum calcium level > 14 mg / dL (> 3.5 mmol / L) · AST and / or ALT > 3 × ULN · Ongoing toxicity due to prior myeloma therapy (excluding alopecia and those described in the eligibility criteria) > Grade 1 as outlined in NCI-CTCAE v4.03 available at ctep.cancer.gov / reporting / ctc.html. · Hypersensitivity to IMiDs® (thalidomide or lenalidomide) defined as any hypersensitivity reaction or reaction meeting the definition of intolerance leading to discontinuation of IMiDs within the first 2 cycles (as shown in the above selection criteria). · Hypersensitivity to dexamethasone, sucrose, histidine (as base and hydrochloride), and polysorbate 80, or any of the components of the study therapy, or H2 blockers that would prohibit further treatment with these agents, not suitable for premedication with steroids. · Significant cardiac dysfunction; myocardial infarction within 12 months; unstable angina not adequately managed. · Diagnosis or treatment of another malignancy within 3 years prior to randomization, excluding basal cell carcinoma or squamous cell carcinoma of the skin with complete resection, in situ malignancy, or low-risk prostate cancer after definitive therapy. · HIV + or known to have active infection with hepatitis A, B, or C. · Malabsorption syndrome or any condition that may significantly affect the absorption of pomalidomide. · Active primary amyloid light chain (AL) amyloidosis (with evidence of end-organ damage or receiving treatment for amyloidosis). · Waldenström macroglobulinemia · Unable to implement or not willing to implement thrombosis prevention. · Require daily administration of corticosteroids (equivalent to 10 mg / day of prednisone) for more than 7 days (excluding inhaled corticosteroids).

[0128] IV. Research treatment A. Investigational medicinal product (IMP) i. Isatuximab (IV) Isatuximab was formulated as a concentrated infusion in vials as a sterile, non-pyrogenic, injectable, colorless 20 mg / ml concentrate for intravenous administration, which may contain white to off-white microparticles, and filled into 30 ml glass vials with elastomeric stoppers. Each vial contained 500 mg of isatuximab of nominal content. The fill volume was determined to ensure removal of 25 ml. For administration to patients, the appropriate volume of isatuximab was diluted in an infusion bag of 0.9% sodium chloride solution. Depending on the dose administered, the final infusion volume corresponding to the dose of isatuximab was administered over a time based on the amount of protein administered per hour.

[0129] Isatuximab was administered intravenously to patients in the IPd group at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle, and then on days 1 and 15 of each subsequent 28-day cycle. (All cycles were 28 days in duration.) Dose adjustment (described in more detail later) was performed in case of toxicity.

[0130] ii. Pomalidomide (oral administration) Pomalidomide was provided in 1 mg, 2 mg, 3 mg, and 4 mg capsules. Pomalidomide was orally (by mouth, i.e., “PO”) administered to patients in both the IPd and Pd groups at a dose of 4 mg on days 1 to 21 of each 28-day cycle. (All cycles were 28 days in duration.) Dose adjustments (described in more detail below) were made if toxicity occurred.

[0131] iii. Dexamethasone (oral or intravenous administration) Dexamethasone was formulated as 4 mg and 8 mg tablets for oral administration and as a 4 mg / ml solution for intravenous injection. Dexamethasone was administered at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day cycle to patients < 75 years of age or at a dose of 20 mg to patients ≥ 75 years of age. (All cycles were 28 days in duration.) Dose adjustments (described in more detail below) were made if toxicity occurred.

[0132] In the IPd group, dexamethasone was administered with a non-investigational medicine (NIMP, described below) as a premedication to prevent infusion-associated reactions commonly observed with the administration of monoclonal antibodies.

[0133] B. Non-investigational medicine (NIMP) - Premedication for prevention of infusion reaction (IR) To reduce the risk and severity of IAR commonly observed with monoclonal antibody administration, all patients assigned to the IPd group received premedication prior to isatuximab infusion. The recommended premedication agents were: IV diphenhydramine 25 - 50 mg (or equivalent: e.g., cetirizine, promethazine, dexchlorpheniramine. However, depending on regional approval and availability. The intravenous route was preferred for at least the first 4 infusions) 15 - 30 minutes (but not exceeding 60 minutes) prior to isatuximab infusion, oral / IV dexamethasone (dose shown below), IV ranitidine 50 mg (or equivalent: other approved H2 antagonists (e.g., cimetidine), oral proton pump inhibitors (e.g., omeprazole, esomeprazole)), and oral acetaminophen 650 - 1000 mg. Once the premedication regimen was completed, isatuximab infusion was initiated immediately.

[0134] On the day of isatuximab infusion, as part of the premedication prior to isatuximab and pomalidomide and part of the backbone treatment, a total of 40 mg of dexamethasone (i.e., the usual dose of dexamethasone when used in combination with pomalidomide), or 20 mg in patients ≥75 years old, was administered.

[0135] When dexamethasone was administered orally, premedication was carried out in the following order: · Oral dexamethasone 40 mg (or PO 20 mg in patients ≥75 years old); then · Oral acetaminophen 650 - 1000 mg; then · IV ranitidine 50 mg (or equivalent); then · IV diphenhydramine 25 - 50 mg (or equivalent).

[0136] When dexamethasone was administered intravenously, premedication was carried out in the following order: · Oral acetaminophen 650 - 1000 mg; then · IV ranitidine 50 mg (or equivalent); then · 25 mg to 50 mg of diphenhydramine IV (or equivalent); then · 40 mg of dexamethasone IV (or 20 mg IV for patients ≥75 years old).

[0137] Regardless of the route of administration (IV or PO), dexamethasone was administered only once (i.e., a single dose was used for both premedication and study treatment).

[0138] Post-infusion corticosteroid or bronchodilator prophylaxis was not required.

[0139] All patients received mandatory thromboprophylaxis with aspirin or low molecular weight heparin.

[0140] C. Dosage and Administration Schedule i. IPd group (experimental group) Patients assigned to the IPd group received premedication prior to isatuximab infusion to reduce the risk and severity of infusion reactions (IR) commonly observed with monoclonal antibodies (see above).

[0141] Drug administration for patients in the IPd group was carried out as follows: · Dexamethasone was administered orally (preferred route) or intravenously (if the oral route was not available) at a dose of 40 mg (or 20 mg if the patient was ≥75 years old) approximately 15 - 30 minutes (but not exceeding 60 minutes) before isatuximab infusion on days 1, 8, 15, and 22. · Isatuximab was administered at a dose of 10 mg / kg on days 1, 8, 15, and 22 of cycle 1, and then at a dose of 10 mg / kg on days 1 and 15 of subsequent cycles. · Pomalidomide was administered at a dose of 4 mg on each day from day 1 to day 21 of each 28-day cycle. On day 1 of each cycle, pomalidomide was taken 1 hour to 30 minutes before isatuximab. On days 8, 15, and 22 of cycle 1, and on day 15 of subsequent cycles, pomalidomide was taken at the most convenient time for the patient (preferably simultaneously for each administration) after the isatuximab infusion.

[0142] ii. Pd group (control group) Drug administration to patients treated with pomalidomide + dexamethasone was carried out as follows: · Dexamethasone was administered orally or intravenously at a dose of 40 mg (or 20 mg if the patient was ≥ 75 years old) on days 1, 8, 15, and 22. · Pomalidomide was administered at a dose of 4 mg on each day from day 1 to day 21 of each 28-day cycle.

[0143] There was no limit to the number of cycles administered to patients unless there were major toxicity, disease progression, or any other reason (e.g., withdrawal of consent for treatment, insufficient compliance, concurrent disease preventing further administration of study treatment, etc.). In the case of progression (PD), the diagnosis made according to the criteria had to be confirmed by two consecutive measurements before treatment was discontinued. Treatment was continued until confirmation of PD was obtained.

[0144] The weight of each patient was measured before each cycle so that the isatuximab dose could be calculated.

[0145] In subsequent treatment cycles, dose adjustments (treatment delays, missed doses, and dose reductions) based on the tolerance of individual patients (for pomalidomide and / or dexamethasone only) were permitted. The dose reduction steps for pomalidomide and dexamethasone are shown in Tables D1 and D2 below, respectively. Missed doses of pomalidomide were possible on one or more occasions. Missed doses of dexamethasone or reduction of dexamethasone administration up to once every week (i.e., twice per 28-day cycle) were possible.

[0146]

Table 7

[0147]

Table 8

[0148] Regarding injection of isatuximab, dose reduction was not permitted.

[0149] V. Disease Assessment The decision made by the principal investigator regarding whether the subject should be allowed to continue treatment was based on efficacy data obtained through the study (from the testing laboratories of the implementing facilities or the central testing agency), radiological assessment, and bone marrow assessment, and, if indicated, was made in accordance with the IMWG criteria. The reference values for assessing treatment response were the values measured on the first day of cycle 1 in samples collected from each patient before treatment. · Assessment of serum M protein levels was performed by immunoelectrophoresis, and by immunofixation if M protein could not be detected by immunoelectrophoresis. · Assessment of urinary M protein levels was performed by immunoelectrophoresis, and by immunofixation if M protein could not be detected by immunoelectrophoresis. · Free light chain (FLC) levels were centrally analyzed only in cases of complete response (CR) (i.e., M protein was undetectable by serum protein electrophoresis / urine protein electrophoresis and immunofixation was negative). · Immunoglobulins: IgG, IgA, IgM, IgD, and IgE (IgD or IgE only if the heavy chain component of the disease is known to be E or D). · Assessment of bone marrow plasma cell infiltration was performed to confirm CR or when there was no biochemical progression but disease progression was suspected and clinically necessary. ·Bone marrow aspirate (or biopsy if clinically necessary) for the assessment of minimal residual disease (MRD) in the case of CR. If the patient was MRD positive, another bone marrow sample was taken 3 months (3 cycles) later to confirm subsequent MRD negativity. If the patient remained MRD positive and was still receiving treatment, a third sample might have been taken 3 months (3 cycles) later. (No patient had more than 3 bone marrow samples taken during treatment.) ·Total skeletal survey or low-dose whole-body CT scan was performed at baseline, then annually, and whenever clinically necessary during the study. Each patient had the same modality (i.e., total skeletal survey or low-dose whole-body CT) used throughout the study. ·For extramedullary disease (including plasmacytoma): -If extramedullary disease was present at baseline, CT scan or MRI was performed at baseline and repeated every 12 weeks (±1 week). (Additional CT scans or MRIs were performed if clinically necessary.) -If extramedullary disease was suspected at baseline, CT scan or MRI was performed at baseline to confirm extramedullary disease. If confirmation was obtained, CT or MRI was repeated every 12 weeks (±1 week). (Additional CT scans or MRIs were performed if clinically necessary.) Each patient had the same modality (CT or MRI) used throughout the study.

[0150] VI. Results A. Patient Characteristics 307 patients were randomized and included in the intention-to-treat (ITT) population (153 in the Pd group and 154 in the IPd group). Overall, the patient demographics and characteristics at baseline were representative of the RRMM population and were generally similar in the two treatment groups. See Table E below.

