Use of isatuximab for the treatment of multiple myeloma

Abstract

The present disclosure provides a method for treating multiple myeloma, comprising administering isatuximab to an individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of an initial 28-day cycle; administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of a 28-day cycle, for example, for at least 11 cycles, or until, for example, the individual achieves, or is determined to achieve, at least a very good partial response (VGPR) to the treatment; and administering isatuximab at a dose of 10 mg / kg once every 28 days for one or more additional 28-day cycles.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 109,305, filed on 3 November 2020, and U.S. Provisional Patent Application No. 63 / 239,108, filed on 31 August 2021, the contents of which, respectively, are incorporated herein by reference in their entirety.

[0002] Submission of sequence listings in ASCII text file The following submission, in ASCII text file format: a computer-readable (CRF) sequence listing (filename: 183952033540SEQLIST.TXT, date: November 1, 2021, size: 10,277 bytes), is incorporated herein by reference in its entirety.

[0003] field This disclosure relates to a method for treating multiple myeloma by administering an anti-CD38 antibody, such as isatuximab. [Background technology]

[0004] Multiple myeloma (MM) is a malignant plasma cell disease characterized by clonal proliferation of plasma cells in the bone marrow (BM) and the production of excessive amounts of monoclonal immunoglobulins (typically IgG or IgA type, or free urinary light chains, i.e., paraproteins, M proteins, or M components). Patients with MM may experience bone pain, fractures, fatigue, anemia, infections, hypercalcemia, and renal problems (Non-Patent Literature 1). CD38 expression is particularly prominent in MM, as over 98% of patients are positive for this protein (Non-Patent Literature 2; Non-Patent Literature 3). The strong and uniform expression of CD38 on malignant clonal MM cells, in contrast to the limited expression pattern on normal cells, suggests that this antigen may be useful for specific targeting of tumor cells.

[0005] Generally, MM patients will receive treatment regimens throughout their lives that include, alone or in combination, drugs such as proteasome inhibitors (e.g., bortezomib, ixazomib, and carfilzomib), immunomodulators or "IMiDs®" (e.g., lenalidomide, pomalidomide, and thalidomide), monoclonal antibodies (e.g., elotuzumab), and histone deacetylase (HDAC) inhibitors (e.g., panobinostat).

[0006] Determining the appropriate administration schedule for antibodies is complicated by potential TMDD (target-mediated drug disposition) and tumor load. The pharmacokinetics of a given antibody require empirical determination. For each antibody-based therapy, individual assessment is essential to determine whether, while preserving patient benefit, the patient should receive antibody administration at longer intervals (e.g., monthly versus bi-weekly), and when.

[0007] All references cited herein, including patent applications, patent publications, and UniProtKB / Swiss-Prot accession numbers, are incorporated herein by reference in whole, just as each individual reference is indicated to be incorporated by reference specifically and individually. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Rollig et al. (2015), Lancet, 385(9983):2197~208 [Non-Patent Document 2] Goldmacher et al. (1994), Blood, 84(9):3017~25 [Non-Patent Document 3] Lin et al. (2004), Am J Clin Pathol., 121(4):482~8 [Overview of the project]

Means for Solving the Problem

[0009] In some embodiments, a method of treating a human individual having multiple myeloma, comprising the steps of administering ixazomib to the individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of an initial 28-day cycle; administering ixazomib at a dose of 10 mg / kg on days 1 and 15 of a 28-day cycle for at least 11 cycles; and administering ixazomib at a dose of 10 mg / kg once every 28 days for one or more additional 28-day cycles following at least 11 cycles. In some embodiments, a method of treating a human individual having multiple myeloma, comprising the steps of administering ixazomib to the individual at a dose of 10 mg / kg weekly for an initial one-month cycle; administering ixazomib at a dose of 10 mg / kg once every other week for at least 11 cycles following the initial one-month cycle; and administering ixazomib at a dose of 10 mg / kg monthly for one or more additional one-month cycles following at least 11 cycles.

[0010] In some embodiments, a method is provided for treating a human individual having multiple myeloma, comprising the steps of: administering isatuximab to the individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle; administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles after the first 28-day cycle until the individual achieves at least a very good partial response (VGPR); and administering isatuximab at a dose of 10 mg / kg once every 28 days for one or more further 28-day cycles after the individual has achieved at least a VGPR response. In some embodiments, a method is provided for treating a human individual having multiple myeloma, comprising the steps of: administering an anti-CD38 antibody to the individual at a dose of 10 mg / kg weekly for the first one-month cycle; administering the anti-CD38 antibody at a dose of 10 mg / kg every other week for one or more one-month cycles after the first one-month cycle until the individual achieves at least a very good partial response (VGPR); and administering the anti-CD38 antibody at a dose of 10 mg / kg once a month for one or more further one-month cycles after the individual has achieved at least a VGPR response.

[0011] In some embodiments, a method of treating a human individual having multiple myeloma, comprising administering isatuximab to the individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of an initial 28-day cycle; after the initial 28-day cycle, administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles; after the initial 28-day cycle, measuring the response of the individual to treatment at one or more time points during one or more 28-day cycles, and selecting individuals having at least a very good partial response (VGPR); and administering isatuximab to the selected individuals at a dose of 10 mg / kg once every 28 days for one or more additional 28-day cycles. In some embodiments, a method of treating a human individual having multiple myeloma, comprising administering an anti-CD38 antibody to the individual at a dose of 10 mg / kg weekly for an initial one-month cycle; after the initial one-month cycle, administering the anti-CD38 antibody at a dose of 10 mg / kg once every other week for one or more one-month cycles; after the initial one-month cycle, measuring the response of the individual to treatment at one or more time points during one or more one-month cycles, and selecting individuals having at least a very good partial response (VGPR); and administering the anti-CD38 antibody to the selected individuals at a dose of 10 mg / kg once a month for one or more additional one-month cycles.

[0012] In some embodiments, a method for treating a human individual with multiple myeloma, comprising the steps of: measuring the individual's serum M protein and urinary M protein at a first time point before administering isatuximab; administering isatuximab to the individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle; administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles after the first 28-day cycle; and administering at least 1 A method is provided comprising the steps of measuring the individual's serum M protein and / or urinary M protein at a second time point in one or more 28-day cycles, and administering isatuximab at a dose of 10 mg / kg once every 28 days for a further 28-day cycle if (a) the individual's serum M protein level at the second time point is reduced by at least 90% compared to the individual's serum M protein level at the first time point, and (b) the individual's urinary M protein level at the second time point is less than 100 mg per 24 hours.In some embodiments, a method for treating a human individual with multiple myeloma, comprising the steps of: measuring the individual's serum M protein and urinary M protein at a first time point before administering an anti-CD38 antibody; administering the individual the anti-CD38 antibody at a dose of 10 mg / kg weekly for the first one-month cycle; administering the anti-CD38 antibody at a dose of 10 mg / kg every other week for one or more one-month cycles after the first one-month cycle; and administering at least one or more one-month cycles after the first one-month cycle. A method is provided comprising the steps of: (a) measuring the individual's serum M protein and / or urinary M protein at a second time point during the intervening cycle; and administering an anti-CD38 antibody at a dose of 10 mg / kg per month for one or more additional one-month cycles if (a) the individual's serum M protein level at the second time point is reduced by at least 90% compared to the individual's serum M protein level at the first time point, and (b) the individual's urinary M protein level at the second time point is less than 100 mg per 24 hours.

[0013] In some embodiments, a method for treating a human individual with multiple myeloma, comprising the steps of: measuring the individual's serum M protein level and / or urinary M protein level before administering isatuximab; administering isatuximab to the individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle; and after the first 28-day cycle, (a) the individual's serum M protein level is reduced by at least 90% compared to the serum M protein level before administration of isatuximab, and (b) the individual's urinary M protein level is reduced by 10 per 24 hours. A method is provided comprising the steps of: administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles until the dose is less than 0 mg; and administering isatuximab at a dose of 10 mg / kg once every 28 days for one or more further 28-day cycles, after it has been determined that (a) the individual's serum M protein level has been reduced by at least 90% compared to the individual's serum M protein level at a first time point, and (b) the individual's urinary M protein level is less than 100 mg per 24 hours. In some embodiments, (a) a reduction in the individual's serum M protein level, and (b) an individual's urinary M protein level of less than 100 mg per 24 hours are maintained for at least one of approximately 6, 7, 8, 9, 10, 11, or 12 months prior to administration of isatuximab at a dose of 10 mg / kg on day 1 of each 28-day cycle.In some embodiments, a method for treating a human individual with multiple myeloma, comprising the steps of: measuring the individual's serum M protein level and / or urinary M protein level before administering an anti-CD38 antibody; administering the individual with the anti-CD38 antibody at a dose of 10 mg / kg per week for the first month cycle; and administering isatuximab until (a) the individual's serum M protein level is reduced by at least 90% compared to the serum M protein level before administration of the anti-CD38 antibody, and (b) the individual's urinary M protein level is less than 100 mg per 24 hours. A method is provided comprising the steps of: (a) administering a dose of 10 mg / kg every other week for one or more one-month cycles after the initial one-month cycle; and (b) administering an anti-CD38 antibody once monthly at a dose of 10 mg / kg for one or more further one-month cycles after it has been determined that (a) the individual's serum M protein level has been reduced by at least 90% compared to the individual's serum M protein level at a first time point, and (b) the individual's urinary M protein level has been determined to be less than 100 mg per 24 hours. In some embodiments, (a) the reduction in the individual's serum M protein level, and (b) the individual's urinary M protein level being less than 100 mg per 24 hours are maintained for at least one of approximately 6, 7, 8, 9, 10, 11, or 12 months prior to the administration of isatuximab once monthly at a dose of 10 mg / kg for one or more further one-month cycles.

[0014] In some embodiments, the individual's response to treatment is measured by assessing the individual's blood M-protein levels and / or urinary M-protein levels. In some embodiments, the individual's blood M-protein levels and / or urinary M-protein levels are assessed via immunofixation and / or electrophoresis. In some embodiments, the VGPR response is maintained for at least approximately 6 months prior to the administration of isatuximab, either once every 28 days in one or more 28-day cycles, or once every month. In some embodiments, the VGPR response is maintained for at least approximately 12 months prior to the administration of isatuximab, either once every 28 days in one or more 28-day cycles, or once every month. In some embodiments, isatuximab is administered at a dose of 10 mg / kg for at least 11 cycles, on days 1 and 15 of one or more 28-day cycles, or every other week of one or more one-month cycles, prior to isatuximab administration. In some embodiments, isatuximab is administered at a dose of 10 mg / kg for at least 23 cycles, on days 1 and 15 of one or more 28-day cycles, or every other week of one or more one-month cycles, prior to isatuximab administration. In some embodiments, the treatment extends progression-free survival (PFS) of the individual.

