Daratumumab.bortezomib, lenalidomide and dexamethasone for treating multiple myeloma

Abstract

The present disclosure is directed to methods of treating, for example, newly diagnosed multiple myeloma.

Description

METHODS FOR TREATING MULTIPLE MYELOMA CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Application Serial number 63 / 678,273, filed August 1, 2024, United States Provisional Application Serial number 63 / 725,700, filed November 27, 2024, and Canadian Patent Application number 3,257,924, filed November 29, 2024, the entire contents of the aforementioned applications are incorporated herein by reference in their entireties. SEQUENCE LISTING

[0002] This application contains a Sequence Listing submitted via EFS-Web, the entire content of which are incorporated herein by reference in its entirety. The file, created on July 31, 2025, is named JBI6932WOPCT1 Sequence Listing.xml and is 20 kilobytes in size. TECHNICAL FIELD

[0003] The present disclosure relates generally to methods of treating multiple myeloma, particularly newly diagnosed multiple myeloma. BACKGROUND

[0004] Induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplant (ASCT), VRd consolidation, and lenalidomide (R) maintenance therapy is a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma. However, novel strategies are needed for patients who are transplant-ineligible or for whom transplant is not planned as initial therapy. The disclosed methods are directed to these and other important needs. SUMMARY

[0005] In certain embodiments, the present disclosure is directed to a method of treating newly diagnosed multiple myeloma in a subject in need thereof comprising administering daratumumab, or a daratumumab biosimilar, to the subject in combination with bortezomib, lenalidomide, and dexamethasone.

[0006] In certain embodiments, the present disclosure is directed to methods of treating newly diagnosed multiple myeloma in a subject in need thereof comprisingadministering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20).

[0007] In certain embodiments, the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT. In some embodiments, the subject who is ineligible for HDC and ASCT is greater than or equal to 70 years of age. In some embodiments, the subject who is ineligible for HDC and ASCT is greater than or equal to 18 and less than 70 years of age and has one or more comorbid conditions.

[0008] In certain embodiments, the method achieves an improved clinical efficacy endpoint of the subject relative to a clinical efficacy endpoint achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar.

[0009] In certain embodiments, the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD)-negativity rate, an improved sustained MRD-negativity rate, an improved complete response (CR) or better rate, an improved progression-free survival (PFS), an improved overall response rate (ORR), an improved overall survival (OS), an improved progression-free survival on next line of therapy (PFS2), an improved time to response (TTR), or an improved duration of response (DOR).

[0010] In certain embodiments, the improved clinical efficacy endpoint is an improved overall MRD-negativity rate. In some embodiments, the improved overall MRD- negativity rate is at or below a sensitivity threshold of 10-5. In some embodiments, the improved overall MRD-negativity rate is 60.9% relative to 39.4% for the reference subject or the reference population of subjects. In some embodiments, the improved overall MRD- negativity rate is an absolute increase of 21.5% relative to the reference subject or the reference population of subjects. In some embodiments, the improved overall MRD- negativity rate is at or below a sensitivity threshold of 10-6. In some embodiments, the improved sustained MRD-negativity rate is 46.2% relative to 27.3% for the reference subject or the reference population of subjects. In some embodiments, the overall MRD-negativityrate is determined prior to progression of the multiple myeloma, subsequent to administration of an antimyeloma therapy, or both.

[0011] In certain embodiments, the subject does not have high cytogenetic risk.

[0012] In certain embodiments, the improved clinical efficacy endpoint is an improved sustained minimal residual disease (MRD)-negativity rate. In further embodiments, the improved sustained MRD-negativity rate is for a period of 1 year, 2 years, and / or 3 years. In some embodiments, the improved sustained MRD-negativity rate is at or below a sensitivity threshold of 10-5. In some embodiments, the improved sustained MRD-negativity rate is 48.7% relative to 26.3% for the reference subject or the reference population of subjects.

[0013] In some embodiments, the improved sustained MRD-negativity rate is at or below a sensitivity threshold of 10-6.

[0014] In some embodiments, the improved overall MRD-negativity rate is 32.0% relative to 15.7% for the reference subject or the reference population of subjects.

[0015] In some embodiments, the improved overall MRD-negativity rate or the improved sustained MRD-negativity rate is evaluated by next-generation sequencing.

[0016] In certain embodiments, the improved overall MRD-negativity rate or the improved sustained MRD-negativity rate is evaluated using bone marrow aspirate samples obtained at day 0, at the time of suspected complete response, and at 12, 18, 24, 30, and 36 months after administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, and yearly thereafter in subjects with a complete response.

[0017] In some embodiments, the improved clinical efficacy endpoint is an improved complete response (CR) or better rate. In some embodiments, the improved CR or better rate is 81.2% relative to 61.6% for the reference subject or the reference population of subjects. In some embodiments, the improved CR or better rate is an absolute increase of 19.6% relative to the reference subject or the reference population of subjects.

[0018] In some embodiments, the improved clinical efficacy endpoint is an improved stringent complete response (sCR). In some embodiments, the improved sCR is about 65.0% relative to about 44.9% for the reference subject or the reference population of subjects. In some embodiments, the improved sCR is an absolute increase of about 20.1% relative to the reference subject or the reference population of subjects.

[0019] In some embodiments, the improved clinical efficacy endpoint is an improved progression-free survival (PFS). In some embodiments, the improved PFS is prolonged relative to the reference subject or the reference population of subjects. In some embodiments, the improved PFS is a 43% reduction of risk of progression or death.

[0020] In some embodiments, the subjects with improved PFS are negative for MRD at a sensitivity threshold of 10-6, 10-5, or both.

[0021] In some embodiments, the subjects with improved PFS are positive for MRD at a sensitivity threshold of 10-6, 10-5, or both.

[0022] In some embodiments, the improved PFS is an improvement in median PFS.

[0023] In certain embodiments, the method achieves an improved median treatment duration relative to a median treatment duration achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar.

[0024] In some embodiments, the improved median treatment duration is 56.3 months relative to 34.3 months for the reference subject or the reference population of subjects.

[0025] In certain embodiments, the method achieves an improved median number of treatment cycles relative to a median number of treatment cycles achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab or a daratumumab biosimilar. In further embodiments, the improved median number of treatment cycles is 59 months relative to 37 months for the reference subject or the reference population of subjects.

[0026] In certain embodiments, the method achieves a comparable EORTC QLQ-C30 global health status domain score relative to a EORTC QLQ-C30 global health status domain score achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab.

[0027] In certain embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.

[0028] In some embodiments, the subject has creatinine clearance of ≥30 mL / min / 1.73 m2.

[0029] In some embodiments, the subject has stage 3 multiple myeloma according to the International Staging System (ISS).

[0030] In some embodiments, the subject has high cytogenetic risk.

[0031] In some embodiments, the pharmaceutical composition comprises about 1,800 mg of daratumumab and about 30,000 U rHuPH20. In some embodiments, the pharmaceutical composition comprises about 1,800 mg of a daratumumab biosimilar and about 30,000 U rHuPH20. In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of daratumumab and about 2,000 U / mL rHuPH20. In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of a daratumumab biosimilar and about 2,000 U / mL rHuPH20. In some embodiments, the pharmaceutical composition comprises one or more excipients.

[0032] In some embodiments, at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0033] In some embodiments, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

[0034] In some embodiments, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of daratumumab, or a daratumumab biosimilar; about 2,000 U / mL of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

[0035] In some embodiments, daratumumab, or daratumumab biosimilar, is administered subcutaneously at a dose of about 1,800 mg, bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2, lenalidomide is administered orally at a dose of about 25 mg, and dexamethasone is administered orally or intravenously at a dose of about 20 mg to about 40 mg.

[0036] In some embodiments, the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles.

[0037] In some embodiments, the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for eight 21-day cycles.

[0038] In some embodiments, the daratumumab, or daratumumab biosimilar, is administered subcutaneously at a dose of about 1,800 mg once a week in cycles 1 through 2, about 1,800 mg once a week every 3 weeks in cycles 3 through 8, and about 1,800 mg once a week every 4 weeks thereafter until disease progression or unacceptable toxicity.

[0039] In some embodiments, the bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2 on days 1, 4, 8 and 11. In some embodiments, the lenalidomide is administered orally at a dose of about 25 mg on days 1-14. In some embodiments, the dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. In some embodiments, the pharmaceutical composition, lenalidomide and dexamethasone are administered for one or more 28-day cycles following the eight 21- day cycles. In some embodiments, the lenalidomide is administered orally at a dose of about 25 mg on days 1-21 of the one or more 28-day cycles and dexamethasone is administered orally or intravenously at a dose of about 40 mg on days 1, 8, 15 and 22 of the one or more 28-day cycles until disease progression. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawing. For the purpose of illustrating the disclosed methods or uses, the drawing shows exemplary embodiments of the methods or uses; however, the methods or uses are not limited to the specific embodiments disclosed. In the drawings:

[0041] FIG.1 is a patient flow diagram.

[0042] FIG.2 is a graph of the Kaplan–Meier estimates of progression-free survival among patients in the intention-to-treat population. The final analysis of progression-free survival was performed after 154 events of disease progression or death occurred (>90% of the planned 162 events).

[0043] FIG.3 is a graph of an analysis of progression-free survival in prespecified subgroups in the intention-to-treat population. The International Staging System (ISS) consists of three stages, with higher stages indicating more severe disease: stage I, serum β2- microglobulin level less than 3.5 mg per liter (300 nmol per liter) and albumin level 3.5 g or more per deciliter; stage II, neither stage I or III; and stage III, serum β2-microglobulin level 5.5 mg or more per liter (≥470 nmol per liter). Cytogenetic risk was assessed by fluorescencein situ hybridization. High risk was defined as the presence of del(17p), t(4;14), and / or t(14;16). D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone. NE denotes could not be estimated.

[0044] FIG.4A is a graph of the primary endpoint of overall minimal residual disease (MRD)–negativity rates in the intention-to-treat population. Overall MRD-negativity rate was defined as the proportion of patients who achieved complete response or better and MRD negativity (at or below a sensitivity threshold of 10–5) after randomization but prior to disease progression, subsequent antimyeloma therapy, or both. FIG.4B shows an exploratory analysis of MRD-negativity rate at or below a sensitivity threshold of 10–6. FIG.4C shows sustained MRD-negativity rate in the intention-to-treat population. Sustained MRD- negativity rate was defined as proportion of patients who achieved complete response or better and MRD-negative status (at or below a sensitivity threshold of 10–5) at two examinations a minimum of one year apart without MRD-positive status in between. MRD status was assessed using bone marrow samples and evaluated using a next-generation sequencing assay (clonoSEQ® assay, version 2.0; Adaptive Biotechnologies) in accordance with International Myeloma Working Group guidelines for assessing MRD. Mantel–Haenszel estimate of the common odds ratio for stratified tables was used. The stratification factors were International Staging System disease stage (I, II, III) and age / transplant eligibility (<70 years ineligible, <70 years and transplant deferred, or ≥70 years). An odds ratio >1 indicates an advantage for D-VRd. P value was calculated using a Fisher’s exact test. D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone. FIG.4D shows sustained MRD-negativity rates at years 1, 2, and 3. Proportion of participants who achieved CR or better response and achieved MRD negative status at two bone marrow assessments that are a minimum of one year apart, without any examination showing MRD positive status in between. Chi-square estimate of the common odds ratio was used. An odds ratio >1 indicates an advantage for D-VRd. P- value was calculated from Fisher's exact test.

[0045] FIG.5A-C are graphs of an analysis of overall MRD-negativity rate, MRD negativity 10-5, and MRD negativity 10-6in prespecified subgroups in the intention-to-treat population. Overall MRD-negativity rate was defined as the proportion of patients who achieved complete response or better and MRD negativity (at or below a sensitivity thresholdof 10–5) after randomization but prior to disease progression, subsequent antimyeloma therapy, or both. The International Staging System (ISS) consists of three stages, with higher stages indicating more severe disease: stage I, serum β2-microglobulin level less than 3.5 mg per liter (300 nmol per liter) and albumin level 3.5 g or more per deciliter; stage II, neither stage I or III; and stage III, serum β2-microglobulin level 5.5 mg or more per liter (≥470 nmol per liter). Cytogenetic risk was assessed by fluorescence in situ hybridization. High risk was defined as the presence of del(17p), t(4;14), and / or t(14;16). D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone. In addition, all pre-specified subgroup analyses demonstrated consistent treatment effect of D-VRd over VRd. Treatment effect of D-VRd over VRd in overall MRD negativity rate remained significant and continued to improve at the interim PFS analysis (52.5% in D-VRd and 44.7% in VRd, odds ratio 1.41 (95% CI: 0.95, 2.10) and at the final PFS analysis (53.5% in D-VRd and 45.7% in VRd, odds ratio 1.41 (95% CI: 0.95, 2.10).

[0046] FIG.6 is a graph of complete response or better (≥CR) rates in the intention- to-treat population. Tumor response was assessed using a validated computer algorithm in accordance with International Myeloma Working Group response criteria. Complete response (CR) or stringent complete response (sCR) was achieved at any time during the trial. Mantel– Haenszel estimate of the common odds ratio for stratified tables was used. The stratification factors were International Staging System disease stage (I, II, III) and age / transplant eligibility (<70 years ineligible, <70 years and transplant deferred, or ≥70 years). An odds ratio >1 indicates an advantage for D-VRd. P value was calculated using the Cochran– Mantel–Haenszel chi-squared test. D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone. VGPR denotes very good partial response. PR denotes partial response.

[0047] FIG.7 is a graph of the Kaplan–Meier estimates of overall survival among patients in the intention-to-treat population. D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone.

[0048] FIG.8 is a graph of the Kaplan–Meier estimates of overall survival among patients in the intention-to-treat population, censoring death due to COVID-19. Twosensitivity analyses were performed to adjust for the impact of COVID-19 deaths: FIG.8A censors death due to COVID-19 and FIG.8B considers COVID-19 as a competing risk (i.e., considers COVID death as a competing event and non-COVID death as the event of interest). D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone.

[0049] FIG.9 is a graph of the Kaplan–Meier estimates of progression-free survival on next line of therapy among patients in the intention-to-treat population. A sensitivity analysis was performed to adjust for the impact of COVID-19 deaths.

[0050] FIG.10 is a graph of quality of life in the intention-to-treat population based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) global health status score. Scores range from 0 to 100, with higher scores indicating a better health status and quality of life.

[0051] FIG.11 is a diagram of the study design provided in Example 1.

[0052] FIG.12 is a diagram of pre-planned efficacy analysis. Approximately 360 subjects (180 / arm) were randomized in a 1:1 ratio in 2 arms. Subjects in Arm A received VRd alone for eight 21-day cycles followed by Rd alone until disease progression or unacceptable toxicity. Subjects in Arm B received D-VRd for eight 21‑day cycles and continued to receive D-Rd therapy until disease progression or unacceptable toxicity.

[0053] FIG.13 is a chart of the demographics of the participants in the study of Example 1. Demographic and baseline characteristics were well balanced between the two treatment groups. Both arms have median age 70. To the sex, in VRd, female has a percentage of 43.9%. And in D-VRd, female has a percentage of 55.8%.

[0054] FIG.14 is a chart of the disease characteristics of the participants in the study of Example 1.

[0055] FIG.15 is a chart of the treatment disposition of the participants in the study of Example 1.

[0056] FIG.16 is a chart of the exposure summary of participants in the study of Example 1.

[0057] FIG.17 is a chart of the treatment delays, interruptions, and reductions for participants in the study of Example 1.

[0058] FIG.18 is a panel of graphs of the primary endpoint - overall MRD negativity rate at 10-5sensitivity threshold.

[0059] FIG.19 is a panel of graphs of the major secondary endpoint – CR or better rate.

[0060] FIG.20 is a panel of graphs of the major secondary endpoint – progression- free survival (PFS).

[0061] FIG.21 is a panel of graphs of the major secondary endpoint – PFS - censored for the events of COVID-19 deaths.

[0062] FIG.22A-C are graphs of PFS by overall MRD negativity (10-5and 10-6).

[0063] FIG.23 is a panel of graphs of the major secondary endpoint – sustained MRD negativity rate.

[0064] FIG.24 is a panel of graphs of other secondary endpoints – overall survival at final analysis.

[0065] FIG.25 is a graph of treatment-emergent adverse events (AEs). Safety Analysis Set N=392.

[0066] FIG.26 is a graph of most commonly (>=30%) reported treatment-emergent AE.

[0067] FIG.27 is a graph of COVID-19 related SAEs and deaths.

[0068] FIG.28 is a graph of COVID-19 related deaths by country and year.

[0069] FIG.29A-B are graphs of cumulative MRD-negativity ≥CR Rate A) Over Time (10–5) and at B) Pre-Specified Timepoints (10–5and 10–6). MRD-negativity rate is defined as the proportion of patients who achieved both MRD negativity and ≥CR in the ITT population. Patients who were not evaluable, did not achieve ≥CR, or had indeterminate results were considered MRD positive. A window of ±3 months at each time point was applied to complete the bone marrow aspiration.

[0070] FIG.30 is a Kaplan-Meier Curve of PFS by MRD-Negativity ≥CR status (10–5) in patients with high cytogenetic risk. MRD-negativity rate is defined as the proportion of patients who achieved both MRD negativity and ≥CR. Patients who were not evaluable or had indeterminate results were considered MRD positive. High risk is defined as the presence of del(17p), t(4;14), and / or t(14;16), as assessed by FISH testing.

[0071] FIG.31 is a Kaplan-Meier Curve of PFS in CEPHEUS at a PFS median follow up of 39 months.

[0072] FIG.32 are graphs of MRD-negativity rates (ITT population). FIG.32A is a graph of the IMWG frailty scale 10-5; FIG.32B is a graph of the IFM simplified frailty scale10-5; FIG.32C is a graph of the IMWG frailty scale 10-6; FIG.32D is a graph of the IFM simplified frailty scale 10-6. P values are from Fisher’s exact test.

[0073] FIG.33 are graphs of Sustained ≥12-month MRD-negativity rates (ITT population). FIG.33A is a graph of IMWG frailty scale 10-5. FIG.33B is a graph of IFM simplified frailty scale 10-5. FIG.33C is a graph of IMWG frailty scale 10-6. FIG.33D is a graph of IFM simplified frailty scale 10-6. P values were calculated using Fisher's exact test.

[0074] FIG.34 are graphs of Progression-free survival (ITT population). HR and 95% CI are from a Cox proportional hazards model with treatment as the sole explanatory variable. A hazard ratio < 1 indicates an advantage for DVRd. P value is based on the unstratified log- rank test.

[0075] FIG.35 are graphs of sustained ≥ 24-month MRD-negativity rates (ITT population). FIG.35A is a graph of IMWG frailty scale 10-5. FIG.35B is a graph of IFM simplified frailty scale 10-5. FIG.35C is a graph of IMWG frailty scale 10-6. FIG.35D is a graph of IFMsimplified frailty scale 10-6.P values were calculated using Fisher's exact test.

[0076] FIG.36 are graphs of ≥ CR rate by treatment arm in (FIG.36A) IMWG fit patients, (FIG.36B) IMWG intermediate-fitness patients, (FIG.36C) IFM nonfrail patients, and (FIG.36D) IFM frail patients. Mantel-Haenszel estimate of the common OR is used. An odds ratio > 1 indicates an advantage for DVRd. P value is from the Cochran Mantel-Haenszel Chi-Squared test.

[0077] FIG.37 is a graph of median PFS with DVRd in transplant eligible patients and transplant ineligible patients.

[0078] FIG.38 is a graph of projected PFS with DVRd in TE NDMM patients.

[0079] FIG.39 is a graph of projected PFS with DVRd TIE NDMM patients. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0080] In the present disclosure the singular forms “a”, “an,” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

[0081] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to beinterpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0082] It is to be appreciated that certain features of the disclosure which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiments and such a combination is considered to be another embodiment. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements or use of a “negative” limitation. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself. Certain Terminology

[0083] Various terms used throughout this specification shall have the definitions set out herein.

[0084] “About” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.

[0085] “About once a week” refers to an approximate number, and can include every 7 days ± two days, i.e., every 5 days to every 9 days. The dosing frequency of “once a week” thus can be every five days, every six days, every seven days, every eight days, or every nine days.

[0086] “About once in two weeks” refers to an approximate number, and can include every 14 days ± two days, i.e., every 12 days to every 16 days.

[0087] “About once in three weeks” refers to an approximate number, and can include every 21 days ± two days, i.e., every 19 to every 23 days.