[0151]

Table 9

Table 10

[0152] The disease stage according to the International Staging System (ISS) for multiple myeloma and the multiple myeloma subtype at initial diagnosis were well balanced between treatment groups (see Table F). Overall, 28% of patients had ISS stage III at initial diagnosis (28.8% in the Pd group and 27.3% in the IPd group).

[0153] [Table 11]

[0154] At study entry, 73.0% of patients were classified as stage I and II according to the ISS criteria, and 25.1% of patients were classified as stage III (see Table G). According to the selection criteria, all patients were refractory at study entry. Disease characteristics were as expected in the heavily pretreated RRMM population and were generally similar between treatment groups.

[0155] [Table 12] [Table 13]

[0156] Overall, the two treatment groups were similar with respect to prior anti-myeloma therapy (see Tables H1 and H2 below). According to the protocol, all patients had received at least two lines of prior therapy, including lenalidomide and proteasome inhibitor (PI). Overall, the median number of prior treatment lines was 3 (range, 2 - 11 lines), and 107 patients (34.9%) had received 4 or more lines of prior therapy. One patient had received prior daratumumab therapy. 92% of patients were resistant to lenalidomide, 75.9% of patients were resistant to PI, and 72.6% of patients were resistant to both lenalidomide and PI. Almost all patients (98.0%) were resistant to the last regimen before study entry.

[0157]

Table 14

Table 15

[0158]

Table 16

[0159] More than one-third (i.e., 36.2%) of the study group participated in the study in a state of having renal dysfunction (defined as GFR < 60 ml / min / 1.73 m 2 ). Patients with impaired renal function tended to participate in the IPd group (38.7%) more than the Pd group (33.8%).

[0160] It has been reported in detail that patients with multiple myeloma having at least one high-risk chromosomal aberration (CA), such as del(17p), t(4;14) translocation, and / or t(14;16) translocation, have a worse prognosis compared to patients without high-risk CA. Therefore, in some patients, assessment of high-risk chromosomal aberrations was performed at baseline. For 21 percent of the patients, CA could not be evaluated. This is within the range usually reported for assessments in MM studies. The percentage of patients with high-risk CA was lower in the IPd group than in the Pd group (15.6% versus 23.5%). Eight patients (2.6%) (5 in the Pd group and 3 in the IPd group) had two high-risk cytogenetic aberrations (see Table I). Such patient populations have a very poor prognosis.

[0161]

Table 17

[0162] B. Dosage and Duration of Exposure to Study Treatments In the IPd group, the exposure period was approximately twice as long as that in the Pd group. The median exposure period was 41 weeks (range = 1.3 to 76.7) in the IPd group and 24 weeks (range = 1 to 73.7) in the Pd group. Fifty-five patients (36.2%) in the IPd group and 38 patients (25.5%) in the Pd group received ≥ 12 cycles. In the IPd group, the median number of cycles of ixazomib was 10 (range = 1 to 19), the median ixazomib exposure period was 40.9 weeks (range = 1.0 to 75.1 weeks), and 35.5% of patients received ≥ 12 cycles of ixazomib treatment. See Table J. The median relative dose intensity (RDI) of ixazomib was 92.3% (range = 19.7% to 111.1%). The median RDI of pomalidomide and dexamethasone was 85.1% (pomalidomide) and 87.8% (dexamethasone) in the IPd group and 93.3% (pomalidomide) and 96.3% (dexamethasone) in the Pd group.

[0163] Missed doses and dose delays of ixazomib were reported in 52% and 10.5% of patients, respectively. Interruptions of ixazomib infusion occurred in 34.9% of patients and 2.1% of ixazomib infusions as part of the management of infusion reactions. Dose interruptions generally occurred only once, with the exception of six patients. Almost all infusion interruptions occurred at the first infusion. The median RDI of pomalidomide was slightly lower in the IPd group than in the Pd group (85.1% (range = 22.9% to 103.7%) in the IPd group and 93.3% (range = 37.2% to 118.5%) in the Pd group). The median RDI of dexamethasone was slightly lower in the IPd group than in the Pd group (87.8% (range = 15.9% to 130%) in the IPd group and 96.3% (range = 30.3% to 300%) in the Pd group). The RDI of pomalidomide and dexamethasone was driven by dose reduction and missed doses for the management of neutropenia and infections.

[0164]

Table 18

[0165] C. Efficacy i. Progression-free survival (PFS) Patients treated with isatuximab + pomalidomide + dexamethasone (IPd) showed a significantly prolonged progression-free survival (PFS) compared to patients treated with pomalidomide + dexamethasone (Pd), as assessed by the Independent Review Committee (IRC). See Figure 2. The stratified log-rank test of the PFS comparison between the two groups had a p-value of 0.001, which was statistically significant. A total of 89 (58.2%) and 73 (47.4%) PFS events were reported in the Pd group and the IPd group, respectively. The median PFS was longer in the IPd group (11.53 months, 95% CI: 8.936 to 13.897) than in the Pd group (6.47 months, 95% CI: 4.468 to 8.279). The stratified hazard ratio was 0.596 (95% CI: 0.436 to 0.814, p = 0.0010). This characterizes a 40% reduction in the risk of disease progression or death with IPd compared to Pd. The IRC assessments of progression and response were based on the central laboratory assessment of M protein and the radiological review of imaging by the central laboratory, applying the International Myeloma Working Group (IMWG) criteria (see Tables A and B).

[0166] Sensitivity analyses were performed to assess the robustness of the primary endpoint analysis using various efficacy assessment methods (investigational physicians) or various stopping rules. The results of all PFS sensitivity analyses were highly consistent with the results of the primary PFS analysis, and there was statistical significance in support of the IPd group. In particular, PFS based on the Investigational Physician Assessment (see Figure 3) was consistent with PFS based on the IRC assessment. The ongoing Investigational Physician Assessment was based on the M protein analysis in the performing institution's laboratory and, if plasmacytoma / bone lesions were present, its performing institution's radiological evaluation. The median PFS by Investigational Physician Assessment was 11.14 months (95% CI: 7.491 to 14.784) in the IPd group compared to 6.54 months (95% CI: 4.468 to 7.885) in the Pd group. The stratified hazard ratio was 0.602 (95% CI: 0.444 to 0.816; p = 0.0009).

[0167] ii. Subgroup analysis for PFS The consistency of the treatment effect on PFS was evaluated for predefined demographics, baseline characteristics, and prognostic factors. The pre-specified subgroup analyses showed no significant interaction at the 10% level between the treatment groups and the stratifying factors, between the treatment groups and the demographic characteristics, or between the treatment groups and the patients' baseline characteristics. This indicates that the overall treatment effect was consistent across those subgroups. As shown in Table K, the subgroup analyses for PFS showed a positive treatment effect in all subgroups, consistent with the overall treatment effect (including subgroups with poor prognosis, e.g., age > 75; HR = 0.479; > 3 lines of prior treatment: HR = 0.59; renal dysfunction: HR = 0.51; ISS stage III: HR = 0.635; R-ISS stage III: HR = 0.605; high-risk cytogenetics HR = 0.655).

[0168]

Table 19

[0169] The advantages of isatuximab in PFS were seen in all subgroups, including patients with poor prognosis. The PFS advantages were seen in patients resistant to lenalidomide (median PFS was 11.4 months in the IPd group compared to 5.6 months in the Pd control group), patients resistant to proteasome inhibitors (median PFS was 11.4 months in the IPd group compared to 5.6 months in the Pd group), patients resistant to both lenalidomide and proteasome inhibitors (median PFS was 11.2 months in the IPd group compared to 4.8 months in the Pd group), and patients resistant to lenalidomide in the last line before study entry (median PFS was 11.6 months in the IPd group compared to 5.7 months in the Pd group). Patients with high-risk cytogenetics treated with IPd also showed PFS advantages compared to patients with high-risk cytogenetics in the Pd group. (High-risk cytogenetics were defined as del(17p), t(4;14), or t(14;16) by FISH; the cut-off for cytogenetic - del17 by the central laboratory was 50%, and the cut-offs for t(4,14) and t(14,16) were 30%). In patients with high-risk cytogenetics, the median PFS was 7.5 (95% CI: 2.628 to NC) in the IPd group and 3.745 (95% CI: 2.793 to 7.885) in the Pd group. See also Figure 5. Figure 5 provides a forest plot showing subgroup analysis of PFS in patients with various baseline characteristics (e.g., age, eGFR, prior treatment history, prior ASCT for treatment, etc.) in the IPd group vs. the Pd group. The improvement in PFS advantage in the IPd group was also observed in patients >75 years old, with ISS stage III at study entry, baseline creatinine clearance (eGFR) <60 ml / min / 1.73m 2 and in patients who had received >3 lines of prior treatment, patients resistant to prior treatment with lenalidomide or proteasome inhibitors, and patients resistant to lenalidomide in the last line before study entry.

[0170] iii. Overall response rate (ORR) In the analysis based on the assessment of the principal investigator, the ORR (i.e., partial response (PR) or better response) was significantly higher in the IPd group than in the Pd group (35.3% and 60.4%, respectively). The p-value of the stratified Cochran-Mantel-Haenszel (CMH) was <0.0001. This indicates that there is a significant difference in ORR between the two groups, supporting IPd at the 0.025 level. In the IPd group, the depth of response was improved. A very good partial response (VGPR) or better response was achieved in 31.8% and 8.5% of the IPd group and Pd group, respectively (P < 0.0001). More patients in the IPd group had a complete response or better response than in the Pd group (4.5% vs. 2.0%). See Table L1. Table L1 shows the results of further analysis of ORR in the IPd group and Pd group.

[0171]

Table 20

[0172] The response rates based on investigator assessment (complete response rate: 32.0% in the Pd group vs. 63.0% in the IPd group; rate of at least VGPR: 7.2% in the Pd group vs. 33.8% in the IPd group) were consistent with the IRC assessment.

[0173] As shown in Table L2, the subgroup analysis of ORR was consistent with the overall treatment effect, showing a tendency for a positive treatment effect in the IPd group in all subgroups tested (including subgroups with poor prognosis, e.g., age >75; >3 lines of prior treatment history; renal dysfunction; ISS stage III; R-ISS stage III; and high-risk cytogenetics). The number of patients with renal dysfunction who achieved a VGPR or better response (i.e., creatinine clearance <60 ml / min / 1.73m 2 ) was higher in the IPd group than in the Pd group (4.1% in the Pd group vs. 32.7% in the IPd group).

[0174]

Table 21

[0175] iv. Impact of Treatments on Renal Impairment Patients with reduced renal function are often excluded from clinical trials or less frequently represented. Furthermore, there is little data on the investigation of reduced renal function in patients receiving monoclonal antibody therapy. Reduced renal function is an independent prognostic factor for poor prognosis in patients with RRMM, and anti-myeloma therapy that also improves renal function is critically needed.