[0015] In some embodiments, the anti-CD38 antibody comprises a heavy chain variable domain (VH) comprising (a) 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 (VL) comprising CDR-L1 containing the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), CDR-L2 containing the amino acid sequence SASYRYI (SEQ ID NO: 5), and CDR-L3 containing the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 7, and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody is isatuximab. [Brief explanation of the drawing]

[0016] [Figure 1] This figure presents a schematic representation of an integrated drug-disease model that combines a kinetic-pharmacodynamic (K-PD) model for pomalidomide (Pom) and dexamethasone (Dex), a pharmacokinetic (PK) model for isatuximab, inhibition of tumor growth, and progression-free survival (PFS). [Figure 2-1]This figure shows individual fits for serum M protein time course and PFS probability in six exemplary patients: three with observational events and three with censoring events. Patients in the Isa-Pd arm are shown in the middle and left figures; patients in the Pd arm are shown in the right figure. Blue dots indicate observed serum M protein levels, and red dots indicate observed BLQ levels. Green curves show predicted values ​​over time using the joint model. Vertical lines indicate the patient's status (solid line: occurrence of progression event, dotted line: censoring). Red solid curves show the PFS probability predicted by the joint model. Black curves represent predicted values ​​for the current slope of the serum M protein reaction rate. BLQ: below limit of quantification; Isa: isatuximab; MP: M protein; Pd: pomalidomide and dexamethasone; PFS: progression-free survival. [Figure 2-2] Continuation of Figure 2-1. [Figure 3] This figure shows the visual predictive checks (VPCs) for the PFS and time-course portions of the final joint model. The shaded areas and dotted lines represent the 90% prediction intervals and predicted median for the 5th, 50th, and 95th percentiles of the simulated data (n=1000). The solid lines represent the 5th, 50th, and 95th percentiles of the observed time-course data or observed Kaplan-Meier estimates (the confidence interval for the 90th percentile is shown as a thin black dotted line). CI: Confidence interval; I: Isatuximab; KM: Kaplan-Meier; MP: M protein; Pd: Pomalidomide and dexamethasone; PFS: Progression-free survival; PI: Prediction interval. [Figure 4] This figure shows the effect of covariates on the reaction rate of serum M protein and the probability of progression-free survival (PFS); it is a figure for the whole serum M protein population (n=256). ALBN: Albumin; B2MG: β2-microglobulin; Ig: Immunoglobulin; PFS: Progression-free survival. [Figure 5A]This figure presents a model assessment of the best serum M protein / PFS joint model (ALBN: albumin; B2MG: β2-microglobulin; PFS: progression-free survival; IG: immunoglobulin; I: isatuximab; LOQ: limit of quantification; M-Prot: M protein; PCYTOMA: presence of plasmacytoma; Pd: pomalidomide / dexamethasone; PFS: progression-free survival; VPC: VPC (visual predictive checks)). Figure 5A shows a comparison of observed values ​​for serum M protein with individual predicted values. [Figure 5B] Figure 5B presents a model assessment for the best serum M protein / PFS joint model (ALBN: albumin; B2MG: β2-microglobulin; PFS: progression-free survival; IG: immunoglobulin; I: isatuximab; LOQ: limit of quantification; M-Prot: M protein; PCYTOMA: presence of plasmacytoma; Pd: pomalidomide / dexamethasone; PFS: progression-free survival; VPC: VPC (visual predictive checks)). Figure 5B shows a comparison of individual weighted residuals (IWRES) with individual predictions for time (days) or serum M protein (g / L). [Figure 5C] This figure presents a model assessment for the best serum M protein / PFS joint model (ALBN: albumin; B2MG: β2-microglobulin; PFS: progression-free survival; IG: immunoglobulin; I: isatuximab; LOQ: limit of quantification; M-Prot: M protein; PCYTOMA: presence of plasmacytoma; Pd: pomalidomide / dexamethasone; PFS: progression-free survival; VPC: VPC (visual predictive checks)). Figure 5C presents predictive-corrected (PC) VPCs for the time-course portion, stratified by arms. [Figure 5D]This figure presents a model assessment of the best serum M protein / PFS joint model (ALBN: albumin; B2MG: β2-microglobulin; PFS: progression-free survival; IG: immunoglobulin; I: isatuximab; LOQ: limit of quantification; M-Prot: M protein; PCYTOMA: presence of plasmacytoma; Pd: pomalidomide / dexamethasone; PFS: progression-free survival; VPC: VPC (visual predictive checks)). Figure 5D shows individual predicted PFS probabilities. Figure 5E shows Cox-Snell residuals. [Figure 5E] This figure presents a model assessment of the best serum M protein / PFS joint model (ALBN: albumin; B2MG: β2-microglobulin; PFS: progression-free survival; IG: immunoglobulin; I: isatuximab; LOQ: limit of quantification; M-Prot: M protein; PCYTOMA: presence of plasmacytoma; Pd: pomalidomide / dexamethasone; PFS: progression-free survival; VPC: VPC (visual predictive checks)). Figure 5E shows the Cox-Snell residual. [Figure 5F] This figure presents a model assessment of the best serum M protein / PFS joint model (ALBN: albumin; B2MG: β2-microglobulin; PFS: progression-free survival; IG: immunoglobulin; I: isatuximab; LOQ: limit of quantification; M-Prot: M protein; PCYTOMA: presence of plasmacytoma; Pd: pomalidomide / dexamethasone; PFS: progression-free survival; VPC: VPC (visual predictive checks)). Figure 5F shows deviation residuals stratified by covariates. [Figure 5G]This figure presents a model assessment for the best serum M protein / PFS joint model (ALBN: albumin; B2MG: β2-microglobulin; PFS: progression-free survival; IG: immunoglobulin; I: isatuximab; LOQ: limit of quantification; M-Prot: M protein; PCYTOMA: presence of plasmacytoma; Pd: pomalidomide / dexamethasone; PFS: progression-free survival; VPC: VPC (visual predictive checks)). Figure 5G shows the trend-removed predictive distribution (pd) for time to event (TTE) data, stratified by arms over time. [Figure 6] This figure shows the characteristics of patients (n=60) who did not experience an early progression risk with a new, hypothetical dosing regimen compared to a standard dosing regimen, in contrast to other patients (n=44). ALBN: Albumin; B2MG: Beta-2 microglobulin; BMPC: Bone marrow plasma cells; GFR: Glomerular filtration rate; W24: Week 24. [Figure 7] This figure shows the PPC (posterior predictive check) for PFS HR using a joint model. The green band represents the 95% prediction interval, the black bars represent the predicted median HR, and the red bars represent the observed HR. PFS stands for progression-free survival; HR stands for hazard ratio. [Modes for carrying out the invention]

[0017] definition As used herein and in the accompanying claims, the singular forms “a,” “an,” and “that” refer to multiple subjects, unless explicitly indicated otherwise. Thus, for example, a reference to “a molecule” may include, in some cases, combinations of two or more such molecules.

[0018] "Sustained response" refers to a sustained effect on preventing or delaying the progression of a disease (e.g., multiple myeloma), and / or improvement in one or more response criteria after discontinuation of treatment. For example, the response to treatment for multiple myeloma is measured according to the criteria in Kumar et al. (2016), "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma," Lancet Oncol., 17(8):e328~e346; and Durie et al. (2006), "International uniform response criteria for multiple myeloma," Leukemia, 20:1467~1473 (see also Table A below). In some embodiments, sustained response has a duration of at least the same duration as the duration of treatment, or at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times the length of the duration of treatment.

[0019] [Table 1-1] [Table 1-2]

[0020] The term "pharmaceutical preparation" refers to a preparation in which a biologically active ingredient is present in a form that enables its effectiveness, and which does not contain any further ingredients that would be unacceptably toxic to the subject to which the preparation is administered. Such preparations are sterile preparations. A "pharmaceutically acceptable" excipient (medium, additive) is an excipient that is administered in a reasonable form to the target mammal in order to deliver the effective dose of the active ingredient to be utilized.

[0021] As used herein, the term “treatment” refers to a clinical intervention designed to alter the natural course of the disease or cells being treated (e.g., cancer cells) in the course of clinicopathology. Desired treatment effects include a reduction in the rate of disease progression, improvement or mitigation of the disease state, and remission or improved prognosis. For example, an individual is “successfully treated” if one or more symptoms associated with cancer are suppressed or eliminated (including, but not limited to, a reduction in the proliferation (or destruction) of cancer cells, a decrease in symptoms resulting from the disease, an improvement in the quality of life of the patient with the disease, a reduction in the dosage of other medications required to treat the disease, and / or an extension of the individual’s survival).

[0022] As used herein, “delay in disease progression” means postponing, preventing, slowing, delaying, stabilizing, and / or postponing the onset of a disease (such as cancer). The length of this delay may vary depending on the disease history and / or the individual being treated. As will be apparent to those skilled in the art, sufficient or significant delay may effectively constitute prevention, in that the individual does not develop the disease. For example, the onset of metastasis in advanced cancer may be delayed.

[0023] "Effective dose" refers to the minimum amount required to produce a measurable improvement or prevention of a particular disorder. The effective dose as used herein may vary depending on factors such as the individual / patient's disease state, age, sex, and weight, as well as the antibody's ability to induce a desired response in the individual. The effective dose is also the amount of treatment in which any toxic or adverse effects are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired outcomes include the elimination or reduction of the risk of the disease, reduction of the severity of the disease, or delay of the onset of the disease, including the biochemical, histological, and / or behavioral symptoms of the disease, complications of the disease, and intermediate pathological phenotypes present at the onset of the disease. For therapeutic use, beneficial or desired outcomes include clinical outcomes such as the reduction of one or more symptoms arising from the disease, improvement of the quality of life of the patient with the disease, reduction of the dose of other medicines required to treat the disease, enhancement of the effect of another medicine, such as through targeting, delay of disease progression, and / or extension of survival. In the case of cancer or tumors, an effective dose of a drug may be effective in reducing the number of cancer cells; reducing tumor size; inhibiting the invasion of cancer cells into peripheral organs (i.e., some degree of slowing or cessation is desired); inhibiting tumor metastasis (i.e., some degree of slowing or cessation is desired); inhibiting tumor growth to some extent; and / or alleviating to some extent one or more of the symptoms associated with the disorder. An effective dose is administered in one or more doses. For the purposes of this invention, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve a prophylactic or therapeutic treatment. As understood in a clinical context, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Therefore, “effective dose” may also be considered in the context of administering one or more therapeutic agents, and if the desired result can or can be achieved in combination with one or more other agents, the single agent should be considered to be administered in an effective dose.

[0024] As used herein, “in combination with” refers to the administration of one treatment modality in addition to another treatment modality. Thus, “in combination with” refers to the administration of one treatment modality to an individual before, during, or after the administration of another treatment modality.

[0025] The “target” or “individual” for which treatment is intended refers to any animal classified as a mammal, including humans, livestock, farm animals, and zoo animals, sports animals, or pets, such as dogs, horses, cats, and cows. Preferably, the mammal is a human.

[0026] In this specification, the term “antibody” is used in its broadest sense and refers to, in particular, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit desired biological activity.