[0088] “About once in four weeks” refers to an approximate number, and can include every 28 days ± two days, i.e., every 26 to every 30 days.

[0089] “About once in five weeks” refers to an approximate number, and can include every 35 days ± two days, i.e., every 33 to every 37 days.

[0090] “About once in six weeks” refers to an approximate number, and can include every 42 days ± two days, i.e., every 40 to every 38 days.

[0091] “About twice a week” refers to an approximate number, can include twice in one week, e.g., a first dose on day 1 and a second dose on day 2, day 3, day 4, day 5, day 6 or day 7 of the week, the fist dose on day 2 and the second dose on day 3, day 4, day 5, day 6 or day 7 of the week, the first dose on day 3 and the second dose on day 4, day 5, day 6 or day 7 of the week, the first dose on day 4 and the second dose on day 5, day 6 or day 7 of the week, the first dose on day 5 and the second dose on day 6 or day 7 of the week, the first dose on day 6 and the second dose on day 7 of the week.

[0092] The conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0093] “Antibody” includes immunoglobulin molecules belonging to any class, IgA, IgD, IgE, IgG and IgM, or sub-class IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4 and including either kappa (κ) and lambda (λ) light chain. Antibodies include monoclonal antibodies including human, humanized and chimeric monoclonal antibodies. Full-length antibody molecules are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed withframework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0094] “Biosimilar” (of an approved reference product / biological drug, i.e., reference listed drug) refers to a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components with no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity and potency, based upon data derived from (a) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and / or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biosimilar. The biosimilar may be an interchangeable product that may be substituted for the reference product at the pharmacy without the intervention of the prescribing healthcare professional. To meet the additional standard of “interchangeability,” the biosimilar is to be expected to produce the same clinical result as the reference product in any given patient and, if the biosimilar is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch. The biosimilar utilizes the same mechanisms of action for the proposed conditions of use to the extent the mechanisms are known for the reference product. The condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biosimilar have been previously approved for the reference product. The route of administration, the dosage form, and / or the strength of the biosimilar are the same as those of the reference product and the biosimilar is manufactured, processed, packed or held in a facility that meets standards designed to ensure that the biosimilar continues to be safe, pure and potent. The biosimilar may include minor modifications in the amino acid sequence when compared to the reference product, such as N- or C-terminal truncations that are not expected to change the biosimilar performance.

[0095] “Cancer” refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread) to other areas of a patient’s body.

[0096] "CD34+” refers to human hematopoietic stem cells that are positive for the antigen CD34.

[0097] “CD38” refers to human cluster of differentiation 38 protein, a glycoprotein expressed on immune cells, including plasma cells, natural killer cells and sub-populations of B and T cells.

[0098] “Clinical efficacy endpoint” or “clinical endpoint” refers to an outcome that represents a clinical benefit, such as overall minimal residual disease (MRD)-negativity rate, sustained MRD-negativity rate, complete response (CR) or better rate, progression-free survival (PFS), overall response rate (ORR), overall survival (OS), progression-free survival on next line of therapy (PFS2), time to response (TTR), or duration of response (DOR)..

[0099] “Clinically proven” refers to clinical efficacy results that are sufficient to meet approval standards of U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) or a corresponding national regulatory agency. For example, the clinical study may be an adequately sized, randomized, double-blinded controlled study used to clinically prove the effects of the drug and / or non-inferiority of the drug.

[0100] “Co-administration,” “administration with,” “administration in combination with,” “in combination with” or the like, encompass administration of two or more therapeutics or drugs to a single patient, and are intended to include treatment regimens in which the therapeutics or drugs are administered by the same or different route of administration or at the same or different time.

[0101] “Complementarity determining regions” (CDRs) are “antigen binding sites” in an antibody. CDRs may be defined based on sequence variability (Wu and Kabat, J Exp Med 132:211-250, 1970; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991) or based on alternative delineations (see Lefranc et al., Dev Comparat Immunol 27:55-77, 2003). The International ImMunoGeneTics (IMGT) database (http_ / / www_imgt_org) provides a standardized numbering and definition of antigen-binding sites.

[0102] “Complete response or better rate” refers to the proportion of patients achieving complete response or stringent complete response based on the computerizedalgorithm according to International Myeloma Working Group (IMWG) response criteria, during or after the study treatment prior to the start of subsequent antimyeloma therapy.

[0103] “Comprising,” “consisting essentially of,” and “consisting of” are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of” excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristics” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of” and “consisting essentially of.”

[0104] “Consolidation”, “consolidation therapy” or “consolidation period” refers to a short duration of treatment given to a subject after the subject has been treated with high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT); i.e., post-HDC and ASCT.

[0105] “Corticosteroid” refers to a class of steroid hormones that are produced in the adrenal cortex or produced synthetically refers to dexamethasone, methylprednisolone, prednisolone and prednisone. Dexamethasone is marketed under the trade name DECARON®.

[0106] “Cycle” refers to the administration schedule of one or more therapeutics or drugs and refers to the period of time when the one or more therapeutics or drugs is administered to a subject. Cycle may include days in which the drug is administered and periods of rest in which the drug is not administered. Cycle length may vary, and can be for example 2 weeks, 3 weeks, 28 days (or 4 weeks), 5 weeks or 6 weeks.

[0107] “Daratumumab” refers to an antibody that specifically binds CD38 comprising a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, a LCDR3 of SEQ ID NO: 6, a heavy chain variable region (VH) of SEQ ID NO: 7, a light chain variable region (VL) of SEQ ID NO: 8, a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10. Daratumumab is marketed under the trade names DARZALEX®,DARZALEX®SC, and DARZALEX FASPRO®. The package inserts and labels for DARZALEX®, DARZALEX FASPRO®, and DARZALEX®SC can be found at fda.gov or ema.europa.eu and are incorporated by reference herein.

[0108] “Dosage” refers to the information of the amount of the therapeutic or the drug to be taken by the subject and the frequency of the number of times the therapeutic is to be taken by the subject.

[0109] “Dose” refers to the amount or quantity of the therapeutic or the drug to be taken each time.

[0110] “Drug product” (DP) refers to a finished dosage form, for example, a tablet, capsule or solution that contains an active pharmaceutical ingredient (e.g., drug substance), generally, but not necessarily, in association with inactive ingredients.

[0111] “Drug substance” (DS) refers to any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or function of the body.

[0112] “Duration of response” refers to the time between the date of initial documentation of a response (partial response (PR) or better) to the date of the first documented evidence of progressive disease according to International Myeloma Working Group criteria, or death due to disease progression, whichever occurred first, for patients who had a partial response or better as their best response.

[0113] “Effective” refers to a dose or dosage of a therapeutic or a drug (such as an antibody that specifically binds CD38) or a combination of therapeutics or drugs that provides a therapeutic effect for a given condition and administration regimen in a subject receiving or who has received the therapeutic or the drug or the combination of the therapeutics or drugs. “Effective” is intended to mean an amount sufficient to reduce and / or prevent a clinically significant deficit in the activity, function and response of the subject, or to cause an improvement in a clinically significant condition in the subject.

[0114] “Frontline” or “first line” therapy refers to the first treatment of a disease, such as multiple myeloma, administered to the subject.

[0115] “Healthcare professional” refers to a medical doctor, a nurse, a nurse’s assistant, or a person working under direct instructions by the medical doctor or the nurse, or any person working in a hospital or a place in which treatment can be provided to the subject.

[0116] “Hyaluronidase” refers to an enzyme that degrades hyaluronic acid (EC 3.2.1.35) and lowers the viscosity of hyaluronan in the extracellular matrix, thereby increasing tissue permeability. An exemplary hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20). rHuPH20 comprises amino acid sequences of SEQ ID NO: 12-16. Enzymatic activity of hyaluronidase, including rHuPH20 can be defined by units per mL (U / mL) or by total enzyme activity in a particular formulation (U). The standard definition for one unit (U) of enzyme activity is the amount of enzyme that catalyzes the reaction of 1 nmol of substrate per minute.

[0117] “High dose chemotherapy” (HDC) or “high dose therapy” and “autologous stem cell transplant” (ASCT) refer to the treatment of subjects with newly diagnosed multiple myeloma who are considered fit (e.g., subjects are “eligible”). Subjects who are not considered candidates for high-dose chemotherapy with stem-cell transplantation due to age (≥70 years) or were age >18 to 70 years with the presence of comorbid conditions (e.g., subjects are “ineligible”) or did not plan high-dose chemotherapy with stem-cell transplantation as initial treatment (e.g., subjects are “transplant deferred”). Exemplary HDC regimens are melphalan at a dose of 200 mg / m2body surface area with dose reductions based on age and renal function, cyclophosphamide and melphalan, carmustine, etoposide, cytarabine, and melphalan (BEAM), high-dose idarubicin, cyclophosphamide, thiotepa, busulfan, and cyclophosphamide, busulfan and melphalan, and high-dose lenalidomide (Mahajan et al., Ther Adv Hematol 9:123-133, 2018). Cyclophosphamide is marketed under the trade name Cyclostin™. Melphalan is marketed under the trade name ALKERAN®. Carmustine is marketed under the trade name BiCNU®. Etoposide is marketed under the trade name VEPESID®. Cytarabine is marketed under the trade name CYTOSAR-U®. Idarubicin is marketed under the trade name IDAMYCIN®. Thitepa is marketed under the trade name THIOPLEX®. Lenalidomide is marketed under the trade name REVLIMID®.

[0118] “High risk multiple myeloma” refers to multiple myeloma that is characterized by one or more cytogenetic abnormalities del17p, t(4;14), t(14;20), t(14;16) or del13, or any combination thereof.

[0119] “Induction”, “induction therapy” or “induction period” refers to the first treatment given for a disease with the intention of reducing the amount of malignant plasma cell burden and improving the depth of response. Induction therapy may be provided prior to treatment with high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT).

[0120] “Information” refers to reported results from clinical trials and can be provided in written or electronic form, or orally, or it can be available on internet.

[0121] “Infusion related reaction” (IRR) refers to any sign or symptom experienced by a subject during the administration of a drug or a therapeutic or any event occurring within 24-hours of administration. IRRs are typically classified as Grade 1, 2, 3 or 4.

[0122] “Maintenance therapy” refers to the treatment given for a disease after remission or best response is achieved, in order to prevent or delay relapse.

[0123] “mg / m2” refers to dosing of a drug in milligrams per square meter of body surface area.

[0124] “Minimal residual disease” (MRD) refers to a small number of clonal multiple myeloma cells that remain in the patient after treatment and / or during remission.

[0125] “MRD negative” or “negative status for MRD” refers to a ratio of 1 : 1x105or less clonal multiple myeloma cells in a bone marrow aspirate sample obtained from the subject.

[0126] “MRD negativity rate” refers to the proportion of patients who achieved complete response or better and had MRD-negative status (at or below a sensitivity threshold of 10–5or 10-6as specified) after randomization but prior to disease progression, subsequent antimyeloma therapy, or both.

[0127] “MRD positive” refers to patients for whom all tested samples were found to be MRD positive or indeterminate, or were MRD negative and had not achieved CR or better status.

[0128] “Multiple myeloma” refers to a malignant disorder of plasma cells characterized by uncontrolled and progressive proliferation of one or more malignant plasma cells. The abnormal proliferation of plasma (myeloma) cells causes displacement of the normal bone marrow leading to dysfunction in hematopoietic tissue and destruction of the bone marrow architecture, resulting in progressive morbidity and eventual mortality.

[0129] “Newly diagnosed” refers to a human subject who has been diagnosed with but has not yet received treatment for a disease, such as a disease involving cells that express CD38, such as multiple myeloma.

[0130] “Overall complete response or better rate” refers to the percentage of patients in the intention-to-treat population who achieved complete response or stringent complete response status at any time during the study per the International Myeloma Working Group criteria. In addition, the specific response must have been achieved prior to the start of subsequent therapies.

[0131] “Overall minimal residual disease–negative rate” refers to the proportion of patients in the intention-to-treat population who achieved minimal residual disease negativity (at or below a sensitivity threshold of 1 tumor cell per 105white cells) by bone marrow aspirate and achieved a complete response or better at any time after the date of randomization during the study (and prior to disease progression, receipt of subsequent therapy, or both). “Sustained MRD-negativity rate” refers to the proportion of patients in the ITT population with 2 consecutive MRD-negative results at least 12 months apart, without any MRD-positive results in between.

[0132] “Overall response rate” (ORR) refers to the proportion of patients achieving partial response or better (i.e., partial response, very good partial response, complete response, or stringent complete response) based on computerized algorithm in accordance with the International Myeloma Working Group (IMWG) criteria, during or after the study treatment but before the start of subsequent antimyeloma therapy.

[0133] “Overall survival” (OS) is defined as the time from initiation of therapy to the date of death due to any cause. For the purpose of the clinical trial described in the example, OS is defined as the time from the date of randomization to the date of the patient’s death due to any cause.

[0134] “Percent w / v” (% w / v) refers to weight in grams per 100 mL.

[0135] “Pharmaceutical combination” refers to a combination of two or more therapeutics or drugs administered either together or separately.

[0136] "Pharmaceutical composition" refers to a product that results from combining an antibody that specifically binds CD38 and a hyaluronidase as a fixed combination. "Fixed combinations" refers to a single pharmaceutical composition comprising the anti-CD38 antibody and the hyaluronidase administered simultaneously in theform of a single entity or dosage. A pharmaceutical composition typically includes a pharmaceutically acceptable carrier.

[0137] “Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, stabilizer or preservative.

[0138] “Placebo” refers to a substance that has no therapeutic effect.

[0139] ‘Post-consolidation” refers to treatment period ending at the end of consolidation therapy.

[0140] “Post-induction” refers to treatment period ending at the end of induction therapy.

[0141] “Potency” as it relates to a composition, dose, dosage regimen, treatment or method with a therapeutic or a drug (such as an antibody that specifically binds CD38 or a combination of an antibody that specifically binds CD38 and one or more therapeutic agents) refers to the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.

[0142] “Progression-free survival” (PFS) means time from initiation of therapy to first evidence of disease progression or death due to any cause, whichever occurs first. For the purpose of the clinical trial described in the example, PFS is defined as the duration from the date of randomization to disease progression or death, whichever came first. Disease progression was determined according to the IMWG criteria. Patients who started subsequent antimyeloma therapies for multiple myeloma without disease progression were censored at the last disease assessment before the start of subsequent therapies.

[0143] “Progression-free survival 2” (PFS2) refers to the time from randomization to progression on the next line of treatment or death (due to any cause), whichever comes first.

[0144] “Progressive disease” (PD), “stable disease” (SD), “partial response” (PR), “very good partial response” (VGPR), “complete response” (CR) and “stringent complete response” (sCR) refer to response to treatment and take their customary meanings as will be understood by a person skilled in the art of designing, conducting, or reviewing clinical trials. Response to treatment may be assessed using International Myeloma Working Group(IMWG) uniform response criteria recommendations (International Uniform Response Criteria Consensus Recommendations) as shown in Table 1.

[0145] “Rate of complete response or better” (CR response rate or better) refers to the proportion of subjects achieving CR or stringent complete response (sCR) during or after the treatment.

[0146] “Rate of stringent complete response rate or better” (sCR rate or better) refers to the proportion of subjects achieving sCR during or after the treatment, which can be measured post-induction, post-transplant, post-consolidation, and overall.

[0147] “Reference Listed Drug” or “RLD” may also refer to an approved biological product such as DARZALEX®SC brand of daratumumab or DARZALEX FASPRO®brand of daratumumab and hyaluronidase against which a biosimilar demonstrates bioequivalence.

[0148] “Reference subject” or “reference population of subjects” refers to a subject or population of subjects having newly diagnosed multiple myeloma who have been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. The reference subject or reference population of subjects are substantially the same as the subject or population of subjects that are treated with daratumumab in combination with bortezomib, lenalidomide, and dexamethasone. Exemplary reference subjects or reference population of subjects are those described in Example 1 herein. In some embodiments, the population of subjects and reference population of subjects contain at least two subjects. In some embodiments, the population of subjects and reference population of subjects contain a number of subjects that allow for a statistically significant analysis of the improvement in safety and / or efficacy.

[0149] “Safe” as it relates to a composition, dose, dosage regimen, treatment or method with a therapeutic or a drug (such as an antibody that specifically binds CD38 or a combination of an antibody that specifically binds CD38 and one or more therapeutic agents) refers to a favorable benefit:risk ratio with an acceptable frequency and / or acceptable severity of adverse events (AEs) and / or treatment-emergent adverse events (TEAEs) compared to the standard of care or to another comparator.

[0150] “Safe and effective” refers to an amount and / or dosage of a drug (such as an antibody that specifically binds CD38) or a combination of drugs (such as a combination of an antibody that specifically binds CD38 and one or more therapeutic agents) that elicits the desired biological or medicinal response in a subject’s biological system without the risksoutweighing the benefits of such response in accordance with the Federal Food, Drug, and Cosmetic Act, as amended (secs.201–902, 52 Stat.1040 et seq., as amended; 21 U.S.C. §§ 321–392). Safety is evaluated in laboratory, animal and human clinical testing to determine the highest tolerable dose or the optimal dose of the drug or the combination of drugs needed to achieve the desired benefit. Efficacy is evaluated in human clinical trials and determining whether the drug or the combination of drugs demonstrates a health benefit over a placebo or other intervention. Safe and effective drugs or a combination of drugs are granted marketing approval by the FDA or other healthcare regulatory agency for their indicated use.

[0151] An antibody that “specifically binds CD38” refers to antibody binding CD38 with greater affinity than to other antigens. Typically, the antibody binds to CD38 with an equilibrium dissociation constant (KD) of about 1x10-8M or less, for example about 1x10-9M or less, about 1x10-10M or less, about 1x10-11M or less, or about 1x10-12M or less, typically with a KD that is at least one hundred-fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein). The KDmay be measured using standard procedures. Antibodies that specifically bind CD38 may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as monkey, for example Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp) or Callithrix jacchus (common marmoset, marmoset).

[0152] “Subcutaneous” or “subcutaneously” refers to administration of a therapeutic under the skin, typically by injection. Administration site may be side or back of upper arm, front of thigh or abdomen.

[0153] “Subject” refers to a human patient. The terms “subject” and “patient” can be used interchangeably herein. It is understood by a person skilled in the art that a patient can also mean a population of patients. It is understood by a person skilled in the art that when a median endpoint is mentioned, for example median progression-free survival, that a patient means a population of patients.

[0154] “Stem cell mobilization” refers to the process by which stem cells are stimulated out of the bone marrow space into the bloodstream, thereby making them available for collection.

[0155] “Sustained MRD-negativity rate ≥1 year” refers to the proportion of patients who achieved complete response or better and MRD-negative status [10–5or 10-6as specified] at two examinations a minimum of one year apart without MRD-positive status in between.

[0156] “Therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics include, for example, improved well-being of the patient, reduction in a tumor burden, arrested or slowed growth of a tumor, and / or absence of metastasis of cancer cells to other locations in the body.

[0157] “Time to response” refers to the time between the randomization and the first efficacy evaluation that the subject has met all criteria for partial response (PR) or better.

[0158] “Time to complete response or better” refers to the time from the date of randomization to the date of first documentation of a confirmed response (CR) of complete response or better for patients who had a response of complete response or better.

[0159] “Treat”, “treating” or “treatment” refers to therapeutic treatment. Individuals in need of treatment include those subjects diagnosed with the disorder of a symptom of the disorder. Subject that may be treated also include those prone or susceptible to having the disorder, or those in which the disorder is to be prevented. Beneficial or desired clinical results include alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, disease remission (whether partial or total) and prolonging survival as compared to expected survival if a subject was not receiving treatment or was receiving another treatment.

[0160] “Treatment emergent adverse events” (TEAE) as used herein takes its customary meaning as will be understood by a person skilled in the art of designing, conducting, or reviewing clinical trials and the data generated in such trials and refers to an AE considered associated with the use of an antibody that specifically binds CD38 if the attribution is possible, probable, or very likely.

[0161] “Unacceptable adverse events” and “unacceptable adverse reaction” refers to all harm or undesired outcomes associated with or caused by administration of a pharmaceutical composition or a therapeutic, and the harm or undesired outcome reaches such a level of severity that a regulatory agency deems the pharmaceutical composition or the therapeutic unacceptable for the proposed use.

[0162] “Unacceptable toxicity” refers to toxicity associated with or caused by administration of a pharmaceutical composition or a therapeutic, and the harm or undesired outcome reaches such a level of severity that a regulatory agency or the treating physician deems the administration of the pharmaceutical composition or therapeutic be stopped.