[0176] In this study, the number of patients with renal dysfunction at baseline (i.e., baseline creatinine clearance (MDRD)) was comparable between the two groups (55 in the IPd group vs. 49 in the Pd group). See Table L3. Table L3 shows the baseline demographics and clinical characteristics of patients with reduced renal function at the start of the study.

[0177]

Table 22

Table 23

[0178] The number of patients showing improvement in renal function after treatment initiation was significantly higher in the IPd group than in the Pd group. Twenty-three patients (16.4%) in the IPd group achieved complete renal response, while in the Pd group, eight patients (5.7%) achieved complete renal response. In the IPd group, there were additional patients (0.7) who achieved minor renal responses, i.e., an increase in eGFR of >50% from <15 mL / min to 15 - <30 mL / min, or from 15 - <30 mL / min to 30 - <60 mL / min. Fewer patients in the IPd group than in the Pd group experienced deterioration of renal function to severe or end-stage (23% in the IPd group vs. 35% in the Pd group).

[0179]

Table 24

[0180] As shown in Table M1, among the 32 patients in the IPd group with a creatinine clearance < 50 ml / min / 1.73m at baseline, 23 patients (71.9%) showed complete renal response, and 10 patients (31.3%) showed sustained complete renal response. In contrast, among the 21 patients in the Pd group with a creatinine clearance < 50 ml / min / 1.73m at baseline, 8 patients (38.1%) showed complete renal response, and 4 patients (19%) showed sustained complete renal response. Complete renal response (CRenal) is characterized by an improvement in creatinine clearance from < 50 ml / min / 1.73m at baseline to ≥ 60 mL / min / 1.73m in ≥ 1 post-baseline assessment. Durable (sustained) CRenal is characterized by a Crenal response that persists for ≥ 60 days (see Dimopoulos, et al., Blood, 2013; 122: 3176). The median time to first complete renal response (CRenal) was 4.1 weeks in the IPd group and 7.3 weeks in the Pd group. CRenal lasted for a median of 57.0 days in the IPd group and 59.5 days in the Pd group. 2 For patients with renal dysfunction at baseline, the median PFS of patients in the IPD group was 9.5 months, while the median PFS of patients in the Pd group was 3.7 months (HR 0.50; 95% CI 0.30 - 0.85). For patients with eGFR < 45 mL / min / 1.73m, the median PFS of patients in the IPD group was 7.5 months, while the median PFS of patients in the Pd group was 2.8 months for Pd (HR 0.50; 95% CI 0.22 - 1.13). Among patients without renal dysfunction at baseline, the median PFS of patients in the IPD group (n = 87) was 12.7 months, while the median PFS of patients in the Pd group (n = 96) was 7.9 months (HR 0.58; 95% CI 0.38 - 0.88). 2 For patients with renal dysfunction at baseline, the median PFS of patients in the IPD group was 9.5 months, while the median PFS of patients in the Pd group was 3.7 months (HR 0.50; 95% CI 0.30 - 0.85). For patients with eGFR < 45 mL / min / 1.73m, the median PFS of patients in the IPD group was 7.5 months, while the median PFS of patients in the Pd group was 2.8 months for Pd (HR 0.50; 95% CI 0.22 - 1.13). Among patients without renal dysfunction at baseline, the median PFS of patients in the IPD group (n = 87) was 12.7 months, while the median PFS of patients in the Pd group (n = 96) was 7.9 months (HR 0.58; 95% CI 0.38 - 0.88). 2 from < 50 ml / min / 1.73m at baseline to ≥ 60 mL / min / 1.73m in ≥ 1 post-baseline assessment 2 For patients with renal dysfunction at baseline, the median PFS of patients in the IPD group was 9.5 months, while the median PFS of patients in the Pd group was 3.7 months (HR 0.50; 95% CI 0.30 - 0.85). For patients with eGFR < 45 mL / min / 1.73m, the median PFS of patients in the IPD group was 7.5 months, while the median PFS of patients in the Pd group was 2.8 months for Pd (HR 0.50; 95% CI 0.22 - 1.13). Among patients without renal dysfunction at baseline, the median PFS of patients in the IPD group (n = 87) was 12.7 months, while the median PFS of patients in the Pd group (n = 96) was 7.9 months (HR 0.58; 95% CI 0.38 - 0.88).

[0181] For patients with renal dysfunction at baseline, the median PFS of patients in the IPD group was 9.5 months, while the median PFS of patients in the Pd group was 3.7 months (HR 0.50; 95% CI 0.30 - 0.85). For patients with eGFR < 45 mL / min / 1.73m, the median PFS of patients in the IPD group was 7.5 months, while the median PFS of patients in the Pd group was 2.8 months for Pd (HR 0.50; 95% CI 0.22 - 1.13). Among patients without renal dysfunction at baseline, the median PFS of patients in the IPD group (n = 87) was 12.7 months, while the median PFS of patients in the Pd group (n = 96) was 7.9 months (HR 0.58; 95% CI 0.38 - 0.88). 2 For patients with eGFR < 45 mL / min / 1.73m, the median PFS of patients in the IPD group was 7.5 months, while the median PFS of patients in the Pd group was 2.8 months for Pd (HR 0.50; 95% CI 0.22 - 1.13). Among patients without renal dysfunction at baseline, the median PFS of patients in the IPD group (n = 87) was 12.7 months, while the median PFS of patients in the Pd group (n = 96) was 7.9 months (HR 0.58; 95% CI 0.38 - 0.88).

[0182] The overall response rate (ORR) was higher in patients treated with IPd than in those treated with Pd, regardless of renal function at baseline. In patients without renal function decline at baseline, the ORR was 67.8% (4.6% CR, 29.9% VGPR, 33.3% PR) in the IPd group (n = 87) and 42.7% (1% sCR, 1% CR, 9.4% VGPR, 31.3% PR) in the Pd group (n = 96). In patients with renal function decline at baseline (eGFR < 60 ml / min / 1.73m 2 ), the ORR was 56.4% (5.5% CR, 27.3% VGPR, 23.6% PR) in the IPd group (n = 55) and 24.5% (2% CR, 2% VGPR, 20.4% PR) in the Pd group (n = 49) (odds ratio [OR] 3.98; 95% CI 1.60 - 10.17). In patients with eGFR > 45 - < 60 ml / min / 1.73m 2 at baseline, the ORR was 68.6% (5.7% CR, 31.4% VGPR, 31.4% PR) in the IPd group (n = 35) and 25% (3.1% CR, 3.1% VGPR, 18.8% PR) in the Pd group (n = 32). In patients with eGFR < 45 mL / min / 1.73m 2 at baseline, the ORR was 35.0% (5% CR, 20% VGPR, 10% PR) in the IPd group (n = 20) and 23.5% (23.5% PR) in the Pd group (n = 17) (OR 1.75; 95% CI 0.34 - 10.11). Among patients with eGFR < 45 mL / min / 1.73m 2 at baseline, one patient per group had eGFR < 30 ml / min / 1.73m 2 ; the patient in the IPd group had SD (stable), while the patient in the Pd group had PD (progressive).

[0183] Three patients with renal function decline in the IPd group achieved minimal residual disease negativity (MRD negativity) (sensitivity level 10 5 per 1).

[0184] In the IPd group, the median OS was not reached in patients with renal function decline at baseline, while in the Pd group, the median OS was 11.6 months (HR 0.53; 95%CI 0.30 - 0.96). For patients with eGFR < 45 mL / min / 1.73m 2 at baseline, the median OS was 6.6 months in the Pd group, compared with 10.7 months in the IPd group (HR 0.62; 95%CI 0.26 - 1.45). For patients without renal function decline at baseline, the median OS was not reached in either group (HR 0.62; 95%CI 0.33 - 1.19).

[0185] The number of patients who developed end-stage renal disease (ESRD; eGFR < 15 mL / min / 1.73m 2 ) during treatment was lower in the IPd group (2.9%) than in the Pd group (7.9%). Among patients with moderate RI at baseline, renal function deteriorated to severe RI or ESRD in 22.6% (12 / 53) of patients in the Isa-Pd group and 34.8% (16 / 46) of patients in the Pd group [OR 0.55; 95%CI (0.20 - 1.45)].

[0186] Treatment with IPd improved PFS and disease response rate compared with treatment with Pd in patients with renal function decline at baseline, including those with eGFR < 45 mL / min / 1.73m 2 These results are consistent with the benefits observed in the overall study population. Treatment with IPd was also associated with an increase in the number of patients with durable renal responses and covering renal function decline compared with treatment with Pd. Pharmacokinetic parameters were comparable between patients with and without renal function decline, suggesting that dose adjustment is not necessary in patients with renal function decline. Based on these data, the addition of isatuximab to pomalidomide + dexamethasone is predicted to benefit patients with RRMM and renal function decline.

[0187] v. Impact of treatment on patients with high-risk cytogenetic abnormalities For the IPd group, the benefit in overall response rate (ORR) observed in the IPd group was maintained among patients who had at least one high-risk cytogenetic abnormality (i.e., one or more of del(17p), t(4;14), and t(14;16)) at baseline. Among patients with standard-risk cytogenetics at baseline, in the IPd group (n = 103), the ORR was 65% (3.9% were CR, 28.2% were VGPR, 33% were PR), while in the Pd group (n = 78), the ORR was 42.3% (1.3% were CR, 7.7% were VGPR, 33.3% were PR). Among patients who had at least one high-risk cytogenetic abnormality at baseline, in the IPd group (n = 24), the ORR was 50.0% (29.2% were VGPR, 20.8% were PR), while in the Pd group (n = 36), the ORR was 16.7% (2.8% were VGPR, 13.9% were PR). Among patients who had del(17p) and t(4;14) cytogenetic abnormalities at baseline, one patient in the IPd group (n = 3) achieved VGPR and one patient in the Pd group (n = 4) achieved PR. Data on odds ratios for response rates are shown in Table M2 below:

[0188]

Table 25

[0189] In patients with at least one high-risk cytogenetic abnormality at baseline, the ORR benefit of treatment with IPd over Pd is maintained regardless of the definition of the high-risk cytogenetic cutoff used. The ORR advantage of treatment with IPd over Pd was observed in patients classified as del(17p) by any one of the following cutoff definitions: at least 5% plasma cells, at least 20% plasma cells, at least 40% plasma cells, at least 50% plasma cells, or at least 60% plasma cells. The ORR benefit of treatment with IPd over Pd was observed in patients classified as t(4;14) by any one of the following cutoff definitions: at least 3% plasma cells, at least 20% plasma cells, at least 30% plasma cells, at least 40% plasma cells, or at least 60% plasma cells.