[0027] Human light chains are typically classified into kappa and lambda light chains, and human heavy chains are typically classified into mu, delta, gamma, alpha, or epsilon, defining antibody isotypes as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including but not limited to IgG1, IgG2, IgG3, and IgG4. IgM has several subclasses, including but not limited to IgM1 and IgM2. IgA is similarly subdivided into subclasses, including but not limited to IgA1 and IgA2. Within the full-length light chain and full-length heavy chain, the variable domain and constant domain are typically connected by a "J" region of about 12 or more amino acids, and the heavy chain also contains a "D" region of about 10 amino acids. For example, for all purposes, refer to "FUNDAMENTAL IMMUNOLOGY" (Paul, W., ed., Raven Press, 2nd edition, 1989), which is incorporated throughout by reference. The variable regions of each light / heavy chain pair typically form antigen-binding sites. The variable domains of antibodies typically exhibit the same general structure of a relatively conserved framework region (FR) connected by three hypervariable regions, also called complementarity-determining regions or CDRs. The CDRs derived from the two chains of each pair are typically aligned by a framework region that can enable binding to a specific epitope. From the amino terminus to the carboxyl terminus, both the light chain variable domain and the heavy chain variable domain typically contain domains in the order of FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0028] The term "CDR set" refers to a group of three CDRs that occur within a single variable region capable of binding to an antigen. The precise boundaries of these CDRs are defined differently, according to different systems. The system described by Kabat et al. in "SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST" (National Institutes of Health, Bethesda, Md. (1987 and (1991)) not only presents a clear residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining three CDRs. These CDRs are referred to as Kabat CDRs.

[0029] As used herein, the term “Fc” refers to a sequence of non-antigen-binding fragments, whether monomeric or polymeric, resulting from the digestion of antibodies or produced by other means, which may contain a hinge region. The original immunoglobulin source of natural Fc is preferably human and may be any of the immunoglobulins. Fc molecules are made from monomeric polypeptides linked to dimeric or polymeric forms by covalent (i.e., disulfide) and non-covalent associations. The number of intermolecular disulfide bonds between subunits of a natural Fc molecule ranges from one to four, 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-bonded dimer resulting from the papain digestion of IgG. As used herein, the term “natural Fc” is a general term encompassing monomeric, dimeric, and polymeric forms.

[0030] As used herein, the term “overall response rate” or “ORR” refers to the ratio of individuals / patients achieving stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR), as assessed by the IRC using the IMWG response criteria described in Kumar et al. (2016), “International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma,” Lancet Oncol., 17(8):e328~e346; and Durie et al. (2006), “International uniform response criteria for multiple myeloma,” Leukemia, 20:1467~1473. See also Table A herein.

[0031] Overview This specification presents methods for treating or delaying the progression of multiple myeloma in individuals who have received one, two, three, or more prior therapies for multiple myeloma. The methods include administering an effective dose of an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone to the individual. In some embodiments, the treatment extends the progression-free survival (PFS) and / or overall survival (OS) of the individual. In some embodiments, the treatment extends the progression-free survival (PFS) and / or overall survival (OS) of the individual compared to an untreated individual. In some embodiments, the treatment extends the progression-free survival (PFS) and / or overall survival (OS) of the individual compared to an individual treated with carfilzomib and dexamethasone, but without an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual is negative for minimal residual disease (MRD) after treatment (e.g., the threshold is 10 -4 Or less than that, 10 -5 Or less than this, or 10-6 or less than this).

[0032] Anti-CD38 antibody In some embodiments, the anti-CD38 antibody binds to human CD38. In some embodiments, the anti-CD38 antibody is a human antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the anti-CD38 antibody comprises (a) a heavy chain variable domain (V H ) comprising a CDR-H1 having the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 having the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 having the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (V L ) comprising a CDR-L1 having the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 having the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 having 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% identical (e.g., at least any one of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99% including any range between these values) to SEQ ID NO: 7. Additionally, or alternatively, in some embodiments, the anti-CD38 antibody comprises a light chain variable domain (V L ) having an amino acid sequence that is at least 90% identical (e.g., at least any one of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99% including any range between these values) to SEQ ID NO: 8 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody comprises a V H comprising SEQ ID NO: 7 and a V L comprising SEQ ID NO: 8 or SEQ ID NO: 9. QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS (Sequence ID 7) DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKR(Sequence ID 8) DIVMAQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKR (Sequence ID 9)

[0033] In some embodiments, the anti-CD38 antibody is isatuximab (CAS Registry No.: 1461640-62-9). Also known as hu38SB19 and SAR650984, isatuximab is an anti-CD38 antibody described in WO2008 / 047242 and U.S. Patent No. 8,153,765, the contents of which are incorporated herein by reference in their entirety.

[0034] The heavy chain of isatuximab has 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(Sequence ID 10) The light chain of isatuximab 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 (Sequence ID 11) Includes.

[0035] Anti-CD38 antibodies are produced using recombinant methods. To recombinantly produce anti-antigen antibodies, the nucleic acid encoding the antibody is isolated and inserted into a replication vector for further cloning (DNA amplification) or expression. The DNA encoding the antibody is readily isolated and sequenced using standard procedures (e.g., by using oligonucleotide probes capable of specifically binding to the genes encoding the heavy and light chains of the antibody). Many vectors are available. The components of a vector generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Host cells suitable for nucleic acid expression are typically transformed by the vector. In some embodiments, the host cell is a eukaryotic or prokaryotic cell. In some embodiments, the eukaryotic host cell is a mammalian cell. Examples of useful mammalian host cell lines include: SV40-transformed monkey kidney CV1 cell line (COS-7; ATCC:CRL1651); human fetal kidney cell line (293 cells or 293 cells subcloned for growth in suspension culture; Graham et al., J. Gen Virol., 36:59 (1977)); baby hamster kidney cells (BHK; ATCC:CCL10); mouse Sertoli cells (TM4; Mather, Biol. Reprod., 23:243~251 (1980)); monkey kidney cells (CV1; ATCC:CCL70); African green monkey kidney cells (VERO-76; ATCC:CRL-1587); human cervical cancer cells (HELA; ATCC:CCL2); canine kidney cells (MDCK; ATCC:CCL34); buffalo rat hepatocytes (BRL 3A;ATCC:CRL1442); human lung cells (W138;ATCC:CCL75); human hepatocytes (Hep G2, HB 8065); mouse mammary tumor cells (MMT 060562;ATCC:CCL51); TRI cells (Mather et al., Annals NYAcad.Sci., 383:44~68 (1982)); MRC 5 cells; FS4 cells; and human hepatoma cell lineage (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 (BKCLo ed., Humana Press, Totowa, NJ), pp. 255-268 (2003). Anti-CD38 antibodies prepared from cells are purified using, for example, hydroxyl apatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being one of the typically preferred purification steps. In general, a variety of methods for preparing antibodies for use in research, testing, and clinical applications are well established in the art, and are consistent with and / or appropriate to those skilled in the art.

[0036] Pharmaceutical compositions and formulations This specification also presents pharmaceutical compositions and formulations for the treatment of multiple myeloma (such as refractory multiple myeloma or relapsed and refractory multiple myeloma), comprising an anti-CD38 antibody (such as isatuximab), carfilzomib, or dexamethasone. In some embodiments, each of the anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone is provided as a separate pharmaceutical composition. In some embodiments, the pharmaceutical compositions and formulations further comprise a pharmaceutically acceptable carrier.

[0037] In some embodiments, the anti-CD38 antibody described herein (such as isatuximab) is present in a pH 6.0 formulation containing approximately 20 mg / mL (500 mg per 25 mL) of antibody, approximately 20 mM histidine, approximately 10% (w / v) sucrose, and approximately 0.02% (w / v) polysorbate 80. In some embodiments, the anti-CD38 antibody described herein (such as isatuximab) is present in a formulation containing approximately 20 mg / mL of antibody, approximately 100 mg / mL of sucrose, 2.22 mg / mL of histidine hydrochloride monohydrate, approximately 1.46 mg / mL of histidine, and approximately 0.2 mg / mL of polysorbate 80. In some embodiments, the formulation contains water for injection (WFI), such as sterile water for injection (SWFI). In some embodiments, the formulation is a sterile formulation. In some embodiments, a single-use formulation contains 5 ml of the formulation (i.e., 100 mg of anti-CD38 antibody). In some embodiments, the 5 ml single-use formulation is provided in a 16 mL clear glass vial fitted with, for example, an elastomer stopper. In some embodiments, the vial's filling capacity is established to ensure a 5 mL removal. In some embodiments, the filling capacity is 5.4 mL. In some embodiments, a single-use formulation contains 25 ml of the formulation (i.e., 500 mg of anti-CD38 antibody). In some embodiments, the 25 ml single-use formulation is provided in a 30 mL clear glass vial fitted with, for example, an elastomer stopper. In some embodiments, the vial's filling capacity is established to ensure a 25 mL removal. In some embodiments, the formulation is stable for at least about 6, 12, 18, 24, 30, or 36 months, including any range between those values, when protected from light at temperatures between about 2°C and about 8°C. In some embodiments, the formulation is diluted in 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, including any range between those values, at temperatures between about 2°C and about 8°C.In some embodiments, the injection diluent is stable for a further 8 hours (including the injection time) at room temperature following storage at approximately 2°C to approximately 8°C. In some embodiments, the injection diluent is stable in the presence of light. In some embodiments, the bag in which the injection diluent is stored is made of polyolefin (PO), polyethylene (PE), polypropylene (PP), or polyvinyl chloride (PVC) with di(ethylhexyl) phthalate (DEHP) or ethylene vinyl acetate (EVA). In some embodiments, the tube used for injection is made of PE, PVC (with or without DEHP), polybutyldiene (PBD), or polyurethane (PU) with a series filter (polyethersulfone (PES), polysulfone, or nylon).

[0038] Treatment method This specification describes a method for treating or delaying the progression of multiple myeloma in an individual (e.g., a human individual), comprising delivering an effective amount of anti-CD38 antibody (e.g., (a) 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) to the individual, comprising a heavy chain variable domain (V H ), and (b) a light chain variable domain (V) comprising CDR-L1 containing the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), CDR-L2 containing the amino acid sequence SASYRYI (SEQ ID NO: 5), and CDR-L3 containing the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L A method is presented which includes the step of administering an anti-CD38 antibody (containing ). In some embodiments, the anti-CD38 antibody is isatuximab.

[0039] In some embodiments, the method includes the steps of: administering isatuximab to an individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle; administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of the 28-day cycle for at least 11 cycles; and administering isatuximab at a dose of 10 mg / kg once every 28 days for one or more further 28-day cycles following at least 11 cycles. In some embodiments, the method includes the steps of: administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of the 28-day cycle for at least 23 cycles; and administering isatuximab at a dose of 10 mg / kg once every 28 days for one or more further 28-day cycles following at least 23 cycles. In some embodiments, the treatment extends the progression-free survival (PFS) of the individual.

