Use of anti-cd38 antibodies in the treatment of newly diagnosed multiple myeloma

Abstract

Provided herein are methods and uses for treating multiple myeloma (such as newly diagnosed multiple myeloma) in a patient in need thereof. These methods include administering to the patient an anti-CD38 antibody, bortezomib, lenalidomide, and dexamethasone.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 607,082, filed December 6, 2023, and U.S. Provisional Application No. 63 / 654,907, filed May 31, 2024, the contents of which are hereby incorporated in their entirety. Reference electronic sequence list

[0002] The contents of the electronic sequence list (183952025640seqlist.xml; size: 11,510 bytes; and creation date: December 4, 2024) are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure provides methods for treating newly diagnosed multiple myeloma (NDMM) using an anti-CD38 antibody in combination with bortezomib, lenalidomide, and dexamethasone, as well as related uses, compositions, and kits. Background Technology

[0004] Multiple myeloma (MM) is a malignant plasma cell disease characterized by the clonal proliferation of plasma cells in the bone marrow (BM) and the production of excessive monoclonal immunoglobulins (usually IgG or IgA or free urinary light chains, i.e., paraproteins, M proteins, or M fractions). Patients with MM may experience bone pain, fractures, fatigue, anemia, infections, hypercalcemia, and kidney problems (Rollig et al. (2015) Lancet. [The Lancet] 385(9983):2197-208).

[0005] Over the past two decades, the treatment of multiple myeloma has significantly improved with the development and introduction of a variety of novel agents, including immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies, which offer more effective treatments. While these new agents have improved overall survival (OS) for patients with MM, the disease remains fatal in most cases. First-line treatment strategies include autologous stem cell transplantation (ASCT); however, many patients are often ineligible or have not yet received ASCT due to age or frailty. Treatment options and survival are based on the patient's age, health status, and disease condition. For example, patients over 65 years of age are generally considered ineligible for autologous SCT. Therefore, this patient population requires new treatment options. Summary of the Invention

[0006] This article provides information on the use of anti-CD38 antibodies in the treatment of human patients with multiple myeloma (MM), methods of treating human patients with MM, and compositions and kits for these uses and methods.

[0007] In one aspect, an anti-CD38 antibody is provided for use in the treatment of multiple myeloma (MM) in a human patient. In one embodiment, the MM is newly diagnosed MM (NDMM), and the patient is ineligible for autologous stem cell transplantation. The anti-CD38 antibody is administered according to a dosing schedule that includes an induction phase followed by a continuous treatment phase. During the induction phase, the anti-CD38 antibody is administered in combination with bortezomib, lenalidomide, and dexamethasone, and during the continuous treatment phase, the anti-CD38 antibody is administered in combination with lenalidomide and dexamethasone, but not with bortezomib. The induction phase comprises four 42-day cycles, and the continuous treatment phase comprises at least one 28-day cycle.

[0008] On the other hand, an anti-CD38 antibody is provided for use in safely increasing progression-free survival (PFS) in human patients with multiple myeloma (MM). In one embodiment, the MM is newly diagnosed MM (NDMM), and the human patient is ineligible for autologous stem cell transplantation. The anti-CD38 antibody is administered according to a dosing schedule as described herein, including an induction phase and a continuous treatment phase, such that administration of the anti-CD38 antibody during the induction and continuous treatment phases results in increased PFS compared to a dosing schedule without the anti-CD38 antibody.

[0009] On the other hand, an anti-CD38 antibody is provided for use in safely increasing the negative rate of minimal residual disease (MRD) in a human patient with MM who has newly diagnosed MM (NDMM) and who is not eligible for autologous stem cell transplantation. The anti-CD38 antibody is administered according to a dosing schedule as described herein, comprising an induction phase followed by a continuous treatment phase, such that administration of the anti-CD38 antibody during the induction and continuous treatment phases results in at least 10 [unclear - possibly related to a specific treatment schedule or timeframe]. -5 The threshold for MRD negativity increases.

[0010] On the other hand, an anti-CD38 antibody is provided for use in safely increasing overall survival (OS) in a human patient with newly diagnosed MM (NDMM) who is ineligible for autologous stem cell transplantation. The anti-CD38 antibody is administered according to a dosing schedule as described herein, including an induction phase followed by a continuous treatment phase, such that administration of the anti-CD38 antibody results in an increase in OS compared to a dosing schedule without the anti-CD38 antibody for both the induction and continuous treatment phases.

[0011] On the other hand, a method for treating multiple myeloma (MM) in a human patient is provided. In some embodiments, the MM is newly diagnosed MM (NDMM), and the human patient is ineligible for autologous stem cell transplantation. In some embodiments, the anti-CD38 antibody is administered according to a dosing schedule as described herein, including an induction phase followed by a continuous treatment phase, thereby treating the NDMM.

[0012] On the other hand, a method is provided for safely increasing progression-free survival (PFS) in human patients with multiple myeloma (MM). In some embodiments, the MM is newly diagnosed MM (NDMM), and the human patient is ineligible for autologous stem cell transplantation. In some embodiments, the anti-CD38 is administered according to a dosing schedule as described herein, including an induction phase followed by a continuous treatment phase, such that administration of the anti-CD38 antibody during the induction and continuous treatment phases results in increased PFS compared to a dosing schedule without the anti-CD38 antibody.

[0013] On the other hand, a method is provided for safely increasing the negative rate of minimal residual disease (MRD) in human patients with MM. In some embodiments, the MM is newly diagnosed MM (NDMM), and the human patient is ineligible for autologous stem cell transplantation. In some embodiments, the anti-CD38 antibody is administered according to a dosing schedule as described herein, including an induction phase followed by a continuous treatment phase, such that administration of the anti-CD38 antibody during the induction and continuous treatment phases results in at least 10 [unclear - possibly related to a specific treatment regimen or regimen]. -5 The negative rate of MRD increases below the threshold.

[0014] On the other hand, a method is provided for safely increasing the overall survival (OS) of human patients with multiple myeloma (MM). In some embodiments, the MM is newly diagnosed MM (NDMM), and the human patient is ineligible for autologous stem cell transplantation. In some embodiments, the anti-CD38 antibody is administered at a dosing schedule as described herein, including an induction phase followed by a continuous treatment phase, such that administration of the anti-CD38 antibody results in an increase in OS compared to a dosing schedule with an induction phase and continuous treatment phase without the anti-CD38 antibody.

[0015] In some embodiments of the uses and methods provided herein, the induction period comprises administering the anti-CD38 antibody together with bortezomib (Velcade®), lenalidomide (Revlimid®), and dexamethasone according to the following dosing schedule. The first part of the dosing schedule is the induction period. During the induction period, the anti-CD38 antibody is administered on days 1, 8, 15, 22, and 29 of the first 42-day cycle, and then on days 1, 15, and 29 of the subsequent three 42-day cycles. Bortezomib is administered on days 1, 4, 8, 11, 22, 25, 29, and 32 of each 42-day cycle. Lenalidomide is administered on days 1–14 and 22–35 of each 42-day cycle. Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32 and 33 of each 42-day cycle, or on days 1, 4, 8, 11, 15, 22, 25, 29 and 32.

[0016] In some embodiments of the uses and methods provided herein, a continuous treatment period is performed after the induction period. The continuous treatment period includes administration of an anti-CD38 antibody together with lenalidomide and dexamethasone, without the administration of bortezomib. In some embodiments, the continuous treatment period comprises at least one 28-day cycle. The anti-CD38 antibody is administered on days 1 and 15 of the 28-day cycle, lenalidomide is administered on days 1–21, and dexamethasone is administered on days 1, 8, 15, and 22. In some embodiments, the anti-CD38 antibody, lenalidomide, and / or dexamethasone are administered until disease progression. Attached Figure Description

[0017] Figure 1 A preliminary analysis of PFS based on disease assessment of the treatment group versus the intention-to-treat population using IRC-Kaplan-Meier curves is shown; the top line represents the isatuximab + bortezomib + lenalidomide + dexamethasone group, the bottom line represents the bortezomib + lenalidomide + dexamethasone group, and plus signs represent patients examined.

[0018] Figure 2 The pre-specified PFS subgroup analysis is shown.

[0019] Figure 3 The MRD rate for patients in the ITT population at any time during the study period is shown. Detailed Implementation

[0020] Based on the phase 3 clinical trial results presented in this article, the combination of anti-CD38 antibody with bortezomib, lenalidomide and dexamethasone showed a favorable benefit-risk profile in treating NDMM patients who were not eligible for transplantation, thereby demonstrating improved progression-free survival in this patient population. definition

[0021] As used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” include the plural references. Thus, for example, references to “molecule” optionally include combinations of two or more such molecules, etc.

[0022] As used herein, the term "about" refers to a typical range of error for a given value that is readily known to those skilled in the art. The "about" values ​​or parameters mentioned herein include (and describe) embodiments relating to such values ​​or parameters themselves.

[0023] "Sustained remission" refers to the sustained effect of stopping or delaying disease progression (e.g., multiple myeloma) and / or improving one or more remission criteria after treatment has ceased. For example, remission to multiple myeloma treatment can be measured according to criteria described in the following literature: Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma." Lancet Oncol. 17(8): e328-e346 and Durie et al. (2006) "International uniform response criteria for multiple myeloma." Leukemia. 20: 1467-1473. (See also Table 1 of this article). In some embodiments, the duration of sustained remission is at least the same as the duration of treatment, at least 1.5X, 2.0X, 2.5X, or 3.0X of the duration of treatment.

[0024] The term "pharmaceutical formulation" refers to a formulation in a form that allows for the effective biological activity of the active ingredient and does not contain any additional components that would have unacceptable toxicity to the subject to which the formulation will be administered. Such formulations are sterile. "Pharmaceutically acceptable" excipients (mediators, additives) are those excipients that can be reasonably administered to the subject mammal to provide an effective dose of the active ingredient employed.

[0025] As used herein, the term "treatment" refers to a clinical intervention designed to alter the typical processes of a disease or cells (e.g., cancer cells) being treated during a clinicopathological process. Desired effects of treatment include reducing the rate of disease progression, improving or alleviating the disease state, and mitigating or improving prognosis. For example, a patient is considered "treated" if one or more cancer-related symptoms are reduced or eliminated (including, but not limited to, reducing the proliferation of cancer cells (or destroying cancer cells), reducing symptoms caused by the disease, improving the quality of life of a patient with the disease, reducing the dosage of other medications required to treat the disease, and / or prolonging the patient's survival.

[0026] As used in this article, "in combination with" means applying one treatment in addition to another. Therefore, "in combination with" means applying another treatment before, during, or after applying one treatment to a patient.

[0027] The term "antibody" is used in the broadest sense and specifically includes monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, provided that these antibodies exhibit the desired biological activity. In some embodiments, the antibody is exathusiamab.

[0028] As used herein, the term “overall response rate” or “ORR” refers to the proportion of patients who have achieved strict complete remission (sCR), complete remission (CR), very good partial remission (VGPR), and partial remission (PR) as assessed by the IRC using the IMWG response criteria described in the following literature: Kumar et al. (2016) “International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol. 17(8): e328-e346 and Durie et al. (2006) “International uniform response criteria for multiple myeloma.” Leukemia. 20: 1467-1473. Table 1:

[0029] The following description illustrates exemplary methods, parameters, etc. However, it should be understood that this description is not intended to be a limitation on the scope of this disclosure, but is provided as a description of exemplary embodiments. Overview

[0030] This document provides methods for treating multiple myeloma (MM) in human patients by administering an anti-CD38 antibody in combination with bortezomib, lenalidomide, and dexamethasone. In some embodiments, the MM is newly diagnosed MM (NDMM), and the human patient is ineligible for autologous stem cell transplantation. In some embodiments, the anti-CD38 antibody is administered according to a dosing schedule as described herein, including an induction phase followed by a continuous treatment phase, thereby treating the NDMM. In some embodiments of the methods and uses provided herein, progression-free survival (PFS) is improved. In some embodiments, the MRD negativity rate is improved. In still other embodiments, overall survival (OS) is improved. Anti-CD38 antibody

[0031] 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 includes: (a) a heavy chain variable domain (V H The heavy chain variable domain comprises: 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) the light chain variable domain (V L The light chain variable domain comprises: 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 domain (V) containing an amino acid sequence having at least 90% identity with SEQ ID NO: 7 (e.g., at least any one of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any range between these values). HAlternatively, in some embodiments, the anti-CD38 antibody comprises a light chain variable domain (V) containing an amino acid sequence having at least 90% identity with SEQ ID NO: 8 or SEQ ID NO: 9 (e.g., at least any one of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any range between these values). L In some embodiments, the anti-CD38 antibody comprises V containing SEQ ID NO: 7. H and V containing SEQ ID NO:8 or SEQ ID NO:9 L .

[0032] In some embodiments, the anti-CD38 antibody is esataxetine (CAS Registry No.: 1461640-62-9). Esataxetine (also known as hu38SB19 and SAR650984) is an anti-CD38 antibody described in WO 2008 / 047242 and U.S. Patent No. 8,153,765, the contents of which are incorporated herein by reference in their entirety.

[0033] The heavy chain of exatuximab contains the following amino acid sequence: Furthermore, the light chain of exatuximab contains the following amino acid sequence:

[0034] Anti-CD38 antibodies can be generated using recombinant methods. To generate antibodies through recombinant methods, the nucleic acid encoding the antibody is isolated and inserted into a reproducible vector for further cloning (DNA amplification) or expression. The DNA encoding the antibody can be readily isolated and sequenced using standard procedures, such as by using oligonucleotide probes capable of specifically binding to the genes encoding the heavy and light chains of the antibody. Many vectors are available. Vector components typically include, but are not limited to, one or more of the following: signal sequences, replication origins, one or more marker genes, enhancer elements, promoters, and transcription termination sequences. The vector is typically transformed into a host cell suitable for expressing the nucleic acid. In some embodiments, the host cell is a eukaryotic or prokaryotic cell. In some embodiments, the eukaryotic host cell is a mammalian cell. Examples of useful mammalian host cell lines include: monkey kidney CV1 line transformed with SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (used for subcloning for growth in suspension culture of 293 or 293 cells, Graham et al., J. Gen Virol. [Journal of General Virology] 36:59 (1977)); juvenile hamster kidney cells (BHK, ATCC CCL 10); mouse Sertoli cells (TM4, Mather, Biol. Reprod. [Journal of Reproductive Biology] 23:243-251 (1980)); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical cancer cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); and buffalo rat hepatocytes (BRL 3A, ATCC CRL). 1442); human lung cells (W138, ATCCCCL 75); human hepatocytes (Hep G2, HB 8065); mouse mammary tumors (MMT 060562, ATCC CCL51); TRI cells (Mather et al., Annals NY Acad. Sci. [Annals of the New York Academy of Sciences] 383:44-68 (1982)); MRC 5 cells; FS4 cells; and human hepatocellular carcinoma cell line (Hep G2). Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences] 77:4216 (1980)); and myeloma cell lines such as NS0 and Sp2 / 0.For reviews of certain mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (edited by BKC Lo, Humana Press, Totowa, NJ, 2003), pp. 255-268. Anti-CD38 antibodies prepared from cells can be purified using, for example, hydroxyapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a typically preferred purification step. In general, various methods for preparing antibodies for research, testing, and clinical applications are recognized in the art and are consistent with and / or considered appropriate by those skilled in the art. Drug composition, formulation, dosage

[0035] This document also provides, for example, pharmaceutical compositions and formulations for treating NDMM, comprising an anti-CD38 antibody (such as ezetoximab), bortezomib, lenalidomide, or dexamethasone. In some embodiments, each of the anti-CD38 antibody (e.g., ezetoximab), bortezomib, lenalidomide, and dexamethasone is provided as a separate pharmaceutical composition. In some embodiments, the pharmaceutical compositions and formulations further comprise a pharmaceutically acceptable carrier.