[0163] “Very good partial response or better” (VGPR rate or better) refers to the proportion of subjects achieving VGPR, complete response (CR) or stringent complete response (sCR) during or after the treatment. Multiple myeloma

[0164] Multiple myeloma causes significant morbidity and mortality. It accounts for approximately 1% of all malignancies and 13% of hematologic cancers worldwide. Approximately 50,000 patients per year are diagnosed with multiple myeloma in the EU and US, and 30,000 patients die per year due to multiple myeloma.

[0165] The majority of patients with multiple myeloma produce a monoclonal protein (paraprotein, M-protein or M-component) which is an immunoglobulin (Ig) or a fragment of one that has lost its function (Kyle and Rajkumar, Leukemia 23:3-9, 2009; Palumbo and Anderson, N Engl J Med 364:1046-1060, 2011). Normal immunoglobulin levels are compromised in patients, leading to susceptibility of infections. The proliferating multiple myeloma cells displace the normal bone marrow leading to dysfunction in normal hematopoietic tissue and destruction of the normal bone marrow architecture, which is reflected by clinical findings such as anemia, paraprotein in serum or urine, and bone resorption seen as diffuse osteoporosis or lytic lesions shown in radiographs (Kyle et al., Mayo Clin Proc 78:21-33, 2003). Furthermore, hypercalcemia, renal insufficiency or failure, and neurological complications are frequently seen. A small minority of patients with multiple myeloma are non-secretory. Multiple Myeloma Diagnosis

[0166] Subjects afflicted with multiple myeloma satisfy the CRAB (calcium elevation, renal insufficiency, anemia and bone abnormalities) criteria, and have clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma, and measurable disease. Measurable disease is defined by any of the following; − IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g / dL or urine M-protein level ≥200 mg / 24 hours; or− IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥0.5 g / dL or urine M-protein level ≥200 mg / 24 hours; or − Light chain multiple myeloma without measurable disease in serum or urine: Serum immunoglobulin free light chain ≥10 mg / dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.

[0167] CRAB criteria • Hypercalcemia: serum calcium >0.25 mM / L (>1 mg / dL) higher than the upper limit of the normal range [ULN] or >2.75 mM / L (>11 mg / dL) • Renal insufficiency: creatinine clearance <40mL / min or serum creatinine >177 µM / L (>2 mg / dL). • Anemia: hemoglobin >2 g / dL below the lower limit of normal or hemoglobin <10 g / dL. • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT.

[0168] Response to treatment may be assessed using International Myeloma Working Group (IMWG) uniform response criteria recommendations (International Uniform Response Criteria Consensus Recommendations) as shown in Table 1. Table 1. Response Response Criteria Stringent • CR as defined below, plus complete • Normal FLC ratio, and Response • Absence of clonal PCs by immunohistochemistry, (sCR) immunofluorescenceaor 2- to 4-color flow cytometry Complete • Negative immunofixation on the serum and urine, and response • Disappearance of any soft tissue plasmacytomas, and (CR)* • <5% PCs in bone marrow Very good • Serum and urine M-component detectable by immunofixation but not partial on electrophoresis, Response or (VGPR)* • ≥90% reduction in serum M-protein plus urine M-protein <100 mg / 24 hours Partial • ≥50% reduction of serum M-protein and reduction in 24-hour urinary response (PR) M-protein by ≥90% or to <200 mg / 24 hours• If the serum and urine M-protein are not measurable, a decrease of ≥50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria • If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, ≥50% reduction in bone marrow PCs is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30% • In addition to the above criteria, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is also required. Stable disease • Not meeting criteria for CR, VGPR, PR, or progressive disease (SD) Progressive Increase of 25% from lowest response value in any one of the following: disease (PD)†• Serum M-component (absolute increase must be ≥0.5 g / dL), • Urine M-component (absolute increase must be ≥200 mg / 24 hours), • Only in subjects without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg / dL) • Only in subjects without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow PC percentage (absolute percentage must be ≥10%) • Bone marrow plasma cell percentage: the absolute percentage must be >10% • Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas • Development of hypercalcemia (corrected serum calcium >11.5 mg / dL) that can be attributed solely to the PC proliferative disorder Abbreviations: CR=complete response; FLC=free light chain; PC=plasma cell; PR=partial response; VGPR=Very good partial response; SD=stable disease. All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the institution of any new therapy; CR, sCR, VGPR, PR, and SD categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of whether disease at baseline was measurable on serum, urine, both, or neither. Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be confirmed. For PD, serum M-component increases of more than or equal to 1 g / dL are sufficient to define relapse if starting M-component is ≥5 g / dL. * Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum FLC levels: CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in such subjects requires a >90% decrease in the difference between involved and uninvolved FLC levels.†Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in subjects without measurable disease by M-protein and by FLC levels; “25% increase” refers to M-protein, FLC, and bone marrow results, and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response value” does not need to be a confirmed value.aPresence / absence of clonal cells is based upon the kappa / lambda ratio. An abnormal kappa / lambda ratio by immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is kappa / lambda of >4:1 or <1:2. Methods of Treatment and Uses

[0169] This disclosure provides methods of treating newly diagnosed multiple myeloma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase. In certain aspects, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase.

[0170] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for the treatment of newly diagnosed multiple myeloma in a subject in need thereof, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar.

[0171] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for the treatment of newly diagnosed multiple myeloma in a subject in need thereof, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase.

[0172] In an aspect, there is provided a pharmaceutical composition for use in the treatment of newly diagnosed multiple myeloma in a subject in need thereof, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical compositioncomprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar.

[0173] In an aspect, there is provided a pharmaceutical composition for use in the treatment of newly diagnosed multiple myeloma in a subject in need thereof, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase.

[0174] For each of the methods of treatment described herein, it will be understood that the methods of treatment may also be framed as methods of manufacturing a medicament for the treatment of the described indications or as a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone for use in the treatment of the described indications.

[0175] In certain embodiments, the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT. In some embodiments, the subject who is ineligible for HDC and ASCT is greater than or equal to 70 years of age. In some embodiments, the subject who is ineligible for HDC and ASCT is greater than or equal to 18 and less than 70 years of age and has one or more comorbid conditions.

[0176] In certain embodiments, the method achieves an improved clinical efficacy endpoint of the subject relative to a clinical efficacy endpoint achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab.

[0177] In certain embodiments, the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD)-negativity rate, an improved sustained MRD-negativity rate, an improved complete response (CR) or better rate, an improved progression-free survival (PFS), an improved overall response rate (ORR), an improved overall survival (OS), an improved progression-free survival on next line of therapy (PFS2), an improved time to response (TTR), or an improved duration of response (DOR).

[0178] In certain embodiments, the improved clinical efficacy endpoint is an improved overall MRD-negativity rate. In some embodiments, the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10-5. In some embodiments, the improved overall MRD-negativity rate is 60.9%. In some embodiments, the overall MRD- negativity rate for the reference subject or the reference population of subjects is 39.4%. In some embodiments, the improved overall MRD-negativity rate is an absolute increase of 21.5% relative to the reference subject or the reference population of subjects.

[0179] In some embodiments, the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10-6. In some embodiments, the improved overall MRD- negativity rate is 46.2%. In some embodiments, the overall MRD-negativity rate for the reference subject or the reference population of subjects is 27.3%. In some embodiments, the overall MRD-negativity rate is determined prior to progression of the multiple myeloma, subsequent to administration of an antimyeloma therapy, or both.

[0180] In certain embodiments, the subject does not have high cytogenetic risk.

[0181] In certain embodiments, the improved clinical efficacy endpoint is an improved sustained minimal residual disease (MRD)-negativity rate. In further embodiments, the improved sustained MRD-negativity rate is for a period of 1 year, 2 years, and / or 3 years. In some embodiments, the improved sustained MRD-negativity rate is at or below a sensitivity threshold of 10-5. In some embodiments, the improved sustained MRD-negativity rate is 48.7% relative to 26.3% for the reference subject or the reference population of subjects.

[0182] In some embodiments, the improved sustained MRD-negativity rate is at or below a sensitivity threshold of 10-6.

[0183] In some embodiments, the improved overall MRD-negativity rate or the improved sustained MRD-negativity rate is evaluated by next-generation sequencing.

[0184] In certain embodiments, the improved overall MRD-negativity rate or the improved sustained MRD-negativity rate is evaluated using bone marrow aspirate samples obtained at day 0, at the time of suspected complete response, and at 12, 18, 24, 30, and 36 months after administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, and yearly thereafter in subjects with a complete response.

[0185] In some embodiments, the improved clinical efficacy endpoint is an improved complete response (CR) or better rate. In some embodiments, the improved CR or better rate is 81.2%. In some embodiments, the CR or better rate for the reference subject or thereference population of subjects is 61.6%. In some embodiments, the improved CR or better rate is an absolute increase of 19.6% relative to the reference subject or the reference population of subjects.

[0186] In some embodiments, the improved clinical efficacy endpoint is an improved stringent complete response (sCR). In some embodiments, the improved sCR is about 65.0% relative to about 44.9% for the reference subject or the reference population of subjects. In some embodiments, the improved sCR is an absolute increase of about 20.1% relative to the reference subject or the reference population of subjects.

[0187] In some embodiments, the improved clinical efficacy endpoint is an improved progression-free survival (PFS). In some embodiments, the improved PFS is prolonged relative to the reference subject or the reference population of subjects. In some embodiments, the improved PFS is a 43% reduction of risk of progression or death.

[0188] In some embodiments, the subjects with improved PFS are negative for MRD at a sensitivity threshold of 10-6, 10-5, or both.

[0189] In some embodiments, the subjects with improved PFS are positive for MRD at a sensitivity threshold of 10-6, 10-5, or both.

[0190] In some embodiments, the improved PFS is an improvement in median PFS.

[0191] In certain embodiments, the method achieves an improved median treatment duration relative to a median treatment duration achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab.

[0192] In some embodiments, the improved median treatment duration is 56.3 months. In certain embodiments, the median treatment duration for the reference subject or the reference population of subjects is 34.3 months.

[0193] In certain embodiments, the method achieves an improved median number of treatment cycles relative to a median number of treatment cycles achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In further embodiments, the improved median number of treatment cycles is 59 months. In further embodiments, the median number of treatment cycles for the reference subject or the reference population of subjects is 37 months.

[0194] In certain embodiments, the method achieves a comparable EORTC QLQ-C30 global health status domain score relative to a EORTC QLQ-C30 global health status domain score achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab.

[0195] In certain embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.

[0196] In some embodiments, the subject has creatinine clearance of ≥30 mL / min / 1.73 m2.

[0197] In some embodiments, the subject has stage 3 multiple myeloma according to the International Staging System (ISS).

[0198] In some embodiments, the subject has high cytogenetic risk.

[0199] In some embodiments, daratumumab, or daratumumab biosimilar, is administered subcutaneously at a dose of about 1,800 mg, bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2, lenalidomide is administered orally at a dose of about 25 mg, and dexamethasone is administered orally or intravenously at a dose of about 20 mg to about 40 mg. In some embodiments, daratumumab, or daratumumab biosimilar, is administered subcutaneously at a dose of about 1,800 mg, bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2, lenalidomide is administered orally at a dose of about 25 mg, and dexamethasone is administered orally or intravenously at a dose of about 20 mg. In some embodiments, daratumumab, or daratumumab biosimilar, is administered subcutaneously at a dose of about 1,800 mg, bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2, lenalidomide is administered orally at a dose of about 25 mg, and dexamethasone is administered orally or intravenously at a dose of about 40 mg.

[0200] In some embodiments, the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles.

[0201] In some embodiments, the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for eight 21-day cycles.

[0202] In some embodiments, daratumumab, or daratumumab biosimilar, is administered subcutaneously at a dose of about 1,800 mg once a week in cycles 1 through 2, about 1,800 mg once a week every 3 weeks in cycles 3 through 8, and about 1,800 mg once a week every 4 weeks thereafter until disease progression or unacceptable toxicity.

[0203] In some embodiments, the lenalidomide is administered orally at a dose of about 25 mg on days 1-14. In some embodiments, the dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. In some embodiments, the pharmaceutical composition, lenalidomide and dexamethasone are administered for one or more 28-day cycles following the eight 21-day cycles. In some embodiments, the lenalidomide is administered orally at a dose of about 25 mg on days 1-21 of the one or more 28-day cycles and dexamethasone is administered orally or intravenously at a dose of about 40 mg on days 1, 8, 15 and 22 of the one or more 28-day cycles until disease progression.

[0204] This disclosure additionally provides methods of improving MRD negativity rate in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase. In certain embodiments, the improvement in MRD negativity rate is relative to the MRD negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in MRD negativity rate is relative to the MRD negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the MRD negativity rate is an overall rate. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0205] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving MRD negativity rate in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein thepharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in MRD negativity rate is relative to the MRD negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in MRD negativity rate is relative to the MRD negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the MRD negativity rate is an overall rate. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0206] In an aspect, there is provided a pharmaceutical composition for use in improving MRD negativity rate in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in MRD negativity rate is relative to the MRD negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in MRD negativity rate is relative to the MRD negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the MRD negativity rate is an overall rate. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0207] This disclosure additionally provides methods of improving an overall MRD- negativity rate in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in overall MRD-negativity rate is relative to the overall MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in overall MRD-negativity rate is relative to the overall MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0208] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving an overall MRD-negativity rate in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in overall MRD-negativity rate is relative to the overall MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in overall MRD-negativity rate is relative to the overall MRD-negativity rate ofa reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0209] In an aspect, there is provided a pharmaceutical composition for use in improving an overall MRD-negativity rate in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in overall MRD- negativity rate is relative to the overall MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in overall MRD-negativity rate is relative to the overall MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0210] This disclosure additionally provides methods of improving a sustained MRD- negativity rate in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in a sustained MRD-negativity rate is relative to thesustained MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in a sustained MRD-negativity rate is relative to the sustained MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0211] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving a sustained MRD-negativity rate in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in a sustained MRD-negativity rate is relative to the sustained MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in a sustained MRD-negativity rate is relative to the sustained MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0212] In an aspect, there is provided a pharmaceutical composition for use in improving a sustained MRD-negativity rate in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, thepharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in a sustained MRD-negativity rate is relative to the sustained MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in a sustained MRD- negativity rate is relative to the sustained MRD-negativity rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0213] This disclosure additionally provides methods of improving a complete response (CR) or better rate in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in complete response (CR) or better rate is relative to the CR or better rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in CR or better rate is relative to the CR or better rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0214] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving a complete response (CR) or better rate in asubject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in complete response (CR) or better rate is relative to the CR or better rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in CR or better rate is relative to the CR or better rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0215] In an aspect, there is provided a pharmaceutical composition for use in improving a complete response (CR) or better rate in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in complete response (CR) or better rate is relative to the CR or better rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in CR or better rate is relative to the CR or better rate of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. Incertain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0216] This disclosure additionally provides methods of improving progression-free survival (PFS) in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in PFS is relative to the PFS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in PFS is relative to the PFS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0217] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving progression-free survival (PFS) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in PFS is relative to the PFS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in PFS is relative to the PFS of areference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0218] In an aspect, there is provided a pharmaceutical composition for use in improving progression-free survival (PFS) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in PFS is relative to the PFS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in PFS is relative to the PFS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0219] This disclosure additionally provides methods of improving an overall response rate (ORR) in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in ORR is relative to the ORR of a reference population of subjects with newly diagnosed multiple myeloma, said reference populationhaving been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in ORR is relative to the ORR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0220] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving an overall response rate (ORR) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in ORR is relative to the ORR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in ORR is relative to the ORR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0221] In an aspect, there is provided a pharmaceutical composition for use in improving an overall response rate (ORR) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in ORR isrelative to the ORR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in ORR is relative to the ORR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0222] This disclosure additionally provides methods of improving overall survival (OS) in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in OS is relative to the OS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in OS is relative to the OS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0223] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving overall survival (OS) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibodythat specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in OS is relative to the OS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in OS is relative to the OS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0224] In an aspect, there is provided a pharmaceutical composition for use in improving overall survival (OS) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in OS is relative to the OS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in OS is relative to the OS of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0225] This disclosure additionally provides methods of improving progression-free survival on next line of therapy (PFS2) in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceuticalcomposition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in PFS2 is relative to the PFS2 of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in PFS2 is relative to the PFS2 of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0226] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving progression-free survival on next line of therapy (PFS2) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in PFS2 is relative to the PFS2 of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in PFS2 is relative to the PFS2 of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0227] In an aspect, there is provided a pharmaceutical composition for use in improving progression-free survival on next line of therapy (PFS2) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceuticalcomposition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in PFS2 is relative to the PFS2 of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in PFS2 is relative to the PFS2 of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0228] This disclosure additionally provides methods of improving time to response (TTR) in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in TTR is relative to the TTR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in TTR is relative to the TTR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0229] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving time to response (TTR) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in TTR is relative to the TTR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in TTR is relative to the TTR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0230] In an aspect, there is provided a pharmaceutical composition for use in improving time to response (TTR) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in TTR is relative to the TTR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in TTR is relative to the TTR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. Incertain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0231] This disclosure additionally provides methods of improving duration of response (DOR) in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in DOR is relative to the DOR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in DOR is relative to the DOR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0232] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving duration of response (DOR) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in DOR is relative to the DOR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in DOR is relative to the DOR of areference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0233] In an aspect, there is provided a pharmaceutical composition for use in improving duration of response (DOR) in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in DOR is relative to the DOR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in DOR is relative to the DOR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0234] This disclosure additionally provides methods of improving sCR in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in sCR isrelative to the sCR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in sCR is relative to the sCR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0235] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving sCR in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in sCR is relative to the sCR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in sCR is relative to the sCR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0236] In an aspect, there is provided a pharmaceutical composition for use in improving sCR in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab,or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in sCR is relative to the sCR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in sCR is relative to the sCR of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0237] This disclosure additionally provides methods of achieving an improved median treatment duration in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in median treatment duration is relative to the median treatment duration of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in median treatment duration is relative to the median treatment duration of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0238] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for achieving an improved median treatment duration in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination withbortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in median treatment duration is relative to the median treatment duration of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in median treatment duration is relative to the median treatment duration of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0239] In an aspect, there is provided a pharmaceutical composition for use in achieving an improved median treatment duration in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in median treatment duration is relative to the median treatment duration of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in median treatment duration is relative to the median treatment duration of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0240] This disclosure additionally provides methods of achieving an improved median number of treatment cycles in a subject or a population of subjects with newly diagnosed multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in median number of treatment cycles is relative to the median number of treatment cycles of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in median number of treatment cycles is relative to the median number of treatment cycles of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0241] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for achieving an improved median number of treatment cycles in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in median number of treatment cycles is relative to the median number of treatment cycles of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in median number of treatment cycles is relative tothe median number of treatment cycles of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0242] In an aspect, there is provided a pharmaceutical composition for use in achieving an improved median number of treatment cycles in a subject or a population of subjects with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. In certain embodiments, the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In certain embodiments, the improvement in median number of treatment cycles is relative to the median number of treatment cycles of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in median number of treatment cycles is relative to the median number of treatment cycles of a reference population of subjects with newly diagnosed multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without daratumumab. In certain embodiments, the subject is ineligible for HDC and ASCT or has deferred HDC and ASCT.

[0243] In any of the disclosed embodiments in which an improvement is mentioned, the improvement may be relative to a reference patient or a reference population of patients with newly diagnosed multiple myeloma, said reference patient or population having been administered bortezomib, lenalidomide, and dexamethasone instead of bortezomib, lenalidomide, and dexamethasone in combination with a pharmaceutical composition comprising an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, or a pharmaceutical composition comprising an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar,, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20).

[0244] The disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy comprising an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, bortezomib, lenalidomide, and dexamethasone. In certain embodiments, daratumumab, or a daratumumab biosimilar, is present as a pharmaceutical composition formulated with hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20).

[0245] The disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy comprising an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, bortezomib, lenalidomide, and dexamethasone.

[0246] The disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy comprising an antibody that specifically binds CD38, in particular daratumumab, bortezomib, lenalidomide, and dexamethasone, wherein the method achieves an improved clinical efficacy endpoint when compared to a clinical efficacy endpoint achieved if the subject were administered a combination of bortezomib, lenalidomide, and dexamethasone.