[0040] In some embodiments, the method involves administering an anti-CD38 antibody (e.g., isatuximab) to an individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle (e.g., once weekly); administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of one or more subsequent 28-day cycles (e.g., once every two weeks); or administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of one or more subsequent 28-day cycles. The procedure includes the steps of measuring the individual's serum M-protein levels and urinary M-protein levels at one or more time points; and, if, at one or more time points, the individual's serum M-protein levels and urinary M-protein levels are detectable by immunofixation but not by electrophoresis, or thereafter, administering isatuximab at a dose of 10 mg / kg on day 1 of one or more further 28-day cycles (e.g., once every four weeks). Methods for measuring serum M-protein levels and urinary M-protein levels are well known in the art, and are described, for example, in Jenkins (2009), Clin Biochem Rev., 30(3):119~122; Leung, Nelson, "Chapter 8: Clinical Tests for Monoclonal Proteins," Onco-Nephrology Curriculum, American Society of Nephrology, 2016, pp. 1-5. In some embodiments, an individual's serum and urinary M protein levels are detectable by immunofixation but not by electrophoresis for at least one period of about 1, 2, 3, or 4 weeks after one or more time points, or for at least one period of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months.In some embodiments, isatuximab is administered once every 28 days in one or more 28-day cycles if, after one or more time points, an individual's serum M protein levels and urinary M protein levels are detectable by immunofixation but not by electrophoresis for at least one period of about 1, 2, 3, or 4 weeks, or for at least one period of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months, or thereafter. In some embodiments, the method includes the steps of: administering an anti-CD38 antibody (e.g., isatuximab) to an individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle (e.g., once weekly); administering an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles (e.g., once every two weeks) after the first 28-day cycle until the individual's serum M protein levels and urinary M protein levels are detectable by immunofixation but not by electrophoresis; and administering an anti-CD38 antibody (isatuximab) on day 1 of each 28-day cycle (e.g., once every four weeks) when it is determined that the individual's serum M protein levels and urinary M protein levels are detectable by immunofixation but not by electrophoresis, or thereafter. In some embodiments, an individual's serum M protein level and urinary M protein level are detectable by immunofixation but not by electrophoresis for at least one period of about 1, 2, 3, or 4 weeks, or for at least one period of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months.In some embodiments, isatuximab is administered once every 28 days in one or more 28-day cycles, or thereafter, when the individual's serum and urinary M protein levels are detectable by immunofixation but not by electrophoresis for at least one period of about 1, 2, 3, or 4 weeks, or for at least one period of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months. In some embodiments, isatuximab is administered at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles for at least 11 cycles, prior to the administration of isatuximab once every 28 days in one or more 28-day cycles. In some embodiments, isatuximab is administered at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles for at least 23 cycles, prior to the administration of isatuximab once every 28 days of one or more 28-day cycles. In some embodiments, the treatment extends progression-free survival (PFS) of the individual.

[0041] In some embodiments, the method involves measuring the individual's serum M protein at a first time point before administering an anti-CD38 antibody (e.g., isatuximab); administering isatuximab to the individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle (e.g., once weekly); administering the anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles after the first 28-day cycle (e.g., once every two weeks); measuring the individual's serum M protein at the first 28-day cycle The procedure includes the steps of: (a) measuring at a second time point in at least one or more 28-day cycles after the cycle; and administering an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg on day 1 of one or more further 28-day cycles (e.g., once every four weeks) if (a) the individual's serum M protein level at the second time point is reduced by at least 90% compared to the individual's serum M protein level at the first time point, and (b) the individual's urinary M protein level at the second time point is less than 100 mg per 24 hours. In some embodiments, the reduction in the individual's serum M protein level and the urinary M protein level of the individual, which is less than 100 mg per 24 hours, are maintained for at least one period of approximately 1, 2, 3, or 4 weeks, or for at least one period of approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months.In some embodiments, isatuximab is administered once every 28 days in one or more 28-day cycles, after a reduction in the individual's serum M protein level and an individual's urinary M protein level of less than 100 mg per 24 hours have been maintained for at least one period of about 1, 2, 3, or 4 weeks, or for at least one period of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months. In some embodiments, the method involves measuring the individual's serum M protein level before administration of an anti-CD38 antibody (e.g., isatuximab); administering the anti-CD38 antibody (e.g., isatuximab) to the individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle (e.g., once weekly); and, after the first 28-day cycle, (a) the individual's serum M protein level is reduced by at least 90% compared to the serum M protein level before administration of isatuximab, and (b) the individual's urinary M protein level at a second time point is less than 100 mg per 24 hours. The procedure includes the steps of: administering an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles (e.g., once every two weeks); and administering an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg on day 1 of each 28-day cycle (e.g., once every four weeks), after it has been determined that (a) the individual's serum M protein level has been reduced by at least 90% compared to the individual's serum M protein level at a first time point, and (b) the individual's urinary M protein level has been determined to be less than 100 mg per 24 hours.In some embodiments, the reduction in the individual's serum M protein level and the urinary M protein level of the individual, which is less than 100 mg per 24 hours, are maintained for at least one period of approximately 1, 2, 3, or 4 weeks, or for at least one period of approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months. In some embodiments, isatuximab is administered once every 28 days in one or more 28-day cycles if the individual's serum M protein level is reduced and the individual's urinary M protein level is maintained at less than 100 mg per 24 hours for at least one period of about 1, 2, 3, or 4 weeks, or for at least one period of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months, or thereafter. In some embodiments, isatuximab is administered at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles for at least 11 cycles, prior to the administration of isatuximab once every 28 days of one or more 28-day cycles. In some embodiments, isatuximab is administered at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles for at least 23 cycles, prior to the administration of isatuximab once every 28 days of one or more 28-day cycles. In some embodiments, the treatment extends progression-free survival (PFS) of the individual.

[0042] In some embodiments, the method includes the steps of: administering an anti-CD38 antibody (e.g., isatuximab) to an individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle (e.g., once weekly); administering the anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles (e.g., once every two weeks) until the individual achieves at least a VGPR ("very good partial response"), and if the individual achieves at least a VGPR, or thereafter, administering the anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg on day 1 of each 28-day cycle (e.g., once every four weeks). In some embodiments, the individual achieves at least a stable VGPR. In some embodiments, stable VGPR means VGPR maintained for at least one period of approximately 1, 2, 3, or 4 weeks, or for at least one period of approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months. In some embodiments, isatuximab is administered once every 28 days in one or more 28-day cycles if the VGPR response is maintained for at least one period of about 1, 2, 3, or 4 weeks, or for at least one period of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months, or thereafter.In some embodiments, the VGPR is evaluated according to the criteria in Kumar et al. (2016), “International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma,” Lancet Oncol., 17(8):e328-e346; and Durie et al. (2006), “International uniform response criteria for multiple myeloma,” Leukemia, 20:1467-1473, the contents of which are incorporated herein by reference in their entirety (see also Table A). In some embodiments, the method includes the steps of: administering isatuximab to an individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle; administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles until the individual achieves at least a very good partial response (VGPR); and, if the individual has achieved at least a VGPR response, or thereafter, administering isatuximab at a dose of 10 mg / kg once every 28 days for one or more further 28-day cycles. In some embodiments, the individual achieves at least a stable VGPR. In some embodiments, stable VGPR means VGPR maintained for at least one period of approximately 1, 2, 3, or 4 weeks, or for at least one period of approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months.In some embodiments, isatuximab is administered once every 28 days in one or more 28-day cycles if the VGPR response is maintained for at least one period of about 1, 2, 3, or 4 weeks, or for at least one period of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months, or thereafter. In some embodiments, the method includes the steps of: administering isatuximab to an individual at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle; administering isatuximab at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles after the first 28-day cycle; measuring the individual's response to treatment at one or more time points during one or more 28-day cycles after the first 28-day cycle and selecting individuals having at least a very good partial response (VGPR); and administering isatuximab to the selected individuals at a dose of 10 mg / kg once every 28 days for one or more further 28-day cycles. In some embodiments, the individuals achieve at least a stable VGPR. In some embodiments, stable VGPR means VGPR maintained for at least one period of approximately 1, 2, 3, or 4 weeks, or for at least one period of approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months.In some embodiments, isatuximab is administered once every 28 days in one or more 28-day cycles if the VGPR response is maintained for at least one period of about 1, 2, 3, or 4 weeks, or for at least one period of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 months, or thereafter. In some embodiments, isatuximab is administered at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles for at least 11 cycles, prior to the administration of isatuximab once every 28 days in one or more 28-day cycles. In some embodiments, isatuximab is administered at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles for at least 23 cycles, prior to the administration of isatuximab once every 28 days of one or more 28-day cycles. In some embodiments, the treatment extends progression-free survival (PFS) of the individual.

[0043] In some embodiments, multiple myeloma is smoldering multiple myeloma (SMM). In some embodiments, multiple myeloma is newly diagnosed multiple myeloma. In some embodiments, multiple myeloma is relapsed multiple myeloma and / or refractory multiple myeloma (RRMM). In some embodiments, the individual received one, two, or three prior therapies for multiple myeloma. In some embodiments, the individual received more than three prior therapies for multiple myeloma. In some embodiments, the individual received prior therapy with a proteasome inhibitor. In some embodiments, the individual received prior therapy with an immunomodulator.

[0044] In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered in combination with at least one further agent. In some embodiments, the at least one further agent includes an immunomodulator. In some embodiments, the immunomodulator is thalidomide, lenalidomide, or pomalidomide. In some embodiments, the at least one further agent includes a proteasome inhibitor. In some embodiments, the proteasome inhibitor is bortezomib, carfilzomib, marizomib, oprozomib, and ixazomib. In some embodiments, the at least one further agent includes a corticosteroid. In some embodiments, the corticosteroid is dexamethasone.

[0045] Product or kit In another embodiment of the present invention, a product or kit comprising an anti-CD38 antibody (such as isatuximab) is provided. In some embodiments, the product or kit further comprises at least one further agent (e.g., one or more further agents as described herein). In some embodiments, the product or kit further comprises a package insert containing instructions for using the anti-CD38 antibody (e.g., isatuximab) in accordance with the methods described herein for treating or delaying the progression of multiple myeloma (e.g., smoldering multiple myeloma, newly diagnosed multiple myeloma, refractory multiple myeloma, or relapsed / refractory multiple myeloma).

[0046] This specification is considered sufficient to enable those skilled in the art to carry out the invention. Those skilled in the art will see from the above description a variety of modifications to the invention, in addition to those shown and described herein, that fall within the scope of the accompanying claims. All publications, patents, and patent applications referenced herein are incorporated in their entirety by reference for all purposes. [Examples]

[0047] This disclosure will be better understood by referring to the following examples. However, these examples should not be considered as limiting the scope of the invention. The examples and embodiments described herein are for illustrative purposes only, as suggested to those skilled in the art, and various modifications or variations should be understood in light of them, and should be included in the spirit and scope of this application and the accompanying claims.

[0048] Example 1 A model-based approach for evaluating monthly isatuximab administration regimens in patients with relapsed / refractory multiple myeloma. background Isatuximab (Isa) is a CD38 monoclonal antibody with multiple mechanisms of action to kill tumor cells through direct tumor targeting and immune cell engagement (Moreno et al. (2019), Clin Cancer Res., 25(10):3176~3187). The addition of Isa to pomalidomide (P) and dexamethasone (d) was associated with a significant and clinically meaningful benefit of progression-free survival (PFS) in patients with relapsed / refractory multiple myeloma (RRMM) who had received multiple prior treatments (Attal et al. (2019), Lancet, 394(10214):2096~2107). Isa in combination with Pd is approved in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult patients with RRMM who have received at least two prior therapies, including lenalidomide and proteasome inhibitors.

[0049] the purpose The objective of this embodiment was to characterize the relationship between serum M protein response rate and PFS in RRMM patients using data from the Phase 3 clinical trial of isatuximab in combination with pomalidomide and dexamethasone ("Isa-Pd trial") discussed above, and to simulate serum M protein and PFS over time to evaluate when to switch isatuximab treatment from Q2W administration to monthly administration in order to preserve the clinical benefit, for example, measured by the length of progression-free survival.