[0036] In some embodiments, the anti-CD38 antibody described herein (e.g., ixartuximab) is in a formulation for dilution and intravenous administration. The dilution formulation comprises about 20 mg / mL (500 mg / 25 mL) of antibody, about 20 mM histidine, about 10% (w / v) sucrose, and about 0.02% (w / v) polysorbate 80 (pH 6.0). In some embodiments, the anti-CD38 antibody described herein (such as ixartuximab) is in a formulation comprising about 20 mg / mL of antibody, about 100 mg / mL of sucrose, 2.22 mg / mL of histidine hydrochloride monohydrate, about 1.46 mg / mL of histidine, and about 0.2 mg / mL of polysorbate 80. In some embodiments, the anti-CD38 antibody is ixartuximab administered intravenously at a dose of 10 mg / kg.

[0037] In some embodiments, the anti-CD38 antibody described herein (such as estradiol 188) is in the form of a formulation comprising approximately 140 mg / mL estradiol 188, 9 mM histidine, 110 mM Arg-Cl, 2% (w / v) sucrose, and 0.4% (w / v) poloxamer 188, and has a pH of 6.2 (high concentration estradiol 188). In some embodiments, the anti-CD38 antibody is a high concentration estradiol 188 administered subcutaneously at a dose of 1400 mg.

[0038] Pharmaceutical formulations of bortezomib, lenalidomide, and dexamethasone are commercially available. For example, bortezomib is known under the brand name VELCADE®. Lenalidomide is known under the brand name REVLIMID®. Dexamethasone is known under various brand names, including DECADRON, MAXIDEX, and HEXADROL. In some embodiments, bortezomib, lenalidomide, and / or dexamethasone are provided in separate containers. In some embodiments, bortezomib, lenalidomide, and / or dexamethasone are each used and / or prepared for administration to a patient, as described in the prescribing information available with the commercially available products.

[0039] In some embodiments of the methods and uses provided herein, bortezomib is administered at a dose of 1.3 mg / m². In some embodiments, lenalidomide is administered at a dose of 25 mg / day (or 10 mg / day in human patients with CrCl ≥ 30 to ≤60 mL / min) during the induction and continuous treatment phases. In some embodiments, dexamethasone is administered at a dose of 20 mg / day. Patient population and treatment

[0040] In some embodiments, anti-CD38 antibodies are administered to human patients who have newly diagnosed MM (NDMM). In some embodiments, the patient is ineligible for autologous stem cell transplantation. In some embodiments, the patient did not receive ASCT at the same time as the treatment provided herein. In some embodiments, the patient has MM as defined by the IMWG criteria (Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014; 15:e538-48). In some embodiments, the patient has measurable evidence of disease, for example, - Serum monoclonal (M) protein ≥ 1.0 g / dL, as measured by serum protein immunoelectrophoresis, and / or - Urinary M protein ≥ 200 mg / 24 hours as measured by urinary protein immunoelectrophoresis, and / or -According to previous criteria, serum free light chain (sFLC) multiple myeloma is defined as the absence of measurable M protein in serum or urine (serum immunoglobulin free light chain ≥ 10 mg / dL, and abnormal serum immunoglobulin κλ free light chain ratio < 0.26 or > 1.65).

[0041] The anti-CD38 antibody is administered according to a dosing schedule that includes an induction period followed by a continuous treatment period. During the induction period, the anti-CD38 antibody is administered in combination with bortezomib, lenalidomide, and dexamethasone, and during the continuous treatment period, the anti-CD38 antibody is administered in combination with lenalidomide and dexamethasone, but not with bortezomib. The induction period consists of four 42-day cycles, and the continuous treatment period consists of at least one 28-day cycle.

[0042] In some embodiments of the methods and uses described herein, the patient is newly diagnosed and not considered for high-dose chemotherapy due to age ≥ 65 years; or < 65 years, with significant comorbidities that may negatively impact tolerance to high-dose chemotherapy and SCT. In some embodiments of the methods and uses of the anti-CD38 antibody described herein, the patient is ≥ 70 years old. In some embodiments, the patient is ≥ 75 years old. In some embodiments, the patient is < 75 years old. In some embodiments, the patient is < 70 years old.

[0043] In some embodiments of the methods and uses provided herein, the patient has stage III multiple myeloma according to the Revised International Staging System (R-ISS). In some embodiments, the patient has stage I or II multiple myeloma according to R-ISS. In some embodiments, stage I of multiple myeloma according to R-ISS is defined as (a) serum β-2 microglobulin level less than 3.5 mg / L, (b) serum albumin greater than or equal to 3.5 g / dL, (c) detection of standard risk chromosomal / cytogenetic abnormalities by interphase fluorescence in situ hybridization (iFISH), and (d) normal serum lactate dehydrogenase (LDH) levels. In some embodiments, stage II of multiple myeloma according to R-ISS is defined as not being stage I or III of R-ISS. In some embodiments, the individual is stage III of multiple myeloma according to the Revised International Staging System (R-ISS). In some embodiments, stage III of multiple myeloma R-ISS is defined as (a) a serum β-2 microglobulin level greater than about 5.5 mg / L and (b) a high-risk cytogenetic abnormality detected by interphase fluorescence in situ hybridization (iFISH) or (c) a serum lactate dehydrogenase (LDH) level greater than the upper limit of normal. In some embodiments, the individual has a high-risk cytogenetic abnormality (CA). In some embodiments, the high-risk cytogenetic abnormality is one or more of del(17p), t(4:14), and / or t(14;16). In some embodiments, the individual is not classified according to R-ISS. In some embodiments, the individual is not classified according to R-ISS due to indeterminate iFISH.

[0044] In some embodiments of the uses and methods provided herein, administration of anti-CD38 antibodies during the induction and continuous treatment periods described herein resulted in increased progression-free survival (PFS) compared to administration during the induction and continuous treatment periods without anti-CD38 antibodies. In some embodiments, the increase in PFS was associated with an increased rate of MRD negativity in patients receiving anti-CD38 antibodies.

[0045] In some embodiments, a patient’s PFS is measured as the time from the start of treatment to the first occurrence of progressive disease (PD). In some embodiments, PD is assessed according to criteria described in the following literature: Kumar et al. (2016) “International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol. 17(8): e328-e346 and Durie et al. (2006) “International uniform response criteria for multiple myeloma.” Leukemia. 20: 1467-1473. In some embodiments, PFS is measured as the time from the start of treatment to death. In some embodiments, the methods and uses provided herein result in improved (e.g., prolonged) progression-free survival (PFS) compared to patients with MM who received treatment including induction and continuous therapy without anti-CD38 antibodies. In some embodiments, this treatment increases the patient's progression-free survival (PFS).

[0046] In some embodiments, overall survival (OS) is measured as the time from the start of treatment to death. In some embodiments, this treatment increases OS in patients with MM compared to those receiving treatment including an induction phase and a continuous treatment phase without anti-CD38 antibodies.

[0047] In some embodiments, patients who receive the induction and continuous therapy described herein with anti-CD38 antibodies are negative for minimal residual disease (MRD) or "MRD-negative" or have a lower MRD rate after receiving the induction and continuous therapy described herein with anti-CD38 antibodies, compared to receiving the induction and continuous therapy described herein in the absence of anti-CD38 antibodies. In some embodiments, MRD status is measured by next-generation flow cytometry (NGF). In some embodiments, an MRD-negative status as measured by NGF (or "flow cytometry MRD-negative") means the absence of phenotypic clonal plasma cells (such as multiple myeloma cells) in bone marrow aspirate (e.g., using EUROFLOW for MRD detection in multiple myeloma). TMThe standard operating procedure for high-throughput flow cytometry (see Flores-Montero et al. (2017) Leukemia. [Leukemia] 31: 2094-2103) or an equivalent method) has a minimum sensitivity of, for example, 1 / 10. 4 10 nucleated cells (or "10") -4 ”), 1 / 10 5 10 nucleated cells (or "10") -5 ”), 1 / 10 6 10 nucleated cells (or "10") -6 () or 1 / 10 7 10 nucleated cells (or "10") -7 In some embodiments, MRD status is measured by next-generation sequencing (NGS). In some embodiments, MRD negative as measured by NGS (or “sequencing MRD negative”) means the absence of clonal plasma cells (e.g., multiple myeloma cells) in the bone marrow aspirate; the presence of a clone is defined as at least two identical sequencing reads obtained after DNA sequencing of the bone marrow aspirate (e.g., using the LYMPHOSIGHT® high-throughput sequencing platform or an equivalent method), where the minimum sensitivity is, for example, 1 / 10. 4 10 nucleated cells (or "10") -4 ”), 1 / 10 5 10 nucleated cells (or "10") -5 ”), 1 / 10 6 10 nucleated cells (or "10") -6 "" or higher. In some embodiments, the minimum sensitivity is 1 cell / 10 7 10 nucleated cells -7 In some embodiments, the patient is negative for both imaging and MRD (or “imaging + MRD negative”). In some embodiments, imaging + MRD negative means (a) MRD negative as detected by NGF or MRD negative as detected by NGS, and (b) the disappearance, or reduction to less than the maximum normalized uptake value of the mediastinal blood pool or less than the value of the surrounding normal tissue, in each region of increased tracer uptake found at baseline or prior to positron emission tomography (PET) / computed tomography (Ct). In some embodiments, the patient is “persistently MRD negative”.

[0048] In some embodiments, persistent MRD negativity refers to a patient who has been confirmed as imaging + MRD negative at two time points after the start of treatment, with these time points spaced at least 1 year apart. In some embodiments, minimal residual disease (MRD) is assessed via NGF or NGS using bone marrow samples collected from patients who have received anti-CD38 antibodies (e.g., ezetixomab), bortezomib, lenalidomide, and dexamethasone, as described herein. In some embodiments, patients being assessed for MRD have achieved complete remission or better (i.e., >CR) or very good partial remission or better (i.e., >VGPR) during or after treatment with anti-CD38 antibodies (e.g., ezetixomab), bortezomib, lenalidomide, and dexamethasone, as described herein. Products or reagent kits

[0049] In another embodiment of the invention, a product or kit comprising an anti-CD38 antibody, such as exatuximab, is provided. In some embodiments, the product or kit further comprises bortezomib, lenalidomide, and / or dexamethasone. In some embodiments, the product or kit further comprises a packaging insert containing instructions for using an anti-CD38 antibody (e.g., exatuximab) in combination with bortezomib, lenalidomide, and dexamethasone to treat a patient with multiple myeloma (e.g., NDMM) or to delay its progression. In some embodiments, the kit comprises exatuximab, bortezomib, lenalidomide, and dexamethasone.

[0050] This specification is intended to enable those skilled in the art to practice the invention. Various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes. Example

[0051] This disclosure will be more fully understood by referring to the examples below. However, these examples should not be construed as limiting the scope of the invention. It should be understood that the examples and embodiments described herein are for illustrative purposes only, and various modifications or alterations made based on the examples and embodiments will be conceived by those skilled in the art and should be included within the spirit and scope of this application and the appended claims.

[0052] To evaluate the clinical benefit of exatuzumab (I) in combination with bortezomib (Velcade®, V), lenalidomide (Revlimid®, R), and dexamethasone (d) (IVRd) compared to bortezomib, lenalidomide, and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for transplantation, a phase 3 randomized, open-label, multicenter study was conducted. The primary endpoint or target was progression-free survival (PFS).

[0053] Key secondary endpoints / targets included complete response (CR) rate, as defined by the IMWG criteria (Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016; 17(8):e328-46); the rate of negative minimal residual disease (MRD) in patients with CR, very good partial response, or better, as defined by the IMWG criteria; and overall survival (OS) evaluated in both the IVRd and VRd groups. Other secondary endpoints / targets include: overall response rate (ORR) as determined by IMWG criteria; overall time to progression (TTP) as determined by MRD status; PFS as determined by MRD status; duration of response (DOR) as determined by MRD status; time to first response (TT1R); time to best response (TTBR); progression-free survival after the next line of therapy (PFS2); sustained MRD negativity rate for ≥ 12 months; safety and pharmacokinetic (PK) characteristics of exatuximab in combination with bortezomib, lenalidomide, and dexamethasone (IVRd group only); immunogenicity of exatuximab in patients receiving exatuximab (IVRd group and crossover group); and disease-specific and general health-related quality of life (HRQL), disease and treatment-related symptoms, health status utility value, and health status.

[0054] Exploratory targets include: the relationship between immunogenetic determinants and efficacy endpoints, the relationship between PK and pharmacodynamics (PDy), the relationship between cytogenetic abnormalities (including but not limited to gain(1q)) not part of the Revised International Staging System (R-ISS) and efficacy endpoints, new methods for measuring serum M protein (such as mass spectrometry), and imaging-positive MRD-negative remission according to IMWG criteria.

[0055] Crossover objectives (patients switching from the VRd group to the IVRd group) include: ORR according to IMWG criteria, duration of response (DOR), safety and immunogenicity of exatuximab in patients receiving exatuximab. Research Design

[0056] This is a prospective, multicenter, international, randomized, open-label, parallel-group, 2-arm study evaluating the efficacy of IVRd compared to VRd in treating patients with NDMM who are ineligible for stem cell transplantation (SCT). This is the first phase 3 study of this drug combination in this patient population. Inclusion criteria Main research

[0057] Patients are considered eligible for randomization in the IVRd or VRd group if they meet all of the following criteria:

[0058] Multiple myeloma, as defined by the IMWG criteria (Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al., International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014; 15:e538-48).