[0247] The disclosure also provides method of treating a subject with newly diagnosed multiple myeloma who is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT), comprising administering or providing for administration to the subject an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, wherein daratumumab is administered as a combination therapy with bortezomib, lenalidomide, and dexamethasone, and wherein the method achieves an improved clinical efficacy endpoint when compared to a clinical efficacy endpoint achieved if the subject were administered a combination of bortezomib, lenalidomide, and dexamethasone.

[0248] In some embodiments, the subject with newly diagnosed multiple myeloma is ineligible for autologous stem cell transplant (ASCT) and high dose chemotherapy (HDC). In some embodiments, the subject is ineligible for autologous stem cell transplant (ASCT). In some embodiments, the subject with newly diagnosed multiple myeloma is ineligible for high dose chemotherapy (HDC). In some embodiments, transplant was not planned as initial therapy for the subject (transplant deferred).

[0249] MRD status may be assessed from bone marrow aspirate samples using, for example, next generation sequencing (NGS) of immunoglobulin heavy and light chains. The updated, analytically validated version of the clonoSEQ® Assay (Version 2) by Adaptive Biotechnologies may be used for the detection, quantification and analysis of MRD. Pharmaceutical Composition

[0250] In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of daratumumab and about 30,000 U hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of a daratumumab biosimilar and about 30,000 U hyaluronidase. In further embodiments, the pharmaceutical composition comprises about 120 mg / mL of daratumumab and about 2,000 U / mL hyaluronidase. In further embodiments, the pharmaceutical composition comprises about 120 mg / mL of a daratumumab biosimilar and about 2,000 U / mL hyaluronidase.

[0251] A number of suitable hyaluronidase enzymes in accordance with the present disclosure are known. The preferred enzyme is a human hyaluronidase enzyme, such as a soluble human PH20 hyaluronidase, preferably the recombinant human hyaluronidase enzyme product known as rHuPH20. The amino acid sequence of soluble human PH20 hyaluronidases include the soluble human PH20 known as rHuPH20 and available under CAS Registry No.757971-58-7. In some embodiments, rHuPH20 is Hylenex®. Soluble human PH20 hyaluronidases are described in Int. Pat. Publ. No. WO2004 / 078140 and U.S. Pat. No.7,767,429 incorporated herein by reference, in its entirety. In some embodiments, soluble hyaluronidases include those whose sequence are set forth in any of SEQ ID NOs: 12-16. Soluble PH20 hyaluronidase, when expressed in a cell, include a signal sequence for trafficking in the cell. In some embodiments, the amino acid sequence of sequence of a soluble PH20 hyaluronidase SEQ ID NO: 13, namely residues 36-482 of wild type human hyaluronidase. In some embodiments, the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 14. In some embodiments, the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 15. In some embodiments, the amino acid sequence a soluble PH20 hyaluronidase rHuPH20 comprises SEQ ID NO: 16. In some embodiments, the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 12. In some embodiments, the soluble PH20 hyaluronidases, when expressed in a cell, comprise a mixture of species that can include any one or more of SEQ ID NO: 12 to SEQ ID NO: 16 in various abundance. The average molecular weight is 61 kDa.

[0252] rHuPH20 refers to the composition produced upon expression in a cell, such as CHO cell. As produced in the culture medium there is heterogeneity at the C-terminus such that the product, designated rHuPH20, includes a mixture of species that can include any one or more of the polypeptides of SEQ ID NO: 12-16, and some shorter polypeptides, in various abundances. Typically, rHuPH20 is produced in cells, such as CHO cells, (for example DG44 CHO cells) that facilitate correct N-glycosylation to retain activity.

[0253] In further embodiments, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. In still further embodiments, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of daratumumab, or a daratumumab biosimilar; about 2,000 U / mL of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

[0254] In some embodiments, the pharmaceutical composition comprises about 1,800 mg of an antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6 and about 30,000 U rHuPH20.

[0255] In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of an antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6 and about 2,000 U / mL rHuPH20.

[0256] In some embodiments, the pharmaceutical composition comprises one or more excipients.

[0257] In some embodiments, the one or more excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0258] In some embodiments, the pharmaceutical composition comprises a) between about 5 mM and about 15 mM histidine; b) between about 100 mM and about 300 mM sorbitol; c) between about 0.01% w / v and about 0.04 % w / v PS-20; andd) between about 1 mg / mL and about 2 mg / mL methionine, at a pH of about 5.5-5.6.

[0259] In some embodiments, the pharmaceutical composition comprises about 10 mM histidine.

[0260] In some embodiments, the pharmaceutical composition comprises about 300 mM sorbitol.

[0261] In some embodiments, the pharmaceutical composition comprises about 0.04% (w / v) PS-20.

[0262] In some embodiments, the pharmaceutical composition comprises about 1 mg / mL methionine.

[0263] In some embodiments, the pharmaceutical composition comprises: about 1,800 mg of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6; about 30,000 U of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine, at a pH of about 5.6.

[0264] In some embodiments, the pharmaceutical composition comprises: about 120 mg / mL of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6; about 2,000 U / mL of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine, at a pH of about 5.6.

[0265] The pharmaceutical composition of the disclosure may alternatively comprise additional or alternative pharmaceutically acceptable carriers are solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible, such as salts, buffers, antioxidants, saccharides, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifying agents, or combinations thereof.

[0266] Exemplary buffers that may be used are acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffers, HEPPSO and HEPES.

[0267] Exemplary antioxidants that may be used are ascorbic acid, methionine, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, lecithin, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol and tartaric acid.

[0268] Exemplary amino acids that may be used are histidine, isoleucine, methionine, glycine, arginine, lysine, L-leucine, tri-leucine, alanine, glutamic acid, L-threonine, and 2- phenylamine.

[0269] Exemplary surfactants that may be used are polysorbates (e.g., polysorbate-20 or polysorbate-80); polyoxamers (e.g., poloxamer 188); Triton; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl- sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl- dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; and the Monaqua™ series (Mona Industries, Inc., Paterson, N.J.), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics™, PF68, etc).

[0270] Exemplary preservatives that may be used are phenol, m-cresol, p-cresol, o- cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof.

[0271] Exemplary saccharides that may be used are monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, nonreducing sugars such as glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, dextran, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, mellibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol or iso-maltulose.

[0272] Exemplary salts that may be used are acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as fromnontoxic organic amines, such as N,N′-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like. An exemplary salt is sodium chloride.

[0273] In some embodiments, the pharmaceutical composition is at pH 5.0 to 6.0.

[0274] In some embodiments, the pharmaceutical composition is at pH 5.3 to 5.8.

[0275] In some embodiments, the pharmaceutical composition is at pH 5.5.

[0276] In some embodiments, the pharmaceutical composition is at pH 5.6.

[0277] In some embodiments, the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8.

[0278] In some embodiments, the antibody that specifically binds CD38 is an IgG1 isotype.

[0279] An exemplary IgG1 constant domain sequence comprises an amino acid sequence of SEQ ID NO: 11. Some variation exists within the IgG1 constant domain (e.g., well-known allotypes), with variation at positions 214, 356, 358, 422, 431, 435 or 436 (residue numbering according to the EU numbering) (see e.g., IMGT Web resources; IMGT Repertoire (IG and TR); Proteins and alleles; allotypes). The antibody that specifically binds CD38 may be of any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27 or G1m28.

[0280] In some embodiments, the antibody that specifically binds CD38 comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10.

[0281] In some embodiments, the antibody that specifically binds CD38 is daratumumab.

[0282] In some embodiments, the antibody that specifically binds CD38 is a daratumumab biosimilar.

[0283] In some embodiments, the antibody that specifically binds CD38 is a biosimilar of DARZALEX®brand of daratumumab.Methods of Administration

[0284] In some embodiments, the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg of daratumumab, or a daratumumab biosimilar, and 30,000 U of rHuPH20 once a week. In some embodiments, the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg of daratumumab, or a daratumumab biosimilar, and 30,000 U of rHuPH20 once in two weeks. In some embodiments, the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg of daratumumab, or a daratumumab biosimilar, and 30,000 U of rHuPH20 once in three weeks. In some embodiments, the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg of daratumumab, or a daratumumab biosimilar, and 30,000 U of rHuPH20 once in four weeks.

[0285] The pharmaceutical composition of the disclosure is administered by subcutaneous administration.

[0286] The pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered by subcutaneous administration.

[0287] The pharmaceutical composition of the disclosure may is be administered in a total volume of about 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 55 mL, 60 mL, 65 mL, 70 mL, 75 mL, 80 mL, 85 mL, 90 mL, 95 mL, 100 mL, 105 mL, 110 mL, 115 mL or 120 mL.

[0288] In some embodiments, the pharmaceutical composition of the disclosure is administered subcutaneously to the abdominal region.

[0289] Subcutaneous administration may be accomplished using a device. The device may be a syringe, a prefilled syringe, an auto-injector, either disposable or reusable, a pen injector, a patch injector, a wearable injector or an ambulatory syringe infusion pump with subcutaneous infusion sets.

[0290] The pharmaceutical composition of the disclosure may be administered over a time period of between about 1 minute (min) to about 60 min.

[0291] In some embodiments, daratumumab, or a daratumumab biosimilar, is administered subcutaneously at a dose of about 1,800 mg, bortezomib is administeredsubcutaneously at a dose of about 1.3 mg / m2, lenalidomide is administered orally at a dose of about 25 mg, and dexamethasone is administered orally or intravenously at a dose of about 20 mg to about 40 mg.

[0292] In some embodiments, the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles.

[0293] In some embodiments, the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for eight 21-day cycles.

[0294] In some embodiments, daratumumab, or a daratumumab biosimilar, is administered subcutaneously at a dose of about 1,800 mg once a week in cycles 1 through 2, about 1,800 mg once a week every 3 weeks in cycles 3 through 8, and about 1,800 mg once a week every 4 weeks thereafter until disease progression or unacceptable toxicity.

[0295] In certain embodiments, bortezomib is administered at a dose of about 1.3 mg / m2twice a week. In further embodiments, bortezomib is administered subcutaneously. In further embodiments, bortezomib is administered intravenously. In some embodiments, the bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2on days 1, 4, 8 and 11.

[0296] In certain embodiments, lenalidomide is administered at a dose of about 25 mg daily. In still further embodiments, lenalidomide is administered at a dose of about 10 mg daily. In still further embodiments, lenalidomide is administered at a dose of about 10 mg daily in the maintenance phase. After three 28-day cycles of maintenance therapy, if well tolerated, the lenalidomide dose may be increased to 15 mg daily. In certain embodiments, if a daily lenalidomide dose is missed, it may be administered if <12 hours have elapsed since the time that it should have been taken. If the next dose is scheduled to be taken within 12 hours, the missed lenalidomide dose should be skipped. In certain embodiments, lenalidomide is administered as a single dose at approximately the same time daily. In certain embodiments, lenalidomide can be taken with or without food. In certain embodiments, lenalidomide is administered orally. In some embodiments, the lenalidomide is administered orally at a dose of about 25 mg on days 1-14.

[0297] In some embodiments, dexamethasone is administered at a dose of about 20 mg to about 40 mg daily. In some embodiments, dexamethasone is administered at a dose of about 20 mg daily. In some embodiments, dexamethasone is administered at a dose of about 40 mg daily. In further embodiments, dexamethasone is administered orally. In furtherembodiments, dexamethasone is administered intravenously. On days when dexamethasone is administered with the pharmaceutical composition, dexamethasone is administered at a dose of 40 mg orally or intravenously 1-3 hours before administration of the pharmaceutical composition. On days when the pharmaceutical composition is not administered, dexamethasone is administered orally. In some embodiments, the dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12.

[0298] In some embodiments, the pharmaceutical composition, lenalidomide and dexamethasone are administered for one or more 28-day cycles following the eight 21-day cycles. In some embodiments, the lenalidomide is administered orally at a dose of about 25 mg on days 1-21 of the one or more 28-day cycles until disease progression. In some embodiments, dexamethasone is administered orally or intravenously at a dose of about 40 mg on days 1, 8, 15 and 22 of the one or more 28-day cycles until disease progression.

[0299] Bortezomib, lenalidomide and dexamethasone doses may be reduced, or the treatment schedule may be modified for the management of the study drug-related toxicities. Subjects who need to discontinue treatment with any one component of study treatment (daratumumab, or a daratumumab biosimilar, bortezomib, lenalidomide or dexamethasone) may continue to receive treatment with the other components.

[0300] In certain embodiments, the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles.

[0301] In some embodiments, the pharmaceutical composition is administered once a week in the first and the second 21-day cycle, once in three weeks in the third, the fourth, the fifth, the sixth, the seventh, and the eight 21-day cycle, and thereafter once in four weeks in any subsequent 21-day cycle.

[0302] In further embodiments, bortezomib is administered at a dose of about 1.3 mg / m2days 1, 4, 8, and 11 for cycles 1-8.

[0303] In still further embodiments, lenalidomide is administered at a dose of about 25 mg on days 1-14 for cycles 1-8, and at a dose of 25 mg on days 1-21 in any subsequent 28-day cycle. In some embodiments, dexamethasone is administered at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1-8, and about 40 mg on days 1, 8, 15, and 22 in any subsequent 28-day cycle. EMBODIMENTS