[0050] method Using data from 256 assessable patients from the Isa-Pd trial, we developed a joint model for serum M protein dynamics and PFS. Patients received Isa intravenously at 10 mg / kg once weekly (QW) for 4 weeks, followed by Isa in combination with standard Pd (Isa-Pd) every other week (Q2W) for a 28-day cycle, or Pd alone in the control arm. The tumor growth suppression model was used to describe the response rate of serum M protein under the effects of Isa-Pd or Pd monotherapy, where exposure to Isa was predicted, using individual PK parameters obtained from PK analysis of the population (Fau et al., "Pharmacokinetic time-dependency and covariates modelling of Isatuximab monoclonal antibody in multiple myeloma patients: analysis from pooled phase I / II & phase III studies," Population Approach Group in Europe 2019 Meeting, Stockholm, Sweden, June 11-14, 2019, "Abstract," 8956). Exposure to Pd was predicted from the K-PD model using administration history. Subsequently, after switching to a monthly dosing regimen, a simulation of the trial was performed using individual patient PK / PD parameters derived from the Isa-Pd trial to assess whether efficacy was maintained.

[0051] result The joint model identified the instantaneous change (slope) of serum M protein as the best treatment-based predictor of PFS, and also identified baseline patient characteristics that influence serum M protein response rate (serum albumin and serum β2 microglobulin affecting baseline serum M protein levels, serum M protein proliferation rate, and non-IgG MM affecting serum M protein slope), as well as baseline patient characteristics that influence PFS (presence of plasmacytoma). The fact that non-IgG MM patients showed similar behavior in serum M protein response rate and similar progression-free survival over the first 60 weeks compared to IgG MM patients, even with high levels of exposure, supports non-dose adjustments based on IgG status. Clinical trial simulations of the regimen used in the Phase 3 Isa-Pd trial confirmed that switching all patients to the monthly Isa regimen at 6 months would shorten the median progression-free survival (TTP) by 4.1 weeks (i.e., increasing serum M-protein by more than 25% compared to the lowest value, and increasing the absolute amount by more than 5 g / L) and shorten the median progression-free survival (PFS) by 2.3 weeks (from 14.03 months to 13.45 months). Based on TTP criteria, patients at no risk of early progression (57.7%) showed reduced baseline tumor volume (decreased serum M-protein and decreased myeloid plasma cell percentage) and improved prognostic factors (increased glomerular filtration rate, increased albumin, and decreased β2-microglobulin) after the switch at 6 months. At 6 months, 85% of these patients had the predicted, stable, "at least" VGPR status.

[0052] conclusion The trial simulations supported the selection of the approved 10 mg / kg, QW / Q2W isatuximab regimen and showed that switching to the monthly isa regimen after 6 months may reduce clinical benefit in the general population. However, a subgroup of patients with a favorable prognosis who achieve stable, or at least VGPR, status by 6 months may be able to switch to the monthly regimen after 6 months without increasing the risk of disease progression. Model-based drug development has successfully supported treatment decisions in RRMM patients.

[0053] Example 2 Joint modeling and simulation of M protein dynamics and progression-free survival with alternative isatuximab administration in conjunction with pomalidomide / dexamethasone. a) Introduction Despite significant progress and extended overall survival (OS), multiple myeloma (MM) remains incurable, with the majority of patients experiencing relapses and requiring further treatment.[1] Isatuximab is an immunoglobulin G1 (IgG1) monoclonal antibody that targets CD38, a transmembrane glycoprotein in MM. Isatuximab kills tumor cells through multiple biological mechanisms, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct induction of apoptosis without crosslinking, and inhibition of CD38 enzyme activity. In a phase 1b study of patients with relapsed / refractory malformations (RRMM), isatuximab (Isa) administration (d, Isa-Pd) at 10 mg / kg once or twice weekly (QW-Q2W) in combination with pomalidomide (P) and low-dose dexamethasone achieved an overall response rate (ORR) of 64.5% and a median progression-free survival (PFS) of 17.6 months. Combined with disease modeling of exposure-response relationships and tumor burden (serum M protein), these results justified the use of Isa-Pd at 10 mg / kg, QW-Q2W [2, 3]. Subsequently, this combination was evaluated in the phase 3 ICARIA-MM study, which showed that the addition of isatuximab to Pd significantly improved PFS in RRMM patients [4]. Based on this pivotal study, isatuximab in combination with pediatric dextrinsic malformation (Pd) has been approved in several countries for patients with relapsed MM who have received two or more prior treatment options, including lenalidomide and proteasome inhibitors. Currently, isatuximab in combination with carfilzomib / dexamethasone is approved in the United States for patients with relapsed MM who have received one to three prior treatment options, based on the Phase 3 IKEMA study, and in the European Union for patients with MM who have received one or more prior treatments [5-7].

[0054] Tumor growth suppression (TGI) models have been developed to predict overall survival (OS) or progression-free survival (PFS) rates, which are clinical responses in cancer patients from diverse clinical contexts [8, 9]. TGI models are used to identify early changes in tumor size that predict OS or PFS. Joint models have emerged as a promising framework for synchronically exploring relationships between successive disease progressions through biomarkers, tumor size, and temporal outcomes such as the incidence of clinical events, including progression and death. These models provide accurate and unbiased estimates of parameters in the context of informed censorship

[10] . Mechanistic joint models have predicted OS in clinical trials of atezolizumab in urothelial carcinoma, cabazitaxel in metastatic prostate cancer, and aflibercept in metastatic colorectal cancer [11-13].

[0055] In most patients, MM is characterized by the secretion of monoclonal Ig protein (M protein), called paraprotein, produced by abnormal plasma cells. Serum M protein levels, as with tumor volume in solid tumors, are part of the response criteria for MM patients

[14] , and therefore their dynamic changes can predict long-term clinical benefit (PFS, OS). Several cases in MM have shown that modeling of TGI based on M protein levels over time can be used to predict OS or PFS [15-18].

[0056] For isatuximab, the joint modeling framework was used to incorporate early drug development outcomes along with end-stage clinical data from Phase 1 / 2 monotherapy studies and Phase 1 combination studies [2, 3, 19]. Disease progression was initially captured using the joint model, taking dropouts into account, in conjunction with serum M protein kinetics. Modeling of serum M protein over time provided deeper, time-course insights into patient responses and supported the selection of dosing regimens in Phase 2 and Phase 3 in MM patients. This framework and modeling methodology can be expanded to explain PFS and thereby improve model-predicted and simulated values ​​in exploring the benefits of different dosing strategies.

[0057] Therefore, the objectives of this work were to (i) quantitatively assess the relationship between serum M protein response rate, baseline covariates, and PFS in RRMM patients in both the Isa-Pd arm and Pd arm of the ICARIA-MM study, and (ii) simulate time-course serum M protein and PFS when switched to a hypothetical monthly isatuximab regimen after 6 months.

[0058] b) Materials and methods Research design and data Data were obtained from the Phase 3 ICARIA-MM study. Isatuximab was administered intravenously at 10 mg / kg QW for 4 weeks, followed by standard pomalidomide (4 mg orally on days 1–21 of each cycle) and dexamethasone (40 or 20 mg orally or intravenously on days 1, 8, 15, and 22 of each cycle for patients aged 75 years and older) every other week for 28-day cycles. The study was conducted in accordance with the principles of the Declaration of Helsinki and the ICH GCP guidelines. The protocol was approved by the institutional review board and independent ethics committees at participating institutions. All patients submitted informed consent. The primary endpoint of the study was progression-free survival (PFS). Response and disease progression were determined by an independent response review board using the International Myeloma Working Group (IMWG) criteria, based on central laboratory assessment of M protein and radiographic differentiation

[14] . Patients with two or more serum M-protein levels, including one baseline value, whose response was assessed by serum M-protein levels, were included in the analysis. Serum M-protein levels were assessed by immunocapture and a hybrid assay using high-resolution mass spectrometry coupled liquid chromatography. Serum M-protein levels were measured at baseline, at the end of each cycle, and at the end of the study, according to the protocol.

[0059] Model Development First, serum M-protein time-course data and PFS data, derived from both research arms, were modeled separately. Exposure to treatment over time was incorporated into a time-course model for isatuximab using concentrations predicted by individual PK parameters, and into kinetic-pharmacodynamic (K-PD) models for pomalidomide and dexamethasone. Several joint models were then used to find the best link between serum M-protein kinetics and PFS.

[0060] Population PK model for isatuximab A two-compartment PK model with linear and nonlinear (Michaelis-Menten) parallel disappearances from the central compartment, and a time-varying linear clearance function, were used to describe plasma concentration-vs-time data for isatuximab collected from four phase 1–3 clinical trials, including ICARIA-MM

[20] . The equation for this structural PK model is presented in Example 2A. Individual PK parameters for ICARIA-MM patients were obtained as ex post facto estimates, and typical PK parameters were assigned to patients for whom PK data was unavailable.

[0061] K-PD models for pomalidomide and dexamethasone In this study, the concentrations of combined Pd were not measured, so the reaction rates for these drugs were simplified using the K-PD modeling method

[21] . Therefore, these PKs were described by a simple, hypothetical one-compartment method with a constant elimination rate constant derived from bolus administration, their central volume of distribution, and estimates of clearance values ​​in the literature [22, 23].

[0062] TGI model and covariate selection for M protein data A TGI model describing the dynamics of tumor growth, the effects of antitumor drugs, and resistance to drug effects was developed by Claret et al.

[24] . This model has also been successfully applied in the literature to describe serum M protein data as a surrogate of tumor growth in MM patients [15, 16, 18, 25, 26]. In this analysis, a mechanism-based model derived from Claret's TGI model was proposed to describe the drug effects on the time course of serum M protein, driven by underlying disease progression and exposure to isatuximab and Pd. The structural model for this TGI model, shown in Figure 1, is given by the following differential equation:

number

[27] comparing pomalidomide alone or pomalidomide in combination with dexamethasone.

[0063] An inter-individual exponential model, implying a log-normal distribution, was incorporated into all parameters. The variance-covariance matrix was modeled using a diagonal matrix. The variability of residuals was modeled using a combination of additive and proportional models.

[0064] After obtaining the base model, covariate analysis was performed. Twenty-six baseline covariates were examined: demographics, baseline laboratory measurements, and disease-related patient characteristics. See Table B below. In cases of data loss, the median was entered for continuous covariates; for categorical covariates, the loss was considered a further category. Using individual parameter estimates, parameter-covariate relationships were first explored graphically. Next, the COSSAC (Conditional Sampling for Stepwise Approach based on Correlation test) covariate selection algorithm was used for automated construction of the covariate model [28, 29]. The best covariate model was selected using the corrected Bayesian Information Criterion (BICc)

[30] . In addition, only significant covariates with a Wald test p-value <0.05 were retained in the final model.

[0065] [Table 2-1] [Table 2-2]

[0066] PFS model and covariate selection A parametric proportional hazards model is used, along with a log-logistic distribution for baseline hazard values, to model PFS:

number

[0067] Joint modeling of serum M protein and PFS Time-course models and PFS models were constructed separately; then, several joint models were used to find the best link between serum M protein reaction rate and PFS (including no link, current serum M protein, slope of current M protein, and AUC). Significant covariates found in the time-course and PFS submodels were assessed, and only significant covariates were retained in the joint models by Wald's test.