[0059] Measurable evidence of disease: - Serum M protein ≥ 1.0 g / dL, as measured by serum protein immunoelectrophoresis, and / or - Urinary M protein ≥ 200 mg / 24 hours as measured by urinary protein immunoelectrophoresis, and / or - According to previous criteria, serum free light chain multiple myeloma with no measurable disease in serum or urine (serum immunoglobulin free light chain ≥ 10 mg / dL, and abnormal serum immunoglobulin κλ free light chain ratio < 0.26 or > 1.65).

[0060] Newly diagnosed patients who are not considered for high-dose chemotherapy are excluded for the following reasons: age ≥ 65 years; or < 65 years, with significant comorbidities that may negatively impact tolerance to high-dose chemotherapy and SCT.

[0061] The patient has voluntarily given written informed consent before undergoing any research-related procedures (which are not part of normal medical care), but it should be understood that the patient may withdraw their consent at any time without affecting their medical care. Intersection

[0062] Patients are considered eligible for cross-examination if they meet all of the following criteria:

[0063] Patients with confirmed PD were in the VRd control group before crossover.

[0064] The patients did not receive any other systemic anticancer therapy besides the VRd group. Exclusion criteria Main research

[0065] Patients meeting all of the above inclusion criteria were screened according to the following exclusion criteria:

[0066] Under 18 years of age (or, if the legal age is > 18, the legal age of adulthood in the country) and not older than 80 years of age.

[0067] The diagnosis is grade 1 peripheral neuropathy with a grade greater than 1 or accompanied by pain.

[0068] The diagnosis includes amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma (multiple myeloma without associated organ or tissue impairment or terminal organ damage).

[0069] A diagnosis of Waldenström's disease, or other conditions in which IgM M protein is present even in the absence of clonal plasma cell infiltration in osteolytic lesions.

[0070] Prior or current systemic therapy or SCT for multiple myeloma is acceptable, except for emergency use of short-course corticosteroids (equivalent to dexamethasone 40 mg / day for 4 days) if completed within 14 days prior to randomization.

[0071] Accompanying plasma cell leukemia.

[0072] Any major surgery performed within 14 days prior to the start of the study: plasma exchange, major surgery (vertebroplasty is not considered a major surgery), radiation therapy (except for palliative purposes).

[0073] Performance status (PS) of the Eastern Cooperative Oncology Group (ECOG) is >2.

[0074] Hemoglobin < 8 g / dL.

[0075] If < 50% of the nucleated cells in the platelet count are plasma cells, then the platelet count is < 70 × 10⁻⁶. 9 / L, and if ≥ 50% of the nucleated cells in the BM are plasma cells, then platelets ≤ 30 × 10 9 / L. Platelet transfusions are not permitted within 3 days prior to screening hematological tests.

[0076] Absolute neutrophil count (ANC) < 1000 / μL (1 × 10⁻⁶) 9 / L). Granulocyte colony-stimulating factor (G-CSF) is not permitted to be used to achieve this level.

[0077] Creatinine clearance rate < 30 mL / min / 1.73 m 2 (Formula for Diet Modification for Kidney Disease (MDRD))

[0078] GFR (mL / min / 1.73 m) 2 = 175 x (Scr) )-1.154 × (age) )-0.203 × (0.742, if F) × (1.212, if AA).

[0079] Abbreviations: AA = African American; F = Female; GFR = Glomerular Filtration Rate; Scr = Serum Creatinine.

[0080] Total bilirubin > 1.5 × upper limit of normal (ULN), except for known Gilbert syndrome.

[0081] Corrected serum calcium > 14 mg / dL (> 3.5 mmol / L).

[0082] Aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) > 3 × ULN.

[0083] Hypersensitivity (or contraindication) to dexamethasone, sucrose, histidine (as a base and hydrochloride), boron, mannitol and polysorbate 80 or any component of the investigational therapy that is unsuitable for preoperative use with steroids or to H2 blockers that inhibit further treatment with these agents.

[0084] Any of the following within the 6 months prior to randomization: - Second-degree / third-degree heart block - Poorly controlled high blood pressure, - Myocardial infarction - Severe / unstable angina - Coronary / peripheral artery bypass grafting, - New York Heart Association Class III or IV congestive heart failure Grade 3 or higher arrhythmia, - Stroke or transient ischemic attack -Left ventricular ejection fraction < 40%.

[0085] Previous malignancy. Allowed for adequately treated basal cell carcinoma or squamous cell skin cancer, or superficial (pTis, pTa, and pT1) bladder cancer, or low-risk prostate cancer, or any in situ malignancy following curative therapy, and any other cancer that has been treated with cytotoxic chemotherapy for ≥ 3 years prior to recruitment and that the patient has been disease-free for ≥ 3 years.

[0086] Known acquired immunodeficiency syndrome (AIDS) related disease or known HIV disease requiring antiviral treatment, or active hepatitis A (defined as positive HA antigen or positive IgM), hepatitis B (defined as positive HBs antigen or positive hepatitis B virus DNA test above the detection limit), or hepatitis C infection (defined as a known positive hepatitis C antibody result or a known quantitative hepatitis C (HCV) ribonucleic acid (RNA) result above the detection limit).

[0087] Malabsorption syndrome or any condition that may significantly affect lenalidomide absorption (e.g., galactose intolerance, genetic problems of Lapp lactose deficiency).

[0088] Based on local clinical practice, people are unable or unwilling to undergo thrombosis prevention.

[0089] Any of the following within the 3 months prior to randomization: anti-therapeutic peptic ulcer disease, corrosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic events.

[0090] Any serious acute or chronic medical condition that may impair a patient’s ability to participate in the study or interfere with the interpretation of the study results (e.g., systemic infection, unless treated with anti-infective therapy), or that prevents the patient from adhering to the study procedures.

[0091] Women who are pregnant or breastfeeding or who intend to become pregnant during the study period. Women who are of fertility potential and do not wish to prevent pregnancy by using two reliable methods of contraception, and / or women who are unwilling or unable to perform pregnancy tests before the start of study treatment (two negative tests), weekly during the first 6 weeks of treatment, every 21 days of induction cycles 2 to 4 and then every 28 days during treatment (or every 14 days in cases of irregular menstruation), and at least 28 days after the discontinuation of study lenalidomide (14 and 28 days in cases of irregular menstruation), or 3 months after the discontinuation of bortezomib, or monthly for 5 months after the discontinuation of exathuximab (whichever occurs last) and / or women who do not wish to or are unable to perform pregnancy tests.

[0092] Note 1: WOCBP is defined as women who: 1) have achieved menarche at some point in time, 2) have not undergone hysterectomy or bilateral oophorectomy, or 3) have not experienced natural menopause (absence of menstruation after cancer therapy does not exclude fertility potential) for at least 24 consecutive months (i.e., have had menstruation at any time within the past 24 consecutive months).

[0093] Note 2: True abstinence is acceptable when it aligns with the patient's preferred lifestyle and daily routine. Periodic abstinence (e.g., calendar method, ovulation method, symptom-basal body method, and post-ovulation method) and withdrawal are not acceptable methods of contraception.

[0094] Male participants who did not agree to practice genuine abstinence or use condoms during sexual contact with pregnant women or WOCBP, even if they had successfully undergone vasectomy, were included in the study, during dose interruption, and at least 28 days after discontinuation of lenalidomide, or 3 months after discontinuation of bortezomib treatment, or 5 months after discontinuation of esartusximab treatment (whichever occurred last). Intersection

[0095] Patients are considered eligible for cross-examination if they do not meet any of the following criteria:

[0096] The diagnosis includes amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma (multiple myeloma without associated organ or tissue impairment or terminal organ damage).

[0097] A diagnosis of Waldenström disease, or other conditions in which IgM M protein is present even in the absence of clonal plasma cell infiltration in osteolytic lesions.

[0098] Accompanying plasma cell leukemia.

[0099] Any major surgery performed within 14 days prior to the start of the study: plasma exchange, major surgery (vertebroplasty is not considered a major surgery), radiation therapy (except for palliative purposes).

[0100] ECOG PS > 2.

[0101] Hemoglobin < 8 g / dL. E 807. If < 50% of the nucleated cells in the platelet count are plasma cells, then platelets < 50 × 10⁻⁶. 9 / L, and if ≥ 50% of the nucleated cells in the BM are plasma cells, then the platelet count is ≤30 × 10⁹ / L. 9 / L. Platelet transfusions are not permitted within 3 days prior to screening hematological tests.

[0102] Absolute neutrophil count < 1000 / μL (1 × 10⁻⁶) 9 / L). G-CSF is not permitted to be used to achieve this level.

[0103] Creatinine clearance rate < 30 mL / min / 1.73 m 2 (MDRD formula; see GFR calculation above).

[0104] Total bilirubin > 1.5 × ULN, excluding known Gilbert syndrome. E 811. Corrected serum calcium > 14 mg / dL (> 3.5 mmol / L).

[0105] Aspartate aminotransferase and / or ALT > 3 × ULN.

[0106] Hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as a base and hydrochloride), boron, mannitol and polysorbate 80 or any component of the investigational therapy that is unsuitable for preoperative use with steroids or to H2 blockers that inhibit further treatment with these agents.

[0107] Any of the following within 6 months prior to the first IMP dose in the crossover group: - Second-degree / third-degree heart block - Poorly controlled high blood pressure, - Myocardial infarction - Severe / unstable angina - Coronary / peripheral artery bypass grafting, - New York Heart Association Class III or IV congestive heart failure Grade 3 or higher arrhythmia, - Stroke or transient ischemic attack.

[0108] Left ventricular ejection fraction < 40%.

[0109] Previous malignancy. Allowed for adequately treated basal cell carcinoma or squamous cell skin cancer, or superficial (pTis, pTa, and pT1) bladder cancer, or low-risk prostate cancer, or any in situ malignancy following curative therapy, and any other cancer for which cytotoxic chemotherapy has been completed ≥ 3 years prior to the first dose and the patient has been disease-free for ≥ 3 years.

[0110] Known acquired immunodeficiency syndrome (AIDS) related disease or known HIV disease requiring antiviral treatment, or active hepatitis A (defined as positive HA antigen or positive IgM), hepatitis B (defined as positive HBs antigen or antibody, positive hepatitis B virus DNA test above the detection limit), or hepatitis C infection (defined as known positive hepatitis C antibody result or known quantitative hepatitis C (HCV) ribonucleic acid (RNA) result above the detection limit).

[0111] Malabsorption syndrome or any condition that may significantly affect lenalidomide absorption (for example: galactose intolerance, Lapp lactose deficiency, and genetic problems).

[0112] During the primary study period, lenalidomide and dexamethasone were prematurely discontinued due to relevant adverse events occurring less than 6 months before the start of the crossover phase, consent to withdrawal, or any reason other than PD.

[0113] Based on local clinical practice, people are unable or unwilling to undergo thrombosis prevention.

[0114] In the crossover group, any of the following must have occurred within 3 months prior to the first IMP administration: anti-therapeutic peptic ulcer disease, corrosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic events.

[0115] Any serious acute or chronic medical condition that may impair a patient’s ability to participate in the study or interfere with the interpretation of the study results (e.g., systemic infection, unless treated with anti-infective therapy), or that prevents the patient from adhering to the study procedures.

[0116] Pregnant or breastfeeding women, or women who intend to become pregnant during the cross-parts. See exclusion criteria.

[0117] Male participants. See exclusion criteria. Investigational drugs Essartucisic acid

[0118] Exatuximab is provided as a concentrated solution for infusion in 20 mg / mL (500 mg / 25 mL) vials containing 20 mM histidine, 10% (w / v) sucrose, and 0.02% (w / v) polysorbate 80 in a pH 6.0 buffer. Exatuximab is provided as a sterile, pyrogen-free, injectable 20 mg / mL infusion solution concentrate (substantially free of visible particles) for parenteral administration and is packaged in 30 mL glass vials with a resilient closure. Each vial contains a nominal concentration of 500 mg of exatuximab. Establish a filling volume to ensure 25 mL is removed. For patient administration, dilute an appropriate volume of exatuximab in a 250-mL infusion bag containing 0.9% sodium chloride solution or 5% glucose solution. Dilution method

[0119] The exatuximab concentrate for infusion is diluted in an infusion bag containing 0.9% sodium chloride or 5% glucose solution to achieve an appropriate drug concentration for infusion. Infusion via a central line is preferred if available. In cases of local intolerance following peripheral IV infusion, the use of a central line is determined by the investigator. The final infusion volume corresponding to the exatuximab dose is administered via IV infusion, with the duration depending on the total dose administered.

[0120] Prior to administration, each patient's dose is prepared individually by the study pharmacist and labeled with the protocol number, patient number, and treatment instructions. The total dose is calculated based on the latest weight available on the day of infusion preparation: the weight on the day of infusion or the latest weight, assuming it is assessed within a reasonable timeframe according to the investigator's assessment. If the infusion is prepared with the latest assessed weight within a reasonable timeframe, this does not preclude a weight assessment on D1 of each cycle. Lenalidomide

[0121] Lenalidomide is available in capsules of 5 mg, 10 mg, 15 mg, 20 mg and 25 mg. Bortezomib

[0122] Bortezomib from a commercial supplier is available in 3.5 mg vials. Dexamethasone

[0123] Dexamethasone IV / oral (PO) is available in tablets (4 mg); ampoules of 3.3 mg / mL or vials of 10 mg / mL for IV injection. Dosage and schedule

[0124] There is no limit to the number of administration cycles in the absence of major toxicity, disease progression, or any other discontinuation criteria. Preferably, the patient's weight is measured before each cycle to allow for calculation of the exatuximab dose.

[0125] Dosage adjustments (dose delay, dose omission, and, specifically for lenalidomide, bortezomib, and dexamethasone, dose reduction) are permitted for subsequent treatment cycles based on individual patient tolerability. Dose reduction is not permitted for exathuximab infusions. Research on treatment

[0126] Study treatment was defined as either exatuximab in combination with bortezomib, lenalidomide, and dexamethasone in the IVRd experimental group or bortezomib in combination with lenalidomide and dexamethasone in the VRd control group. Patients assigned to the IVRd group routinely received preoperative medication prior to exatuximab infusion to reduce the risk and severity of IR commonly observed with monoclonal antibodies.

[0127] Lenalidomide should be taken with water and swallowed whole. Patients are not permitted to break, chew, or open the capsule. Lenalidomide can be taken with or without food, preferably at the same time each day. Patients should keep a paper diary to record lenalidomide dosages. If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day. If a dose is missed throughout the day, it should not be recorded as an omission and should be replaced. The next scheduled dose should be taken at the next scheduled time.