[0190] The PFS advantage observed in the IPd group over the Pd group was maintained among patients who had at least one high-risk cytogenetic abnormality (i.e., one or more of del(17p), t(4;14), and t(14;16)) at baseline. In the IPd group, the median PFS for patients with standard-risk cytogenetics at baseline was 11.6 months, while in the Pd group, the median PFS for patients with standard-risk cytogenetics at baseline was 7.4 months. In the IPd group, the median PFS for patients with high-risk cytogenetics at baseline was 7.5 months, while in the Pd group, the median PFS for patients with high-risk cytogenetics at baseline was 3.7 months. Among patients with del(17p) at baseline, the median PFS was 9.1 months in the IPd group compared to 7.4 months in the Pd group. Among patients with t(4;14) at baseline, the median PFS was 7.5 months in the IPd group compared to 2.8 months in the Pd group. The PFS benefit of IPd treatment over Pd was observed in patients classified as del(17p) by any one of the following cutoff definitions: at least 5% plasma cells, at least 20% plasma cells, at least 40% plasma cells, at least 50% plasma cells, or at least 60% plasma cells. The PFS benefit of IPd treatment over Pd was observed in patients classified as t(4;14) by any one of the following cutoff definitions: at least 3% plasma cells, at least 20% plasma cells, at least 30% plasma cells, at least 40% plasma cells, or at least 60% plasma cells.

[0191] vi. Safety in cytogenetic subgroups The number of TEAEs experienced by high-risk or standard-risk patients treated with either IPd or Pd is shown in Table M3.

[0192] [Table 26]

[0193] In high-risk patients, although there were more grade ≥3 treatment-emergent adverse events (TEAEs), the addition of Isa to Pd did not increase the events leading to treatment discontinuation. Treatment-related deaths did not increase in any subgroup.

[0194] The number of grade ≥3 events in >5% of patients for the shown laboratory abnormalities and TEAEs experienced by high-risk and standard-risk patients treated with either IPd or Pd is shown in Table M4.

[0195]

Table 27

[0196] Ixazomib + pomalidomide + dexamethasone had a manageable safety profile in patients with at least one high-risk cytogenetic abnormality at baseline. The ORR benefit of Isa-Pd over Pd was maintained among patients with high-risk cytogenetics, and the benefit was independent of the cytogenetic cut-off definition used. Similar PFS benefits of Isa-Pd over Pd were observed for high-risk (del[17p], t[4;14], and / or t[14;16]) and standard-risk patients. Isa-Pd provides a consistent benefit over Pd in a subgroup of patients with difficult-to-treat high-risk cytogenetics and may be a new treatment option for RRMM.

[0197] vii. Overall survival (OS) As per the protocol, the OS efficacy boundary was to be derived based on the α-expenditure functions of O'Brien and Fleming, following the actual number of deaths observed during the interim analysis of OS. At the interim analysis of OS, adding isatuximab to the Pd treatment prolonged OS, and a tendency for the survival curves to clearly separate from the start was observed. The median OS remained unreached in any of the treatment groups. At the time of analysis, the probability of survival at 12 months was 0.633 (95% CI: 0.545 - 0.709) in the Pd group and 0.720 (95% CI: 0.636 - 0.787) in the IPd group. Adding isatuximab to Pd led to a statistically significant (one-sided, p = 0.001) and clinically meaningful improvement in the primary evaluation item of PFS (by IRC). See Figure 4.

[0198] viii. Time to subsequent treatment At this point of analysis, 54% of the patients in the Pd group and 39% of the patients in the IPd group had initiated subsequent treatment. The median time to subsequent treatment was 9.1 months in the Pd group and unreached in the IPd group (HR: 0.538; 95% CI: 0.382 - 0.758).

[0199] ix. Other evaluation items The response to treatment occurred faster and was more durable in the IPd group compared to the Pd group.

[0200] Duration of response (DOR): The median duration of response was longer in the IPd group than in the Pd group (13.27 months [from 10.612 to NC] vs. 11.07 months [from 8.542 to NC (i.e., not calculated)] respectively). See Table N below.

[0201] Time to first response: Among the patients who achieved a response, the median time to first response was shorter in the IPd group (1.1 months / 35 days) than in the Pd group (1.9 months / 58 days). In the ITT analysis, the median time to first response was slightly shorter in the IPd group than in the Pd group (1.94 months [1.314 - 2.004] vs. 3.02 months [2.825 - 5.060] respectively). See Table N.

[0202]

Table 28

[0203] Improvement in efficacy was observed in all subgroups. Among patients who had received prior treatment for multiple myeloma with 2 or 3 lines, the efficacy rate was 38.6% in the Pd group versus 56.9% in the IPd group. Among patients who had received prior treatment for multiple myeloma with >3 lines, the efficacy rate was 28.8% in the Pd group versus 67.3% in the IPd group.

[0204] Interference assay evaluation: The IRC identified patients (historical near-CR category, undetectable M protein, and immunofixation positive) who met the criteria for CR within the VGPR category, excluding residual immunofixation positivity. Twenty-four patients in the IPd group (15.6%) and 5 patients in the Pd group (3.3%) had near-CR as their best response. Serum samples from 22 of these patients in the IPd group were tested by mass spectrometry after separating the isatuximab signal from the myeloma M-protein signal. Residual myeloma M protein detectable at the sensitivity level of the immunofixation test (25 mg / dL, Hydragel, Sebia) performed by the central laboratory of this study was no longer present in 11 of the 22 patients (50%). This means that the immunofixation was due to the presence of isatuximab. The depth of response, particularly complete response, may be underestimated due to potential interference of isatuximab with the assessment of M protein by immunofixation.

[0205] Minimal Residual Disease (MRD): Assessment of minimal residual disease (MRD) was performed using bone marrow aspirate samples (ID calibration samples) collected at screening, at the time of confirmation of complete response or stringent complete response, and 3 months later if MRD was positive, by the Adaptive clonoSEQ® assay (version 2.0; Adaptive Biotechnologies, Seattle, WA, USA). If the patient remained positive for MRD, an additional sample could be collected. Up to 3 post-treatment samples were obtained.

[0206] The clonoSEQ assay is a next-generation sequencing (NG)-based assay that identifies rearranged IgH (VDJ), IgH (DJ), IgK, and IgL receptor gene sequences as well as translocated BCL1 / IgH (J) and BCL2 / IgH (J) sequences. This assay includes primers that amplify specific genomic regions that exist as diploid copies in normal genomic DNA (gDNA), thereby enabling measurement of the total nucleated cell content.

[0207] The test started with genomic DNA (gDNA) extracted from bone marrow aspirates. The quality of the extracted gDNA was assessed, and multiplex PCR was used to amplify rearranged immune receptors. Reaction-specific index barcode sequences for sample identification were added to the receptor sequences amplified by PCR. A sequencing library was prepared from the barcoded amplified DNA and then sequenced by synthesis using NGS. The raw sequence data were uploaded from the sequencing instrument to the Adaptive analysis pipeline. These sequence data were analyzed in a multi-step process: First, the sequence data of the samples were confirmed using the sample index sequences. Next, data processing was performed using a proprietary algorithm with an in-line control to remove amplification bias.

[0208] When performing clonoSEQ clonality (ID) assessment, the immune repertoire of the sample was checked to see if there was a DNA sequence specific to the "dominant" clone that was consistent with the presence of a lymphoid tumor. To assess whether the clone sequence was suitable as the ID sequence (for subsequent tracking), first, sequences were assembled that required a high degree of similarity and a frequency of that sequence of at least 3% of all sequences at that locus, and the clone sequence was assessed by aggregating these sequences. Clones had to have a frequency of at least 0.2% of all nucleated cells in the sample, along with sufficient abundance and differentiation from the polyclonal background. Each sequence considered for MRD tracking was compared to the B cell repertoire database, and a uniqueness value was assigned to it for use in assigning the sequence to sensitivity bins used to evaluate the detection limit and quantification limit reported in the patient report, along with its relative abundance compared to other sequences.

[0209] During clonoSEQ tracking (MRD) assessment, the assessment of the complete immunoglobulin receptor repertoire was performed again, and the previously identified dominant clone type sequences were detected and quantified to determine the MRD level of the sample.

[0210] The MRD negative rate was defined as the proportion of patients who were MRD negative by bone marrow aspirate at any time after the first dose. For the purpose of analysis, patients in the treatment intention population without MRD assessment were considered MRD positive.

[0211] Bone marrow samples for MRD assessment were taken by the principal investigator of the clinical trial for patients with complete response as assessed by the principal investigator of the clinical trial, or if clinically necessary. Analyses were performed on 16 patients, including all patients in whom CR or sCR was confirmed by IRC review (7 patients in the isatuximab group and 3 patients in the control group). Although the principal investigator's assessment was based on M protein test results at the facility, the IRC assessment was based on M protein results from the central testing facility, so it should be noted that responses different from CR may have been assigned by the IRC.

[0212] MRD negativity within the ITT population in the IPd group was observed in 10 patients (6.5%) at a sensitivity of 10 -4 (i.e., 1 multiple myeloma cell per 10 4 nucleated cells); in 8 patients (5.2%) at a sensitivity of 10 -5 (i.e., 1 multiple myeloma cell per 10 5 nucleated cells); and in 2 patients (1.3%) at a sensitivity of 10 -6 (i.e., 1 multiple myeloma cell per 10 6 nucleated cells). No MRD negativity was observed in patients in the Pd (control) group.

[0213] Quality of life: Overall quality of life (measured by the general health score of the QLQ-C30) was maintained over time and was similar in both treatment groups. The addition of isatuximab to Pom+Dex did not negatively impact the quality of life of patients. Further analysis showed that the addition of isatuximab to Pom+Dex maintained the health-related quality of life of patients.

[0214] Pre-treatment line and efficacy analysis by refractory status: The PFS benefit of IPd compared to Pd was maintained across all subgroups analyzed, regardless of the number of prior treatment lines or refractory status (see Table O below). This included patients who had received 4 lines of prior treatment (8.54 months vs. 3.29 months; HR 0.498; 95% CI 0.258 - 0.962), patients resistant to Len and PI (11.20 months vs. 4.76 months; HR 0.579; 95% CI 0.401 - 0.835), and those resistant to Len in the final line (11.6 months vs. 5.7 months; HR 0.50; 95% CI 0.34 - 0.76). In a subsequent analysis, the number of patients in the IPd group who were resistant to lenalidomide in the final line of treatment was determined to be 93, and the number of patients in the Pd group who were resistant to lenalidomide in the final line of treatment was determined to be 88.

[0215]

Table 29

[0216] Furthermore, regardless of the number of prior treatment lines, more patients responded to treatment with IPd than to Pd. In patients who received 2 - 3, >3, and 4 lines of prior treatment, the overall response rate (ORR) was higher in the IPd group than in the Pd group. Among patients who received 2 - 3 lines of prior treatment, the ORR was 56.9% (32.4% achieved a VGPR or better response) in the IPd group (n = 102), compared with 38.6% (10.9% achieved a VGPR or better response) in the Pd group (n = 101). Among patients who received >3 lines of prior treatment, the ORR was 67.3% (30.8% achieved a VGPR or better response) in the IPd group (n = 52), compared with 28.8% (3.8% achieved a VGPR or better response) in the Pd group (n = 52). Among patients who received 4 lines of prior treatment, the ORR was 56.3% (31.3% achieved a VGPR or better response) in the IPd group (n = 32), compared with 28.6% (7.1% achieved a VGPR or better response) in the Pd group (n = 28).