[0068] Parameter Estimation Parameter estimation for all models was performed using the SAEM (Stochastic Approximation Expectation Maximization) algorithm implemented in the Monolix v.2019R1 software. For serum M protein, data below the limit of quantification (LOQ) were examined using the extended SAEM algorithm implemented in Monolix.

[0069] Model selection and assessment Model selection was based on BIC, and the model yielding the smallest BIC was retained. Model assessment was performed by exploring both residual-based and simulation-based diagnostic methods, including individual weighted residuals (IWRES), visual predictive checks (VPCs) for the time-series portion, Cox-Snell residuals and deviant residuals

[31] , trend-removed predictive distributions (pd)

[32] , and Kaplan-Meier VPCs for PFS. Further goodness-of-fit plots were evaluated by visually inspecting individual fits or by comparing observed values ​​against individual predictive values. Time-series VPCs using the method described by Friberg et al.

[33] described the risk of progression. Briefly, time-series VPCs involved the reproduction of event mechanisms in simulations and the omission of simulations performed after the simulated progression time. PFS VPCs examined the design for each patient, i.e., dose regimen and follow-up period. In fact, the simulated time to progression (TTP) was censored during the follow-up period, at the end of treatment, and at the maximum observed TTP time.

[0070] Simulation of a monthly administration regimen To assess the time course of serum M protein and PFS after switching to a hypothetical monthly isatuximab dosing regimen at 6 months, 1,000 trials over 80 weeks were simulated, including both the Isa-Pd arm and the Pd arm. Patients received isatuximab at 10 mg / kg QW for 4 weeks, then at Q2W for 20 weeks, and then monthly in the Isa-Pd arm. The standard Pd combination regimen was the same as that used in ICARIA-MM. At 6 months, patients at risk were assessed for the impact on TTP (a serum M protein increase of more than 25% compared to the lowest value, with an absolute change of 5 g / L or more) and PFS. The original ICARIA-MM Isa-Pd arm, which included patients receiving isatuximab at 10 mg / kg QW-Q2W, was also simulated, and the results are presented as the median difference (5th to 95th percentile) from the original arm. Hazard ratios (HRs) for the two regimens were also compared against the control arm.

[0071] c) Result Data used for model building This analysis examined 256 patients (128 patients per arm) with assessable serum M-protein levels from the 307 randomized patients in the ICARIA-MM trial. Within this serum M-protein population (N=256), the median PFS measured by Isa-Pd was significantly longer compared to Pd alone (11.4 months [95% CI: 8.5–13.8] vs. 6.96 months [95% CI: 4.4–8.5]; HR: 0.618, 95% CI: 0.44–0.87; p=0.0048). Similar observations for PFS and HR were obtained in the general population (N=307), although 16.6% of ICARIA-MM patients could not be included in this analysis.

[0072] Baseline patient characteristics were balanced across arms. See Table C. The median age was 67 years (50%: female). Median serum β2-microglobulin and serum albumin levels at baseline were 3.5 mg / L and 0.67 g / L, respectively. High-risk cytogenetic factors were present in 53 patients (21%), and the median estimated glomerular filtration rate (e-GFR) was 70 mL / min. The majority of patients had IgG-type MM (190 patients [74%]) and did not have plasmacytoma (232 patients [91%]). 64 patients (25%) and 164 patients (64%) presented with stage I or II according to the Revised International Staging System (R-ISS), respectively, at diagnosis. Median serum M protein levels at baseline were 23 g / L, and at treatment, they ranged widely (5–95 g / L), along with diverse profiles. In a study of 256 assessable patients, a total of 2637 serum M-protein measurements were examined. The median number of assessments per patient was 14 (range: 2-22). Data below the LOQ accounted for 14% (22% within the Isa-Pd arm; 6% within the Pd arm).

[0073] [Table 3]

[0074] Modeling of serum M protein reaction rates and PFS The proposed TGI model provided a good fit for the time-course serum M protein data in all study arms. The TGI model performed better than the Wang model

[34] . In addition, the fit improved when isatuximab PK was added compared to the K-PD model alone. Twenty-six potential covariates were assessed by examining their relationship to all time-course model parameters. The final time-course model included three covariates: the effect of baseline serum albumin and β2-microglobulin on baseline serum M protein levels, as well as the effect of non-IgG MM on KL and serum M protein proliferation rate. Patients with low baseline albumin levels and high β2-microglobulin levels were more likely to have high baseline serum M protein levels. It is noteworthy that these laboratory tests are part of the ISS and R-ISS and are relevant to prognosis. Patients with non-IgG MM tended to have more rapid tumor regrowth (i.e., more rapid rise in serum protein levels) compared with patients with IgG MM.

[0075] Regarding PFS, the log-logistic model best characterized the underlying baseline hazard distribution. Baseline covariates, such as the presence of plasmacytoma, serum albumin, and serum M protein, were significant (p<0.005). Patients with high baseline serum M protein, low baseline albumin, and the presence of plasmacytoma had lower median PFS. Further information on time-series data and PFS modeling results is included in Tables B and D.

[0076] [Table 4]

[0077] [Table 5]

[0078] Joint modeling of serum M protein and PFS The performance of the joint model using the slope of serum M protein outperformed all other models relying on serum M protein in terms of Bayesian Information Criterion (BIC), with a 196-point decrease compared to the unlinked model, i.e., the parametric log-logistic model without a correlation between serum M protein and PFS. Alternative models based on current serum M protein levels or cumulative serum M protein (area under the curve for serum M protein) resulted in a BIC improvement of less than 103. A comparison of the joint model with different link functions is presented in Table F. In the best final joint model, the time-course model still includes the same three covariates; only the presence of plasmacytoma remains in the PFS portion. The parameter estimates obtained with the joint model using the slope of serum M protein are summarized in Table G. These parameter estimates were reasonably well estimated, with small relative standard errors for both fixed effects and variance components.

[0079] [Table 6]

[0080] [Table 7]

[0081] The estimated link value between serum M-protein slope and PFS was a high 11.9, consistent with the IMWG criteria, which indicate that a decrease in serum M-protein in response to treatment is a major component directly influencing PFS. Therefore, in the case of an early response, a decrease in serum M-protein is associated with a current slope lower than 0, thus reducing the risk of progression. The relationship between serum M-protein response rate, slope, and PFS is illustrated in Figure 2 for six representative patients who exhibited or did not exhibit a PFS event. The probability of PFS increased during tumor growth, i.e., when the serum M-protein slope increased. Furthermore, baseline covariates were found to modify parameters related to serum M-protein response rate and PFS.

[0082] Model appraisal The model successfully captured diverse serum M-protein reaction rate patterns, and the predicted PFS probability corresponded to the timing of progression or censorship events. Figure 3 shows VPC plots generated for both the time-course and PFS models by simulating 1000 clinical trials using the same design and patient characteristics as the data under the final joint model. The model reasonably and well described the observed serum M-protein data and PFS data, and the observed medians were generally within the 90% prediction interval. However, the model did not capture a small group of patients who switched treatments without achieving the PFS criteria, resulting in the observation of early abnormal events. The final joint model also well predicted the observed HRs between arms (Figure 4), and the observed HRs were close to the predicted median HRs. Further goodness-of-fit plots are presented in Figures 5A–5G.

[0083] Evaluation of covariate effects Simulations were performed to quantify the effect of each covariate using population parameters and visualized in typical patients (Figure 6). Covariate effects were evaluated individually by setting other covariates to their median values ​​for continuous covariates, and categorical covariates (i.e., IgG type MM) to their median values ​​for their highest frequency class. The effects of the continuous covariates, baseline serum albumin and serum β2-microglobulin, were examined for variability within the 5th to 95th percentiles of the database.

[0084] Non-IgG MM patients, even with high levels of isatuximab exposure, exhibited similar behavior in serum M protein response rates to IgG MM patients during the first 60 weeks, and subsequently tended to experience more rapid tumor regrowth (i.e., a re-elevation of serum M protein). Similar progression-free survival (PFS) probabilities are predicted for non-IgG MM patients compared to IgG MM patients.

[0085] Patients with low baseline albumin levels and high β2-microglobulin levels were more likely to have elevated baseline serum M-protein levels. However, the impact on the shape of the M-protein profile was slightly more rapid tumor regrowth compared to other patients, and this decreased slightly at the end of treatment. Patients with plasmacytoma shared similar PFS profiles over 20 weeks, but tended to have a lower PFS probability of up to 25% at 80 weeks.

[0086] Simulation of a monthly administration regimen In 1000 simulated trials, the median (minimum to maximum) number of patients at risk at 6 months (i.e., patients who did not progress by 6 months) was 97 (86 to 107) in the Isa-Pd arm. In patients at risk at 6 months who were switched to a monthly isatuximab regimen after a 6-month QW-Q2W period, median progression (5th to 95th percentile) was predicted to occur 2.29 (0.57 to 4.73) weeks earlier compared to the original Isa-Pd arm, and the HR was predicted to increase (0.7 vs. 0.66). In addition, when examining the TTP criterion (i.e., a greater than 25% increase in serum M protein, with an absolute increase greater than 5 g / L), 44 out of 104 patients (42.3%) in the original Isa-Pd arm who did not progress at 6 months had a more rapid re-increase in their serum M protein. Assessment of baseline patient characteristics showed that patients affected by these factors had a greater disease burden at baseline, i.e., higher serum M protein levels, higher myeloid plasma cell (BMPC) levels, longer time between diagnosis and first administration, lower eGFR levels, lower serum albumin levels, and higher serum β2-microglobulin levels, indicating a worsening prognosis and a higher frequency of stage II / III disease according to R-ISS (80% vs. 53.2%) (Figure 7). Conversely, patients without a risk of early progression tended to have smaller tumor loads (low serum M protein levels and low BMPC levels) and a favorable prognosis at baseline (high eGFR and albumin levels, low β2-microglobulin levels, and a higher frequency of stage I disease according to R-ISS). In addition, at 6 months, patients without a risk of early progression had significantly lower M protein levels (median 0.31 vs. 3.04 g / L), a more stable response, and a serum M protein slope close to zero (i.e., M protein levels reached a plateau; median: -0.01 vs. -0.06 g / L per day), with 85% of these having a predicted response state, or at least a very good partial response (VGPR).

[0087] d) Discussion Since a joint model can provide efficient estimates and reduced bias for treatment effects for both time-to-event and time-series markers, we developed a nonlinear joint model under MM conditions. First, we developed a TGI model using time-series serum M-protein data, and then a PFS model. Next, we performed joint modeling to explore the best link between time-series serum M-protein and PFS. The model was constructed based on 256 out of 307 patients with ICARIA-MM in whom serum M-protein data was used to assess treatment response.

[0088] Using time-course serum M-protein data from ICARIA-MM, the inventors developed a TGI model from Claret et al. and compared it to the Wang et al. model [24, 34] used for elotuzumab + lenalidomide / dexamethasone (ELOQUENT-2) data. The inventors selected the Claret et al. model, which yielded a good fit and included pomalidomide / dexamethasone combination administration and PK exposure to isatuximab as predictors. This allowed the inventors to use this model to simulate serum M-protein responses under other administration regimens. This model describes three key clinical features of tumor progression in anticancer drug treatment, including the dynamics of tumor growth / serum M-protein production, the effect of antitumor drugs, and resistance to the effect of the drugs.