[0128] BSA > 2.2 m 2 Patients using 2.2 m 2 To determine the bortezomib dosage, oral administration of dexamethasone and lenalidomide was recorded in the patient diary. IVRd group (experimental group)

[0129] For patients treated with a combination of exatuximab, lenalidomide, bortezomib, and dexamethasone, medication administration (after preoperative administration) follows the prescribed dosing regimen:

[0130] Dexamethasone 20 mg / day was administered intravenously on the same day as exartuximab administration, and orally in other cases: -During the induction period (cycles 1 to 4), dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33. If the patient's age is ≥ 75 years, dexamethasone is administered on days 1, 4, 8, 11, 15, 22, 25, 29, and 32. - On days 1, 8, 15, and 22 of continuous treatment, administer 15 to 30 minutes (but no more than 60 minutes) before exatuximab. Dosage recommendations may have been modified based on dose toxicity. If dexamethasone is discontinued early and other study treatments continue, methylprednisolone 100 mg IV may be considered as a pre-operative steroid administration, at the investigator's discretion, if an infusion response (IR) is still required for exatuximab.

[0131] Exartuximab 10 mg / kg IV: - 10 mg / kg on days 1, 8, 15, 22, and 29 of cycle 1, and for subsequent cycles during the induction period, on days 1, 15, and 29. -During the continuous treatment period, on days 1 and 15 of each cycle, - Following the first dose (cycle 1 - day 1 [induction phase]), continue with 10 mg / kg exatuximab every 2 weeks for 17 cycles, followed by administration every 4 weeks thereafter. - If available, infusion via a central line is preferred. In cases of local intolerance following peripheral IV infusion, the use of a central line is determined by the investigator.

[0132] For IV infusions, use an IV tubing application device with a 0.20 μm inline filter. If the inline filter is unavailable, a 0.20 μm filter unit can be connected to the application device before administration.

[0133] rate and duration of essartucimbrine infusion:

[0134] During the study, exatuximab administration was switched to a fixed-volume (250 mL) rapid infusion as follows: For the first fixed-volume rapid infusion of exatuximab, preoperative medication for the prevention of IR was administered. Patients who did not experience IR after four consecutive administrations of exatuximab may have reconsidered their need for subsequent preoperative medication, which was at the investigator's discretion. The first exatuximab infusion was started at 25 mL / hour. If no IR was observed after 1 hour of infusion, the infusion rate was increased in increments of 25 mL / hour every 30 minutes, up to a maximum of 150 mL / hour. If grade 2 IR was present during the first infusion, the infusion could be restarted at half the initial infusion rate (12.5 mL / hour) when the IR improved to ≤ grade 1. If symptoms did not recur after 30 minutes, the infusion rate could be increased in increments of 25 mL / hour every 30 minutes until the total infusion volume was reached. The second infusion was started at 50 mL / hour. If no grade 2 IR is observed after 30 minutes of infusion, the rate is increased to 100 mL / h for 30 minutes, then increased to 200 mL / h until the total infusion volume is reached. If a grade 2 IR is observed during the second infusion, the infusion can be restarted at half the initial infusion rate (25 mL / h) when the IR improves to ≤ grade 1. If symptoms do not recur after 30 minutes, the infusion rate can be increased in increments of 50 mL / h every 30 minutes until the total infusion volume is reached. The third and subsequent infusions begin at a fixed infusion rate of 200 mL / h until the total infusion volume is reached. If a grade 2 IR is observed during the third infusion, the infusion can be restarted at half the infusion rate (100 mL / h) when the IR improves to ≤ grade 1. If symptoms do not recur after 30 minutes, the infusion rate can be increased in increments of 50 mL / h every 30 minutes until the total infusion volume is reached.

[0135] Only during the induction period (cycles 1 to 4), on days 1, 4, 8, 11, 22, 25, 29, and 32, at a dose of 1.3 mg / m². 2 Administer bortezomib SC. Lenalidomide PO was administered at 25 mg / day (10 mg / day for patients with CrCl ≥ 30 to < 60 mL / min) during the 42-day induction period (cycles 1 to 4) and from day 1 to day 21 during the continuous treatment period (cycles 1 to 4). Dosage may have been modified based on dose toxicity recommendations during the treatment period. Lenalidomide should be taken at the time most convenient for the patient, preferably at the same time as the previous dose. VRd group (control group)

[0136] For patients treated with the combination of bortezomib and lenalidomide, drug administration should follow the same instructions as for the IVRd group.

[0137] For dexamethasone, follow these instructions: -During the induction period (cycles 1 to 4), administer dexamethasone on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33. If the patient is ≥ 75 years old, administer dexamethasone on days 1, 4, 8, 11, 15, 22, 25, 29, and 32. - On days 1, 8, 15, and 22 during the continuous treatment period. Cross group

[0138] Patients in the VRd group who were eligible for the crossover group received exatuximab, lenalidomide, and dexamethasone. In the crossover group, drug administration (following preoperative administration) followed the instructions for use:

[0139] Dexamethasone 20 mg was administered intravenously on the same day as the ethatuximab administration, and otherwise administered orally on days 1, 8, 15 and 22 of each cycle, 15 to 30 minutes (but no more than 60 minutes) before the ethatuximab administration. - If treatment is stopped for reasons other than safety before the start of crossover therapy (unless more than 6 months prior to crossover and based on the investigator's judgment), add dexamethasone to the crossover portion. - If the dexamethasone dose is reduced for safety reasons, then begin the final dose of dexamethasone.

[0140] Exatuximab was administered IV at 10 mg / kg on days 1, 8, 15 and 22 of the first crossover cycle, and then at 10 mg / kg on days 1 and 15 of subsequent cycles.

[0141] rate and duration of essartucimbrine infusion:

[0142] During the study, the administration of exatuximab was switched to a fixed-volume (250 mL) rapid infusion, as described above for the fixed-volume rapid infusion of exatuximab.

[0143] Lenalidomide 25 mg PO is administered on days 1 to 21 of a 28-day cycle, or 10 mg / day for patients with CrCl ≥ 30 to < 60 mL / min (see GFR calculation above). Lenalidomide should be taken at the time most convenient for the patient, preferably at the same time as the previous dose. - If lenalidomide decreases in the control group, it should be increased back to 25 mg / day, unless the dose is reduced for safety purposes and the criteria for reincreasing are not met. Dosage modification General Rules

[0144] Dosage modifications are permitted according to the guidelines described in this section. In cases of toxicity, dose reduction and / or cycle delay are allowed. If toxicity occurs and does not resolve on the scheduled infusion / administration day, the patient may omit one or more doses within the cycle (exatuximab and / or lenalidomide and / or bortezomib and / or dexamethasone). If the patient experiences several toxicities and there is a conflict of recommendations, the most conservative recommended dose adjustment should be followed (the dose reduction / omission / delay appropriate for the most severe toxicity). Once the dose of lenalidomide, bortezomib, or dexamethasone has been reduced, it is not permitted to escalate back to the previous dose level within the patient unless the patient switches to a crossover group (if the dose was reduced for safety reasons, escalation is not permitted). If a dose reduction is required, it should be applied compared to the last dose level received by the patient.

[0145] In the event of persistent adverse events despite appropriate dose modifications or any other adverse events for which discontinuation is approved based on the investigator's opinion, administration of study therapy (exatusimab and / or lenalidomide and / or bortezomib and / or dexamethasone) shall be discontinued.

[0146] After the toxicity subsides, the patient will undergo the next study treatment cycle, as described below.

[0147] If the following criteria are met, a new study treatment cycle may have already begun on the scheduled first day of the subsequent cycle. - Absolute neutrophil count ≥ 1000 / mm 3 . - Platelet count ≥ 70,000 / mm 3 For patients with BM nucleated cells ≥ 50% at baseline, a platelet count ≥ 30,000 / mm² is required to initiate cycle 2. 3 Regardless of the remission status at the end of cycle 1, during cycles 2-4, if the final remission is not better than stable disease (SD), the platelet count should be ≥ 30,000 / mm³. 3 However, if the final remission during cycles 2-4 is PR or better, then only if the platelet count is ≥ 70,000 / mm³ 3 The next cycle can only be administered on day 1. For administration on day 1 after cycle 4, and for the crossover portion, regardless of the cycle, the platelet count should be ≥ 50,000 / mm². 3 . - Any other lenalidomide, bortezomib, dexamethasone, or eshatuximab-related adverse events that may have occurred in previous cycles have recovered to grade ≤ 1 or baseline severity.

[0148] If these criteria are not met on the scheduled Day 1, Day 1 of the next cycle should be delayed until the patient recovers as defined above, and if Day 1 is delayed by more than 3 days, the reason should be documented. If these criteria are not met within 14 days of the scheduled Day 1 (the planned Day 1 of cycle n+1 corresponds to day 43 of the induction phase of cycle n and day 29 of the continuous treatment phase of cycle n), the patient should discontinue study treatment unless there is strong evidence of clinical benefit justifying continued administration of study treatment. The investigator must discuss the reasons with the sponsor before making a decision to continue study treatment. Delays for the patient's convenience should be avoided during the first cycle, and delays exceeding 14 days or temporary suspension of IMP must be discussed with the sponsor before making a decision.

[0149] If a dose modification occurred in a previous cycle, follow these guidelines to start a new cycle or during that cycle: - Dosage reduction of exatuximab is not permitted. - If lenalidomide, bortezomib, or dexamethasone administration was stopped during a previous cycle and restarted at a reduced dose level, this reduced dose level will begin on day 1 of the new cycle. Once the dose of lenalidomide, bortezomib, or dexamethasone has been reduced, it is not permitted to escalate back to the previous dose level in the patient unless specific conditions for lenalidomide are met. - During the cycle, no dose delay is permitted for lenalidomide and bortezomib, except within a ±1-day time window. During the induction period, no dose delay for dexamethasone is permitted, following the recommended initial schedule. No dose delay is permitted for esartanuximab (weekly administration) during cycle 1, except within a ±1-day time window. For subsequent cycles, the time window for administering esartanuximab on day 15 is ±2 days, and any omissions due to adverse events (AEs) will be recorded in the eCRF. - If one or more adverse events do not resolve on the day of the scheduled administration or the following day (or 2 days for esatuximab if administered every 2 weeks), the patient may omit the dose of esatuximab, bortezomib, or dexamethasone (administered once weekly during the continuous period). If toxicity is not resolved within the permitted time window, IMP administration may be omitted. The patient receives the next administration after recovery from toxicity. - If one or more doses of lenalidomide are omitted during days 1 to 14, or days 22 to 35 (induction period) or days 1 to 21 (continuous treatment period), treatment is not administered on day 14, day 35, or day 21, respectively, to compensate for the omitted doses. - If there are no other adverse events requiring dose reduction and thrombocytopenia and / or neutropenia are managed with supportive measures, dose reduction is not necessary.

[0150] If one of the study treatments is prematurely discontinued, one or more other medications may continue until disease progression or unacceptable toxicity occurs, or the patient wishes to discontinue further study treatment. In this case, the study treatment will end 30 days after the date of the last study treatment administration. Modify dose level when dose is reduced

[0151] Dosage reduction of exatuximab is not permitted.

[0152] The dose reduction steps for lenalidomide are shown in Table A. One or more doses of lenalidomide may be omitted. If CrCl is between 30 and 60 mL / min, the starting dose is 10 mg / day. Table A - Dose Levels at which Lenalidomide Dosage is Reduced Abbreviation: PO = Oral.

[0153] The dexamethasone dose reduction procedure is shown in Table B. One or more doses of dexamethasone may be omitted, and administration may be reduced to once weekly or once every two weeks. Based on the investigator's decision, on the day of exatuximab infusion, the dexamethasone dose may be maintained at 20 mg and reduced only on days when exatuximab is unavailable. Table B - Dose Levels at which dexamethasone dosage is reduced Abbreviations: IV = intravenous; PO = oral.

[0154] The dosage reduction steps for bortezomib are shown in Table C. One or more doses of bortezomib may be omitted, and administration may be reduced to once weekly. Table C - Dosage levels at which bortezomib dosage is reduced Abbreviation: SC = Subcutaneous. Dosage adjustment

[0155] In cases of hematologic toxicity, dose adjustments for patients treated with a combination of exatuximab, bortezomib, lenalidomide, and dexamethasone are shown in Table 2. In cases of non-hematologic toxicity, dose adjustments for patients treated with a combination of exatuximab, lenalidomide, bortezomib, and dexamethasone are shown in Table 3. Table 2 - Dosage Adjustment Guidelines for Hematologic Toxicity - Esatuximab / Bortezomib / Lenalidomide / Dexamethasone Combination a For hematologic toxicity, after BM function improves, the next higher dose level of lenalidomide (up to the starting dose) can be introduced (with at least two consecutive cycles without hematologic toxicity: ANC ≥ 1.5 × 10⁻⁶ at the start of a new cycle). 9 / L and platelet count ≥ 100 x 10 9 / L). In patients with a baseline CrCl < 60 mL / min, a 10 mg lenalidomide dose may be increased to up to 25 mg during treatment. If CrCl > 60 mL / min, such a change is recommended after a duration of at least 4 weeks of normal values. This is not permitted if the lenalidomide dose is reduced due to a non-hematologic adverse event. b For patients with >50% nucleated plasma cells at baseline, a platelet count ≥30,000 / mm³ is required to initiate cycle 2. 3 Regardless of the remission status at the end of cycle 1, during cycles 2 through 4, if the final remission is not better than SD, the platelet count should be ≥ 30,000 / mm³. 3 However, if the final remission during cycles 2 to 4 is PR or better, then only if the platelet count is ≥ 70 × 10⁻⁶. 9 The next cycle can only be administered on day 1 when the platelet count is / L. For administration on day 1 after cycle 4, and for the crossover portion, the platelet count should be ≥ 50 × 10⁹ / L. 9 / L. c Dosage delays of up to 14 days are permitted between cycles to allow patients to return to their baseline status. Beyond 14 days, patients must permanently discontinue study treatment (see section 8.1.6.1). d If certain toxicities do not resolve within one day of the scheduled infusion (or two days for every two-week administration), the patient may omit the exatuximab dose during the cycle (see section 8.1.6.1). Abbreviations: ANC = Absolute neutrophil count; G-CSF = Granulocyte colony-stimulating factor; PR = Partial remission; SD = Stable disease. Table 3 A dose delay of up to 14 days is permitted between cycles to allow the patient to return to baseline status. Beyond 14 days, the patient must permanently discontinue the study (see section 8.1.6). abbreviation AE = Adverse events; CrCl = Creatinine clearance; DVT / PE = Deep vein thrombosis / pulmonary embolism. Non-investigation drugs Preoperative medication for the prevention of infusion reactions

[0156] Patients assigned to the IVRd and crossover groups routinely received preoperative medication prior to esartanuximab infusion to reduce the risk and severity of IR, which is typically observed with monoclonal antibodies. The recommended preoperative medication regimen was: diphenhydramine 25 to 50 mg IV (or equivalent), dexamethasone IV / PO (dosage defined below), ranitidine 50 mg IV (or equivalent), and acetaminophen (paracetamol) 650 to 1000 mg PO, followed by esartanuximab infusion. Esartanuximab infusion was initiated immediately upon completion of the preoperative medication regimen. Patients who did not experience IR after four consecutive doses of esartanuximab may have reconsidered their need for subsequent preoperative medication; this was at the investigator's discretion. Dexamethasone

[0157] On the day of the ethatuximab infusion, a total of 20 mg of dexamethasone was administered before the ethatuximab infusion as a preoperative medication and as part of the basic treatment.