[0217] In patients resistant to lenalidomide (Len), patients resistant to proteasome inhibitors (PI), patients resistant to both Len and PI, and patients resistant to Len in the final line of treatment, the ORR was higher in the IPd group than in the Pd group. Among Len-resistant patients, the ORR was 59.0% (30.6% achieved a VGPR or better response) in the IPd group (n = 144), while the ORR was 31.4% (7.1% achieved a VGPR or better response) in the Pd group (n = 140). Among PI-resistant patients, the ORR was 60.2% (30.5% achieved a VGPR or better response) in the IPd group (n = 118), while the ORR was 32.2% (7.8% achieved a VGPR or better response) in the Pd group (n = 115). Among patients resistant to both Len and PI, the ORR was 58.6% (29.7% achieved a VGPR or better response) in the IPd group (n = 111), while the ORR was 29.9 (8.4% achieved a VGPR or better response) in the Pd group (n = 107). Among patients resistant to Len in the final line of treatment, the ORR was 55.9% (32.3% achieved a VGPR or better response) in the IPD group (n = 93), while the ORR was 29.5% (4.5% achieved a VGPR or better response) in the IPd group (n = 88).

[0218] The PFS benefit of IPd over Pd was consistent with that of the overall population regardless of the number of prior treatment lines or refractory status. The addition of isatuximab to pomalidomide + dexamethasone improved the treatment response rate in all subsets analyzed by prior treatment. In particular, the benefit of IPd over Pd was maintained in patients resistant to Len in the final line of treatment.

[0219] D. Safety Safety assessments were conducted via standard hematology and blood chemistry for the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to treatment discontinuation, and other significant AEs (e.g., infusion reactions, second primary malignancies, respiratory AEs, neutropenia and neutropenic complications, infections, thrombocytopenia and bleeding, tumor lysis syndrome, hemolytic disorders and blood transfusions, autoimmune disorders). The safety analysis population actually included patients in the ITT population who received at least one dose or a portion of one dose of the study treatment. All analyses using this population were based on the treatment actually received. The overall safety profile of IPd was well characterized. It was also manageable and did not adversely affect the duration of treatment and the ongoing clinical benefit. The addition of isatuximab to Pd was mostly associated with low-grade infusion reactions as well as increased neutropenia and infections. Positive ADA (i.e., anti-drug antibodies, particularly anti-isatuximab antibodies) were not identified.

[0220] In patients with relapsed / refractory multiple myeloma who received intensive treatment, the addition of isatuximab to pomalidomide and dexamethasone demonstrated a statistically significant and clinically meaningful PFS benefit. Kaplan–Meier curves (Figures 2 and 3) showed a persistent separation starting from early on, corresponding to a 41% reduction in the risk of death or disease progression in patients in the isatuximab group. The PFS benefit was seen in all subgroups, including patients with high-risk cytogenetics (HR 0.66), patients aged >75 years, patients with renal impairment, and patients who had received 2–3 lines of prior therapy, >3 lines of prior therapy, were resistant to lenalidomide and proteasome inhibitors, and were resistant to lenalidomide in the final line. PFS with isatuximab, pomalidomide, and dexamethasone was the longest observed to date in this patient population. High-risk cytogenetics were determined to be positive by central laboratory FISH analysis using internationally recognized thresholds. In addition, a complete response benefit was seen in all subgroups. The results of the subgroup analysis provide the first evidence of improvement in renal function with CD38-targeted therapy in patients with RRMM.

[0221] IPd (i.e., the combination of isatuximab with pomalidomide and dexamethasone) significantly improved the response rate and depth of response compared with Pd (i.e., pomalidomide and dexamethasone). IPd treatment also covered renal function decline. 10 -5 Levels of minimal residual disease negativity were achieved in 5.2% of patients in the isatuximab group and 0% of the control group (ITT).

[0222] Example 2: Subgroup analysis of East Asian patients in a Phase III randomized open-label multicenter joint study comparing the combination of isatuximab (SAR650984) with pomalidomide and low-dose dexamethasone to pomalidomide and low-dose dexamethasone in patients with refractory or relapsed / refractory multiple myeloma This example describes a subgroup analysis of East Asian patients in the Phase III multi-site, multi-national, randomized, open-label, parallel-group, two-arm study described in Example 1. This subgroup analysis evaluated the safety and efficacy of the combination of isatuximab, pomalidomide, and low-dose dexamethasone compared to pomalidomide and low-dose dexamethasone for treating East Asian patients with refractory or relapsed / refractory multiple myeloma (RRMM) who had received at least two lines of prior treatment (e.g., two or more lines of prior treatment) for multiple myeloma, including lenalidomide and proteasome inhibitors (e.g., bortezomib, carfilzomib, or ixazomib), either alone or in combination, and were resistant to their last treatment.

[0223] As detailed in Example 1, East Asian patients were randomized to the Isa-Pd (IPd) experimental group or the Pd control group. Patients in the IPd group were administered isatuximab at a dose of 10 mg / kg on days 1, 8, 15, and 22 of cycle 1, and then at a dose of 10 mg / kg on days 1 and 15 of subsequent 28-day cycles. Patients in the IPd group and the Pd group were administered pomalidomide at a dose of 4 mg per day on days 1 to 21 of each 28-day cycle, and dexamethasone was administered orally or intravenously at a dose of 40 mg (or 20 mg if the patient was ≥75 years old) on days 1, 8, 15, and 22.

[0224] Results A. Patient characteristics This subgroup analysis included 36 East Asian patients (13 Japanese patients, 9 Korean patients, and 14 Taiwanese patients). Twenty-one patients from the East Asian subgroup were assigned to the IPd experimental treatment group, and 15 patients were assigned to the Pd control treatment group. Of the 13 Japanese patients in this subgroup, 9 patients were assigned to the IPd experimental treatment group and 4 patients were assigned to the Pd control treatment group.

[0225] The characteristics of the patients in the East Asian subgroup were similar to those of all the populations in the Phase III study described in Example 1. The median age was 65 (range: 41 - 85). The median number of prior treatment lines was 3 (range: 2 - 7). 91.7% of the patients in this subgroup were resistant to prior treatment with lenalidomide, and 69.4% of the patients in this subgroup were resistant to prior treatment with PI. 13.9% of the East Asian patients had high - risk cytogenetics.

[0226] B. Efficacy i. Progression - free survival (PFS) In the IPd group, after a median follow - up of 11.6 months, the median PFS was not reached. In the Pd group, the median PFS was 7.9 months (HR 0.517 [95% CI 0.19 - 1.39]).

[0227] ii. Overall response rate (ORR) The ORR (≥PR) was 71.4% in the IPd group and 60% in the Pd group.

[0228] The rate of VGRP or better response was 61.9% in the IPd group and 13.3% in the Pd group.

[0229] The median time to first response was 32 days in the IPd group and 59 days in the Pd group.

[0230] C. Safety In the IPd and Pd groups, grade ≥3 AEs were observed in 90.5% and 93.3% of the patients, respectively. Treatment was discontinued due to grade ≥3 AEs in 9.5% of the patients in the IPd group.

[0231] Infusion reactions were reported in 57.1% of the patients administered IPd. There were no grade 3 - 4 infusion reactions.

[0232] Conclusion In the subgroup analysis of 36 East Asian patients in the Phase III study described in Example 1, it was shown that the efficacy and safety of Isa-Pd in the East Asian population, including Japanese patients, were equivalent to those in all the populations of the study in Example 1. Isa-Pd is a new treatment option for East Asian patients with RRMM.

[0233] Example 3: Depth of response and response dynamics in a study of isatuximab + pomalidomide + dexamethasone in patients with relapsed / refractory multiple myeloma In multiple myeloma (MM), deep response was associated with improvement in progression-free survival (PFS) and overall survival (OS). Response dynamics data, including renal response time, are extremely important for patients with reduced renal function (RI), but are rarely reported. The relationship between depth of response + response dynamics, including minimal residual disease (MRD) negativity, and long-term outcomes was analyzed using data from the randomized open-label active-controlled Phase 3 study described in Example 1.

[0234] Methods As described in Example 1, all patients were administered standard-dose pomalidomide + dexamethasone (“Pd”), and patients randomized to the Isa-Pd group were administered Pd in addition to 10 mg / kg of isatuximab IV on days 1, 8, 15, and 22 (cycle 1) and days 1 and 15 of subsequent 28-day cycles until progression. Depth of response and dynamics were analyzed for each treatment group. Assessment of minimal residual disease (“MRD”) was performed at 10 -5 by next-generation sequencing in patients with complete response [CR] / stringent CR [sCR]. Time to biochemical response, time to renal response (CRenal; using the MDRD GFR equation (see www.kidney.org / content / mdrd-study-equation) from <50 mL / min / 1.73 m 2 at baseline to ≧60 mL / min / 1.73 m in ≧1 post-baseline assessment 2The improvement in estimated glomerular filtration rate (eGFR) up to, and the time to sustained CRenal (CRenal lasting ≥ 60 days) were recorded. For patients with IgG kappa clone, a neutralization assay was not used.

[0235] Results Overall, 307 patients were randomized to Isa-Pd (n = 154) or Pd (n = 153), of whom 33 / 142 (23.2%) and 24 / 145 (16.6%) patients had eGFR < 50 mL / min / 1.73 m at baseline measurement. 2 Patients had received a median of 3 lines of prior therapy (range 2 - 11), and 73.4% and 71.9% of patients in the Isa-Pd and Pd groups, respectively, were double resistant (i.e., resistant to IMiD® and proteasome inhibitors). The median PFS was 11.53 months in Isa-Pd and 6.47 months in Pd (hazard ratio [HR] 0.596 [95% confidence interval (CI) 0.436 - 0.814]). Biochemical responses were more frequent and deeper with Isa-Pd than with Pd. The overall response rate (ORR) was 60.4% versus 35.3% (odds ratio [OR] 2.80; 95% confidence interval [CI] 1.72 - 4.56; p < 0.0001); ≥ very good partial response rate (VGPR) was 31.8% versus 8.5% (OR 5.03; 95% CI 2.51 - 10.59; p < 0.0001). Since the isatuximab interference assay was not performed, near-complete response rates (immunofixation remained positive) were reported: 15.6% in the Isa-Pd group versus 3.3% in the Pd group (OR 5.47; 95% CI 1.96 - 18.78; p = 0.0002). The MRD negativity rate in the ITT population (10 -5The negative rate at the sensitivity of was 0% in the Pd group, while it was 5.2% in the Isa-Pd group. The depth of response correlated with the improvement of long-term outcomes in both groups. After a median observation period of 11.6 months in the Isa-Pd group, 100% of the MRD-negative patients (MRDneg) had no disease progression and were alive. The median PFS was longer and the depth of response was greater in the Isa-Pd group. The median PFS was not reached (NR) in the MRDneg patients of the Isa-Pd group (n = 8). In the Isa-Pd group with MRD± (n = 42) and ≥VGPR, the median PFS was 15.21 months. In the Isa-Pd group of patients who achieved PR (n = 44), the median PFS was 11.53 months. In the Isa-Pd group of patients who achieved less than PR (n = 57), the median PFS was 3.29 months (see Figure 6A). In the Pd group, the median PFS could not be calculated in patients who achieved a response of ≥PR, while the median PFS in patients with <PR was 2.86 months (range: 2.6 to 3.81 months).