[0089] Furthermore, the inventors studied the effects of numerous covariates on the response rate and risk of progression of serum M protein at baseline. In the joint model, significant baseline covariates were MM type I, albumin, β2-microglobulin, and the presence of plasmacytoma. Patients with low baseline albumin levels and high baseline β2-microglobulin levels were more likely to have high baseline serum M protein levels. It is noteworthy that these laboratory tests are part of the ISS and R-ISS staging system relevant to prognosis, as patients with advanced disease stages (i.e., stage III according to ISS) are less likely to respond to treatment. The high probability that the presence of plasmacytoma induced a reduced probability of PFS is consistent with the results of exposure-response analysis [3]. In addition, the association of a transient slope of serum M protein with PFS is consistent with the IMWG criteria, which state that a decrease in serum M protein in response to treatment is a major component that directly impacts PFS.

[0090] Simulations of typical patients indicated that non-IgG type MM patients, even with high steady-state isatuximab exposure, exhibited similar behavior in serum M protein response rates over the first 60 weeks compared to IgG type MM patients, and subsequently tended to have more rapid tumor regrowth and similar PFS. The IgG type of MM was also identified as a major contributing factor explaining the inter-individual variability in PK for isatuximab, and the variability in clearance being more rapid in IgG type MM patients. Elevated levels of IgG type M protein may result in increased clearance of IgG-based monoclonal antibodies as a result of competition for the neonatal Fc receptor, which protects IgG from degradation [35-37]. This results in half the exposure in steady state in IgG type MM compared to non-IgG type MM patients.

[0091] However, in exposure-response analysis, the Ig type of MM is a predictor of ORR, but after 4 weeks, Ctrough When this was included in the model, it was no longer significant. In addition, in the univariate analysis for efficacy, MM Ig type was not a significant covariate. Finally, subgroup analysis showed that, compared to non-IgG patients, the treatment effect of the Isa-Pd regimen on PFS or ORR in IgG patients was not significantly superior to that of the Pd regimen, but an improvement in response rate was observed with Isa-Pd compared to Pd in ​​both IgG and non-IgG patients

[38] . Linear clearance was approximately 110% higher in IgG patients than in non-IgG patients, resulting in a 70% higher predicted trough serum concentration in non-IgG patients on day 1 of cycle 3, and similar results were observed for daratumumab

[39] . Despite the differences in clearance levels between IgG and non-IgG patients, the response rates were similar in these populations. The similarity in ORR is consistent with our findings that non-IgG MM affects the proliferation rate of serum M protein, exhibiting similar behavior in serum M protein dynamics over the first 60 weeks, followed by more rapid regrowth. Therefore, the effect of Ig type MM (IgG vs. non-IgG) on isatuximab exposure is not considered clinically significant.

[0092] The drug-disease modeling platform established based on ICARIA-MM data was further applied to predict the impact of using a hypothetical monthly dosing regimen 6 months after isatuximab QW-Q2W in RRMM patients. In patients still under treatment, simulations of the hypothetical switch to monthly dosing at 6 months predicted that progression would occur 2.3 weeks earlier compared to the original Isa-Pd arm, and that 42.3% of patients would experience more rapid regrowth of their serum M protein. Although the number of patients was limited, those affected and experiencing accelerated progression were thought to have a greater disease burden and worsening prognosis at baseline. Patients not at risk of early progression had a smaller tumor burden and a better prognosis at baseline, and tended to have a stable, or at least very good partial response (VGPR), at 6 months.

[0093] These results confirm the isatuximab QW-Q2W dosing regimen, which is selected and approved for ICARIA-MM.

[0094] e) Summary and conclusions Objective: The addition of isatuximab to pomalidomide / dexamethasone (Pd) significantly improved progression-free survival (PFS) in patients with relapsed / refractory multiple myeloma (RRMM). The inventors aimed to characterize the relationship between serum M protein response rates and PFS in the Phase 3 ICARIA-MM trial and to assess alternative isatuximab dosing regimens through simulation.

[0095] Methods: Data from the ICARIA-MM trial were used to compare isatuximab in combination with pallidum (Pd) at a dose of 10 mg / kg once weekly for 4 weeks, followed by isatuximab every other week (QW-Q2W), compared to Pd alone, in 256 assessable RRMM patients. A joint model was developed for serum M protein kinetics and PFS. Subsequently, a simulation of the trial was performed to assess whether efficacy was maintained after switching to a monthly dosing regimen.

[0096] Results: The model identified the instantaneous change (slope) in serum M protein as the best treatment-based predictor of PFS, as well as baseline patient characteristics that affect the response rate of serum M protein (albumin and β2-microglobulin affecting baseline levels; non-IgG type MM affecting proliferation rate), and baseline patient characteristics that affect PFS (presence of plasmacytoma). Simulations of the trial confirmed that switching to monthly isatuximab prednisolone at 6 months shortened the median PFS by 2.3 weeks and induced early progression in 42.3% of patients.

[0097] Conclusion: The trial simulations supported the selection of the approved 10 mg / kg, QW-Q2W isatuxima regimen and showed that switching to a monthly regimen after 6 months may reduce clinical benefit in the general population. However, patients with favorable prognosis and stable VGPR (very good partial response) can switch to a monthly regimen after 6 months without increasing the risk of disease progression.

[0098] (f) References for Examples 2 and 2A 1. Kumar SK, Rajkumar V, Kyle RA, et al. Multiple myeloma. Nat Rev Dis Primer. 2017;3: 17046. 2. Thai H-T, Liu L, Koiwai K, et al. Exposure-response analysis and disease modeling for selection of optimal dosing regimen of isatuximab as single agent in patients with multiple myeloma. European Hematology Association Annual Meeting 2019: Abstract PF645. 3. Rachedi F, Koiwai K, Gaudel-Dedieu N, et al. Exposure-response analyses and disease modeling for selection and confirmation of optimal dosing regimen of isatuximab in combination treatment in patients with multiple myeloma. Blood. 2019;134(Supplement_1):1897-1897. 4. Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. The Lancet. 2019;394(10214):2096-2107. 5. Moreau P, Dimopoulos M-A, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. The Lancet2021:397(10292):2361-2371. 6. SARCLISA(R) (isatuximab-irfc) injection, for intravenous use. Prescribing Information. March 2021. https: / / products.sanofi.us / Sarclisa / sarclisa.pdf. Accessed June 16, 2021. 7. European Medicines Agency. Sarclisa, INN-Ixatuximab. Summary of product characteristics. 2021. https: / / www.ema.europa.eu / en / documents / product-information / sarclisa-epar-product-information_en.pdf. Accessed June 16, 2021. 8. Ribba B, Holford N, Magni P, et al. A review of mixed-effects models of tumor growth and effects of anticancer drug treatment used in population analysis. CPT Pharmacomet Syst Pharmacol. 2014;3(5):113. 9. Bruno R, Bottino D, de Alwis DP, et al. Progress and opportunities to advance clinical cancer therapeutics using tumor dynamic models. Clin Cancer Res. 2020;26(8):1787-1795. 10. Desmee S, Mentre F, Veyrat-Follet C, Guedj J. Nonlinear mixed-effect models for prostate-specific antigen kinetics and link with survival in the context of metastatic prostate cancer: a comparison by simulation of two-stage and joint approaches. AAPS J.2015;17(3):691-699. 11. Tardivon C, Desmee S, Kerioui M, et al. Association between tumor size kinetics and survival in patients with urothelial carcinoma treated with atezolizumab: implication for patient follow-up. Clin Pharmacol Ther. 2019;106(4):810-820. 12. Desmee S, Guedj J, Veyrat-Follet C, Comets E. Mechanistic joint modelling for longitudinal PSA and survival data in advanced metastatic prostate cancer. Annual Meeting of the Population Approach Group in Europe. 2017: Abstract 7154. 13. Thai H-T, Fau J, France M, Comets E, Veyrat-Follet C. Joint modeling of longitudinal tumor burden and time-to-event data to predict survival: application to aflibercept in second line metastatic colorectal cancer. Annual Meeting of the Population Approach Group in Europe. 2015: Abstract 3527. 14. Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-1473. 15. Chanu P, Claret L, Bruno R, Carpenter S, Woolridge J, Cronier D. PK / PD relationship of the monoclonal anti-BAFF antibody tabalumab in combination with bortezomib in patients with previously treated multiple myeloma: comparison of serum M-protein and serum free light chains as predictors of progression free survival. Annual Meeting of the Population Approach Group in Europe. 2013: Abstract 2732. 16. Marchand M, Claret L, Losic N, Puchalski T, Bruno R. Population pharmacokinetics and exposure-response analyses to support dose selection of daratumumab in multiple myeloma patients. Annual Meeting of the Population Approach Group in Europe. 2013: Abstract 2668. 17. Bruno R, Jonsson F, Zaki M, et al. Simulation of clinical outcome for pomalidomide plus low-dose dexamethasone in patients with refractory multiple myeloma based on week 8 M-protein response. Blood. 2011;118(21):1881-1881. 18. Jonsson F, Ou Y, Claret L, et al. A Tumor growth inhibition model based on M-protein levels in subjects with relapsed / refractory multiple myeloma following single-agent carfilzomib use. CPT Pharmacomet Syst Pharmacol. 2015;4(12):711-719. 19. Thai H-T, Liu L, Semiond D, et al. Model-based drug development to support isatuximab dosing regimen selection in Phase II multiple myeloma patients. Annual Meeting of the Population Approach Group in Europe. 2016: Abstract 6018. 20. Fau J, El-Cheikh R, Brillac C, et al. Drug-disease interaction and time-dependent population pharmacokinetics of isatuximab in relapsed / refractory multiple myeloma patients. CPT Pharmacomet Syst Pharmacol. 2020;9(11):649-658. 21. Jacqmin P, Snoeck E, Schaick EA van, et al. Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model. J Pharmacokinet Pharmacodyn. 2007;34(1):57-85. 22. Li Y, Xu Y, Liu L, Wang X, Palmisano M, Zhou S. Population pharmacokinetics of pomalidomide. J Clin Pharmacol. 2015;55(5):563-572. 23. Spoorenberg SMC, Deneer VHM, Grutters JC, et al. Pharmacokinetics of oral vs. intravenous dexamethasone in patients hospitalized with community-acquired pneumonia. Br J Clin Pharmacol. 2014;78(1):78-83. 24. Claret L, Girard P, Hoff PM, et al. Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics. J Clin Oncol. 2009;27(25):4103-4108. 25. Chanu P, Claret L, Marchand M, Losic N, Puchalski T, Bruno R. Population pharmacokinetic / pharmacodynamic models to support dose selection of daratumumab in multiple myeloma patients. Annual Meeting of the Population Approach Group in Europe. 2014: Abstract 3281. 26. Jonsson F, Claret L, Knight R, et al. A longitudinal tumor growth inhibition model based on serum M-protein levels in patients with multiple myeloma treated by dexamethasone. Annual Meeting of the Population Approach Group in Europe. 2010: Abstract 1705. 27. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood.2014;123(12):1826-1832. 28. Ayral G, Si Abdallah J, Magnard C, Chauvin J. A novel method based on unbiased correlations tests for covariate selection in nonlinear mixed effects models: The COSSAC approach. CPT Pharmacomet Syst Pharmacol. 2021;10(4):318-329. 29. Lavielle M, Ribba B. Enhanced method for diagnosing pharmacometric models: random sampling from conditional distributions. Pharm Res. 2016;33(12):2979-2988. 30. Traynard P, Ayral G, Twarogowska M, Chauvin J. Efficient pharmacokinetic modeling workflow with the MonolixSuite: A case study of remifentanil. CPT Pharmacomet Syst Pharmacol.2020;9(4):198-210. 31. Therneau TM, Grambsch PM, Fleming TR. Martingale-based residuals for survival models. Biometrika.1990;77(1):147-160. 32. Cerou M, Lavielle M, Brendel K, Chenel M, Comets E. Development and performance of npde for the evaluation of time-to-event models. Pharm Res. 2018;35(2). 33. Friberg L, de Greef R, Kerbusch T, Karlsson M. Modeling and simulation of the time course of asenapine exposure response and dropout patterns in acute schizophrenia. Clin Pharmacol Ther.2009;86(1):84-91. 34. Wang Y, Sung C, Dartois C, et al. Elucidation of relationship between tumor size and survival in non-small-cell lung cancer patients can aid early decision making in clinical drug development. Clin Pharmacol Ther. 2009;86(2):167-174. 35. Ryman JT, Meibohm B. Pharmacokinetics of monoclonal antibodies. CPT Pharmacomet Syst Pharmacol. 2017;6(9):576-588. 36. Xu XS, Schecter JM, Jansson R, Yan X. Response to “The role of FcRn in the pharmacokinetics of biologics in patients with multiple myeloma.” Clin Pharmacol Ther. 2017;102(6):905. 37. Jacobs J, Mould D. The role of FcRn in the pharmacokinetics of biologics in patients with multiple myeloma. Clin Pharmacol Ther. 2017;102(6):903-904. 38. Food and Drug Administration Center For Drug Evaluation And Research. BLA Multi-disciplinary Review and Evaluation BLA 761113 Sarclisa (isatuximab). 2016. https: / / www.accessdata.fda.gov / drugsatfda_docs / nda / 2020 / 761113Orig1s000MultidisciplineR.pdf. Accessed June 16, 2021. 39. Yan X, Clemens PL, Puchalski T, et al. Influence of disease and patient characteristics on daratumumab exposure and clinical outcomes in relapsed or refractory multiple myeloma. Clin Pharmacokinet. 2018;57(4):529-538.