[0158] On the day of administration of exartuximab, the following order is recommended: - Acetaminophen 650 mg to 1000 mg PO. - Ranitidine 50 mg IV (or equivalent). - Diphenhydramine 25 mg to 50 mg IV (or equivalent). -Dexamethasone 20 mg IV.

[0159] Regardless of the route of administration (IV or PO), dexamethasone is administered only once (a single administration is used for both preoperative medication and investigational treatment).

[0160] If dexamethasone is discontinued early and other research treatments continue, then, based on the investigator's judgment, if preoperative administration of methylprednisolone 100 mg IV may be considered as a preoperative steroid administration for exatuximab if IR is still required. ranitidine or equivalent

[0161] The medical determination is whether ranitidine or its equivalent should be used or not used as part of pre-operative medication for intravenous infusion (IR). Ranitidine is presented as a solution for IV infusion. If administered, the drug is given at a dose of 50 mg 15 to 30 minutes (but no more than 60 minutes) prior to the exathusiamumab infusion.

[0162] Equivalent drugs can be administered (e.g., other approved H2 antagonists, such as cimetidine, oral proton pump inhibitors, such as omeprazole, esomeprazole). Diphenhydramine or its equivalent.

[0163] Diphenhydramine is presented as a solution for intravenous infusion. This drug is administered at a dose of 25 to 50 mg 15 to 30 minutes (but no more than 60 minutes) prior to exatuximab infusion.

[0164] Equivalent drugs (e.g., cetirizine, promethazine, dexchlorpheniramine) can be administered. Intravenous administration is preferred for at least the first four infusions. However, in countries where diphenhydramine or an equivalent IV formulation is unavailable, oral administration is permitted from the start of the first esatuximab infusion. In this case, the oral formulation should be taken 1 to 2 hours prior to the start of the esatuximab infusion. Acetaminophen (paracetamol)

[0165] Administer this drug at a dose of 650 to 1000 mg 15 to 30 minutes (but no more than 60 minutes) before the infusion of ethatuzumab. Methods of assigning patients to treatment groups

[0166] Using the IRT central randomization system, all eligible patients were randomly assigned to the treatment group (IVRd or VRd) at a ratio of 3:2. Patients were assigned to the treatment group based on a stratified randomization list that considered age (< 70 years vs. ≥ 70 years) and R-ISS stage (Stage I or II vs. Stage III vs. unclassified).

[0167] After each patient completes the necessary screening access procedures, the corresponding baseline eCRF is completed, and the investigator or designated personnel determine the patient's eligibility for the study based on laboratory evaluation.

[0168] Patients who fail screening can be screened again, and all procedures can be restarted for these patients.

[0169] The site entered the following information about the clinical site and research patients: -Personal identification number. - The patient's date of birth (in accordance with specific national regulations). - Revision of the international tranche system.

[0170] The IRT uses the above-described randomization stratification to assign patients to the IVRd or VRd group according to a predefined randomization schedule. Concomitant drug therapy

[0171] Concomitant medication is any treatment a patient receives alongside any one or more study treatments. All treatments administered to a patient within 21 days prior to randomization, at any time during the treatment period, and up to 30 days after the last dose are considered prior and concomitant treatments, respectively, and are reported on the appropriate page of the eCRF.

[0172] Concomitant medications are permitted if they are deemed necessary for the patient's health and unlikely to interfere with the investigation product. Investigators are permitted to administer these concomitant medications at their discretion and record them in the eCRF. Prophylactic urate-lowering agents (e.g., allopurinol or rasburicase) and IV fluids are highly recommended in patients at risk for TLS. Antibiotic prophylaxis is recommended for all patients during induction therapy, provided it conforms to current guidelines and literature (NCCN rel. 1.2018, [Drayson MT, Bowcock S, Planche T, Iqbal G, Wood J, Raynes K et al. Tackling early morbidity and mortality in myeloma (TEAMM): assessing the benefit of antibiotic prophylaxis and its effect on healthcare-associated infections in 977 patients. Blood. [Blood] 2017; 130:903]).

[0173] Recommended antimicrobial prophylaxis includes cotrimoxazol PO or quinolone PO (according to NCCN Guideline 1.2018, quinolone is the preferred choice for intermediate risk factors such as MM disease). As an example: Cotrimoxazol 2 x 960 mg / day PO. Or Ciprofloxacin 2 x 500 mg / day PO.

[0174] Other preventative measures may be permitted if deemed appropriate, at the researcher's discretion. It is recommended that such preventative measures begin no later than day 1 of study treatment and continue for up to six weeks after the end of the induction treatment period.

[0175] Antifungal prophylaxis: Antifungal prophylaxis should be administered according to local policy. For patients with negative hepatitis B serological tests, hepatitis B vaccination should be considered. Virus prevention

[0176] For patients receiving bortezomib, prophylaxis against shingles should be initiated with oral acyclovir or valacyclovir or an equivalent antiviral therapy, as determined by institutional guidelines and at the discretion of the field investigator, unless the participant experiences a hypersensitivity reaction to these agents. Dosage should be adjusted based on serum creatinine levels, as indicated in the package insert. Antithrombotic therapy

[0177] Lenalidomide increases the risk of venous thromboembolism. Anticoagulation prophylaxis is required after assessing each patient's potential risk factors. All patients receive prophylactic antithrombotic therapy unless there is an excessive risk of bleeding. If aspirin is contraindicated, patients receive an alternative form of antithrombotic therapy according to hospital guidelines or physician preference.

[0178] For patients with at least one risk factor (i.e., a history of previous venous thromboembolism, immobilization, and concomitant use of erythropoiesis-stimulating agents), aspirin prophylaxis is recommended for patients with standard risk and low molecular weight heparin. Granulocyte colony-stimulating factor prevention

[0179] G-CSF prophylactic administration may be considered in patients with difficulty experiencing relapses of neutropenia, or therapeutically in patients with severe neutropenia complications such as tissue infection, sepsis syndrome, or fungal infection, at the investigator's discretion, consistent with the American Society of Clinical Oncology guidelines (2006) to reduce the risk of neutropenia, particularly in patients with extensive baseline BM involvement and / or low neutrophil counts (Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L et al. 2006 update of recommendations for the use of white blood cell growth factors: anevidence-based clinical practice guideline. J Clin Oncol. 2006:24:3187-205.). Concomitant therapy

[0180] Concurrent treatment with any other antimyeloma therapies not specified in the protocol (including immunotherapy, hormone therapy, targeted therapy or biotherapy, other investigational drugs, or curative radiotherapy) is prohibited. However, palliative radiotherapy is permitted to control pain. Within any given 3-week timeframe, the irradiated area should be as small as possible and should not exceed 20% of the tumor's wall area (BM). In all such cases, the possibility of tumor progression should be ruled out through physical, biochemical, and radiological assessment of the tumor. The irradiated area is not used as a parameter for assessing response.

[0181] Systemic corticosteroids are prohibited except as part of the treatment regimen specified in the protocol or for the treatment of hypersensitivity reactions. Additional glucocorticoids, antihistamines, and analgesics are permitted for IR management. Inhaled glucocorticoids are also permitted upon instruction.

[0182] Avoid live vaccines. However, given the increased risk of infection, routine vaccination is recommended for patients and their contacts. Prophylactic vaccination against influenza A and B viruses, pneumococcus, and Haemophilus influenzae is recommended.

[0183] Avoid co-administration of strong CYP3A4 inhibitors. Monitor the safety of patients receiving bortezomib, and if bortezomib is administered in combination with a strong CYP3A4 inhibitor, reduce the dose of bortezomib. Avoid co-treatment with dexamethasone and CYP3A inhibitors unless the benefit outweighs the increased risk of systemic corticosteroid side effects; in such cases, monitor patients for systemic corticosteroid side effects.

[0184] The concomitant use of strong CYP3A4 inducers (e.g., rifampin) is not recommended. St. John's wort (Hypericumper foratum) can unpredictably reduce bortezomib exposure and avoid St. John's wort.

[0185] The risk of rhabdomyolysis increases when statins are administered concurrently with lenalidomide. Approval greatly enhances clinical and laboratory monitoring during the first few weeks of treatment. Monitoring of creatine phosphokinase (CPK) is required when clinically indicated.

[0186] Concomitant administration of lenalidomide increases digoxin plasma exposure. Therefore, monitoring of digoxin concentrations is recommended during lenalidomide treatment. Hepatitis B reactivation

[0187] In the event of viral reactivation during study treatment (an increase in HBV DNA greater than 1 log10 IU / mL or the reappearance or detection of HBV DNA in patients with regressed infection), study treatment should be discontinued and a specialist consulted to initiate antiviral therapy and patient monitoring. If the infection is controlled, study treatment may be restarted upon agreement between the sponsor, investigator, and specialist (hepatologist). Close monitoring of ALT and AST is required monthly until study treatment is discontinued. HBV DNA testing should be performed as advised by a specialist.

[0188] A prior history of acute or chronic hepatitis B or presence of total anti-HBc, with / without anti-HBs; HBsAg negative; undetectable serum HBV DNA; normal ALT levels. Evaluation of research drugs Primary endpoint

[0189] The primary endpoint is progression-free survival (PFS), defined as the time from the randomization date to the first recorded date of progressive disease (PD) (as determined by IRC) or the date of death from any cause (whichever comes first).

[0190] The following disease assessment procedures should be performed at screening (for eligibility), on day 1 of cycle 1 before administration of study treatment (baseline for response assessment), on day 1 of each remaining cycle during treatment until progression or discontinuation for other reasons, at EOT visits, and during follow-up: -M protein quantification (serum and 24-hour urine, protein immunoelectrophoresis and immunofixation; central laboratory). Immunofixation was performed after Day 1 of Cycle 1 when M protein was undetectable (serum and urine). - Serum-free light chain quantification (central laboratory). - Quantitative immunoglobulin (central laboratory).

[0191] Other examinations for disease assessment include: • Bone marrow sample for evaluation of potential CR at VGPR or better (local laboratory). • Bone marrow aspiration for MRD assessment at baseline and at the end of the induction phase and during continuous treatment in the case of CR or VGPR (Central Laboratory). • Radiation assessment for osteolytic disease: -At baseline, then annually (±7 days) (except when the patient presents with soft tissue plasmacytoma) and at any time during the study period (if clinically indicated), bone examination (plain X-ray) or low-dose whole-body (LDWB) CT scan or PET-CT scan or WB-MRI. • Assessment of bone diseases and soft tissue plasmacytoma: - PET-CT scans are the preferred option performed at baseline and, if positive, are repeated at CR and / or at the end of the induction period. These examinations should not be performed within one month of each other. During continuous treatment, repeat radiation examinations at the following time points: -During CR and / or at the end of the induction period. These tests should not be performed within one month of each other. - One year after the start of the study treatment, that is, after 6 months (±7 days) of continuous treatment. - During the second year of the study treatment, every 6 months (±7 days). -Starting from year 3 of study treatment, annually until PD (even for patients who will begin further anti-myeloma therapy without PD), or if PD is suspected, or until the cutoff date of the final PFS analysis (whichever occurs first). - Plasma cell tumor measurements are collected only in e-CRF, and all other bone parameters are evaluated on PET via central imaging review. WB-MRI is permitted as an alternative in cases where baseline PET-CT scanning is unavailable. - In the crossover group, a CT or MRI scan is required; if soft tissue plasmacytoma is known, evaluation should be performed before day 1 of crossover cycle 1 and repeated every 12 weeks, and if clinically indicated during treatment, until PD, or until the cutoff date of the final PFS analysis (whichever comes first). If soft tissue plasmacytoma is suspected, a CT or MRI scan should be performed before day 1 of cycle 1. If soft tissue plasmacytoma is confirmed, the same schedule mentioned above should be followed. - Perform a PET-CT scan or MRI in patients with no previously positive images of soft tissue plasmacytoma, in cases of suspected PD, or if clinically indicated. -Note: For the assessment of bone lesions or soft tissue plasmacytomas, the same approach (bone examination or LDWB CT; PET-CT or MRI) was used for each individual patient throughout the study. MRI examinations were permitted during treatment, except at baseline, and were limited to the disease-related area. However, for patients who underwent only WB-MRI at baseline, the same examination was repeated annually if lytic lesions were present.

[0192] Send all imaging scans for central review (except during cross-checking).

[0193] Based on central laboratory findings on day 1 of each cycle, decisions that may affect recovery treatment and efficacy assessments for primary and secondary endpoints are made. Response / progression is determined according to IMWG criteria.

[0194] Remission / progression based on paraprotein assessment was confirmed using two consecutive assessments. Blinded IRC evaluated disease assessments for each cycle and determined progression and remission status for each patient according to IMWG criteria (Appendix D) and as described in the IRC charter.

[0195] IRC is not required during the crossover.

[0196] Diseases are assessed according to the IMWG remission criteria. Key secondary efficacy endpoints

[0197] Four key secondary efficacy endpoints were considered: • Complete response rate: defined as the proportion of patients with CR / sCR, as assessed by IRC using IMWG criteria. • The negative rate of minimal residual disease (MRD) in CR patients is defined as the proportion of patients who are MRD negative. Bone marrow aspirates are collected at screening, and for patients with CR or VGPR, bone marrow aspirates are collected at the end of the induction period, then every 6 months for the first 2 years (12, 18, and 24 months after randomization), and then annually until PD or until the cutoff date of the final PFS analysis, whichever comes first. The threshold for negativity is at least 10. -5 . • Very good partial response rate or better rate: defined as the proportion of patients with sCR, CR and VGPR, as assessed by IRC using IMWG criteria. • Overall survival (OS): Defined as the time from the randomization date to death from any cause.