[0304] Embodiments Section 1

[0305] This invention provides the following non-limiting embodiments: 1) A method of treating newly diagnosed multiple myeloma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). 1a) The method of embodiment 1, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). 2) The method of embodiment 1 or 1a, wherein the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT. 3) The method of embodiment 2, wherein the subject who is ineligible for HDC and ASCT is greater than or equal to 70 years of age. 4) The method of embodiment 2, wherein the subject who is ineligible for HDC and ASCT is greater than or equal to 18 and less than 70 years of age and has one or more comorbid conditions. 5) The method of any one of the preceding embodiments, wherein the method achieves an improved clinical efficacy endpoint of the subject relative to a clinical efficacy endpoint achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 6) The method of embodiment 5, wherein the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD)-negativity rate , an improved sustained MRD-negativity rate, an improved complete response (CR) or better rate, an improved progression-free survival (PFS), an improved overall response rate (ORR), an improved overall survival (OS), an improved progression-free survival on next line of therapy (PFS2), an improved time to response (TTR), or an improved duration of response (DOR). 7) The method of embodiment 6, wherein the improved clinical efficacy endpoint is an improved overall MRD-negativity rate.8) The method of embodiment 7, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10-5. 9) The method of embodiment 8, wherein the improved overall MRD-negativity rate is 60.9% relative to 39.4% for the reference subject or the reference population of subjects. 10) The method of embodiment 8, wherein the improved overall MRD-negativity rate is an absolute increase of 21.5% relative to the reference subject or the reference population of subjects. 11) The method of embodiment 7, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10-6. 12) The method of embodiment 11, wherein the improved overall MRD-negativity rate is 46.2% relative to 27.3% for the reference subject or the reference population of subjects. 13) The method of any one of embodiments 7-12, wherein the overall MRD-negativity rate is determined prior to a progression of the multiple myeloma, subsequent to administration of an antimyeloma therapy, or both. 14) The method of any one of embodiments 7-13 wherein the subject does not have high cytogenetic risk. 15) The method of embodiment 6, wherein the improved clinical efficacy endpoint is an improved sustained minimal residual disease (MRD)-negativity rate. 16) The method of embodiment 15, wherein the improved sustained MRD-negativity rate is for a period of 1 year, 2 years, and / or 3 years. 17) The method of embodiment 15 or 16, wherein the improved sustained MRD- negativity rate is at or below a sensitivity threshold of 10-5. 18) The method of embodiment 17, wherein the improved sustained MRD-negativity rate is 48.7% relative to 26.3% for the reference subject or the reference population of subjects. 19) The method of embodiment 15 or 16, wherein the improved sustained MRD- negativity rate is at or below a sensitivity threshold of 10-6. 20) The method of embodiment 19, wherein the improved overall MRD-negativity rate is 32.0% relative to 15.7% for the reference subject or the reference population of subjects. 21) The method of any one of embodiments 6-20, wherein the improved overall MRD- negativity rate or the improved sustained MRD-negativity rate is evaluated by next- generation sequencing.22) The method of any one of embodiments 6-21, wherein the improved overall MRD- negativity rate or the improved sustained MRD-negativity rate is evaluated using bone marrow aspirate samples obtained at day 0, at the time of suspected complete response, and at 12, 18, 24, 30, and 36 months after administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, and yearly thereafter in subjects with a complete response. 23) The method of embodiment 6, wherein the improved clinical efficacy endpoint is an improved complete response (CR) or better rate. 24) The method of embodiment 23, wherein the improved CR or better rate is 81.2% relative to 61.6% for the reference subject or the reference population of subjects. 25) The method of embodiment 23 or 24, wherein the improved CR or better rate is an absolute increase of 19.6% relative to the reference subject or the reference population of subjects. 26) The method of embodiment 6, wherein the improved clinical efficacy endpoint is an improved progression-free survival (PFS). 27) The method of embodiment 26, wherein the improved PFS is prolonged relative to the reference subject or the reference population of subjects. 28) The method of embodiment 26 or 27, wherein the improved PFS is a 43% reduction of risk of progression or death. 29) The method of any one of embodiments 26-28, wherein the subjects with improved PFS are negative for MRD at a sensitivity threshold of 10-6, 10-5, or both. 30) The method of any one of embodiments 26-28, wherein the subjects with improved PFS are positive for MRD at a sensitivity threshold of 10-6, 10-5, or both. 31) The method of any one of embodiments 26-30, wherein the improved PFS is an improvement in median PFS. 32) The method of any one of the preceding embodiments, wherein the method achieves an improved median treatment duration relative to a median treatment duration achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab.33) The method of embodiment 32, wherein the improved median treatment duration is 56.3 months relative to 34.3 months for the reference subject or the reference population of subjects. 34) The method of any one of the preceding embodiments, wherein the method achieves an improved median number of treatment cycles relative to a median number of treatment cycles achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 35) The method of embodiment 34, wherein the improved median number of treatment cycles is 59 months relative to 37 months for the reference subject or the reference population of subjects. 36) The method of any one of the preceding embodiments, wherein the method achieves a comparable EORTC QLQ-C30 global health status domain score relative to a EORTC QLQ- C30 global health status domain score achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 37) The method of any one of the preceding embodiments, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2. 38) The method of any one of the preceding embodiments, wherein the subject has creatinine clearance of ≥30 mL / min / 1.73 m2. 39) The method of any one of the preceding embodiments, wherein the subject has stage 3 multiple myeloma according to the International Staging System (ISS). 40) The method of any one of the preceding embodiments, wherein the subject has high cytogenetic risk. 41) The method of any one of the preceding embodiments, wherein the pharmaceutical composition comprises about 1,800 mg of daratumumab, or a daratumumab biosimilar, and about 30,000 U rHuPH20. 42) The method of embodiment 41, wherein the pharmaceutical composition comprises about 120 mg / mL of daratumumab, or a daratumumab biosimilar, and about 2,000 U / mL rHuPH20.43) The method of any one of the preceding embodiments, wherein the pharmaceutical composition comprises one or more excipients. 44) The method of embodiment 43, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof. 45) The method of any one of the preceding embodiments, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. 46) The method of any one of the preceding embodiments, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of daratumumab, or a daratumumab biosimilar; about 2,000 U / mL of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. 47) The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered subcutaneously at a dose of about 1,800 mg, bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2, lenalidomide is administered orally at a dose of about 25 mg, and dexamethasone is administered orally or intravenously at a dose of about 20 mg to about 40 mg. 48) The method of any one of the preceding embodiments, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles. 49) The method of embodiment 48, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for eight 21-day cycles. 50) The method of embodiment 49, wherein daratumumab or the daratumumab biosimilar is administered subcutaneously at a dose of about 1,800 mg once a week in cycles 1 through 2, about 1,800 mg once a week every 3 weeks in cycles 3 through 8, and about 1,800 mg once a week every 4 weeks thereafter until disease progression or unacceptable toxicity. 51) The method of embodiment 49, wherein the bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2 on days 1, 4, 8 and 11. 52) The method of embodiment 49, wherein the lenalidomide is administered orally at a dose of about 25 mg on days 1-14.53) The method of embodiment 49, wherein the dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. 54) The method of embodiment 49, wherein the pharmaceutical composition, lenalidomide and dexamethasone are administered for one or more 28-day cycles following the eight 21-day cycles. 55) The method of embodiment 54, wherein the lenalidomide is administered orally at a dose of about 25 mg on days 1-21 of the one or more 28-day cycles and dexamethasone is administered orally or intravenously at a dose of about 40 mg on days 1, 8, 15 and 22 of the one or more 28-day cycles until disease progression. 56) The method of any one of the preceding embodiments, wherein the improved clinical efficacy endpoint is an improved stringent complete response (sCR). 57) The method of embodiment 56, wherein the improved sCR is about 65.0% relative to about 44.9% for the reference subject or the reference population of subjects. 58) The method of embodiment 56 or 57, wherein the improved sCR is an absolute increase of about 20.1% relative to the reference subject or the reference population of subjects. 59) A method of treating newly diagnosed multiple myeloma in a subject in need thereof comprising administering daratumumab, or a daratumumab biosimilar, to the subject in combination with bortezomib, lenalidomide, and dexamethasone. 60) The method of embodiment 59, wherein the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT. Embodiments Section 2 1) Use of a pharmaceutical composition for the manufacture of a medicament for treating newly diagnosed multiple myeloma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. 1a) The use of embodiment 1, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20).2) The use of embodiment 1 or 1a, wherein the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT. 3) The use of embodiment 2, wherein the subject who is ineligible for HDC and ASCT is greater than or equal to 70 years of age. 4) The use of embodiment 2, wherein the subject who is ineligible for HDC and ASCT is greater than or equal to 18 and less than 70 years of age and has one or more comorbid conditions. 5) The use of any one of the preceding embodiments, wherein the use achieves an improved clinical efficacy endpoint of the subject relative to a clinical efficacy endpoint achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 6) The use of embodiment 5, wherein the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD)-negativity rate , an improved sustained MRD-negativity rate, an improved complete response (CR) or better rate, an improved progression-free survival (PFS), an improved overall response rate (ORR), an improved overall survival (OS), an improved progression-free survival on next line of therapy (PFS2), an improved time to response (TTR), or an improved duration of response (DOR). 7) The use of embodiment 6, wherein the improved clinical efficacy endpoint is an improved overall MRD-negativity rate. 8) The use of embodiment 7, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10-5. 9) The use of embodiment 8, wherein the improved overall MRD-negativity rate is 60.9% relative to 39.4% for the reference subject or the reference population of subjects. 10) The use of embodiment 8, wherein the improved overall MRD-negativity rate is an absolute increase of 21.5% relative to the reference subject or the reference population of subjects. 11) The use of embodiment 7, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10-6. 12) The use of embodiment 11, wherein the improved overall MRD-negativity rate is 46.2% relative to 27.3% for the reference subject or the reference population of subjects.13) The use of any one of embodiments 7-12, wherein the overall MRD-negativity rate is determined prior to a progression of the multiple myeloma, subsequent to administration of an antimyeloma therapy, or both. 14) The use of any one of embodiments 7-13 wherein the subject does not have high cytogenetic risk. 15) The use of embodiment 6, wherein the improved clinical efficacy endpoint is an improved sustained minimal residual disease (MRD)-negativity rate. 16) The use of embodiment 15, wherein the improved sustained MRD-negativity rate is for a period of 1 year, 2 years, and / or 3 years. 17) The use of embodiment 15 or 16, wherein the improved sustained MRD-negativity rate is at or below a sensitivity threshold of 10-5. 18) The use of embodiment 17, wherein the improved sustained MRD-negativity rate is 48.7% relative to 26.3% for the reference subject or the reference population of subjects. 19) The use of embodiment 15 or 16, wherein the improved sustained MRD-negativity rate is at or below a sensitivity threshold of 10-6. 20) The use of embodiment 19, wherein the improved overall MRD-negativity rate is 32.0% relative to 15.7% for the reference subject or the reference population of subjects. 21) The use of any one of embodiments 6-20, wherein the improved overall MRD- negativity rate or the improved sustained MRD-negativity rate is evaluated by next- generation sequencing. 22) The use of any one of embodiments 6-21, wherein the improved overall MRD- negativity rate or the improved sustained MRD-negativity rate is evaluated using bone marrow aspirate samples obtained at day 0, at the time of suspected complete response, and at 12, 18, 24, 30, and 36 months after administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, and yearly thereafter in subjects with a complete response. 23) The use of embodiment 6, wherein the improved clinical efficacy endpoint is an improved complete response (CR) or better rate. 24) The use of embodiment 23, wherein the improved CR or better rate is 81.2% relative to 61.6% for the reference subject or the reference population of subjects.25) The use of embodiment 23 or 24, wherein the improved CR or better rate is an absolute increase of 19.6% relative to the reference subject or the reference population of subjects. 26) The use of embodiment 6, wherein the improved clinical efficacy endpoint is an improved progression-free survival (PFS). 27) The use of embodiment 26, wherein the improved PFS is prolonged relative to the reference subject or the reference population of subjects. 28) The use of embodiment 26 or 27, wherein the improved PFS is a 43% reduction of risk of progression or death. 29) The use of any one of embodiments 26-28, wherein the subjects with improved PFS are negative for MRD at a sensitivity threshold of 10-6, 10-5, or both. 30) The use of any one of embodiments 26-28, wherein the subjects with improved PFS are positive for MRD at a sensitivity threshold of 10-6, 10-5, or both. 31) The use of any one of embodiments 26-30, wherein the improved PFS is an improvement in median PFS. 32) The use of any one of the preceding embodiments, wherein the use achieves an improved median treatment duration relative to a median treatment duration achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 33) The use of embodiment 32, wherein the improved median treatment duration is 56.3 months relative to 34.3 months for the reference subject or the reference population of subjects. 34) The use of any one of the preceding embodiments, wherein the use achieves an improved median number of treatment cycles relative to a median number of treatment cycles achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 35) The use of embodiment 34, wherein the improved median number of treatment cycles is 59 months relative to 37 months for the reference subject or the reference population of subjects.36) The use of any one of the preceding embodiments, wherein the use achieves a comparable EORTC QLQ-C30 global health status domain score relative to a EORTC QLQ- C30 global health status domain score achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 37) The use of any one of the preceding embodiments, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2. 38) The use of any one of the preceding embodiments, wherein the subject has creatinine clearance of ≥30 mL / min / 1.73 m2. 39) The use of any one of the preceding embodiments, wherein the subject has stage 3 multiple myeloma according to the International Staging System (ISS). 40) The use of any one of the preceding embodiments, wherein the subject has high cytogenetic risk. 41) The use of any one of the preceding embodiments, wherein the pharmaceutical composition comprises about 1,800 mg of daratumumab, or a daratumumab biosimilar, and about 30,000 U rHuPH20. 42) The use of embodiment 41, wherein the pharmaceutical composition comprises about 120 mg / mL of daratumumab, or a daratumumab biosimilar, and about 2,000 U / mL rHuPH20. 43) The use of any one of the preceding embodiments, wherein the pharmaceutical composition comprises one or more excipients. 44) The use of embodiment 43, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof. 45) The use of any one of the preceding embodiments, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. 46) The use of any one of the preceding embodiments, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of daratumumab, or a daratumumab biosimilar; about 2,000 U / mL ofrHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. 47) The use of any one of the preceding embodiments, wherein the pharmaceutical composition is administered subcutaneously at a dose of about 1,800 mg, bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2, lenalidomide is administered orally at a dose of about 25 mg, and dexamethasone is administered orally or intravenously at a dose of about 20 mg to about 40 mg. 48) The use of any one of the preceding embodiments, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles. 49) The use of embodiment 48, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for eight 21-day cycles. 50) The use of embodiment 49, wherein daratumumab, or daratumumab biosimilar, is administered subcutaneously at a dose of about 1,800 mg once a week in cycles 1 through 2, about 1,800 mg once a week every 3 weeks in cycles 3 through 8, and about 1,800 mg once a week every 4 weeks thereafter until disease progression or unacceptable toxicity. 51) The use of embodiment 49, wherein the bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2 on days 1, 4, 8 and 11. 52) The use of embodiment 49, wherein the lenalidomide is administered orally at a dose of about 25 mg on days 1-14. 53) The use of embodiment 49, wherein the dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. 54) The use of embodiment 49, wherein the pharmaceutical composition, lenalidomide and dexamethasone are administered for one or more 28-day cycles following the eight 21- day cycles. 55) The use of embodiment 54, wherein the lenalidomide is administered orally at a dose of about 25 mg on days 1-21 of the one or more 28-day cycles and dexamethasone is administered orally or intravenously at a dose of about 40 mg on days 1, 8, 15 and 22 of the one or more 28-day cycles until disease progression. 56) The use of any one of the preceding embodiments, wherein the improved clinical efficacy endpoint is an improved stringent complete response (sCR).57) The use of embodiment 56, wherein the improved sCR is about 65.0% relative to about 44.9% for the reference subject or the reference population of subjects. 58) The use of embodiment 56 or 57, wherein the improved sCR is an absolute increase of about 20.1% relative to the reference subject or the reference population of subjects. 59) Use of a pharmaceutical composition for the manufacture of a medicament for treating newly diagnosed multiple myeloma in a subject in need thereof, comprising administering daratumumab, or a daratumumab biosimilar, to the subject in combination with bortezomib, lenalidomide, and dexamethasone. 60) The use of embodiment 59, wherein the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT. Embodiments Section 3 1) A pharmaceutical composition for use in the treatment of newly diagnosed multiple myeloma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar. 1a) The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises an antibody that specifically binds CD38, in particular daratumumab, or a daratumumab biosimilar, and hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). 2) The pharmaceutical composition of embodiment 1 or 1a, wherein the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT. 3) The pharmaceutical composition of embodiment 2, wherein the subject who is ineligible for HDC and ASCT is greater than or equal to 70 years of age. 4) The pharmaceutical composition of embodiment 2, wherein the subject who is ineligible for HDC and ASCT is greater than or equal to 18 and less than 70 years of age and has one or more comorbid conditions. 5) The pharmaceutical composition of any one of the preceding embodiments, wherein the administration achieves an improved clinical efficacy endpoint of the subject relative to a clinical efficacy endpoint achieved in a reference subject or a reference population ofsubjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 6) The pharmaceutical composition of embodiment 5, wherein the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD)-negativity rate , an improved sustained MRD-negativity rate, an improved complete response (CR) or better rate, an improved progression-free survival (PFS), an improved overall response rate (ORR), an improved overall survival (OS), an improved progression-free survival on next line of therapy (PFS2), an improved time to response (TTR), or an improved duration of response (DOR). 7) The pharmaceutical composition of embodiment 6, wherein the improved clinical efficacy endpoint is an improved overall MRD-negativity rate. 8) The pharmaceutical composition of embodiment 7, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10-5. 9) The pharmaceutical composition of embodiment 8, wherein the improved overall MRD-negativity rate is 60.9% relative to 39.4% for the reference subject or the reference population of subjects. 10) The pharmaceutical composition of embodiment 8, wherein the improved overall MRD-negativity rate is an absolute increase of 21.5% relative to the reference subject or the reference population of subjects. 11) The pharmaceutical composition of embodiment 7, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10-6. 12) The pharmaceutical composition of embodiment 11, wherein the improved overall MRD-negativity rate is 46.2% relative to 27.3% for the reference subject or the reference population of subjects. 13) The pharmaceutical composition of any one of embodiments 7-12, wherein the overall MRD-negativity rate is determined prior to a progression of the multiple myeloma, subsequent to administration of an antimyeloma therapy, or both. 14) The pharmaceutical composition of any one of embodiments 7-13 wherein the subject does not have high cytogenetic risk. 15) The pharmaceutical composition of embodiment 6, wherein the improved clinical efficacy endpoint is an improved sustained minimal residual disease (MRD)-negativity rate.16) The pharmaceutical composition of embodiment 15, wherein the improved sustained MRD-negativity rate is for a period of 1 year, 2 years, and / or 3 years. 17) The pharmaceutical composition of embodiment 15 or 16, wherein the improved sustained MRD-negativity rate is at or below a sensitivity threshold of 10-5. 18) The pharmaceutical composition of embodiment 17, wherein the improved sustained MRD-negativity rate is 48.7% relative to 26.3% for the reference subject or the reference population of subjects. 19) The pharmaceutical composition of embodiment 15 or 16, wherein the improved sustained MRD-negativity rate is at or below a sensitivity threshold of 10-6. 20) The pharmaceutical composition of embodiment 19, wherein the improved overall MRD-negativity rate is 32.0% relative to 15.7% for the reference subject or the reference population of subjects. 21) The pharmaceutical composition of any one of embodiments 6-20, wherein the improved overall MRD-negativity rate or the improved sustained MRD-negativity rate is evaluated by next-generation sequencing. 22) The pharmaceutical composition of any one of embodiments 6-21, wherein the improved overall MRD-negativity rate or the improved sustained MRD-negativity rate is evaluated using bone marrow aspirate samples obtained at day 0, at the time of suspected complete response, and at 12, 18, 24, 30, and 36 months after administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, and yearly thereafter in subjects with a complete response. 23) The pharmaceutical composition of embodiment 6, wherein the improved clinical efficacy endpoint is an improved complete response (CR) or better rate. 24) The pharmaceutical composition of embodiment 23, wherein the improved CR or better rate is 81.2% relative to 61.6% for the reference subject or the reference population of subjects. 25) The pharmaceutical composition of embodiment 23 or 24, wherein the improved CR or better rate is an absolute increase of 19.6% relative to the reference subject or the reference population of subjects. 26) The pharmaceutical composition of embodiment 6, wherein the improved clinical efficacy endpoint is an improved progression-free survival (PFS).27) The pharmaceutical composition of embodiment 26, wherein the improved PFS is prolonged relative to the reference subject or the reference population of subjects. 28) The pharmaceutical composition of embodiment 26 or 27, wherein the improved PFS is a 43% reduction of risk of progression or death. 29) The pharmaceutical composition of any one of embodiments 26-28, wherein the subjects with improved PFS are negative for MRD at a sensitivity threshold of 10-6, 10-5, or both. 30) The pharmaceutical composition of any one of embodiments 26-28, wherein the subjects with improved PFS are positive for MRD at a sensitivity threshold of 10-6, 10-5, or both. 31) The pharmaceutical composition of any one of embodiments 26-30, wherein the improved PFS is an improvement in median PFS. 32) The pharmaceutical composition of any one of the preceding embodiments, wherein the administering achieves an improved median treatment duration relative to a median treatment duration achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 33) The pharmaceutical composition of embodiment 32, wherein the improved median treatment duration is 56.3 months relative to 34.3 months for the reference subject or the reference population of subjects. 34) The pharmaceutical composition of any one of the preceding embodiments, wherein the administering achieves an improved median number of treatment cycles relative to a median number of treatment cycles achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 35) The pharmaceutical composition of embodiment 34, wherein the improved median number of treatment cycles is 59 months relative to 37 months for the reference subject or the reference population of subjects. 36) The pharmaceutical composition of any one of the preceding embodiments, wherein the administering achieves a comparable EORTC QLQ-C30 global health status domain score relative to a EORTC QLQ-C30 global health status domain score achieved in areference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 37) The pharmaceutical composition of any one of the preceding embodiments, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2. 38) The pharmaceutical composition of any one of the preceding embodiments, wherein the subject has creatinine clearance of ≥30 mL / min / 1.73 m2. 39) The pharmaceutical composition of any one of the preceding embodiments, wherein the subject has stage 3 multiple myeloma according to the International Staging System (ISS). 40) The pharmaceutical composition of any one of the preceding embodiments, wherein the subject has high cytogenetic risk. 41) The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises about 1,800 mg of daratumumab, or a daratumumab biosimilar, and about 30,000 U rHuPH20. 42) The pharmaceutical composition of embodiment 41, wherein the pharmaceutical composition comprises about 120 mg / mL of daratumumab, or a daratumumab biosimilar, and about 2,000 U / mL rHuPH20. 43) The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises one or more excipients. 44) The pharmaceutical composition of embodiment 43, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof. 45) The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. 46) The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of daratumumab, or a daratumumab biosimilar;about 2,000 U / mL of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. 47) The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is administered subcutaneously at a dose of about 1,800 mg, bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2, lenalidomide is administered orally at a dose of about 25 mg, and dexamethasone is administered orally or intravenously at a dose of about 20 mg to about 40 mg. 48) The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles. 49) The pharmaceutical composition of embodiment 48, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for eight 21-day cycles. 50) The pharmaceutical composition of embodiment 49, wherein daratumumab or daratumumab biosimilar is administered subcutaneously at a dose of about 1,800 mg once a week in cycles 1 through 2, about 1,800 mg once a week every 3 weeks in cycles 3 through 8, and about 1,800 mg once a week every 4 weeks thereafter until disease progression or unacceptable toxicity. 51) The pharmaceutical composition of embodiment 49, wherein the bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2 on days 1, 4, 8 and 11. 52) The pharmaceutical composition of embodiment 49, wherein the lenalidomide is administered orally at a dose of about 25 mg on days 1-14. 53) The pharmaceutical composition of embodiment 49, wherein the dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. 54) The pharmaceutical composition of embodiment 49, wherein the pharmaceutical composition, lenalidomide and dexamethasone are administered for one or more 28-day cycles following the eight 21-day cycles. 55) The pharmaceutical composition of embodiment 54, wherein the lenalidomide is administered orally at a dose of about 25 mg on days 1-21 of the one or more 28-day cycles and dexamethasone is administered orally or intravenously at a dose of about 40 mg on days 1, 8, 15 and 22 of the one or more 28-day cycles until disease progression.56) The pharmaceutical composition of any one of the preceding embodiments, wherein the improved clinical efficacy endpoint is an improved stringent complete response (sCR). 57) The pharmaceutical composition of embodiment 56, wherein the improved sCR is about 65.0% relative to about 44.9% for the reference subject or the reference population of subjects. 58) The pharmaceutical composition of embodiment 56 or 57, wherein the improved sCR is an absolute increase of about 20.1% relative to the reference subject or the reference population of subjects. 59) A pharmaceutical composition for use in the treatment of newly diagnosed multiple myeloma in a subject in need thereof, comprising administering daratumumab, or a daratumumab biosimilar, to the subject in combination with bortezomib, lenalidomide, and dexamethasone. 60) The pharmaceutical composition of embodiment 59, wherein the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT. EXAMPLES

[0306] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims. EXAMPLE 1: Daratumumab, Bortezomib, Lenalidomide & Dexamethasone for Multiple Myeloma

[0307] An efficacy and safety data analysis of the CEPHEUS study of subcutaneous daratumumab in combination with bortezomib / lenalidomide / dexamethasone (VRd) versus VRd alone in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) or for whom transplant is not intended as initial therapy, is provided herein. Introduction:

[0308] Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action. In this phase 3 CEPHEUS study, daratumumab plus VRd (D-VRd) was evaluated as a quadruplet therapy in patients with transplant-ineligible (TIE) newly diagnosed multiple myeloma or for whom transplantwas not planned as initial therapy (TIE or transplant deferred). Observations from the final progression-free survival analysis of CEPHEUS are reported herein. Study Design:

[0309] This study was a randomized, open-label, multicenter phase 3 study enrolled patients at 92 sites in 13 countries. An independent ethics committee or institutional review board approved the protocol at each site. Patients

[0310] Enrolled patients had newly diagnosed multiple myeloma and were not considered candidates for high-dose chemotherapy with stem-cell transplantation due to age (≥70 years) or were age >18 to 70 years with the presence of comorbid conditions likely to have a negative impact on tolerability of high-dose chemotherapy with stem-cell transplantation as initial treatment (transplant deferred).

[0311] Patients had an Eastern Cooperative Oncology Group performance status of 0 to 2, an absolute neutrophil count of 1.0×109or more per liter (granulocyte colony stimulating factor [G-CSF] was permitted), a hemoglobin level of 7.5 g or more per deciliter (without prior red blood cell transfusion within 7 days before the laboratory test; recombinant human erythropoietin use was permitted), a platelet count of 70×109or more per liter (if <50% of bone marrow nucleated cells were plasma cells; otherwise, platelet count >50×109per liter), a calculated creatinine clearance of 30 mL or more per minute, a corrected serum calcium level of 13.5 mg or less per deciliter (≤3.4 mmol per liter) or free ionized calcium level of 6.5 mg or less per deciliter (≤1.6 mmol per liter), aspartate and alanine aminotransferase levels 2.5 or fewer times the upper limit of normal, and a total bilirubin level 1.5 or fewer times the upper limit of normal. Excluded were patients with a frailty index of ≥2 according to the Myeloma Geriatric Assessment score, prior therapy for multiple myeloma other than a short course of corticosteroids, prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years of randomization, grade 2 or higher peripheral neuropathy or neuropathic pain (per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 5), focal radiation therapy within 14 days of randomization, plasmapheresis within 28 days of randomization, clinical signs of meningeal involvement of multiple myeloma, chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal, or moderate or severe persistent asthma within the past 2 years or currently uncontrolled asthma.Inclusion Criteria

[0312] 1. Newly diagnosed and not considered candidate for high-dose chemotherapy with stem cell transplantation (SCT) due to: being age ≥ 70 years or age 18-70 years with presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with SCT or who refuse high-dose chemotherapy with SCT as initial treatment.