[0099] Example 2A Supplementary information regarding Example 2 pharmacokinetic model of isatuximab The formula for the structural pharmacokinetic model of isatuximab is as follows:

number

[0100] K-PD models for pomalidomide and dexamethasone The reaction rate for the combination of pomalidomide (p) and dexamethasone (d) is shown in detail below, in a simple hypothetical single compartment with bolus injection:

number

[0101] Mixtran code for joint models Model description: A joint model of the M protein and progression-free survival (PFS). PK for isatuximab, K-PD for pomalidomide / dexamethasone Description of parameters: M0, KL, KDi, Ri, KDpd, Rpd, Te, s, E, Beta [LONGITUDINAL] input = 1Ri, KDpd, Rpd, Te, s, E, beta, CLinf, CLm, KCL, gamma, V, Q, V2, Vm, Km, Tstart CLinf = {use = regressor} CLm = {use = regressor} KCL = {use = regressor} gamma = {use = regressor} V = {use = regressor} Q = {use = regressor} V2 = {use = regressor} Vm = {use = regressor} Km = {use = regressor} Tstart = {use = regressor} PK: compartment(cmt = 1, amount = Aic, volume = V) iv(cmt = 1, adm = 1) compartment(cmt = 2, amount = Aip, volume = V2) compartment(cmt = 3, amount = Ap) iv(adm = 3, cmt = 3) compartment(cmt = 4, amount = Ad) iv(adm = 4, cmt = 4) Equation: odeType = stiff Initial conditions: t_0 = 0 Aic_0 = 0 Aip_0 = 0 Ap_0 = 0 Ad_0 = 0 M_0 = M0 k12 = Q / V k21 = Q / V2 Cic = Aic / V ddt_Aic = -1 / V×CLinf×(exp(CLm×(1 - 1 / ((KCL / t) gamma+1))))×Aic - Vm×Aic / (Km + Cic) - k12×Aic + k21×Aip ddt_Aip = k12×Aic - k21×Aip KDEp = 3.51 KDEd = 2.42 ddt_Ap = -KDEp×Ap ddt_Ad = -KDEd×Ad MW_ISA = 150000 [ MW_POM = 273.24 MW_DEX = 392.46 Cp = Ap / (58.3×0.73); V / F = 58.3 F = 0.73 Cd = Ad / 76.3 CiM = Cic / MW_ISA×1000; M CpM = Cp / MW_POM×1000; M CdM = Cd / MW_DEX×1000; M if M < 150 dM = KL×M - KDi×exp(-Ri×t)×CiM×M - KDpd×exp(-Rpd×t)×(CpM + CdM)×M Other: dM = 0 end ddt_M = dM SlopeM = dM if t < Tstart haz = 0 Other: haz = s / Te × (t / Te) (s-1) / (1 + (t / Te) s [ )×E×exp(beta×SlopeM) end ddt_H = haz S = exp(-H) Definition: PFS = {type = event, maxEventNumber = 1, rightCensoringTime = 540, hazard = haz} Output: output = {M, PFS}

[0102] Each embodiment described herein can be combined with any one or more other embodiments unless expressly indicated otherwise. In particular, any feature or embodiment designated as preferred or advantageous can be combined with any one or more other feature or embodiment designated as preferred or advantageous, unless expressly indicated otherwise.

[0103] All references cited in this application are expressly incorporated herein by reference.

Claims

1. A pharmaceutical composition comprising an anti-CD38 antibody for use in a method of treating a human individual having multiple myeloma, wherein the method is: The process involves administering anti-CD38 antibody to the individual at a dose of 10 mg / kg per week for the first month of the cycle; The process involves administering an anti-CD38 antibody at a dose of 10 mg / kg every other week for one or more one-month cycles after the initial one-month cycle, until the individual achieves at least a very good partial response (VGPR); and The procedure includes administering an anti-CD38 antibody at a dose of 10 mg / kg once a month for one or more additional one-month cycles, after the individual has achieved at least a VGPR response and the VGPR response has been maintained for at least six months. The anti-CD38 antibody is isatuximab. The method further includes administering pomalidomide and dexamethasone to the individual. Pharmaceutical composition.

2. A pharmaceutical composition comprising an anti-CD38 antibody for use in a method of treating a human individual having multiple myeloma, wherein the method is: The process involves administering anti-CD38 antibody to the individual at a dose of 10 mg / kg per week for the first month of the cycle; The process involves administering an anti-CD38 antibody at a dose of 10 mg / kg every other week for one or more one-month cycles, following the initial one-month cycle; The steps include: measuring the individual's response to treatment at one or more time points within one-month cycles after the initial one-month cycle, and selecting individuals that have at least a VGPR (very good partial response) and whose VGPR is maintained for at least six months; and The process includes administering an anti-CD38 antibody to selected individuals at a dose of 10 mg / kg once a month for one or more additional one-month cycles, The anti-CD38 antibody is isatuximab. The method further includes administering pomalidomide and dexamethasone to the individual. Pharmaceutical composition.

3. A pharmaceutical composition comprising an anti-CD38 antibody for use in a method of treating a human individual having multiple myeloma, wherein the method is: A step of measuring the serum M protein and urinary M protein of an individual at a first time point before administering the anti-CD38 antibody; The process involves administering anti-CD38 antibody to the individual at a dose of 10 mg / kg per week for the first month of the cycle; The process involves administering an anti-CD38 antibody at a dose of 10 mg / kg every other week for one or more one-month cycles, following the initial one-month cycle; The process involves measuring the serum M protein and / or urinary M protein of an individual at at least one or more second time points during a one-month cycle, after the initial one-month cycle; and (a) At a second time point, the individual's serum M protein level is reduced by at least 90% compared to the individual's serum M protein level at a first time point; (b) At a second time point, the individual's urinary M protein level is less than 100 mg per 24 hours; and after (a) the reduction in the individual's serum M protein level and (b) the urinary M protein level of less than 100 mg per 24 hours have been maintained for at least six months, an anti-CD38 antibody is administered at a dose of 10 mg / kg per month for one or more further one-month cycles. The anti-CD38 antibody is isatuximab. The method further includes administering pomalidomide and dexamethasone to the individual. Pharmaceutical composition.

4. A pharmaceutical composition comprising an anti-CD38 antibody for use in a method of treating a human individual having multiple myeloma, wherein the method is: A step of measuring the serum M protein level and / or urinary M protein level of an individual before administering an anti-CD38 antibody; The process involves administering anti-CD38 antibody to the individual at a dose of 10 mg / kg per week for the first month of the cycle; (a) administering anti-CD38 antibody at a dose of 10 mg / kg every other week for one or more one-month cycles after the first one-month cycle until the individual's serum M protein level is reduced by at least 90% compared to the serum M protein level before administration of anti-CD38 antibody, and (b) the individual's urinary M protein level is less than 100 mg per 24 hours; and (a) Reduction in the individual's serum M protein level, and (b) Maintenance of the individual's urinary M protein level to less than 100 mg per 24 hours for at least 6 months, followed by the administration of one or more anti-CD38 antibodies at a dose of 10 mg / kg once a month. This includes a process of administering the drug over a one-month cycle. The anti-CD38 antibody is isatuximab. The method further includes administering pomalidomide and dexamethasone to the individual. Pharmaceutical composition.

5. The pharmaceutical composition according to claim 3 or 4, wherein (a) the individual's serum M protein level is reduced, and (b) the individual's urinary M protein level is maintained at less than 100 mg per 24 hours for at least 12 months prior to the administration of an anti-CD38 antibody at a dose of 10 mg / kg once every 28-day cycle.

6. The pharmaceutical composition according to claim 1 or 2, wherein the response to the treatment is measured by evaluating the blood M protein level and / or urinary M protein level of one or more individuals.

7. The pharmaceutical composition according to any one of claims 3 to 6, wherein blood M protein levels and / or urinary M protein levels are evaluated by immunofixation and / or electrophoresis.

8. The pharmaceutical composition according to any one of claims 1, 2, 6, or 7, wherein the VGPR response is maintained for at least 12 months prior to the administration of an anti-CD38 antibody once a month in one or more one-month cycles.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the anti-CD38 antibody is administered for at least 11 cycles, once every two weeks in one or more one-month cycles, at a dose of 10 mg / kg, before administering the anti-CD38 antibody once a month for one or more further one-month cycles.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the anti-CD38 antibody is administered for at least 23 cycles, once every two weeks in one or more one-month cycles, at a dose of 10 mg / kg, before administering the anti-CD38 antibody once a month for one or more further one-month cycles.

11. A pharmaceutical composition according to any one of claims 1 to 10, wherein the treatment extends the progression-free survival (PFS) of the individual.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein pomalidomide is administered at a dose of 4 mg per day during the first month cycle and on days 1 to 21 of one or more one-month cycles thereafter.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein dexamethasone is administered at a dose of 40 or 20 mg during the first month cycle and on the 1st, 8th, 15th, and 22nd days of one or more one-month cycles thereafter.

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