[0198] Follow-up of M protein by serum immunofixation electrophoresis (IFE) is part of the IMWG criteria for assessing treatment response. Therefore, it is important that the ezetuzumab band not be confused with the patient's endogenous M protein during IFE interpretation. For participants suspected of having ezetuzumab interference on serum IFE, the central laboratory used the SEBIA HYDRASHIFT 2 / 4 ezetuzumab IFE test to specifically measure endogenous M protein. Participants who met all other IMWG criteria for CR and confirmed negative immunofixation after the HYDRASHIFT ezetuzumab test were considered to have achieved complete remission. This defines the final CR rate according to the IMWG criteria.

[0199] Minimal residual disease negative is defined according to IMWG standards. Other secondary endpoints

[0200] Other secondary efficacy endpoints are as follows: • Overall response rate: Defined as the proportion of patients with a BOR that is recorded as sCR, CR, VGPR, and PR, as assessed by the IRC using the IMWG response criteria. The following assessments were considered to arrive at the BOR: - Randomization group: From the randomization date until the first recorded PD, death, antimyeloma treatment start, or crossover start, whichever occurs first, the timeframe will be used. - For the crossover group: Optimal continuous response is defined as the period from the first intake of exartuximab until the first recorded PD, death, or start of antimyeloma treatment, whichever occurs first. • Time to Progress: Defined as the time from the randomization date to the date the first PD is recorded (as determined by IRC). Use the same progress definition as the PFS endpoint. • Duration of response: Defined as the time from the date of initial IRC-determined response to the date of initial IRC PD or death (whichever occurs first). Duration of response is determined only for patients who achieved sCR, CR, VGPR, or PR. •TT1R: Defined as the time from randomization to the subsequent confirmation of the first IRC-determined relief (PR or better). •TTBR: Defined as the time from randomization to the date of the best-case remission (PR or better) determined by the subsequently confirmed IRC. • PFS2: Defined as the time from randomization to the date of first recorded PD (as assessed by the investigator) or death from any cause (whichever occurs first) after initiation of further antimyeloma therapy. The crossover group is considered the next line of treatment. • PFS determined by MRD status. • ≥ 12-month sustained MRD negativity rate: defined as the proportion of patients who maintained MRD negativity for ≥ 12 months without any MRD positive test during that period. Safety endpoint

[0201] The safety of AE / SAE, laboratory parameters, vital signs (blood pressure, heart rate, and body temperature), weight, ECOGPS, and physical examination was evaluated through research and reported in the eCRF.

[0202] Adverse event data are collected by reporting at specified intervals throughout the study. Treatment-related adverse events (TEAEs) are defined as AEs that occur, worsen (according to the investigator), or become serious during the treatment period. Crossover TEAEs are defined as AEs that occur, worsen (according to the investigator), or become serious during the crossover treatment period.

[0203] Use NCI CTCAE v4.03, which is available online at the following NCI website, to classify adverse events and laboratory parameters: https: / / ctep.cancer.gov / protocolDevelopment / electronic_applications / ctc.htm. Immunogenicity

[0204] Throughout the study, human ADA response to exatuximab was evaluated only in the IVRd and crossover groups. Blood samples were collected for ADA detection. Bioanalytical methods used for immunogenicity assessment are summarized in Table 4. Table 4 - Bioanalytical methods for assessing antidrug antibody immune responses

[0205] If ADA is detected, the sample is considered ADA-positive, meaning it generates a test signal equal to or greater than the threshold in the screening assay and tests positive in the confirmatory assay. If ADA is not detected, but the drug is present in the same sample at a level that may interfere with the ADA detection method, and therefore a negative ADA result cannot be definitively confirmed, the sample is considered ADA-indeterminate.

[0206] In the case of a positive or indeterminate ADA sample in cycle 10, additional ADA samples are taken 3 months later. No further ADA sampling is performed, even if the sample taken at this 3-month mark is positive. If ezatuximab was discontinued before cycle 10 prior to lenalidomide, bortezomib, and dexamethasone, and the last ADA sample was positive or indeterminate, additional ADA samples are taken 3 months later. No further ADA sampling is performed, even if the sample taken at this 3-month mark is positive. For patients with fewer than 10 cycles at the final PFS analysis cutoff date, ADA sample collection ceases from the cutoff date. If the last ADA sample before the final PFS analysis cutoff date is positive or indeterminate, an additional sampling period is taken 3 months later for ADA evaluation. No further ADA sampling is performed, even if the sample taken at this 3-month mark is positive. definition:

[0207] Pre-existing ADA: defined as ADA present in samples taken during the pre-treatment period (i.e., prior to the first administration of exartuximab).

[0208] Treatment-induced ADA: defined as ADA that develops at any time during the treatment period in patients without pre-existing ADA (including patients without a pre-treatment sample).

[0209] Treatment-enhanced ADA: defined as pre-existing ADA with increased titers during the study observation period.

[0210] Transient ADA response: • Treatment-induced ADA detected only at one sampling time point during the treatment or follow-up observation period (excluding the last sampling time point, which should be considered persistent unless it shows to be undetectable at a later time), or • Treatment-induced ADA detected at two or more sampling time points during treatment (if any, including follow-up periods), wherein the interval between the first and last ADA-positive samples (regardless of any negative samples in between) is less than 16 weeks, and the patient's last sampling time point was ADA-negative. •Continuous ADA response: - Treatment-induced ADA detected at two or more sampling time points during treatment (including follow-up periods, if applicable), wherein the first and last ADA-positive samples (without regard to any negative samples in between) are at least 16 weeks apart.

[0211] Uncertain ADA response: • Treatment-induced ADA was detected only at the last sampling time point, after all previous samples were negative, or • The last two samples were ADA positive and the interval between them was less than 16 weeks.

[0212] ADA response endpoint: • ADA-negative patients are those who did not receive any treatment to induce or enhance ADA during the study observation period. • The incidence of ADA was defined as the proportion of ADA-positive patients (i.e., patients who had at least one treatment-induced or treatment-enhanced ADA at any time during the study observation period). • ADA prevalence is defined as the proportion of all patients who test positive for ADA at any time point (including pre-existing ADA, treatment-enhanced ADA, and treatment-induced ADA). Exploratory endpoint

[0213] Blood samples were collected and analyzed for immunogenetic determinants (such as Fcγ receptor polymorphism) and correlated with efficacy endpoints (including ORR, DOR, PFS, and OS).

[0214] Study pharmacokinetic estimates as prognostic factors for clinical outcomes, including safety and efficacy endpoints (if possible).

[0215] In addition to identifying three cytogenetic abnormalities (del[17p], t[4;14], and t[14;16]) as stratification factors in the R-ISS stage by FISH assessment at baseline, other cytogenetic abnormalities of BM, such as, but not limited to, gain(1q), and parameters related to clinical response were analyzed.

[0216] In the IVRd group only, additional serum samples were collected at all time points assessing M protein to evaluate novel serum M protein measurement methods, such as mass spectrometry (central laboratory), up to cycle 30. This sample was collected after cycle 30 only for patients who achieved at least VGPR by the end of this cycle, until disease progression. In cases where exatuximab was discontinued before progression, this sample was collected up to 3 months after discontinuation or upon observation of PD (whichever occurs first).

[0217] An exploratory analysis of imaging-positive MRD-negative reactions on PET imaging will be conducted through independent central imaging review, which will include (but is not limited to) assessment of: BM involvement, focal lesions, and extramedullary / paramedullary lesions. Treatment period

[0218] The induction period lasts for 42 days (±3 days) and the continuous treatment period lasts for 28 days (±3 days). Day 1 of Cycle 1 refers to the day the patient receives the first dose of study treatment. Day 1 of each subsequent cycle corresponds to day 43 or day 29 of the previous cycle in the induction and continuous treatment periods, respectively. The time windows for days 8, 15, and 22 of Cycle 1 are ±1 day. For subsequent cycles, the day 15 time window is ±2 days, and any delays beyond these time windows or any omissions due to adverse events (AEs) are recorded in the eCRF. For bortezomib administration, a ±1-day window is acceptable. Duration of participation in the study

[0219] The study duration for each patient included a screening period of up to 4 weeks, an induction period of 24 weeks (4 cycles, each lasting 42 ± 3 days), a continuous treatment period, and a crossover period (where applicable). During the continuous treatment and crossover periods, each cycle lasted 28 ± 3 days. Patients continued study treatment until disease progression, unacceptable adverse events (AEs), or the patient decided to discontinue the study, whichever occurred first.

[0220] Following treatment discontinuation, patients (including those in the crossover group) returned to the study site 30 days after the last dose of study treatment for an end-of-treatment (EOT) assessment and 90 days after the last dose of study treatment to complete the HRQL questionnaire. Additionally, during the follow-up period, all relevant adverse events (AEs) and all (related or unrelated) serious adverse events (SAEs) occurring at the time of treatment discontinuation were tracked until they resolved or stabilized, regardless of their relationship to the study treatment. During the follow-up period, all new (serious or non-serious) AEs related to the study treatment were collected and tracked until they resolved or stabilized. result Patient Management

[0221] Throughout the study, a total of 446 patients were randomized (ITT population): 181 patients in the VRd group and 265 patients in the IVRd group. Of the 446 randomized patients, 263 received IVRd and 181 received VRd, and 2 patients did not receive treatment. The median follow-up period was 59.73 months. At the data cutoff (September 26, 2023), 47.2% (Isa-VRd) and 24.3% (VRd) of patients were still on treatment; 138 (52.1%, Isa-VRd) and 137 (75.7%, VRd) patients discontinued treatment, primarily due to adverse events (AEs) or progressive disease; 2 randomized Isa-VRd patients did not receive treatment; and 25 VRd patients switched to Isa-Rd. Of the adverse events (AEs) that led to definitive treatment discontinuation, 8 (3.0%, Isa-VRd) and 4 (2.2%, VRd) were related to COVID-19.

[0222] The median duration of treatment was 53.2 months (range, 0.5–68.8; Isa-VRd) and 31.3 months (0.6–67.2; VRd); the median number of cycles started were 52 (range, 1–69) and 29 (1–69), respectively. Correspondingly, the median relative dose intensity was 93.6% for exatuximab; 90.3% (Isa-VRd) and 86.7% (VRd) for bortezomib; 77.7% and 83.5% for lenalidomide; and 81.6% and 79.3% for dexamethasone. Crossover therapy with exatuximab + lenalidomide + dexamethasone during continuous treatment. Demographic and baseline characteristics

[0223] The median age was 72 years (range, 55–80), 16.6% had high-risk cytogenetic abnormalities, 37.0% had chromosomal 1q21+ abnormalities, and 28.7% had eGFR < 60 ml / min / 1.73 m 2 Patient demographics and baseline disease characteristics were well balanced between the IVRd and VRd groups. A total of 237 patients (53.1%) were male, 323 (72.4%) were white, and 48 (10.8%) were Asian. The median age was 72 years, with 67.9% of the population aged 65 to < 75 years and 28.3% aged ≥ 75 years. The median time from initial MM diagnosis to randomization was 1.18 months (range 0.3 to 48.9). 30.7% of patients were in ISS stage I at study entry, 41.9% in stage II, 26.9% in stage III, and 0.4% in an unknown stage. One patient in the Isa-VRd group had an ECOG PS of 3. High risk is defined as the presence of del(17p) and / or t(4;14) and / or t(14;16), where the cutoff value is in the footnote. Defined in the Chinese. Abnormalities were defined as the presence of at least 30% of abnormal bone marrow plasma cells for t(4;14) and t(14;16) and 1q21+ (at least 3 copies), and for del(17p), the presence of at least 50% of abnormal plasma cells. Only one patient had two high-risk cytogenetic abnormalities: del(17p) and t(4;14). 1q21+ is defined as at least 3 copies of 1q21. Amplification of 1q21 is defined as at least 4 copies of 1q21. In addition, 67 (25.3%; Isa-VRd) and 49 (27.1%; VRd) patients had extramedullary disease, and one patient in each group had both extramedullary and paramedullary disease. IRC, Independent Review Committee; IRT, Interactive Response Technology. Treatment exposure

[0224] The median duration of exposure was longer in the IVRd group than in the VRd group: 53.2 months (range 0.5 to 68.8) in the IVRd group and 31.3 months (range 1 to 114) in the VRd group. Summary of treatment exposure - safety population effect Primary endpoint:

[0225] Compared with VRd, adding exartuximab to VRd treatment significantly increased PFS based on blinded IRC assessment. At the cutoff date, 84 (31.7%) and 78 (43.1%) patients in the IVRd and VRd groups, respectively, had PFS events, with a median follow-up of 59.73 months. The hazard ratio was 0.596 (98.5% CI: 0.406 to 0.876), corresponding to a 40.4% reduction in the risk of disease progression or death with IVRd compared to VRd. Median PFS was not reached in the IVRd group, and was 54.34 months in the VRd group (95% CI: 45.207 and not reached the upper limit). The one-sided stratified log-rank test for the comparison of PFS between the two groups was statistically significant, with a one-sided p-value of 0.0005, which met the pre-specified power boundary of 0.0074. Early separation between the IVRd and VRd groups was observed in the PFS curves. Figure 1 ).

[0226] The results of the PFS sensitivity analysis were consistent with those of the primary PFS analysis, thus supporting the robustness of the primary PFS analysis. For all analyses, the HR ranged from 0.509 to 0.632, with no median PFS reached in the IVRd group and from 45.86 to 59.66 months in the VRd group. Both showed statistically significant differences relative to VRd for IVRd (range p < 0.0001 to 0.0012). PFS - Summary of Key Sensitivity Analysis - ITT Population

[0227] Pre-specified PFS subgroup analyses confirmed consistent benefit across most subgroups, including some difficult-to-treat populations with negative prognostic factors. Figure 2 Isa-VRd had a longer time to progression than VRd (HR 0.414; 95% CI 0.286–0.598). Figure 2 ). Key secondary endpoints:

[0228] Consistent and clinically meaningful improvements were observed across all key secondary endpoints based on remission. The key secondary endpoints of complete remission rate and MRD-negative CR rate, as determined by NGS, were statistically significant, meeting the pre-specified efficacy boundary of 0.025. The rate of VGPR or better (p = 0.0259) slightly missed the 0.025 efficacy boundary. Interim overall survival results showed a favorable OS trend for IVRd compared to VRd (OS HR: 0.776, 99.97% CI 0.407 to 1.48). Results of key secondary endpoints - ITT population Using a user-defined alpha consumption function, the operating system (OS) tested at a one-sided significance level is 0.0001375. A 99.97% confidence interval is provided.

[0229] In the ITT population, although the overall response rates for Isa-VRd and VRd were similarly high (91.3% and 92.3%, respectively), significantly more patients with Isa-VRd achieved ≥ CR compared to VRd (74.7% vs. 64.1%; P = 0.008). Furthermore, a significant improvement in the CR rate for MRD was observed at all time points (55.5% vs. 40.9%; P = 0.0013). Figure 3 ).