[0236] In the Isa-Pd group, the 1-year OS rate was highest in MRD- patients and correlated with the depth of response. The 1-year OS rate was 100% in the MRDneg patients of the Isa-Pd group. In the Isa-Pd group with MRD± and ≥VGPR, the 1-year OS rate was 92.9%. In the Isa-Pd group of patients who achieved PR, the 1-year OS rate was 82.4%. In the Isa-Pd group of patients who achieved less than PR, the 1-year OS rate was 46.4% (see Figure 6B). The 1-year OS rate also correlated with the depth of response in the Pd group. In the Pd group with MRD± and ≥VGPR, the 1-year OS rate was 88.9%. In the Pd group of patients who achieved PR, the 1-year OS rate was 90.6%. In the Pd group of patients who achieved less than PR, the 1-year OS rate was 54.3%

[0237] Biochemical responses occurred more rapidly with Isa-Pd than with Pd. Among patients who achieved a ≥PR response (93 in the Isa-Pd group and 54 in the Pd group), the median time to first response was shorter with Isa-Pd (1.1 months) than with Pd (1.9 months). Among patients who achieved a VGPR response (49 and 13 in the Isa-Pd and Pd groups, respectively), the time to first VGPR or better response was similar, i.e., 2.9 months with Isa-Pd and 3.0 months with Pd. Among patients who achieved a CR response (7 patients in the Isa-Pd group and 3 in the Pd group), the median time to first CR or better response was shorter with Isa-Pd (5.7 months) than with Pd (7.9 months). The time to best response was 2.5 months in the Isa-Pd group compared to 2.8 months in the Pd group.

[0238] Renal responses occurred more rapidly in patients receiving Isa-Pd than in those receiving Pd. Complete renal response (CRenal) was observed in 23 / 32 (71.9%) of patients in the Isa-Pd group (median time to first CRenal was 4.1 weeks), compared to 8 / 21 (38.1%) of patients in the Pd group (median time to first response was 7.3 weeks). Sustained CRenal (i.e., CRenal ≥ 60 days, also known as "durable CRenal") was observed in 10 / 32 (31.3%) of patients in the Isa-Pd group (median time to first response was 2.4 weeks), compared to 4 / 21 (19.0%) of patients in the Pd group (median time to first response was 4.8 weeks). Additionally, renal responses occurred more rapidly in patients in the Isa-Pd group than in those in the Pd group. See Figure 7. As noted above, the median time to CRenal was 7.3 weeks in the Pd group compared to 4.1 weeks in the Isa-Pd group. The median time to sustained CRenal (i.e., CRenal ≥ 60 days) was 4.8 weeks in the Pd group compared to 2.4 weeks in the Isa-Pd group. The median time to first renal response (including minor and partial responses) was 7.3 weeks in the IPd group compared to 3.1 weeks in the IPd group.

[0239] Conclusion In the heavily pretreated population studied in Example 1, Isa-Pd induced biochemical responses (i.e., antitumor effects) and renal responses more frequently and rapidly than Pd. The depth of response, including MRD negativity, was improved by Isa-Pd and was associated with better long-term survival outcomes (i.e., PFS and OS). The results of the subgroup analysis provide the first evidence of improvement in renal function with CD38-targeted therapy in patients with RRMM.

[0240] Example 4: Efficacy of Ixazomib in combination with pomalidomide and dexamethasone in elderly patients with relapsed / refractory multiple myeloma Multiple myeloma (MM) is most frequently diagnosed in people aged 65 - 74 years, and approximately one-third of patients are ≥ 75 years old. Advanced age has a negative impact on the prognosis of patients with MM. Example 1 compared treatment with the anti-CD38 monoclonal antibody ixazomib (Isa) in combination with pomalidomide and dexamethasone (Pd) to Pd. Patients had relapsed / refractory MM (RRMM) after two or more lines of prior therapy, including lenalidomide and proteasome inhibitors. This subgroup analysis investigated efficacy and safety in elderly patients (≥ 75 years) compared to younger patients.

[0241] Methods Patients were randomized (1:1) to receive Isa-Pd or Pd. Isa (10 mg / kg IV) was administered on days 1, 8, 15, and 22 (cycle 1) and days 1 and 15 of subsequent 28-day cycles. All patients received 4 mg of pomalidomide on days 1 - 21 of each cycle and dexamethasone 40 mg (20 mg for patients ≥ 75 years old) on days 1, 8, 15, and 22 of each cycle. The primary endpoint was progression-free survival (PFS) as assessed by an independent efficacy review committee. Subgroup analyses were performed for patients aged < 65 years, 65 - 74 years, and ≥ 75 years.

[0242] Results Overall, 307 patients were randomized to Isa-Pd (n = 154) or Pd (n = 153) and included in the intention-to-treat population. The median age of the patients was 68.0 years in the Isa-Pd group and 66.0 years in the Pd group. In the Isa-Pd group and Pd group, there were 54 (35%) and 70 (46%) patients < 65 years old, 68 (44%) and 54 (35%) patients 65 - 74 years old, and 32 (21%) and 29 (19%) patients ≥ 75 years old, respectively.

[0243] Overall, the median PFS was significantly improved with Isa-Pd compared to Pd (11.53 months vs. 6.47 months; hazard ratio [HR] 0.596 [95% confidence interval (CI) 0.436 - 0.814], p = 0.001). Consistent with this, in patients ≥ 75 years old, the median PFS was 11.40 months with Isa-Pd compared to 4.47 months with Pd (HR 0.479 [95% CI, 0.242 - 0.946]). Similarly, in the Isa-Pd group and Pd group, respectively, patients 65 - 74 years old had a PFS of 11.57 months and 8.58 months (HR 0.638 [0.385 - 1.059]), and in patients < 65 years old, the PFS was 11.53 months and 5.03 months (HR 0.656 [95% CI, 0.401 - 1.074]). See Table P.

[0244]

Table 30

[0245] The overall response rate (ORR) for all patients was 60.4% for Isa-Pd and 35.3% for Pd, and the odds ratio (OR) was 2.80 (95% CI, 1.72 - 4.56). For patients administered Isa-Pd compared to Pd, the age-stratified ORR was: 53.1% and 31.0% (OR 2.52 [95% CI, 0.79 - 8.26]) in the ≥75-year-old group; 64.7% and 38.9% (OR 2.88 [95% CI, 1.29 - 6.46]) in the 65 - 74-year-old group; and 59.3% and 34.3% (OR 2.79 [95% CI, 1.26 - 6.20]) in the <65-year-old group.

[0246] 31.8% of patients administered Isa-Pd and 8.5% of patients administered Pd achieved at least a very good partial response (VGPR), and the OR was 5.03 (95% CI, 2.51 - 10.59). The rates of ≥VGPR by age in Isa-Pd and Pd administered patients were: 31.3% and 0% (no OR calculated) in the ≥75-year-old group; 32.4% and 13.0% (OR 3.21 [95% CI, 1.17 - 9.70]) in the 65 - 74-year-old group; and 31.5% and 8.6% (OR 4.90 [95% CI, 1.64 - 16.35]) in the <65-year-old group.

[0247] Overall, 8 patients in the Isa-Pd group had -5 minimal residual disease negativity at 10. Two of the 8 were ≥75 years old and two were 65 - 74 years old. The remaining 4 patients were <65 years old. There were no patients in the Pd group who achieved MRD negativity.

[0248] At the time of the interim analysis, the overall survival (OS) data were immature. However, in the elderly population, the median OS was not reached, 8 / 32 (25%) of patients in the Isa-Pd group died, and in the Pd group, 15 / 29 (51.7%) died, with a median OS of 10.25 months (HR 0.404 (95% CI 0.171 - 0.956).

[0249] In the subsequent OS analysis in patients aged 65-74 years, the median OS was not reached in the Isa-Pd group, while in the Pd group, the median OS was 14.5 months (HR 0.75; 95% CI 0.38-1.45). In patients <65 years old, the median OS was not reached in either treatment group (HR of Isa-Pd vs Pd was 0.85 (95% CI 0.46-1.59)).

[0250] In the Isa-Pd group, the 1-year OS rates were similar in patients aged ≥75 years, 65-74 years, and <65 years. See Table Q below.

[0251]

Table 31

[0252] In the Isa-Pd group, the incidence of treatment-emergent adverse events (TEAEs) occurring under all grades was similar across all age groups: <65 years, 98.1%; 65-74 years (100%); and ≥75 years, 100%. The incidence of TEAEs was equivalent between the two groups.

[0253] Grade ≥3 TEAEs due to Isa-Pd administration were more frequent in patients aged ≥75 years (93.8%) compared to those aged <65 years (85.2%), and a similar trend was observed in the Pd group (64.7% and 75.0% respectively). Treatment discontinuation due to TEAEs was also more common in patients aged ≥75 years compared to those aged <65 years in both the Isa-Pd group (7.4% vs 15.6%) and the Pd group (10.3% vs 14.3%). The incidence of serious TEAEs (SAEs) was higher in patients aged ≥75 years compared to those aged <65 years in both groups (Isa-Pd, 57.4% and 68.8%; Pd, 47.1% and 57.1% respectively). The incidence of TEAEs with fatal outcomes was lower in patients aged ≥75 years (6.3%) compared to those aged <65 years (11.1%) in the Isa-Pd group, while the opposite trend (5.9% vs 14.3%) was observed in the Pd group.

[0254] Conclusion The addition of Isa to Pd improved the degree of PFS, ORR, ≥VGPR, and OS in elderly patients. This is consistent with the benefits observed in the overall study population. In the Isa-Pd group, PFS and 1-year OS rates were similar in patients <65 years, 65 - 74 years, and ≥75 years. In both the Isa-Pd group and the Pd group, there was a consistent tendency for the rate of discontinuation due to SAE and TEAE to be higher in patients ≥75 years compared to younger patients. However, there was no increase in fatal AEs in the Isa-Pd group.

[0255] Example 5: Relationship between baseline biomarkers in RRMM and the efficacy of the combination of isatuximab and pomalidomide and dexamethasone Baseline biomarker analysis was performed on samples obtained from two clinical studies (i.e., a Phase I study to evaluate the safety and maximum tolerated dose of the combination of isatuximab and pomalidomide and dexamethasone in patients with relapsed / refractory multiple myeloma, and the Phase III study described in Example 1). Evaluations were performed on CD38 receptor density (RD), FCGR3A (Fc immunoglobulin receptor) genotype, and bone marrow or peripheral blood immunophenotype tests to determine whether they provide information regarding the response to the Isa-Pd regimen.