[0313] 2. Diagnosis of multiple myeloma as documented per IMWG criteria: Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the CRAB (calcium, renal, anemia, bone) criteria or biomarkers of malignancy criteria.

[0314] CRAB criteria: a. Hypercalcemia: serum calcium >0.25 mmol / L (>1 mg / dL) higher than upper limit of normal (ULN) or >2.75 mmol / L (>11 mg / dL) b. Renal insufficiency: creatinine clearance <40mL / min or serum creatinine >177 μmol / L (>2 mg / dL) c. Anemia: hemoglobin >2 g / dL below the lower limit of normal or hemoglobin <10 g / dL d. Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT

[0315] Biomarkers of Malignancy a. Clonal bone marrow plasma cell percentage ≥60% b. Involved: uninvolved serum free light chain (FLC) ratio ≥100 c. >1 focal lesion on magnetic resonance imaging (MRI) studies

[0316] 3. Must have measurable disease, as assessed by central laboratory, defined by any of the following: a. IgG, IgA, IgM, IgD, or IgE multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g / dL or urine M-protein level ≥200 mg / 24 hours; or b. Light chain multiple myeloma without measurable disease in serum or urine: Serum Ig FLC ≥10 mg / dL and abnormal serum Ig kappa lambda FLC ratio

[0317] 4. ECOG performance status score of 0, 1, or 2.

[0318] 5. Clinical laboratory values meeting the following criteria during the Screening Phase: a. hemoglobin >7.5 g / dL ( mmol / L) (without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted); b. absolute neutrophil count (ANC) >1.0 x109 / L (granulocyte colony stimulating factor [G-CSF] use is permitted); c. platelet count >70 x109 / L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise, platelet count >50 ×109 / L (transfusions are not permitted within 7 days); d. aspartate aminotransferase (AST) ≤2.5 x ULN; e. alanine aminotransferase (ALT) ≤2.5 x ULN; f. total bilirubin ≤1.5 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN); g. Estimated creatinine clearance (CrCl) ≥30 mL / min. Creatinine clearance can be calculated using the Cockcroft-Gault formula9 or eGFR, or CKD-epi formula, or for subjects with over- or underweight, CrCl may be measured from a 24-hours urine collection. If Cockcroft-Gault formula is used and body mass index (BMI) is ≥30 kg / m2 then adjusted body weight should be used in calculation; h. corrected serum calcium ≤13.5 mg / dL (≤3.4 mM / L); or free ionized calcium ≤6.5 mg / dL (≤1.6 mM / L)

[0319] 6. Female subjects of reproductive childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the Treatment Period, during any dose interruptions, and for 3 months after the last dose of any component of the treatment as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. This birth control method must include one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated evenwhere there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.

[0320] 7. A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing

[0321] 8. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 3 months after receiving the last dose of any component of the treatment regimen.

[0322] 9. Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 3 months after discontinuing study treatment (even after a successful vasectomy).

[0323] 10. Male subjects of reproductive potential must not donate sperm during the study or for 3 months after the last dose of study treatment.

[0324] 11. Must sign an informed consent form (ICF) or their legally designated representative must sign indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.

[0325] 12. Able to adhere to the prohibitions and restrictions specified in this protocol Exclusion Criteria

[0326] 1. Frailty index of ≥2 according to Myeloma Geriatric Assessment score.

[0327] 2. Prior therapy for multiple myeloma other than a short course of corticosteroids (not to exceed 40 mg of dexamethasone, or equivalent per day, total of 160 mg dexamethasone or equivalent.

[0328] 3. Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years of date of randomization (exceptions are adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other non- invasive lesion that in the opinion of the investigator, with concurrence with the sponsor’s medical monitor, is considered cured with minimal risk of recurrence within 3 years).

[0329] 4. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.

[0330] 5. Focal radiation therapy within 14 days of randomization with the exception of palliative radiotherapy for symptomatic pain management. Radiotherapy within 14 days prior to randomization on measurable extramedullary plasmacytoma is not permitted even in the setting of palliation for symptomatic management.

[0331] 6. Plasmapheresis within 28 days of randomization.

[0332] 7. Clinical signs of meningeal involvement of multiple myeloma.

[0333] 8. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted. (FEV1 testing is required for subjects suspected of having COPD).

[0334] 9. Moderate or severe persistent asthma within the past 2 years, uncontrolled asthma of any classification. (Subjects who have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).

[0335] 10. Subject is: a. Known to be seropositive for human immunodeficiency virus (HIV). b. seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to total hepatitis B core antigen [anti-HBc] and / or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. c. Known to be seropositive for hepatitis C virus (HCV; anti-HCV antibody positive or HCV-RNA quantitation positive), except in the setting of a sustained virologic response (SVR), defined as a viremia at least 12 weeks after completion of antiviral therapy.

[0336] 11. Concurrent medical or psychiatric condition or disease (such as but not limited to, systemic amyloidosis, POEMS, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard if enrolled in the study.

[0337] 12. Has clinically significant cardiac disease, including: Myocardial infarction within 6 months before signing the ICF, or unstable or uncontrolled disease / condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV, Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities, Screening 12-lead ECG showing a baseline QT interval as corrected by Frederica’s formula (QTcF) >470 msec

[0338] 13. Received a strong CYP3A4 inducer within 5 half-lives prior to randomization

[0339] 14. Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the Investigator's Brochure), or sensitivity to mammalian-derived products or lenalidomide Study Treatments

[0340] 395 transplant-ineligible (TIE) or transplant-deferred patients with newly diagnosed multiple myeloma were randomly assigned to eight 21-day cycles of VRd, followed by 28-day cycles of Rd until disease progression. Patients in the D-VRd group also received subcutaneous daratumumab weekly in Cycles 1-2, every 3 weeks in Cycles 3-8, and every 4 weeks thereafter until disease progression. The primary endpoint was overall minimal residual disease (MRD)–negativity rate (10–5).

[0341] Patients were randomly assigned (1:1) to D-VRd or VRd using an interactive web-response system. Randomization was stratified by International Staging System (ISS) disease stage (I, II, or III) and age / transplant eligibility (<70 years ineligible, <70 years and transplant deferred, or ≥70 years).

[0342] All patients received eight 21-day cycles of VRd, which consisted of subcutaneous bortezomib (1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11), oral lenalidomide (25 mg on days 1-14), and oral or intravenous dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12), after which point bortezomib was discontinued per protocol and patients continued to receive 28-day cycles of Rd, which consisted of oral lenalidomide (25 mg on days 1-21) and oral dexamethasone (40 mg on days 1, 8, 15, and 22). Patients in the D-VRd group also received subcutaneous daratumumab (daratumumab 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [2,000 U / mL; ENHANZE®drug delivery technology, Halozyme, Inc., San Diego, CA, USA]) weekly in Cycles 1 to 2, every 3 weeks in Cycles 3 to 8, and every 4 weeks in Cycles 9+. Treatment continued untilprogression or unacceptable toxicity. The primary endpoint was MRD-negativity rate (10–5; assessed by next-generation sequencing), defined as patients achieving ³CR and MRD negativity. Pre- and Post-administration Medications

[0343] To decrease the risk of injection-related reactions, all patients in the daratumumab plus bortezomib, lenalidomide and dexamethasone (D-VRd) group received intravenous or oral acetaminophen (650-1000 mg), an antihistamine (intravenous or oral diphenhydramine 25-50 mg or equivalent), and oral montelukast (10 mg, recommended on cycle 1 day 1) only up to 24 hours prior to daratumumab injection.

[0344] Patients with mild asthma or chronic obstructive pulmonary disease who have a FEV1 of <80% could receive post-injection medications, including an antihistamine, a short-acting b2 adrenergic receptor agonist (such as salbutamol), and control medications for lung disease (e.g., inhaled corticosteroids ± long-acting b2 adrenergic receptor agonists for patients with asthma or long-acting bronchodilators [such as tiotropium or salmeterol] ± inhaled corticosteroids for patients with chronic obstructive pulmonary disease).

[0345] Endpoints and Assessments

[0346] The primary endpoint was overall minimal residual disease (MRD)–negativity rate, defined as the proportion of patients who achieved complete response or better and had MRD-negative status (at or below a sensitivity threshold of 10–5) after randomization but prior to progression, subsequent antimyeloma therapy, or both. Major secondary endpoints were complete response or better rate, progression-free survival, and sustained MRD- negativity rate ≥12 months.

[0347] MRD-positive patients included patients for whom all tested samples were found to be MRD positive or indeterminate, or were MRD negative but not CR or better. For patients with missing MRD samples, failure to calibrate baseline MRD, or otherwise unevaluable samples, MRD status was considered as MRD positive.

[0348] Complete response or better rate was defined as the proportion of patients achieving complete response or stringent complete response based on the computerized algorithm according to International Myeloma Working Group (IMWG) response criteria, during or after the study treatment prior to the start of subsequent antimyeloma therapy. Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniformreporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood.2011;117:4691-4695.

[0349] Progression-free survival was defined as the duration from the date of randomization to disease progression or death, whichever came first. Disease progression was determined according to the IMWG criteria. Patients who started subsequent antimyeloma therapies for multiple myeloma without disease progression were censored at the last disease assessment before the start of subsequent therapies. Patients who withdrew consent from the study before disease progression were censored at the last disease assessment. Patients who were lost to follow-up were censored at the last disease assessment before patients were lost to follow-up. Patients who had not progressed and were still alive at the cutoff date for the analysis were censored at the last disease assessment. Patients without any post-baseline disease assessment were censored at the date of randomization.

[0350] Sustained MRD-negativity rate was defined as the proportion of patients who achieved complete response or better and MRD-negative status (10–5) at two examinations a minimum of one year apart (and the two examinations should be prior to disease progression, subsequent antimyeloma therapy, or both), without MRD-positive status in between.

[0351] Overall response rate was defined as the proportion of patients achieving partial response or better (i.e., partial response, very good partial response, complete response, or stringent complete response) based on computerized algorithm in accordance with the International Myeloma Working Group (IMWG) criteria, during or after the study treatment but before the start of subsequent antimyeloma therapy.

[0352] Overall survival was defined as the time from the date of randomization to the date of the patient’s death due to any cause. Patients who are lost to follow-up are censored at the time of lost to follow-up. Patients who died after consent withdrawal were considered as having an overall survival event. If the patient was alive at the cutoff date for the analysis or the survival status was unknown, then the patient’s data was censored at the date the patient was last known to be alive.

[0353] Progression-free survival on next line of therapy (PFS2) was defined as the time from randomization to progression on the next line of treatment or death (due to any cause), whichever came first. Disease progression was based on investigator judgement. Patients who were still alive and had not yet progressed on the next line of therapy were censored on the last date of follow-up. Patients who withdrew consent or were lost to follow-up prior to any subsequent antimyeloma therapy were censored at the date of last disease assessment during the course of study. Patients without any post-baseline follow-up were censored at randomization.

[0354] Quality of life was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) version 3.0. The EORTC QLQ-C30 includes 30 items, within a 1-week recall, resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Results:

[0355] Patients and Treatment

[0356] A total of 395 patients were enrolled, with 197 and 198 assigned to D-VRd and VRd, respectively. Enrollment by country is summarized in Table S1. Demographic and baseline characteristics were generally balanced between groups (Table 2). Median patient age was 70.0 years (range, 31 to 80); 28.1% had ISS stage III disease, and 13.2% had high cytogenetic risk (t[4;14], t[14;16], or del[17p]). The percentage of patients with an ECOG score of 2 was 11.7% for D-VRd versus 7.1% for VRd; 36.0% and 42.4%, respectively, had an ECOG score of 0.. Table 2. Demographic and Clinical Characteristics in the Intention-to-Treat Population at Baseline.* D-VRd VRd Characteristic (N = 197) (N = 198) Age Median (range) – yr 70.0 (42-79) 70.0 (31-80) Distribution – no. (%) <65 yr 36 (18.3) 35 (17.7) 65 to <70 yr 52 (26.4) 53 (26.8) ≥70 yr109 (55.3) 110 (55.6) Male sex – no. (%) 87 (44.2) 111 (56.1) Race no. (%)†White 162 (82.2) 156 (78.8) Black or African American 10 (5.1) 9 (4.5) Asian 11 (5.6) 14 (7.1) Native Hawaiian or other Pacific Islander 0 1 (0.5) Other 1 (0.5) 2 (1.0) Not reported 13 (6.6) 16 (8.1)ECOG performance status – no. (%) 0 71 (36.0) 84 (42.4) 1 103 (52.3) 100 (50.5) 2 23 (11.7) 14 (7.1) Type of measurable disease – no. (%) IgG 89 (45.2) 76 (38.4) IgA 27 (13.7) 31 (15.7) Other§4 (2.0) 1 (0.5) Detected in serum and urine 41 (20.8) 45 (22.7) Detected in urine only 20 (10.2) 24 (12.1) Detected in serum free light-chains only 16 (8.1) 21 (10.6) ISS disease stage – no. (%)¶I 68 (34.5) 68 (34.3) II 73 (37.1) 75 (37.9) III 56 (28.4) 55 (27.8) Cytogenetic risk profile – no. (%)||Standard risk 149 (75.6) 149 (75.3) High risk 25 (12.7) 27 (13.6) Indeterminate** 23 (11.7) 22 (11.1) Median time since diagnosis of multiple 1.2 (0.4-5.8) 1.3 (0.3-8.0) myeloma (range) – mo D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone. *The intention-to-treat population was defined as all patients who underwent randomization.†Race was reported by the patient. Eastern Cooperative Oncology Group (ECOG) performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.§Includes IgD, IgM, IgE, and biclonal.¶International Staging System (ISS) disease stage is based on the combination of serum β2- microglobulin and albumin levels. Higher stages indicate more advanced disease.||Cytogenetic risk was assessed by fluorescence in situ hybridization. High risk was defined as the presence of del(17p), t(4;14), and / or t(14;16). **Indeterminate includes patients with missing or unevaluable samples.

[0357] Among randomized patients, 392 (197 for D-VRd and 195 for VRd) received at least one dose of assigned treatment (FIG.1). At clinical cutoff (May 7, 2024) at the time of the final progression-free survival analysis, 102 patients (51.8%) in the D-VRd group and 67 patients (34.4%) in the VRd group remained on treatment. The most common reason for treatment discontinuation was progressive disease (D-VRd, 13.7%; VRd, 26.2%).

[0358] Median duration of study treatment was 22 months longer for D-VRd compared to VRd (56.3 vs 34.3 months)(Table 3). Median number of treatment cycles wasalso longer for D-VRd versus VRd (59 [range, 1 to 71] vs 37 [range, 1 to 70]). The relative dose intensities were similar between treatment arms(Table 3). Table 3. Duration of Treatment and Relative Dose Intensities* in the Safety Population.†D-VRd VRd (n = 197) (n = 195) Median (range) duration 56.3 (0.1-64.6) 34.3 (0.5-63.8) of treatment, months Median (range) no. of 59 (1-71) 37 (1-70) treatment cycles Median (range) relative dose intensity Bortezomib 84.5 (12.7-104.3) 81.6 (22.4-102.1) Lenalidomide 80.6 (2.5-248.2) 83.8 (25.7-246.0) Dexamethasone 81.5 (19.6-177.0) 77.9 (23.4-173.4) Cycles 1-2 Cycles 3-8 Cycle 9+ (n = 197) (n = 191) (n = 175) Daratumumab 100 (33.3- 100 (33.3- 100 (10.0- NA 105.6) 101.1) 100.4) D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone. NA denotes not applicable. *Dose intensity was defined as the ratio of total administered dose to total planned dose.†The safety population included all patients who received at least one dose of study treatment.

[0359] Efficacy

[0360] With a median follow-up of 58.7 months (range, 0.1-64.7), overall MRD- negativity rate (MRD-negative status [10-5] with complete response or better) was significantly higher with D-VRd versus VRd (60.9% vs 39.4%; odds ratio, 2.37; 95% CI, 1.58-3.55; P<0.0001; FIG.4A). Overall MRD-negativity rates and MRD-negativity at 10-5and at 10-6were consistently higher with D-VRd versus VRd across all prespecified subgroups, except patients with high cytogenetic risk (FIG.5A-C). MRD-negativity rate at 10-6was also higher with D-VRd versus VRd (46.2% vs 27.3%; odds ratio, 2.24; 95% CI, 1.48-3.40; P=0.0001; FIG.4B). Sustained MRD-negativity rate (≥12 months) was significantly higher with D-VRd versus VRd (48.7% vs 26.3%; odds ratio, 2.63; 95% CI, 1.73-4.00; P<0.0001; FIG.4C). D-VRd almost doubled sustained MRD-negativity rates at years 1, 2, and 3 versus VRd (FIG.4D).

[0361] The treatment effect with D-VRd was less pronounced in the small subgroup of patients with high cytogenetic risk (D-VRd, n=25; VRd, n=27); however, notably, overall MRD-negativity rates (10–5) were unexpectedly high among patients with high cytogeneticrisk treated with VRd, with rates much higher than the VRd ITT population (55.6% vs 39.4%, respectively). Furthermore, patients with high cytogenetic risk receiving D-VRd treatment had a shorter median duration of treatment versus patients receiving VRd (27 vs 35.5 cycles, respectively), primarily due to early discontinuation of treatment, thus leading to a higher proportion of missing post-baseline MRD values in the high cytogenetic risk D-VRd group (n=6 [24.0%]) compared with the VRd group (n=4 [14.8%]. Double the number of patients in the high cytogenetic risk D-VRd group (n=6 [24.0%]) discontinued treatment prior to their first post-baseline MRD sample compared with the VRd group (n=3 [11.1%]), meaning fewer patients in the high cytogenetic risk D-VRd group had the opportunity to be tested for achievement of MRD negativity. Regardless, among those patients with high cytogenetic risk who did achieve MRD negativity at the 10–5threshold (D-VRd, 48.0% [12 / 25]; VRd, 55.6% [15 / 27]), a trend in favorable PFS benefit was observed with D-VRd versus VRd (HR, 0.33; 95% CI, 0.07-1.57; FIG.30).

[0362] Disease progression or death had occurred in 63 patients (32.0%) in the D- VRd group and 91 patients (46.0%) in the VRd group. D-VRd significantly improved progression-free survival compared to VRd, with a hazard ratio of 0.57 (95% CI, 0.41-0.79; P=0.0005; FIG.2). Median progression-free survival was not reached for D-VRd versus 52.6 months for VRd; estimated 54-month progression-free survival rates were 68.1% (95% CI, 60.8-74.3) versus 49.5% (95% CI, 41.8-56.8), respectively. Treatment effect of progression- free survival favored D-VRd over VRd across all prespecified subgroups, including patients with high cytogenetic risk (FIG.3).

[0363] Complete response or better rate was significantly higher with D-VRd versus VRd (81.2% vs 61.6%; odds ratio, 2.73; 95% CI, 1.71-4.34; P<0.0001; FIG.6). Additional response data are in Table 4.

[0364] The overall survival hazard ratio trended in favor of D-VRd versus VRd (hazard ratio, 0.85; 95% CI, 0.58-1.24; FIG.7). Overall survival was immature and follow up is ongoing. Fifty-one patients in the D-VRd group and 60 patients in the VRd group died overall. There were 24 total deaths due to COVID-19 (21.6% of all deaths on study; 15 for D- VRd and 9 for VRd), 21 of which occurred during the peak of global pandemic fatalities in 2020 and 2021, with only 3 more occurring in 2022 (with availability of COVID-19 vaccines) and none in 2023 or 2024. There was significant regional variation, with 54.2% of the total COVID-19 deaths occurring in Brazil and 16.7% in Poland. Two sensitivity analysesof overall survival that adjusted for the impact of COVID-19 deaths showed a more pronounced treatment effect for D-VRd versus VRd: censoring any death due to COVID-19 (hazard ratio, 0.69; 95% CI, 0.45-1.05) and considering COVID-19 death as a competing risk (hazard ratio for non-COVID mortality, 0.67; 95% CI, 0.44-1.03;).