[0230] Figure 3 The MRD rate at any time during the study period is shown for patients in the ITT population. The median (95% CI) time to MRD- was 14.72 (11.53–24.08) months in the Isa-VRd group and 32.79 (17.51–45.11) months in the VRd group. Response was assessed based on IMWG recommendations (details of the criteria for disease response are provided in the protocol). The following secondary endpoints were tested sequentially using a sequential testing method, each with a total two-sided alpha level of 0.05: ≥ CR, MRD-CR, and ≥ VGPR. Criteria for sCR included CR plus the ratio of normal free light chains and the absence of clonal plasma cells, assessed by immunofluorescence or immunohistochemical analysis or by two- to four-color flow cytometry. The sensitivity threshold of MRD is defined as 1 / 10 of the time during the study. 5 Nucleated cells were collected. Bone marrow aspiration was performed at baseline, at the end of the induction phase in the case of CR or VGPR, and during the continuous treatment phase for central laboratory evaluation. MRD status was assessed based on randomized post-evaluation of bone marrow samples using a FDA-approved next-generation sequencing assay (clonoSEQ® assay, version 2.0; Adaptive Biotechnologies) in accordance with IMWG guidelines on MRD assessment. (Kumar et al.) P-value not reported; not a key secondary endpoint. One-sided p-values ​​were calculated using a stratified Cochran-Mantel-Haenszel chi-square test. CI, confidence interval; CR, complete response; IRC, independent review committee; Isa-VRd, esatuzumab-bortezomib-lenalidomide-dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; MRD-, MRD-negative; NC, not calculated; ORR, overall response rate; sCR, strict complete response; VRd, bortezomib-lenalidomide-dexamethasone; VGPR, very good partial response. Isa-VRd had a higher proportion of MRD- (58.1% vs. 43.6%) and sustained MRD- ≥ 12 months (46.8% vs. 24.3%) than VRd.

[0231] In the case of Isa-VRd, MRD- patients showed a PFS benefit relative to MRD-positive patients (HR 0.220; 95% CI 0.139–0.349), and the difference was smaller in the case of VRd (HR 0.314; 95% CI 0.190–0.517). Patients with persistent MRD- ≥ 12 months had a PFS benefit relative to patients with MRD- < 12 months. Sequential test results . Use a sequential procedure to test key secondary endpoints while controlling for multiplicity. The efficacy p-value boundary was 0.025, therefore this result was not significant, and no other comparisons were tested. CI, confidence interval; ≥ CR, complete response or better; HR, hazard ratio; Isa-VRd, estuximab-bortezomib-lenalidomide-dexamethasone; MRD-, minimal residual disease negative; NGS, next-generation sequencing; OR, odds ratio; OS, overall survival; ≥ VGPR, very good partial response or better; VRd, bortezomib-lenalidomide-dexamethasone. PFS determined by MRD status. Stratification is based on age (< 70 years old vs. ≥ 70 years old) and Revised International Staging System (R-ISS) stage (I or II vs. III or unclassified) according to interactive response technology. Estimate using the Kaplan-Meier method. CI, confidence interval; Isa-VRd, esatuzumab-bortezomib-lenalidomide-dexamethasone; MRD, minimal residual disease; NC, not calculated; PFS, progression-free survival; VRd, bortezomib-lenalidomide-dexamethasone. Additional mitigation data. The assessment of remission is based on the recommendations of the International Myeloma Working Group (details on the criteria for disease remission are provided in the protocol). CI, confidence interval; Isa-VRd, esatuzumab-bortezomib-lenalidomide-dexamethasone; MRD-, minimal residual disease negative; NC, not calculated; VRd, bortezomib-lenalidomide-dexamethasone.

[0232] At the data cutoff, 128 patients had died (69 [26.0%] Isa-VRd; 59 [32.6%] VRd). In either group, the median OS was NR (HR 0.776; 99.97% CI 0.407–1.48), but the HR exceeded the pre-specified nullipopulation threshold (>1.1); follow-up is ongoing. Overall mortality rates (including treatment-related adverse events [TEAEs] and post-treatment periods) tended to favor Isa-VRd (26.2% and 32.6% [VRd]), primarily due to lower mortality rates at disease progression (4.9% [Isa-VRd]; 12.2% [VRd]), supported by the time to death obtained through cause-specific analysis of competing risks.

[0233] At the data cutoff, 19.6% (Isa-VRd) and 44.2% (VRd) of patients initiated further anti-myeloma therapy; among them, fewer patients in the Isa-VRd group (34.6%) received anti-CD38 compared to 68.8% in the VRd group. Although the median PFS2 was NR in both groups, fewer patients in the Isa-VRd group (31.7%) had a second progression event compared to 41.4% in the VRd group. The benefit of Isa-VRd persisted with subsequent therapy lines (PFS2 HR 0.697; 95% CI 0.510–0.952). The time to next treatment was longer in the Isa-VRd group than in the VRd group (HR 0.376; 95% CI 0.265–0.534).

[0234] In both groups, the EORTC-QLQ-C30 overall health status score remained stable over time, and the addition of exatuximab did not have a negative impact. Security: Overview of treatment-associated adverse events (TEAEs)

[0235] The safety profile of IVRd was consistent with the established safety profiles of both exatuximab and the VRd regimen. No new safety issues were identified. The rate of grade 5 TEAEs was 11.0% in the IVRd group and 5.5% in the VRd group.

[0236] The table below summarizes hematological laboratory abnormalities and common adverse events (AEs); serious treatment-induced AEs were reported in 70.7% (Isa-VRd) and 67.4% (VRd) of patients. The incidence of ≥ grade 3 infections in Isa-VRd and VRd was 44.9% and 38.1%, respectively, and was lower in patients receiving antibiotic prophylaxis than in those not receiving antibiotic prophylaxis (43.5% vs. 51.0%, Isa-VRd; 35.2% vs. 48.7%, VRd). Within 60 days of the first dose, there were 29 (11.0%, Isa-VRd) and 10 (5.5%, VRd) grade 5 TEAEs, comprising 4 (1.5%) and 1 (0.6%), respectively; this difference was partly driven by different treatment exposures (0.031 [Isa-VRd] and 0.019 [VRd] events / patient-year). Level 5 TEAEs are primarily caused by infection, including COVID-19-related deaths (12, Isa-VRd; 6, VRd). Hematologic laboratory abnormalities, adverse events of any grade (the worst grade for patients) (≥ 20% of patients in any group), and second primary malignancies reported in the safety population. The safety cohort includes all patients who received at least one dose of the trial treatment. Adverse events of any grade reported by at least 20% of patients in any treatment group are listed. Listed in preferred terminology (worst grade for each patient). Laboratory abnormalities during treatment (worst grade for each patient). Toxicity grades are based on NCI CTCAEv4.03. The three categories presented are not exclusive. This includes COVID-19 and COVID-19 pneumonia. Two patients in the Isa-VRd group and one patient in the VRd group experienced both COVID-19 pneumonia and COVID-19. These events were counted only once when all events related to COVID-19-related TEAEs were grouped. The presence of a second primary malignancy was pre-designated as an adverse event of particular interest in the statistical analysis plan. Identification was performed using the MedDRA Custom MedDRA Query (CMQ) 'Second Primary Malignancy'. This included both events occurring during and after treatment. This included melanoma and one case of peritoneal metastasis. Additionally, 19 patients (Isa-VRd) and 7 patients (VRd) had non-melanoma skin cancer. In the Isa-VRd group, 2 out of 19 patients also had melanoma. In the VRd group, 1 out of 7 patients also presented with colon adenocarcinoma. Isa-VRd, Isatuximab-bortezomib-lenalidomide-dexamethasone; no., quantity; VRd, bortezomib-lenalidomide-dexamethasone. Overview of Treatment-Acting Adverse Events (TEAEs) - Safety Population Isa-VRd, Isatuximab-bortezomib-lenalidomide-dexamethasone; TEAE, adverse events that occur during treatment; VRd, Bortezomib-lenalidomide-dexamethasone. The data is n (%). Treatment-related TEAEs are TEAEs associated with at least one of the drugs in combination. Causes of death during the treatment period in the Isa-VRd group included COVID-19 pneumonia (n = 7), COVID-19 pneumonia / multiple organ failure (n = 1), renal tubular acidosis / TLS (n = 1), septic shock (n = 1), pneumonia (n = 4), sudden death (n = 4), undetermined cause (n = 1), Pseudomonas pneumonia (n = 1), Candida sepsis (n = 1), cirrhosis (n = 1), cutaneous neuroendocrine carcinoma (n = 1), pulmonary embolism (n = 1), febrile neutropenia (n = 1), Klebsiella pneumonia and sepsis (n = 1), respiratory failure (n = 1), dyspnea (n = 1), and sepsis (n = 1). Causes of death in the VRd group included pneumonia (n = 2), COVID-19 (n = 2), aspiration pneumonia (n = 1), undetermined cause (n = 1), pulmonary embolism (n = 1), sepsis (n = 1), and bronchitis (n = 1).

[0237] Because the median duration of exposure was significantly longer in the IVRd group compared to the VRd group (53.2 months in the IVRd group and 31.3 months in the VRd group), the incidence of TEAEs was also assessed based on exposure duration. Overall, the incidence of exposure adjustment was similar between the IVRd and VRd groups. The incidence of exposure adjustment for any grade 5 TEAE was 0.03 and 0.02 events / patient-year in the IVRd and VRd groups, respectively. Patient-year analysis: Overview of TEAEs - Safety population TEAE incidence rate in preferred terminology

[0238] The following presents the most frequent TEAEs with a frequency of 5% or higher in any treatment group. Number of patients with one or more TEAEs at an incidence of ≥ 5% in any treatment group, based on PT (patient's worst grade) - safety population

[0239] The adverse events leading to definitive treatment discontinuation were 22.8% (Isa-VRd) and 26.0% (VRd). These are the treatment-related adverse events leading to definitive treatment discontinuation, categorized by major system organ class and preferred terminology (safety population). Isa-VRd, Isatuximab-bortezomib-lenalidomide-dexamethasone; TEAE, adverse events that occur during treatment; VRd, Bortezomib-lenalidomide-dexamethasone. The data represents the percentage of patients (n). in conclusion:

[0240] This interim analysis demonstrated overwhelming efficacy in patients receiving IVRd compared to those receiving VRd. Adding esartanuximab to VRd resulted in a statistically significant improvement in PFS, as assessed by blinded IRC. This clinically meaningful improvement was robust, as confirmed by multiple sensitivity analysis. Adding esartanuximab to VRd also led to improvements in depth of response, as demonstrated by the CR response rate and MRD-negative CR (via NGS within 10 minutes). -5 The rates (at the sensitivity level) and VGPR rates, or better, were assessed. An OS trend favoring the IVRd group was also observed.

[0241] With an unprecedented median follow-up of 5 years, adding esartuximab to VRd significantly reduced the risk of progression or death by 40.4%, with median PFS of NR and 54.34 months for Isa-VRd and VRd, respectively, highlighting the substantial PFS benefit in ineligible NDMM patients ≤ 80 years of age. The median PFS for VRd in this phase 3 trial was longer than in other phase 3 trials in comparable populations. Importantly, the PFS benefit of Isa-VRd was maintained through subsequent lines of therapy and time to the next treatment, and was achieved in most subgroups.

[0242] Isa-VRd produces deep and sustained remission, with a significantly improved MRD-CR rate, an even higher MRD- rate, and sustained MRD- ≥ 12 months (at any point; ITT population). In 10 -6 Exploratory analysis of MRD-CR rate at sensitivity levels showed a difference compared to 10 -5 The results were consistent with those observed in the previous studies (40% vs. 22.7%; OR 2.270 [95% CI 1.483–3.477]). Additionally, MRD was associated with improved PFS.

[0243] Isa-VRd demonstrated a favorable safety profile with no new safety signals. A higher rate of ≥ Grade 3 infection (44.9% vs. 38.1%) and ≥ Grade 3 neutropenia (laboratory abnormalities; 54.4% vs. 37.0%) was observed with Isa-VRd compared to VRd; however, a lower infection rate was observed with antibiotic prophylaxis (initiated at induction) in both groups compared to no prophylaxis. In the IMROZ, there was no increase in peripheral sensory neuropathy with Isa-VRd compared to VRd. Overall, 78 patients (29.7%; Isa-VRd) and 37 patients (20.4%; VRd) experienced COVID-19-related TEAEs. Despite being studied during the COVID-19 pandemic, the incidence of ≥ Grade 3 COVID infection (including COVID-19 pneumonia) remained low (8.7% in Isa-VRd; 6.6% in VRd). Twelve (4.5%) and six (3.3%) COVID-19-related deaths occurred.

[0244] Although the mortality rate from AEs was higher in the Isa-VRd group (11%) than in the VRd group (5.5%), including more deaths due to COVID-19, the VRd group had higher all-cause mortality and disease progression-related mortality (12.2% vs. 4.9%). Overall, the imbalance in grade 5 TEAEs between treatment groups is likely attributable to differences in treatment exposure and COVID-19-related mortality. Similarly, the differences in SPM and ≥ grade 3 infection rates between treatment groups appear to be primarily due to the longer treatment duration in the Isa-VRd group (53.2 months vs. 31.3 months).

Claims

1. An anti-CD38 antibody for use in the treatment of a human patient with multiple myeloma (MM), wherein the MM is newly diagnosed MM (NDMM) and the human patient is ineligible for autologous stem cell transplantation, wherein the anti-CD38 antibody is administered according to a dosing schedule comprising an induction phase followed by a continuous treatment phase, wherein during the induction phase the anti-CD38 antibody is administered in combination with bortezomib, lenalidomide, and dexamethasone, and during the continuous treatment phase the anti-CD38 antibody is administered in combination with lenalidomide and dexamethasone, but not in combination with bortezomib, and wherein the induction phase comprises four 42-day cycles, and the continuous treatment phase comprises at least one 28-day cycle; wherein during the induction phase, • The anti-CD38 antibody was administered on days 1, 8, 15, 22 and 29 of the first 42-day cycle, and then on days 1, 15 and 29 of the subsequent three 42-day cycles; • Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, and 32 of each induction cycle. • Lenalidomide is administered on days 1–14 and 22–35 of each induction cycle; • Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each induction cycle, or on days 1, 4, 8, 11, 15, 22, 25, 29, and 32; and among these... During this continuous treatment period, • The anti-CD38 antibody was administered on days 1 and 15 of the 28-day cycle; • Lenalidomide is administered on days 1-21 of the 28-day cycle until disease progression; and • Dexamethasone is administered on days 1, 8, 15, and 22 of the 28-day cycle until disease progression. This will help treat the patient's MM.