[0256] Method Both studies enrolled a similar population of patients with RRMM who had received two or more lines of prior treatment, including lenalidomide and proteasome inhibitors. In both studies, baseline blood samples were collected prior to the first treatment administration; in addition, bone marrow samples were collected during screening in the Phase I study. In the Phase I study, bone marrow plasma cells were analyzed for CD38 RD. Blood samples and bone marrow aspirates were used to analyze immune cell populations (CD19 + B cells, CD3 + T cells, CD4 + T cells, regulatory T cells (Treg), and natural killer (NK) cells [CD56 + bright CD16 + low subset and CD56 + dim CD16+ characterized by a bright subset]). Blood samples obtained from both studies were analyzed for FCGR3A genotyping (V158 and F158 high- and low-affinity alleles). Biomarker results correlated with responses defined as at least partial efficacy according to the International Myeloma Working Group criteria.

[0257] Results The Phase I study enrolled 45 patients and treated them with Isa-Pd. As discussed in Example 1, the Phase III study randomized 154 patients to Isa-Pd and 153 patients to Pd. Baseline patient demographics were similar in both studies, with a median number of prior treatment lines of 3 (range: 1-10) in the Phase I study and 3 (2-11) in the Phase III study. The overall response rate (ORR) with Isa-Pd was 62.2% (28 / 45) in the Phase I study and 60.4% (93 / 154) in the Phase III study. In the Phase I study, the median CD38 RD of the 31 treated patients with evaluable results was 108,172 receptors / cancer cell (range: 12,950-337,335). In patients who responded to Isa-Pd (n = 21), the median CD38 RD value was 120,931 (48,770-337,335) receptors / cancer cell; in patients who did not respond to Isa-Pd (n = 10), the median CD38 RD value was 85,370 (range: 12,950-309,003) receptors / cancer cell. Across all 5 Phase I / II clinical studies with Isa, 4 / 198 patients (2.0%) had CD38 RD levels < 48,770. This was the lowest value among responder patients.

[0258] In both studies, the FCGR3A genotype determination results were available. Across both studies, the distribution of the F158V single nucleotide polymorphism of the FCGR3A gene was F / F at 42%, F / V at 42%, and V / V at 16%, as seen in the general population. In both studies, efficacy was observed in all three genotypes (Table R). In the Phase I study, the ORRs of the three genotypes observed with the Isa-Pd regimen were in the range of 50.0% to 80.0%, while in the larger Phase III study, the ORRs with the Isa-Pd regimen were more similar across those genotypes (range: 56.9% - 65.5%). The progression-free survival (PFS) was in the range of 8.97 months to 14.78 months, and for all three genotypes, Isa-Pd showed a PFS benefit over Pd (see Table R).

[0259]

Table 32

[0260] In the Phase I study, 42 patients had at least one baseline peripheral blood immune biomarker value, of which 17 patients were non-responders and 25 patients were responders. In addition, 41 patients had at least one baseline bone marrow immune biomarker measurement (16 were non-responders and 25 were responders). No significant differences were observed between responders and non-responders for the immune biomarkers tested in the bone marrow during screening. The p-values were 0.2817 (CD19 + B cells), 0.6446 (CD3 + T cells), 0.7780 (CD4 + T cells), 0.1620 (Tregs), 0.9591 (NK cells), 0.8275 (CD56 + bright / CD16 + low NK cells), and 0.7389 (CD56 + dim / CD16 +were bright NK cells). Similarly, there was no significant difference in immune biomarkers in the blood between responders and non-responders.

[0261] Conclusion Biomarker analysis of samples obtained from patients treated with Isa-Pd showed that the benefits of Isa-Pd treatment were seen in all groups, regardless of baseline bone marrow plasma cell CD38 RD, FCGR3A genotype, or immunophenotype in bone marrow plasma cells or peripheral blood.

[0262] Example 6: Development of a pharmaceutical preparation containing isatuximab for intravenous administration Development of formulation 1 (containing 5 mg / ml of isatuximab) To achieve the desired pH, osmotic pressure, and stability requirements, formulation 1 containing isatuximab at a concentration of 5 mg / ml was developed. Several different formulations were developed and tested under various stress conditions designed to mimic the conditions encountered during manufacturing, transportation, storage, and handling. The stress conditions under which each formulation was tested included: · Mechanical stress by shaking (350 rpm for 15 hours), · Thermal stress at 40 °C or 45 °C, · Freeze-thaw cycles (3 - 5 cycles from -20 °C or -30 °C to room temperature), · Light exposure (SUNTEST), and · Dilution by infusion.

[0263] Formulations containing one of the following buffers at one of the following pH values were also tested: · Citrate 10 mM, pH = 5.0, 5.5, 6.0, 6.5, or 7.0; · Histidine 10 mM, pH = 5.5, 6.0, or 6.5; · Phosphate 10 mM, pH = 6.5, 7.0, or 7.4 · 10 mM succinate, pH 5.0, 5.5, or 6.0; and, · Acetate 10 mM, pH = 5.0 or 5.5.

[0264] The buffer - pH systems were selected based on their buffering capacity in the target pH range. The buffer - pH systems were evaluated in terms of their effect on cetuximab in terms of the formation of visible and sub - visible particles and the formation of high - molecular - weight molecular species (HMWS, e.g., soluble aggregates) after shaking and heat stress.

[0265] Formulations containing histidine or acetate buffers were found to provide higher stability than formulations containing citrate, phosphate, or succinate buffers. Furthermore, citrate and succinate buffers were found to reduce the solubility of cetuximab as the solutions became milky white when each of these two buffers was included. Dynamic light scattering (DLS) showed an increase in the Z - average value, and static light scattering (SLS) showed the virial coefficient A22, indicating molecular attraction in formulations containing sodium citrate or sodium succinate and molecular repulsion in formulations containing histidine. Furthermore, the histidine buffer showed less formation of cetuximab HMWS (measured by size - exclusion high - performance liquid chromatography (SE - HPLC)) during ultrafiltration / diafiltration than the citrate and succinate buffers.

[0266] Formulations containing histidine and acetate buffers were further tested under heat stress for their effect on stability towards charge heterogeneity and were found to show similar stability. Based on the research results, the following buffer - pH systems for stabilizing cetuximab were selected for further development steps: histidine 10 mM, pH = 5.5 to pH 6.5; acetate 10 mM, pH = 5.0 and pH 5.5.

[0267] NaCl (0.8% w / v), sucrose (5% w / v), and mannitol (3% w / v) were tested for their ability to improve the stability of isatuximab (measured by the aggregation of isatuximab) in combination with a selected pH buffer system. Assessment of aggregation was performed by measuring the amount of visible and subvisible particles, soluble aggregates (HMWS), and fragments (low molecular weight molecular species (LMWS)) after agitation, heat stress, and / or freeze-thaw cycles.

[0268] Significant destabilization of isatuximab (indicated by an increase in subvisible particle concentration) was found in formulations containing NaCl under heat, freeze-thaw, and agitation stress.

[0269] Formulations containing sucrose or mannitol were found to have a stabilizing effect on isatuximab.

[0270] Formulations containing acetate buffer showed a higher degree of post-translational modification (PTM) than formulations containing histidine under heat stress. Relatively high amide degradation was found in formulations containing acetate buffer.

[0271] No significant difference in the behavior of isatuximab was observed between formulations containing histidine with a pH value between 6.0 and 6.5 and formulations containing sucrose or mannitol (e.g., using the assays described above and the criteria discussed above). Therefore, a histidine buffer at pH 6.5 was selected for further development testing. To target isotonicity in formulation 1, the concentration of mannitol was increased to 5% (w / v) and the concentration of sucrose was increased to 10% (w / v). Sucrose 10% (w / v) corresponds to an osmotic pressure of 292 mOsm / kg and mannitol 5% (w / v) corresponds to an osmotic pressure of 330 mOsm / kg.

[0272] Next, various surfactants at various concentrations were evaluated. Polysorbate 80 (PS80) was tested at concentrations from 0.001% to 0.01% in the presence of 10 mM histidine at pH 6.5 and 5% mannitol. The test formulations were either exposed to agitation stress (15 h at 350 rpm) or diluted to 2 mg / ml in 0.9% NaCl solution or 5% glucose solution. Sub-visible particles under light obscuration (LO) were extrapolated. For formulations containing PS80, equivalent results were obtained at all tested concentrations, even at the lowest level of 0.001% PS80. This indicates that under the applied stress, isatuximab was efficiently stabilized by PS80. A PS80 concentration of 0.005% was selected in preparation for the possibility of PS80 adsorption during the manufacturing steps (i.e., compounding, filtration, and filling operations of the formulated drug substance).

[0273] From formulation development studies, two formulations, namely, histidine 10 mM, PS80 0.005% (w / v), pH 6.5 containing 5% (w / v) mannitol or 10% (w / v) sucrose, were selected and tested for 6-month stability as shown in Table S.

[0274]

Table 33

[0275] Based on the variability of the various analytical procedures, no significant differences were observed in any of the formulations. However, as an exception, under Suntest exposure, the prototype containing mannitol had more acidic forms. Furthermore, mannitol has the potential to crystallize at sub-zero temperatures. Therefore, sucrose was selected as the stabilizer.

[0276] As a result, pharmaceutical formulation 1 containing the following was developed: · 5 mg / ml isatuximab · 10 mM histidine · 10% (w / v) sucrose · 0.005% (w / v) polysorbate 80 · pH 6.5.

[0277] Isatuximab formulated in Formulation 1 was shown to have a 24-month shelf life at +5°C ± 3°C. The 5 mg / ml concentration of isatuximab was compatible with a very low dose of isatuximab that met the estimated minimum pharmacological effect level (MABEL) dosing schedule; however, formulations containing higher concentrations of isatuximab were also needed to enable higher dose administrations.

[0278] Development of Formulation 2 (containing 20 mg / ml of isatuximab) The pH and molar concentration of the histidine buffer were tested for potential improvements in stability and buffering capacity. Histidine was tested at the following concentration and pH values: 10 mM, pH = 6.0; 10 mM, pH = 6.5; 20 mM, pH = 6.0; and 20 mM, pH 6.5. Under stressed heat conditions, i.e., at 40°C for 1 month, the stability of isatuximab in each test formulation was evaluated by measuring aggregation (HMWS and LMWS by SE-HPLC), subvisible particle count (using flow cell microscopy (FCM)), charge heterogeneity (using weak cation exchange chromatography (WCX)), hydrodynamic radius value (Z-average), and polydispersity index (PdI) by DLS. Surprisingly, better stabilization of isatuximab was observed in formulations at pH 6.0 (10 mM or 20 mM histidine) than in formulations at pH 6.5. Thus, 20 mM histidine at pH 6.0 was selected for Formulation 2 due to increased stability and improved buffering capacity of isatuximab.

[0279] Effect of PS80 surfactant content In formulations containing PS80 between 0.015% (w / v) and 0.025% (w / v), the effect of PS80 content was assessed. As stress conditions, shaking and dilution in infusion were performed.