[0365] Progression-free survival on next line of therapy data are immature; the hazard ratio also favors D-VRd versus VRd (hazard ratio, 0.78; 95% CI, 0.54-1.14; FIG.9). A sensitivity analysis of progression-free survival on next line of therapy censoring death due to COVID-19 supported a further improved outcome with D-VRd (hazard ratio, 0.60; 95% CI, 0.40-0.93; FIG.8). A higher proportion of patients who received subsequent therapy received an anti-CD38–based first subsequent therapy in the VRd group (39 of 65 patients [60.0%]) than in the D-VRd group (3 of 22 patients [13.6%]).

[0366] The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) global health status domain score improved over time in both groups, with no negative impact from the addition of daratumumab (FIG. 10). Table 4. Summary of Response Rates in the Intention-to-Treat Population.* D-VRd VRd Variable (N = 197) (N = 198) P Value†Overall response No. with response 191 184 Rate – % (95% CI) 97.0 (93.5-98.9) 92.9 (88.4-96.1) 0.0698 Response – no. (%) Stringent complete response 128 (65.0) 88 (44.4) <0.0001 Complete response 32 (16.2) 34 (17.2) – Very good partial response 23 (11.7) 50 (25.3) – Partial response 8 (4.1) 12 (6.1) – Complete response or better – no. (%) 160 (81.2) 122 (61.6) <0.0001 Very good partial response or better – no. (%) 183 (92.9) 172 (86.9) 0.0495 Stable disease – no. (%) 5 (2.5) 7 (3.5) – Progressive disease – no. (%) 0 0 – Response could not be evaluated – no. (%) 1 (0.5) 7 (3.5) – D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone. *Response rates at any time during the study. Response was assessed based on International Myeloma Working Group response criteria.†P values were calculated with the use of the stratified Cochran–Mantel–Haenszel chi- squared test.Safety

[0367] The most common adverse events of any grade (≥20% of patients in either group) and most common grade 3 or 4 adverse events (≥10% of patients in either group) are shown in Table 5. The most common grade 3 or 4 adverse events were neutropenia (44.2% in the D-VRd group and 29.7% in the VRd group), and thrombocytopenia (28.4% and 20.0%). Peripheral neuropathy of any grade occurred in 61.9% of patients in the D-VRd group and 66.2% of patients in the VRd group; grade 2 peripheral neuropathy occurred in 31.5% and 36.9%, and grade 3 or 4 peripheral neuropathy occurred in 11.2% and 10.8%, respectively. Table 5. Most Common Adverse Events During Treatment in the Safety Population.* D-VRd VRd Event (N = 197) (N = 198) Any Grade Grade 3 or 4 Any Grade Grade 3 or 4 number of patients (percent) Hematologic adverse events Neutropenia 110 (55.8) 87 (44.2) 76 (39.0) 58 (29.7) Thrombocytopenia 92 (46.7) 56 (28.4) 66 (33.8) 39 (20.0) Anemia 73 (37.1) 26 (13.2) 62 (31.8) 23 (11.8) Lymphopenia 36 (18.3) 24 (12.2) 34 (17.4) 20 (10.3) Nonhematologic adverse events Diarrhea 112 (56.9) 24 (12.2) 115 (59.0) 18 (9.2) Peripheral sensory 110 (55.8) 16 (8.1) 119 (61.0) 16 (8.2) neuropathy Peripheral edema 83 (42.1) 4 (2.0) 76 (39.0) 1 (0.5) Constipation 75 (38.1) 4 (2.0) 82 (42.1) 5 (2.6) Insomnia 63 (32.0) 4 (2.0) 63 (32.3) 2 (1.0) Fatigue 63 (32.0) 18 (9.1) 60 (30.8) 16 (8.2) Hypokalemia 58 (29.4) 24 (12.2) 25 (12.8) 12 (6.2) Cataract 55 (27.9) 17 (8.6) 51 (26.2) 17 (8.7) Back pain 55 (27.9) 6 (3.0) 43 (22.1) 6 (3.1) Cough 53 (26.9) 1 (0.5) 38 (19.5) 2 (1.0) Asthenia 51 (25.9) 7 (3.6) 40 (20.5) 5 (2.6) Rash 50 (25.4) 5 (2.5) 48 (24.6) 3 (1.5) Nausea 49 (24.9) 0 48 (24.6) 4 (2.1) Pyrexia 46 (23.4) 2 (1.0) 30 (15.4) 1 (0.5) Arthralgia 45 (22.8) 3 (1.5) 39 (20.0) 0 Decreased appetite 42 (21.3) 2 (1.0) 39 (20.0) 5 (2.6) Dizziness 41 (20.8) 1 (0.5) 41 (21.0) 2 (1.0) Infection 181 (91.9) 79 (40.1) 167 (85.6) 62 (31.8) Respiratory tract infection 78 (39.6) 0 64 (32.8) 2 (1.0)COVID-19 75 (38.1) 22 (11.2) 48 (24.6) 9 (4.6) Pneumonia 48 (24.4) 28 (14.2) 39 (20.0) 25 (12.8) Urinary tract infection 41 (20.8) 7 (3.6) 29 (14.9) 5 (2.6) Second primary malignancy 15 (7.6) NA 18 (9.2) NA Any injection-related reaction 7 (3.6) 1 (0.5%)†NA NA D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone. NA denotes not applicable. *The safety population included patients who received at least one dose of study treatment. Adverse events of any grade that were reported in at least 20% of patients in either treatment group and grade 3 or 4 adverse events that were reported in at least 10% of patients in either treatment group are listed.†Grade 3.

[0368] Serious adverse events occurred in 72.1% of patients in the D-VRd group and 67.2% of patients in the VRd group (Table 6). The most common serious adverse event was pneumonia (D-VRd, 13.7%; VRd, 12.8%). The rate of discontinuation of study drugs due to adverse events was as follows: bortezomib 12.7% D-VRd and 16.4% VRd, lenalidomide 32.0% D-VRd and 24.6% VRd, dexamethasone 23.9% D-VRd and 35.4% VRd, and daratumumab 17.3% D-VRd. Grade 5 adverse events occurred in 16.8% of patients in the D- VRd group (10.7% non-COVID related and 6.1% COVID related) and 10.8% in the VRd group (7.7% non-COVID related and 3.1% COVID related). Most grade 5 events took place after discontinuation of bortezomib (cycle 8) in both arms (13% D-VRd vs 9% VRd). Addition of Daratumumab did not substantially affect relative dose intensity of VRd. When adjusted for treatment exposure, the rate of Grade 5 adverse events was comparable between groups (D-VRd, 0.39 / 100 patient-months; VRd, 0.31 / 100 patient months). Table 6. Serious Adverse Events in the Safety Population.* D-VRd VRd (n = 197) (n = 195) Total no. of patients with serious adverse event – no. (%) 142 (72.1) 131 (67.2) Serious adverse events occurring in ≥2% of patients in either treatment group – no. (%) Infections 78 (39.6) 69 (35.4) Pneumonia 27 (13.7) 25 (12.8) COVID-19 22 (11.2) 16 (8.2) COVID-19 pneumonia 8 (4.1) 4 (2.1) Sepsis 7 (3.6) 4 (2.1) Urinary tract infection 7 (3.6) 4 (2.1) Septic shock 6 (3.0) 1 (0.5) Gastroenteritis 4 (2.0) 4 (2.1)Influenza 4 (2.0) 1 (0.5) Pulmonary embolism 11 (5.6) 5 (2.6) Diarrhea 10 (5.1) 6 (3.1) Atrial fibrillation 7 (3.6) 7 (3.6) Acute kidney injury 6 (3.0) 3 (1.5) Asthenia 6 (3.0) 2 (1.0) Anemia 6 (3.0) 2 (1.0) Cataract 5 (2.5) 4 (2.1) Pyrexia 5 (2.5) 3 (1.5) Hyperkalemia 5 (2.5) 3 (1.5) Hyponatremia 5 (2.5) 1 (0.5) Febrile neutropenia 4 (2.0) 4 (2.1) Thrombocytopenia 4 (2.0) 2 (1.0) Deep vein thrombosis 4 (2.0) 2 (1.0) Syncope 3 (1.5) 6 (3.1) Hypotension 3 (1.5) 4 (2.1) Orthostatic hypotension 2 (1.0) 5 (2.6) Dehydration 0 5 (2.6) D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone. *The safety population included patients who received at least one dose of study treatment.

[0369] Second primary malignancies were observed in 15 patients (7.6%) in the D- VRd group and 18 patients (9.2%) in the VRd group (Table 7). Table 7. Summary of Second Primary Malignancies in the Safety Population.* D-VRd VRd Total (n = 197) (n = 195) (N = 392) Total no. of patients with new malignancy – no. (%) 15 (7.6) 18 (9.2) 33 (8.4) Cancer type / dictionary-derived term – no. (%) Cutaneous 7 (3.6) 7 (3.6) 14 (3.6) Basal cell carcinoma 3 (1.5) 2 (1.0) 5 (1.3) Squamous cell carcinoma 2 (1.0) 3 (1.5) 5 (1.3) Squamous cell carcinoma of skin 2 (1.0) 1 (0.5) 3 (0.8) Bowen’s disease 1 (0.5) 1 (0.5) 2 (0.5) Carcinoma in situ of skin 1 (0.5) 0 1 (0.3) Kaposi’s sarcoma 1 (0.5) 0 1 (0.3) Malignant melanoma 0 1 (0.5) 1 (0.3) Malignant melanoma in situ 0 1 (0.5) 1 (0.3) Malignant melanoma stage II 0 1 (0.5) 1 (0.3) Metastatic squamous cell carcinoma 0 1 (0.5) 1 (0.3) Squamous cell carcinoma of the oral cavity 0 1 (0.5) 1 (0.3) Hematologic 1 (0.5) 1 (0.5) 2 (0.5) Myelodysplastic syndrome 1 (0.5) 0 1 (0.3)Noncutaneous 7 (3.6) 10 (5.1) 17 (4.3) Adenocarcinoma of colon 1 (0.5) 1 (0.5) 2 (0.5) Transitional cell carcinoma 1 (0.5) 1 (0.5) 2 (0.5) Bladder cancer 1 (0.5) 0 1 (0.3) Breast cancer 1 (0.5) 0 1 (0.3) Clear cell renal cell carcinoma 1 (0.5) 0 1 (0.3) Intraductal proliferative breast lesion 1 (0.5) 0 1 (0.3) Esophageal adenocarcinoma 1 (0.5) 0 1 (0.3) Prostate cancer 0 4 (2.1) 4 (1.0) Cholangiocarcinoma 0 1 (0.5) 1 (0.3) Colon cancer 0 1 (0.5) 1 (0.3) Colon neoplasm 0 1 (0.5) 1 (0.3) Neoplasm malignant 0 1 (0.5) 1 (0.3) D-VRd denotes subcutaneous daratumumab plus bortezomib / lenalidomide / dexamethasone. VRd denotes bortezomib / lenalidomide / dexamethasone. *The safety population included patients who received at least one dose of study treatment. Discussion and Conclusions:

[0370] Results from this final progression-free survival analysis of CEPHEUS, with a median follow-up of 58.7 months, demonstrated that the addition of daratumumab to VRd significantly improved clinical outcomes, including overall MRD negativity and progression- free survival, versus VRd alone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma. The deeper responses with D-VRd translated into a superior progression-free survival, with a significant 43% lower risk of disease progression or death. Overall survival data, though immature, showed a positive trend emerging, favoring D- VRd. Additional sensitivity analyses provided stronger evidence of the treatment effect on overall survival after adjusting for the impact of COVID-19.

[0371] Prespecified subgroup analyses showed that overall MRD-negativity rates were consistently higher with D-VRd across all subgroups, except for patients with high cytogenetic risk. Treatment effect of progression-free survival favored D-VRd over VRd across all prespecified subgroups, including patients with high cytogenetic risk. The progression-free survival treatment effect was not as pronounced at this clinical cutoff in patients with cytogenetic high-risk disease, which suggests longer follow-up is warranted in this small, difficult-to-treat, patient population.

[0372] Because triplet therapy such as D-Rd is the mainstay for transplant-ineligible patients, it is important to look at the tolerability of adding bortezomib in the D-VRd regimen. In the phase 3 ALCYONE study, adding daratumumab to bortezomib, melphalan,and prednisone did not increase overall toxicity versus triplet therapy alone, and incidence of peripheral neuropathy was lower in the daratumumab group. The most common grade 3 or 4 adverse events in this study were neutropenia and thrombocytopenia. The incidence of grade 2 peripheral neuropathy was lower with D-VRd versus VRd, and the incidence of grade 3 or 4 peripheral neuropathy was similar between groups. There was no difference in the incidence of pneumonia. The incidence of grade 5 adverse events was higher in the D-VRd group, due to more grade 5 COVID-19 events. With the majority of grade 5 adverse events occurring after bortezomib discontinuation, the higher incidence of grade 5 adverse events with D-VRd likely reflects the prolonged treatment exposure rather than increased toxicity from quadruplet therapy. When adjusted for exposure, taking into account the nearly two years additional treatment received in the D-VRd arm, the rate of grade 5 adverse events was comparable between groups. The incidence of second primary malignancies was numerically lower in the D-VRd group.

[0373] Prior to this study, results from a previous study established D-Rd as a standard of care for transplant-ineligible patients, with a median overall survival of 7.5 years and consistent benefit across age, fitness, and risk status subgroups. It is important to note that all patients enrolled in a previous study were transplant ineligible, the population included frail patients, and there was no upper age limit (~19% were age ≥80 years), whereas this study enrolled transplant-ineligible and transplant-deferred patients, excluded frail patients, and no patients were aged >80 years. While the progression-free survival benefit observed in a previous study was impressive, particularly considering the inclusion of frail and older patients, quadruplet therapy with D-VRd offers an opportunity for improved depth of response and prolonged progression-free survival. With the advent of this study, physicians have an increased ability to tailor frontline daratumumab-based combination therapy to the patient’s age, frailty, and other patient-related and disease-related risk factors. It will be important to balance the higher depth of response and longer progression-free survival achievable with quadruplet D-VRd therapy with the improved tolerability offered by triplet D-Rd therapy, with the ultimate decision likely to be based on the individual patient’s overall treatment goals and perceived ability to tolerate the addition of bortezomib.

[0374] Cross-trial comparisons should be interpreted with caution due to differences in patient populations and trial designs but can help to contextualize our findings. Overall, MRD-negativity rates in ALCYONE and MAIA were lower than that observed in CEPHEUS(10–5: D-VMP, 28%; D-Rd, 32.1%; D-VRd, 60.9%, respectively), demonstrating the benefits of a D-VRd quadruplet in transplant-ineligible or transplant-deferred patients who are able to tolerate D-VRd. However, while head-to-head comparative trials are lacking, these varying MRD rates may have been due to inherent differences in study eligibility and patient characteristics (transplant ineligible in ALCYONE and MAIA with a median age of 71 [range, 40-93] years and 73 [45-90] years respectively, vs transplant ineligible / deferred in CEPHEUS with a median age of 70 [31-80] years). The phase 3 IMROZ study evaluated intravenous isatuximab plus VRd versus VRd alone in transplant-ineligible patients with newly diagnosed multiple myeloma. This study’s patient population included both transplant- ineligible and transplant-deferred patients and represents a more real-world population. Median age was similar in this study (70 years) and IMROZ (72 years) and a similar proportion of patients had high cytogenetic risk (13.2% and 16.6%, respectively). At a median follow-up of 59.7 months, the hazard ratio for disease progression or death was 0.60 (95% CI, 0.41-0.88; P<0.001). Median progression-free survival for VRd was similar in both studies (54.3 months in IMROZ and 52.6 months in this study). MRD-negativity rates (55.5% vs 40.9%; P=0.003) and complete response or better rates (74.7% vs 64.1%; P=0.01) were higher with isatuximab plus VRd versus VRd alone.23 As expected, the incidence of grade 5 adverse events was higher with quadruplet versus triplet therapy (approximately twice as high in both studies). There were differences in terms of timing of study enrollment, with this study being initiated later relative to the start of the COVID-19 pandemic (December 2018 vs December 2017 for IMROZ ), meaning that more patients were likely to still be on study treatment and at risk during the pandemic. It is also noteworthy that IMROZ did not enroll any patients from Brazil, while over half of the COVID-related deaths in this study occurred in Brazil.

[0375] Use of quadruplet therapy was also recently reported in the transplant-eligible population. The phase 3 of a previous study showed significant and clinically meaningful benefit in terms of progression-free survival (hazard ratio, 0.42; P<0.001), complete response or better rate (87.9% vs 70.1%; P<0.001), and MRD-negativity rate (75.2% vs 47.5%; P<0.001) with D-VRd induction / consolidation followed by daratumumab-lenalidomide maintenance versus VRd induction / consolidation and lenalidomide maintenance alone. Taken together, these data from this study combined with the results from previous studies further demonstrate the important role of daratumumab-based triplet and quadruplet therapy indeepening and prolonging responses for all patients across the frontline treatment spectrum. Many older patients with newly diagnosed multiple myeloma may not receive subsequent therapy, highlighting the importance of choosing the most effective regimen in the first-line setting. Frontline quadruplet D-VRd therapy provides an opportunity to further deepen responses and improve clinical outcomes.

[0376] In conclusion, with almost 5 years of follow-up, results from this study show that the addition of daratumumab to VRd significantly increased depth of response, including rates of overall MRD negativity, complete response or better, and sustained MRD negativity, which translated to significantly improved progression-free survival versus VRd alone in transplant-ineligible or transplant-deferred patients with newly diagnosed multiple myeloma. Moreover, the results add further validity to the use of MRD negativity as an accelerated approval endpoint to predict progression-free survival outcomes in newly diagnosed multiple myeloma. The safety profile was consistent with that of each individual agent. These data, together with the phase 3 of a previous study, demonstrate the consistent benefit of quadruplet daratumumab plus VRd therapy compared with triplet VRd therapy and support D-VRd quadruplet therapy as a new standard of care for newly diagnosed multiple myeloma, regardless of transplant eligibility. EXAMPLE 2: Daratumumab Plus Bortezomib, Lenalidomide, and Dexamethasone (D- VRd) in Patients With Newly Diagnosed Multiple Myeloma: Subgroup Analysis of Transplant-ineligible Patients in the Phase 3 CEPHEUS Study

[0377] D-VRd is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). In CEPHEUS (NCT03652064), D-VRd improved minimal residual disease (MRD) negativity and progression-free survival (PFS) versus VRd in transplant-ineligible (TIE) or transplant-deferred patients with NDMM. As transplant deferral is uncommon in many regions, a post hoc analysis of D-VRd efficacy in TIE-only patients is reported. Materials and Methods:

[0378] CEPHEUS enrolled TIE or transplant-deferred patients with NDMM, ECOG performance status 0-2, and an International Myeloma Working Group (IMWG) frailty score of 0-1. Patients who provided informed consent were randomized 1:1 to D-VRd or VRd. The primary endpoint was overall MRD-negativity rate (10–5threshold with complete response orbetter [≥CR]); secondary endpoints included PFS and sustained MRD negativity (confirmed MRD negativity ≥12 months without MRD positivity). Results:

[0379] Of 395 patients, 289 were TIE (D-VRd, n=144; VRd, n=145). Baseline characteristics were generally balanced between treatment groups. In the TIE versus intent- to-treat populations, median age was older (72 vs 70 years) and a higher percentage was intermediate fit per IMWG criteria (41.2% vs 35.2%) among TIE patients. In TIE patients, overall MRD-negativity rate (10−5) was 60.4% for D-VRd and 39.3% for VRd (odds ratio [OR], 2.37 [95% CI, 1.47-3.80]; P<0.0001); MRD-negativity rate at 10–6 was 45.8% versus 26.9% (OR, 2.28 [95% CI, 1.40-3.73]; P=0.001). Sustained MRD-negativity rate (10−5) was 46.5% versus 27.6% (OR, 2.27 [95% CI, 1.39-3.70]; P=0.0010). Overall ≥CR rate was 80.6% versus 61.4% (OR, 2.73 [95% CI, 1.71-4.34]; P<0.0001). At a median follow-up of 58.7 months, median PFS was not reached for D-VRd versus 49.6 months for VRd (54- month rates: 69.0% vs 48.0%; hazard ratio [HR], 0.51 [95% CI, 0.35-0.74]; P=0.0003). Of TIE patients who achieved MRD negativity (10–5; D-VRd, n=87; VRd, n=57), median PFS was not reached in either treatment group (54-month rates: 79.5% for D-VRd vs 70.6% for VRd; HR, 0.62 [95% CI, 0.33-1.17]; P=0.1382). Of TIE patients who remained MRD positive (10–5; D-VRd, n=57; VRd, n=88), median PFS was not reached for D-VRd versus 34.5 months for VRd (54-month rates: 51.0% vs 30.2%; HR, 0.62 [95% CI, 0.38-1.02]; P=0.0569). Overall survival favored D-VRd versus VRd (HR, 0.66 [95% CI, 0.42-1.03]; censored for COVID-19–related deaths, HR, 0.55 [95% CI, 0.34-0.90]). Treatment effect was consistent across subgroups. Safety results aligned with the known safety profiles for subcutaneous daratumumab and VRd.