2. An anti-CD38 antibody for use in safely increasing progression-free survival (PFS) in human patients with multiple myeloma (MM) who are newly diagnosed MM (NDMM) and who are ineligible for autologous stem cell transplantation, wherein the anti-CD38 antibody is administered according to a dosing schedule that includes an induction phase followed by a continuous treatment phase. During the induction phase, the anti-CD38 antibody was administered in combination with bortezomib, lenalidomide, and dexamethasone. During the continuous treatment phase, the anti-CD38 antibody was administered in combination with lenalidomide and dexamethasone, but not with bortezomib. • The anti-CD38 antibody was administered on days 1, 8, 15, 22 and 29 of the first 42-day cycle, and then on days 1, 15 and 29 of the subsequent three 42-day cycles; • Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, and 32 of each induction cycle. • Lenalidomide is administered on days 1–14 and 22–35 of each induction cycle; • Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each induction cycle, or on days 1, 4, 8, 11, 15, 22, 25, 29, and 32; and among these... During this continuous treatment period, • The anti-CD38 antibody was administered on days 1 and 15 of the 28-day cycle; • Lenalidomide is administered on days 1-21 of the 28-day cycle until disease progression; and • Dexamethasone is administered on days 1, 8, 15, and 22 of the 28-day cycle until disease progression. Compared to the induction and continuous treatment periods without the anti-CD38 antibody, administration of the anti-CD38 antibody during the induction and continuous treatment periods resulted in increased PFS.

3. An anti-CD38 antibody for use in safely increasing minimal residual disease (MRD) negativity in human patients with multiple myeloma (MM), wherein the MM is newly diagnosed MM (NDMM) and the human patient is ineligible for autologous stem cell transplantation, wherein the anti-CD38 antibody is administered according to a dosing schedule including an induction phase followed by a continuous treatment phase, wherein during the induction phase the anti-CD38 antibody is administered in combination with bortezomib, lenalidomide, and dexamethasone, and during the continuous treatment phase the anti-CD38 antibody is administered in combination with lenalidomide and dexamethasone, but not in combination with bortezomib, and wherein... • The anti-CD38 antibody was administered on days 1, 8, 15, 22 and 29 of the first 42-day cycle, and then on days 1, 15 and 29 of the subsequent three 42-day cycles; • Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, and 32 of each induction cycle. • Lenalidomide is administered on days 1–14 and 22–35 of each induction cycle; • Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each induction cycle, or on days 1, 4, 8, 11, 15, 22, 25, 29, and 32; and among these... During this continuous treatment period, • The anti-CD38 antibody was administered on days 1 and 15 of the 28-day cycle; • Lenalidomide is administered on days 1-21 of the 28-day cycle until disease progression; and • Dexamethasone is administered on days 1, 8, 15, and 22 of the 28-day cycle until disease progression. Compared to the induction and continuous treatment periods without the administration of the anti-CD38 antibody, administration of the anti-CD38 antibody during the induction and continuous treatment periods resulted in at least 10 [unclear text - possibly related to a specific 10] ... -5 The threshold for MRD negativity increases.

4. An anti-CD38 antibody for use in safely increasing overall survival (OS) in human patients with multiple myeloma (MM) who are newly diagnosed MM (NDMM) and who are ineligible for autologous stem cell transplantation, wherein the anti-CD38 antibody is administered according to a dosing schedule comprising an induction phase followed by a continuous treatment phase, wherein during the induction phase the anti-CD38 antibody is administered in combination with bortezomib, lenalidomide, and dexamethasone, and during the continuous treatment phase the anti-CD38 antibody is administered in combination with lenalidomide and dexamethasone, but not in combination with bortezomib, and wherein... • The anti-CD38 antibody was administered on days 1, 8, 15, 22 and 29 of the first 42-day cycle, and then on days 1, 15 and 29 of the subsequent three 42-day cycles; • Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, and 32 of each induction cycle. • Lenalidomide is administered on days 1–14 and 22–35 of each induction cycle; • Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each induction cycle, or on days 1, 4, 8, 11, 15, 22, 25, 29, and 32; and among these... During this continuous treatment period, • The anti-CD38 antibody was administered on days 1 and 15 of the 28-day cycle; • Lenalidomide is administered on days 1-21 of the 28-day cycle until disease progression; and • Dexamethasone is administered on days 1, 8, 15, and 22 of the 28-day cycle until disease progression. Compared with the induction and continuous treatment periods without the anti-CD38 antibody, administration of the anti-CD38 antibody resulted in an increase in overall survival (OS).

5. The anti-CD38 antibody according to any one of claims 1-4, wherein the anti-CD38 antibody is exartuximab.

6. The anti-CD38 antibody of claim 5, wherein the exartuximab is administered at a dose of 10 mg / kg.

7. The anti-CD38 antibody of claim 5, wherein the exartuximab is administered at a dose of 1400 mg.

8. The anti-CD38 antibody as described in any one of claims 1-4, wherein the human patient is not a candidate for autologous transplantation and / or the human patient does not receive autologous transplantation as part of this line of treatment.

9. The anti-CD38 antibody as described in any one of claims 1-4, wherein the anti-CD38 antibody is administered once every four weeks after cycle 17.

10. The anti-CD38 antibody of claim 9, wherein the anti-CD38 antibody is administered on day 1 of each cycle until disease progression.

11. The anti-CD38 antibody as claimed in claim 1, 3 or 4, wherein administration of the anti-CD38 antibody during the induction and continuous treatment periods results in increased PFS compared to administration during the induction and continuous treatment periods without the anti-CD38 antibody.

12. The anti-CD38 antibody according to any one of claims 1-4, wherein the bortezomib is administered at a concentration of 1.3 mg / m². 2 Dosage administration.

13. The anti-CD38 antibody according to any one of claims 1-4, wherein during the induction and continuous treatment periods, the lenalidomide is administered at a dose of 25 mg / day (or 10 mg / day in human patients with CrCl ≥ 30 to ≤ 60 mL / min).

14. The anti-CD38 antibody according to any one of claims 1-4, wherein the dexamethasone is administered at a dose of 20 mg / day.

15. The anti-CD38 antibody of claim 2, wherein increased PFS is associated with an increased MRD negativity rate in patients receiving the anti-CD38 antibody.

16. The anti-CD38 antibody according to any one of claims 1-4, wherein the patient has stage III MM according to the Revised International Staging System (R-ISS).

17. The anti-CD38 antibody according to any one of claims 1-4, wherein the patient has R-ISS stage I or II MM.

18. The anti-CD38 antibody according to any one of claims 1-4, wherein the patient's age is ≥ 70 years.

19. The anti-CD38 antibody according to any one of claims 1-4, wherein the patient is ≥ 75 years old.

20. The anti-CD38 antibody according to any one of claims 1-4, wherein the patient's age is < 75 years.

21. The anti-CD38 antibody according to any one of claims 1-4, wherein the patient's age is < 70 years.

22. The anti-CD38 antibody of claim 3, wherein the MRD is measured by next-generation sequencing (NGS) or next-generation flow cytometry (NGF).

23. A method for safely treating multiple myeloma (MM) in a human patient, wherein the MM is newly diagnosed MM (NDMM) and the human patient is ineligible for autologous stem cell transplantation, the method comprising administering the anti-CD38 antibody according to a dosing schedule including an induction phase followed by a continuous treatment phase, wherein during the induction phase the anti-CD38 antibody is administered in combination with bortezomib, lenalidomide, and dexamethasone, and during the continuous treatment phase the anti-CD38 antibody is administered in combination with lenalidomide and dexamethasone, but not with bortezomib, and wherein the induction phase comprises four 42-day cycles, and the continuous treatment phase comprises at least one 28-day cycle; wherein during the induction phase, • The anti-CD38 antibody was administered on days 1, 8, 15, 22 and 29 of the first 42-day cycle, and then on days 1, 15 and 29 of the subsequent three 42-day cycles; • Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, and 32 of each induction cycle. • Lenalidomide is administered on days 1–14 and 22–35 of each induction cycle; • Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each induction cycle, or on days 1, 4, 8, 11, 15, 22, 25, 29, and 32; and among these... During this continuous treatment period, • The anti-CD38 antibody was administered on days 1 and 15 of the 28-day cycle; • Lenalidomide is administered on days 1-21 of the 28-day cycle until disease progression; and • Dexamethasone is administered on days 1, 8, 15, and 22 of the 28-day cycle until disease progression. This will help treat the patient's MM.

24. A method for safely increasing progression-free survival (PFS) in human patients with multiple myeloma (MM), wherein the MM is newly diagnosed MM (NDMM) and the human patient is ineligible for autologous stem cell transplantation, the method comprising administering an anti-CD38 antibody according to a dosing schedule including an induction phase followed by a continuous treatment phase. During the induction phase, the anti-CD38 antibody was administered in combination with bortezomib, lenalidomide, and dexamethasone. During the continuous treatment phase, the anti-CD38 antibody was administered in combination with lenalidomide and dexamethasone, but not with bortezomib. • The anti-CD38 antibody was administered on days 1, 8, 15, 22 and 29 of the first 42-day cycle, and then on days 1, 15 and 29 of the subsequent three 42-day cycles; • Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, and 32 of each induction cycle. • Lenalidomide is administered on days 1–14 and 22–35 of each induction cycle; • Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each induction cycle, or on days 1, 4, 8, 11, 15, 22, 25, 29, and 32; and among these... During this continuous treatment period, • The anti-CD38 antibody was administered on days 1 and 15 of the 28-day cycle; • Lenalidomide is administered on days 1-21 of the 28-day cycle until disease progression; and • Dexamethasone is administered on days 1, 8, 15, and 22 of the 28-day cycle until disease progression. The administration of the anti-CD38 antibody during the induction and continuous treatment periods resulted in increased PFS compared to the administration of the anti-CD38 antibody during the induction and continuous treatment periods without it.

25. A method for safely increasing the minimal residual disease (MRD) negative rate in human patients with multiple myeloma (MM), wherein the MM is newly diagnosed MM (NDMM) and the human patient is ineligible for autologous stem cell transplantation, wherein the anti-CD38 antibody is administered according to a dosing schedule including an induction phase followed by a continuous treatment phase, wherein during the induction phase the anti-CD38 antibody is administered in combination with bortezomib, lenalidomide, and dexamethasone, and during the continuous treatment phase the anti-CD38 antibody is administered in combination with lenalidomide and dexamethasone, but not in combination with bortezomib, and wherein... • The anti-CD38 antibody was administered on days 1, 8, 15, 22 and 29 of the first 42-day cycle, and then on days 1, 15 and 29 of the subsequent three 42-day cycles; • Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, and 32 of each induction cycle. • Lenalidomide is administered on days 1–14 and 22–35 of each induction cycle; • Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each induction cycle, or on days 1, 4, 8, 11, 15, 22, 25, 29, and 32; and among these... During this continuous treatment period, • The anti-CD38 antibody was administered on days 1 and 15 of the 28-day cycle; • Lenalidomide is administered on days 1-21 of the 28-day cycle until disease progression; and • Dexamethasone is administered on days 1, 8, 15, and 22 of the 28-day cycle until disease progression. Compared to the induction and continuous treatment periods without the administration of the anti-CD38 antibody, administration of the anti-CD38 antibody during the induction and continuous treatment periods resulted in at least 10 [unclear text - possibly related to a specific 10] ... -5 The threshold for MRD negativity increases.

26. An anti-CD38 antibody for use in safely increasing overall survival (OS) in human patients with multiple myeloma (MM) who are newly diagnosed MM (NDMM) and who are ineligible for autologous stem cell transplantation, wherein the anti-CD38 antibody is administered according to a dosing schedule comprising an induction phase followed by a continuous treatment phase, wherein during the induction phase the anti-CD38 antibody is administered in combination with bortezomib, lenalidomide, and dexamethasone, and during the continuous treatment phase the anti-CD38 antibody is administered in combination with lenalidomide and dexamethasone, but not in combination with bortezomib, and wherein... • The anti-CD38 antibody was administered on days 1, 8, 15, 22 and 29 of the first 42-day cycle, and then on days 1, 15 and 29 of the subsequent three 42-day cycles; • Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, and 32 of each induction cycle. • Lenalidomide is administered on days 1–14 and 22–35 of each induction cycle; • Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each induction cycle, or on days 1, 4, 8, 11, 15, 22, 25, 29, and 32; and among these... During this continuous treatment period, • The anti-CD38 antibody was administered on days 1 and 15 of the 28-day cycle; • Lenalidomide is administered on days 1-21 of the 28-day cycle until disease progression; and • Dexamethasone is administered on days 1, 8, 15, and 22 of the 28-day cycle until disease progression. Compared with the induction and continuous treatment periods without the anti-CD38 antibody, administration of the anti-CD38 antibody resulted in an increase in overall survival (OS).

27. The method of any one of claims 23-26, wherein the anti-CD38 antibody is exartuximab.

28. The method of claim 27, wherein the exartuximab is administered at a dose of 10 mg / kg.

29. The method of claim 27, wherein the exartuximab is administered at a dose of 1400 mg.

30. The method of any one of claims 23-26, wherein the human patient is not a candidate for autologous transplantation and / or the human patient does not receive autologous transplantation as part of this line of treatment.

31. The method of any one of claims 23-26, wherein the anti-CD38 antibody is administered every four weeks after cycle 17.

32. The method of claim 31, wherein the anti-CD38 antibody is administered on day 1 of each cycle until disease progression.

33. The anti-CD38 antibody as claimed in claim 23, 25 or 26, wherein administration of the anti-CD38 antibody during the induction and continuous treatment periods results in increased PFS compared to administration during the induction and continuous treatment periods without the anti-CD38 antibody.

34. The method of any one of claims 23-26, wherein the bortezomib is administered at a concentration of 1.3 mg / m³. 2 Dosage administration.

35. The method of any one of claims 23-26, wherein during the induction and continuous treatment periods, the lenalidomide is administered at a dose of 25 mg / day (or 10 mg / day in human patients with CrCl ≥ 30 to ≤ 60 mL / min).

36. The method of any one of claims 23-26, wherein the dexamethasone is administered at a dose of 20 mg / day.

37. The method of claim 24, wherein the increase in PFS is associated with an increase in the MRD negativity rate in patients who have received the anti-CD38 antibody.

38. The method of any one of claims 23-26, wherein the patient has stage III MM according to the Revised International Staging System (R-ISS).

39. The method of any one of claims 23-26, wherein the patient has R-ISS stage I or II MM.

40. The method of any one of claims 23-26, wherein the patient's age is ≥ 70 years.

41. The method of any one of claims 23-26, wherein the patient's age is ≥ 75 years.

42. The method of any one of claims 23-26, wherein the patient's age is < 75 years.

43. The method of any one of claims 23-26, wherein the patient's age is < 70 years.

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