[0280] There was no difference in the number of subvisible particles observed by flow cell microscopy after shaking the test formulations for PS80 contents ranging from 0.015% (w / v) to 0.025% (w / v).

[0281] The stability of a formulation with a PS80 content between 0.015% (w / v) and 0.025% (w / v) was tested after dilution in a 0.9% NaCl solution. The formulation was diluted to 2 mg / ml of isatuximab in a 0.9% NaCl infusion bag. Samples were measured for sub-visible particles. No differences were observed between the formulations. Thus, it was found that formulations with a PS80 concentration between 0.015% (w / v) and 0.025% have similar stability profiles for 20 mg / ml of isatuximab.

[0282] During long-term storage, PS80 may decompose over time. To mimic the effects of long-term storage, a formulation with a PS80 concentration of 0.0057% (w / v) was evaluated by applying stirring, shaking, and freeze / thaw stress conditions. Such conditions are equivalent to storing a sample containing an initial concentration of 0.020%, i.e., 200 ppm of PS80, at 5 °C for 50 months.

[0283] No changes in the aggregation properties were observed after exposure to stirring stress (stirring and shaking) or after freeze / thaw stress. This demonstrates that when formulated into a 20 mg / ml isatuximab formulation containing 20 mM histidine, 10% (w / v) sucrose at pH 6.0 by reducing the PS80 content to a reduced concentration of 57 ppm, the stability of isatuximab is not affected even after exposure to stirring or freeze / thaw stress.

[0284] As a result, a pharmaceutical formulation 2 was developed containing: · 20 mg / ml of isatuximab · 20 mM histidine · 10% (w / v) sucrose · 0.02% (w / v) polysorbate 80 · pH 6.0.

[0285] For the purpose of a clear understanding, the present disclosure has been described in some detail by way of illustration and example, but these descriptions and examples should not be construed as limiting the scope of the present disclosure. The disclosures of all patents and scientific documents cited herein are hereby incorporated by reference in their entirety into this specification.

Claims

1. A pharmaceutical composition comprising an anti-CD38 antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 9 for use in a method of restoring renal dysfunction in an individual with multiple myeloma, the method comprising administering to the individual the anti-CD38 antibody, pomalidomide, and dexamethasone, the anti-CD38 antibody is administered at a dose of 10 mg / kg, the pomalidomide is administered at a dose of 4 mg, and the dexamethasone is administered at a dose of 40 mg to individuals less than 75 years of age or the dexamethasone is administered at a dose of 20 mg to individuals 75 years of age or older, the individual has received at least two prior treatments for multiple myeloma, at least one of the at least two prior treatments for multiple myeloma is lenalidomide and at least one of the two prior treatments is a proteasome inhibitor, the individual, after the treatment, is likely to achieve complete renal response as compared to a treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody, said pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the at least two prior treatments did not include treatment with an anti-CD38 antibody and / or treatment with pomalidomide.

3. The pharmaceutical composition according to claim 1 or 2, wherein the individual did not respond to at least one of the at least two prior treatments, or the individual relapsed after at least one of the at least two prior treatments, or the individual experienced disease progression during or after treatment with at least one of the two prior treatments.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the individual with multiple myeloma is selected for administration based on an individual having kidney impairment.

5. The individual has an estimated glomerular filtration rate (eGFR) of less than about 60 mL / min / 1.73 m 2 The pharmaceutical composition according to claim 4, having an estimated glomerular filtration rate (eGFR) of less than about 60 mL / min / 1.73 m

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the treatment prolongs the progression-free survival (PFS) of the individual.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the treatment prolongs the overall survival (OS) of the individual.

8. The pharmaceutical composition according to claim 6 or 7, wherein the treatment prolongs the PFS of the individual by at least about 9 months.

9. The treatment was received with pomalidomide and dexamethasone without an anti-CD38 antibody The pharmaceutical composition according to any one of claims 6 to 8, which extends the PFS of an individual by at least about 4.5 months compared to an individual having multiple myeloma.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein an individual achieves a response to treatment more rapidly than an individual having multiple myeloma who has received treatment with pomalidomide and dexamethasone without an anti-CD38 antibody.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein an individual achieves renal response to treatment more rapidly than an individual having multiple myeloma who has received treatment with pomalidomide and dexamethasone without an anti-CD38 antibody.

12. The pharmaceutical composition according to claim 11, wherein the renal response is a complete renal response.

13. The pharmaceutical composition according to claim 11 or 12, wherein the complete renal response lasts for at least 60 days.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the anti-CD38 antibody is isatuximab.

15. The anti-CD38 antibody, pomalidomide, and dexamethasone are administered in a first 28-day cycle, the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first 28-day cycle, the pomalidomide is administered daily from days 1 to 21 of the first 28-day cycle, and the dexamethasone is administered on days 1, 8, 15, and 22 of the first 28-day cycle. The pharmaceutical composition according to any one of claims 1 to 14.

16. The anti-CD38 antibody, pomalidomide, and dexamethasone are further administered in one or more 28-day cycles after the first 28-day cycle, the anti-CD38 antibody is administered on days 1 and 15 of the one or more 28-day cycles after the first 28-day cycle, the pomalidomide is administered daily from days 1 to 21 of the one or more 28-day cycles after the first 28-day cycle, and the dexamethasone is administered on days 1, 8, 15, and 22 of the one or more 28-day cycles after the first 28-day cycle. The pharmaceutical composition according to claim 15.

17. The pharmaceutical composition according to claim 15 or 16, wherein pomalidomide and dexamethasone are administered before the anti-CD38 antibody on day 1 of the first 28-day cycle.

18. Dexamethasone is administered before the anti-CD38 antibody on days 8, 15, and 22 of the first 28-day cycle, and the anti-CD38 antibody is administered before pomalidomide on days 8 and 15 of the first 28-day cycle. The pharmaceutical composition according to any one of claims 15 to 17.

19. Pomalidomide and dexamethasone are administered before the anti-CD38 antibody on day 1 of one or more 28-day cycles after the first 28-day cycle. The pharmaceutical composition according to any one of claims 15 to 18.

20. Dexamethasone is administered before the anti-CD38 antibody, and the anti-CD38 antibody is administered before pomalidomide on day 15 of one or more 28-day cycles after the first 28-day cycle. The pharmaceutical composition according to any one of claims 15 to 19.

21. The anti-CD38 antibody, pomalidomide, and dexamethasone are administered in the first 28-day cycle. The anti-CD38 antibody is administered once a week in the first 28-day cycle, pomalidomide is administered for 21 days in the first 28-day cycle, and dexamethasone is administered once a week in the first 28-day cycle. The pharmaceutical composition according to any one of claims 1 to 14.

22. The anti-CD38 antibody, pomalidomide, and dexamethasone are further administered in one or more 28-day cycles after the first 28-day cycle. The anti-CD38 antibody is administered once every other week in the one or more 28-day cycles after the first 28-day cycle, pomalidomide is administered for 21 days in the one or more 28-day cycles after the first 28-day cycle, and dexamethasone is administered once a week in the one or more 28-day cycles after the first 28-day cycle. The pharmaceutical composition according to claim 21.

23. Pomalidomide and dexamethasone are administered before the anti-CD38 antibody in the first 28-day cycle. The pharmaceutical composition according to claim 21 or 22.

24. Dexamethasone is administered before the anti-CD38 antibody, and the anti-CD38 antibody is administered before pomalidomide in the first 28-day cycle. The pharmaceutical composition according to any one of claims 21 to 23.

25. Pomalidomide and dexamethasone are administered before the anti-CD38 antibody in one or more 28-day cycles after the first 28-day cycle. The pharmaceutical composition according to any one of claims 21 to 24.

26. The dexamethasone is administered before the anti-CD38 antibody, and the anti-CD38 antibody is administered before pomalidomide in one or more 28-day cycles after the first 28-day cycle, the pharmaceutical composition according to any one of claims 21 to 25.

27. The anti-CD38 antibody is administered intravenously, the pharmaceutical composition according to any one of claims 1 to 26.

28. Pomalidomide is administered orally, the pharmaceutical composition according to any one of claims 1 to 27.

29. Dexamethasone is administered orally, the pharmaceutical composition according to any one of claims 1 to 28.

30. Dexamethasone is administered intravenously, the pharmaceutical composition according to any one of claims 1 to 28.

31. The individual was resistant to the most recent previous treatment for multiple myeloma, the pharmaceutical composition according to any one of claims 1 to 30.

32. The most recent previous treatment was lenalidomide, the pharmaceutical composition according to claim 31.

33. The most recent previous treatment was a proteasome inhibitor, the pharmaceutical composition according to claim 31.

34. The proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib and ixazomib, the pharmaceutical composition according to any one of claims 1 to 33.

35. Lenalidomide and the proteasome inhibitor were administered in combination, the pharmaceutical composition according to any one of claims 1 to 34.

36. The individual has chronic obstructive pulmonary disease (COPD), the pharmaceutical composition according to any one of claims 1 to 35.

37. The individual has asthma, the pharmaceutical composition according to any one of claims 1 to 36.

38. The individual has bronchospasm, the pharmaceutical composition according to any one of claims 1 to 37.

39. The individual has one or more cytogenetic abnormalities selected from the group consisting of del(17p), t(4;14) and t(14;16), the pharmaceutical composition according to any one of claims 1 to 38.

40. The individual is at least 65 years old and less than 75 years old, the pharmaceutical composition according to any one of claims 1 to 39.

41. The individual is 75 years old or older, the pharmaceutical composition according to any one of claims 1 to 39.

42. The individual has received at least three previous treatments for multiple myeloma, the pharmaceutical composition according to any one of claims 1 to 41.

43. The pharmaceutical composition according to any one of claims 1 to 42, wherein the individual is of East Asian origin.

44. The pharmaceutical composition according to any one of claims 1 to 43, wherein the individual is in stage III according to the International Staging System (ISS).

45. The pharmaceutical composition according to any one of claims 1 to 44, wherein the individual is in stage III according to the Revised International Staging System (R-ISS).

46. The individual is 10 after treatment -4 The pharmaceutical composition according to any one of claims 1 to 45, which is minimal residual disease (MRD) negative at the following threshold value

47. The individual is MRD-negative after treatment at 10 -5 The pharmaceutical composition according to claim 46, wherein the individual is MRD-negative at the following threshold value.

48. The individual is MRD negative at the following threshold of 10 after treatment -6 The pharmaceutical composition according to claim 46 or 47, wherein the individual is MRD negative at the following threshold of

49. The pharmaceutical composition according to any one of claims 46 to 48, wherein MRD is investigated through next-generation sequencing (NGS).

50. The pharmaceutical composition according to any one of claims 46 to 49, wherein MRD is investigated through next-generation flow cytometry (NGF).

51. A kit comprising an anti-CD38 antibody for use in combination with pomalidomide and dexamethasone for treating an individual with multiple myeloma with the pharmaceutical composition according to any one of claims 1 to 50.

Images