[0380] In CEPHEUS TIE patients, the ≥CR rate was 80.6%, overall MRD-negativity rate (10−5) was 60.4%, and 12-month sustained MRD-negativity rate was 46.5%, all strongly favoring D-VRd over VRd. In addition, nearly 70% of TIE patients in the D-VRd group were alive and progression-free at 4.5 years. These data demonstrate the strong efficacy of D-VRd over VRd in TIE patients with NDMM. EXAMPLE 3: Frailty Subgroup Analysis of CEPHEUS

[0381] Transplant-ineligible patients – included in both MAIA and CEPHEUS – are typically deemed ineligible for autologous stem cell transplantation due to age or comorbidities. Both of these factors are also criteria for categorizing frailty, and increasedfrailty is a predictor of increased risk of disease progression and death in patients with multiple myeloma (MM). Of note, the poorer prognosis of frailer patients is associated with the higher rates of nonhematological adverse events and treatment discontinuation observed in this population. Criteria to assess frailty are thus essential to guide treatment decisions that balance efficacy with the increased risk of toxicity in frail patients. Several indices have been developed to measure frailty in patients with MM. Two of the most commonly used indices are the International Myeloma Working Group (IMWG) frailty index, recommended by the European Myeloma Network, and the Intergroupe Francophone du Myélome (IFM) simplified frailty index. Both indices incorporate the patient’s age and number of comorbidities, but they differ in that the IMWG index incorporates functional status by using patient-reported assessments – the Katz Activity of Daily Living (ADL) and the Lawton Instrument Activity of Daily Living (IADL), which assess the ability to perform daily activities such as self-care and household management – whereas the IFM simplified frailty index uses Eastern Cooperative Oncology Group (ECOG) performance status.

[0382] A post hoc analysis of MAIA data using the IFM simplified frailty scale identified approximately 50% of study participants as frail and demonstrated a progression- free survival (PFS) benefit with DRd versus RD regardless of baseline frailty status. CEPHEUS excluded patients who were frail according to IMWG criteria but not those who were categorized as frail per IFM criteria. Therefore, a subgroup analysis of CEPHEUS comparing DVRd versus VRd across frailty subgroups based on protocol-defined IMWG frailty status at baseline as well as a post hoc analysis based on the IFM simplified frailty scale is presented.

[0383] A total of 395 patients were randomized to DVRd (n = 197) or VRd (n = 198) in CEPHEUS; median (range) follow-up was 58.7 (0.1–64.7) months. On the IMWG frailty scale, 256 patients were categorized as fit (DVRd, n = 124; VRd, n = 132) and 139 patients as having intermediate fitness (DVRd, n = 73; VRd, n = 66). On the IFM simplified frailty scale, 297 patients were nonfrail (DVRd, n = 140; VRd, n = 157) and 98 were frail (DVRd, n = 57; VRd, n = 41). Baseline demographics and disease characteristics were generally similar between treatment arms across the frailty subgroups, except a higher proportion of the frailer subgroups had ISS stage III disease and, as expected, were older and had poorer ECOG performance status.Table 8: Most common adverse events during treatment in the safety population by IMWG frailty subgroup (safety population)aEvent, n (%) IMWG fit IMWG intermediate fitness DVRd (n = 124) VRd (n = 132) DVRd (n = 73) VRd (n = 63) Any Grade Any Grade Any Grade Any Grade grade 3 or 4 grade 3 or 4 grade 3 or 4 grade 3 or 4 Any 124 111 132 111 73 71 63 56 (100.0) (89.5) (100.0) (84.1) (100.0) (97.3) (100.0) (88.9) Hematological adverse events Neutropenia 63 51 50 36 47 36 26 22 (50.8) (41.1) (37.9) (27.3) (64.4) (49.3) (41.3) (34.9) Thrombocytopenia 48 27 49 27 44 29 17 12 (38.7) (21.8) (37.1) (20.5) (60.3) (39.7) (27.0) (19.0) Anemia 41 14 35 11 (8.3) 32 12 27 12 (33.1) (11.3) (26.5) (43.8) (16.4) (42.9) (19.0) Lymphopenia 19 15 22 14 17 9 (12.3) 12 6 (9.5) (15.3) (12.1) (16.7) (10.6) (23.3) (19.0) Nonhematological adverse events Diarrhea 71 16 70 12 (9.1) 41 8 (11.0) 45 6 (9.5) (57.3) (12.9) (53.0) (56.2) (71.4) Peripheral sensory 71 11 (8.9) 82 9 (6.8) 39 5 (6.8) 37 7 neuropathy (57.3) (62.1) (53.4) (58.7) (11.1) Peripheral edema 52 2 (1.6) 52 1 (0.8) 31 2 (2.7) 24 0 (41.9) (39.4) (42.5) (38.1) Constipation 44 2 (1.6) 55 4 (3.0) 31 2 (2.7) 27 1 (1.6) (35.5) (41.7) (42.5) (42.9) Cataract 43 15 38 12 (9.1) 12 2 (2.7) 13 5 (7.9) (34.7) (12.1) (28.8) (16.4) (20.6) Fatigue 40 9 (7.3) 40 9 (6.8) 23 9 (12.3) 20 7 (32.3) (30.3) (31.5) (31.7) (11.1) Insomnia 39 3 (2.4) 47 2 (1.5) 24 1 (1.4) 16 0 (31.5) (35.6) (32.9) (25.4) Back pain 37 3 (2.4) 26 4 (3.0) 18 3 (4.1) 17 2 (3.2) (29.8) (19.7) (24.7) (27.0) Hypokalemia 36 13 14 6 (4.5) 22 11 11 6 (9.5) (29.0) (10.5) (10.6) (30.1) (15.1) (17.5) Cough 36 1 (0.8) 29 0 17 0 9 (14.3) 2 (3.2) (29.0) (22.0) (23.3) Rash 31 4 (3.2) 34 2 (1.5) 19 1 (1.4) 14 1 (1.6) (25.0) (25.8) (26.0) (22.2) Nausea 31 0 29 3 (2.3) 18 0 19 1 (1.6) (25.0) (22.0) (24.7) (30.2) Pyrexia 29 2 (1.6) 19 0 17 0 11 1 (1.6) (23.4) (14.4) (23.3) (17.5) Arthralgia 28 2 (1.6) 28 0 17 1 (1.4) 11 0 (22.6) (21.2) (23.3) (17.5) Asthenia 28 4 (3.2) 31 3 (2.3) 20 3 (4.1) 12 2 (3.2) (21.2) (25.0) (27.4) (19.0)Decreased appetite 24 0 20 2 (1.5) 18 2 (2.7) 19 3 (4.8) (19.4) (15.2) (24.7) (30.2) Dizziness 23 0 24 2 (1.5) 18 1 (1.4) 17 0 (18.5) (18.2) (24.7) (27.0) Pain in extremity 18 0 19 0 17 1 (1.4) 11 1 (1.6) (14.5) (14.4) (23.3) (17.5) Infection 117 49 118 39 64 71 49 56 (94.4) (39.5) (89.4) (29.5) (87.7) (97.3) (77.8) (88.9) COVID-19b54 18 40 10 (7.6) 29 12 14 3 (4.8) (43.5) (14.5) (30.3) (39.7) (16.4) (22.2) Upper respiratory 50 1 (0.8) 48 1 (0.8) 28 0 16 0 tract infection (40.3) (36.4) (38.4) (25.4) Pneumonia 31 21 25 15 17 7 (9.6) 14 10 (25.0) (16.9) (18.9) (11.4) (23.3) (22.2) (15.9) Nasopharyngitis 25 0 17 0 10 0 5 (7.9) 0 (20.2) (12.9) (13.7) Urinary tract 24 2 (1.6) 16 2 (1.5) 17 5 (6.8) 13 3 (4.8) infection (19.4) (12.1) (23.3) (20.6)aAdverse events of any grade that were reported in at least 20% of patients in at least 1 treatment arm of 1 frailty subgroup and adverse events grade 3 or 4 that were reported in at least 10% of patients of at least 1 treatment arm of 1 frailty subgroup are listed.bCOVID-19 here includes preferred term COVID-19 and COVID-19 pneumonia. DVRd, daratumumab plus bortezomib, lenalidomide, and dexamethasone; IMWG, International Myeloma Working Group; NA, not applicable; VRd, bortezomib, lenalidomide, and dexamethasone. Table 9: Most common adverse events during treatment in the safety population by IFM frailty subgroup (safety population)aEvent IFM nonfrail IFM frail DVRd (n = 140) VRd (n = 156) DVRd (n = 57) VRd (n = 39) Any Grade Any Grade Any Grade Any Grade grade 3 or 4 grade 3 or 4 grade 3 or 4 grade 3 or 4 Any 140 126 156 132 57 56 39 35 (100.0) (90.0) (100.0) (84.6) (100.0) (98.2) (100.0) (89.7) Hematological adverse events, n (%) Neutropenia 74 60 62 47 36 27 14 11 (52.9) (42.9) (39.7) (30.1) (63.2) (47.4) (35.9) (28.2) Thrombocytopenia 58 32 55 31 34 24 11 8 (20.5) (41.4) (22.9) (35.3) (19.9) (59.6) (42.1) (28.2) Anemia 49 15 46 16 24 11 16 7 (17.9) (35.0) (10.7) (29.5) (10.3) (42.1) (19.3) (41.0) Lymphopenia 21 14 30 19 15 10 4 (10.3) 1 (2.6) (15.0) (10.0) (19.2) (12.2) (26.3) (17.5) Leukopenia 17 8 (5.7) 14 (9.0) 5 (3.2) 11 7 (12.3) 5 (12.8) 2 (5.1) (12.1) (19.3) Nonhematological adverse events, n (%) Diarrhea 81 17 92 13 (8.3) 31 7 (12.3) 23 5 (12.8) (57.9) (12.1) (59.0) (54.4) (59.0)Peripheral sensory 78 12 (8.6) 103 14 (9.0) 32 4 (7.0) 16 2 (5.1) neuropathy (55.7) (66.0) (56.1) (41.0) Peripheral edema 60 3 (2.1) 62 1 (0.6) 23 1 (1.8) 14 0 (42.9) (39.7) (40.4) (35.9) Constipation 53 3 (2.1) 69 4 (2.6) 22 1 (1.8) 13 1 (2.6) (37.9) (44.2) (38.6) (33.3) Insomnia 46 3 (2.1) 58 2 (1.3) 17 0 5 (12.8) 1 (1.8) (32.9) (37.2) (29.8) Cataract 45 13 (9.3) 42 12 (7.7) 10 4 (7.0) 9 (23.1) 5 (12.8) (32.1) (26.9) (17.5) Fatigue 43 10 (7.1) 48 10 (6.4) 20 8 (14.0) 12 6 (15.4) (30.7) (30.8) (35.1) (30.8) Cough 41 1 (0.7) 32 0 12 0 6 (15.4) 2 (5.1) (29.3) (20.5) (21.1) Back pain 40 3 (2.1) 36 6 (3.8) 15 3 (5.3) 7 (17.9) 0 (28.6) (23.1) (26.3) Rash 39 4 (2.9) 39 3 (1.9) 11 1 (1.8) 9 (23.1) 0 (27.9) (25.0) (19.3) Hypokalemia 37 14 18 9 (5.8) 21 10 7 (17.9) 3 (7.7) (26.4) (10.0) (11.5) (36.8) (17.5) Asthenia 36 4 (2.9) 32 3 (1.9) 15 3 (5.3) 8 (20.5) 2 (5.1) (25.7) (20.5) (26.3) Nausea 33 0 38 2 (1.3) 16 0 10 2 (5.1) (23.6) (24.4) (28.1) (25.6) Pyrexia 32 2 (1.4) 26 0 14 0 4 (10.3) 1 (2.6) (22.9) (16.7) (24.6) Arthralgia 31 2 (1.4) 34 0 14 1 (1.8) 5 (12.8) 0 (22.1) (21.8) (24.6) Dizziness 29 0 36 2 (1.3) 12 1 (1.8) 5 (12.8) 0 (20.7) (23.1) (21.1) Muscular weakness 29 12 (8.6) 21 6 (3.8) 9 (15.8) 5 (8.8) 8 (20.5) 3 (7.7) (20.7) (13.5) Muscle spasms 28 1 (0.7) 29 0 8 (14.0) 0 2 (5.1) 0 (20.0) (18.6) Decreased appetite 27 1 (0.7) 23 4 (2.6) 15 1 (1.8) 16 1 (2.6) (19.3) (14.7) (26.3) (41.0) Dyspnea 20 1 (0.7) 24 0 15 2 (3.5) 5 (12.8) 1 (2.6) (14.3) (15.4) (26.3) Pain in extremity 20 1 (0.7) 23 0 15 0 7 (17.9) 1 (2.6) (14.3) (14.7) (26.3) Infection 131 53 136 44 50 18 31 (79.5 26 (93.6) (37.9) (87.2) (28.2) (87.7) (46.2) (45.6) Upper respiratory 56 1 (0.7) 55 1 (0.6) 22 0 9 (23.1) 0 tract infection (40.0) (35.3) (38.6) COVID-19b62 22 47 11 (7.1) 19 8 (14.0) 6 (15.4) 2 (5.1) (44.3) (15.7) (30.1) (33.3) Pneumonia 33 19 28 18 15 9 (15.8) 11 7 (17.9) (23.6) (13.6) (17.9) (11.5) (26.3) (28.2)Urinary tract 30 3 (2.1) 20 3 (1.9) 11 4 (7.0) 9 (23.1) 2 (5.1) infection (21.4) (12.8) (19.3) Nasopharyngitis 28 0 20 0 7 (12.3) 0 2 (5.1) 0 (20.0) (12.8) aAdverse events of any grade that were reported in at least 20% of patients in either treatment group and adverse events grade 3 or 4 that were reported in at least 10% of patients in either treatment group are listed. bCOVID-19 here includes preferred term COVID-19 and COVID-19 pneumonia. COVID-19, coronavirus disease 2019; DVRd, daratumumab plus bortezomib, lenalidomide, and dexamethasone; IFM, Intergroupe Francophone du Myélome; NA, not applicable; VRd, bortezomib, lenalidomide, and dexamethasone.

[0384] Overall, 392 patients (DVRd: n = 197; DVRd, n = 195) received at least one dose of study treatment. Across frailty subgroups, median treatment duration was longer with DVRd than with VRd but was shorter in fitter patients than in frailer patients. In IMWG frailty subgroups, median (range) treatment duration was 57.1 months (0.3–64.6) with DVRd and 40.1 months (0.5–63.8) with VRd in the fit subgroup and in the intermediate-fitness subgroup was 45.8 months (0.1–63.7 months) with DVRd and 32.4 months (0.5–62.4) with VRd. In IFM simplified frailty subgroups, median treatment duration was 57.1 months (0.1– 64.6) with DVRd and 36.2 months (0.5–63.8) with VRd in the nonfrail subgroup and in the frail subgroup was 44.7 months (0.5–63.7 months) with DVRd and 25.7 months (0.5–62.4 months) with VRd.

[0385] Across frailty subgroups, the rate of overall MRD-negativity with ≥CR was consistently higher with DVRd versus VRd across at the 10-5and 10-6thresholds (FIG.32). In IMWG frailty subgroups, overall rates of MRD-negativity (10-5) with ≥ CR were 63.7% with DVRd versus 44.7% with VRd (P = 0.0026) in fit patients and were a respective 56.2% versus 28.8% (P = 0.0019) in intermediate-fitness patients. Rates at 10-6were 46.8% with DVRd versus 31.8% with VRd (P = 0.0153) in fit patients and 45.2% versus 18.2% (P = 0.0010) in intermediate-fitness patients. In IFM simplified frailty subgroups, overall rates of MRD-negativity (10-5) with ≥CR were 63.6% with DVRd versus 42.0% with VRd (P = 0.0003) in nonfrail patients and 54.4% versus 29.3% (P = 0.0148) in frail patients. Respective rates at 10-6were 47.9% vs 29.3% (P = 0.0012) in nonfrail patients and 42.1% vs 19.5% in frail patients (P = 0.0283).

[0386] Higher proportions of patients sustained MRD-negativity with DVRd versus VRd across frailty subgroups at the 10-5and 10-6thresholds. In IMWG frailty subgroups, rates of ≥ 12-month sustained MRD-negativity at the 10-5threshold were 50.0% with DVRd versus 31.1% with VRd (P = 0.0023) in fit patients and were a respective 47.9% versus 19.7% (P = 0.0006) in intermediate-fitness patients (FIG.33A). At the 10-6threshold, rateswere 34.7% with DVRd versus 18.2% with VRd (P = 0.0029) in fit patients and 32.9% versus 12.1% (P = 0.0045) in intermediate-fitness patients (FIG.33B). In IFM simplified frailty subgroups, MRD-negativity was sustained with DVRd versus VRd for ≥ 12 months at the 10-5threshold in 52.1% versus 30.6% (P = 0.0002) of nonfrail patients and in 42.1% versus 14.6% (P = 0.0040) of frail patients and, at the 10-6threshold, in 36.4% versus 17.2% (P = 0.0002) of nonfrail patients and 28.1% vs 12.2% (P = 0.0808) of frail patients (FIG. 33C–D). Rates of ≥ 24-month sustained MRD-negativity at both thresholds were also higher with DVRd versus VRd across IMWG and IFM frailty subgroups (FIG.35).

[0387] DVRd improved PFS versus VRd across IMWG frailty subgroups. Median PFS in fit patients was not reached with DVRd versus 60.6 months with VRd (HR, 0.59; 95% CI: 0.39–0.91; P = 0.0149) and was not reached versus 38.7 months (HR, 0.56; 95% CI: 0.34–0.91; P = 0.0189) in intermediate-fitness patients (FIG.34A). Similarly, DVRd improved PFS versus VRd across IFM simplified frailty subgroups. Median PFS in nonfrail patients was not reached with DVRd versus 60.6 months with VRd (HR, 0.58; 95% CI: 0.39– 0.86; P = 0.0054) and was not reached versus 31.7 months (HR, 0.51; 95% CI: 0.28–0.93; P = 0.0242) in frail patients (FIG.34B).

[0388] The rate of ≥CR was higher with DVRd versus VRd across all frailty subgroups (FIG.36). In IMWG frailty subgroups, the proportion of patients who achieved ≥ CR was 86.3% with DVRd versus 68.9% with VRd in the fit subgroup (P = 0.0009) and was 72.6% versus 47.0%, respectively, in the intermediate-fitness subgroup (P = 0.0021). In IFM simplified frailty subgroups, respective rates were 85.7% versus 65.0% (P < 0.0001) in nonfrail patients and 70.2% versus 48.8% (P = 0.0329) in frail patients.

[0389] Health-related quality of life, assessed on the EORTC QLQ-C30 global health status domain, was worse (lower score) at baseline in frailer (i.e., IMWG intermediate fitness and IFM frail) patients than in fitter (i.e., IMWG fit and IFM nonfrail) patients. In both treatment arms, scores in the fitter subgroups remained near baseline; in the frailer subgroups, scores improved (increased) over time and became comparable to those in the fitter subgroups.

[0390] The most common treatment-emergent adverse events (TEAEs) are shown in Table 8 (IMWG frailty subgroups) and Table 9 (IFM simplified frailty subgroups). Rates of grade 3 or 4 TEAEs were higher in both treatment arms in the less fit IMWG subgroups (fit: 89.5% with DVRd and 84.1% with VRd; intermediate: 97.3% with DVRd and 88.9% withVRd) and in the frailer IFM subgroups (nonfrail: 90.0% with DVRd and 84.6% with VRd; frail: 98.2% with DVRd and 89.7% with VRd). The most common grade 3 or 4 TEAE across all subgroups, in both treatment arms, was neutropenia. In IMWG frailty subgroups, grade 3 or 4 neutropenia rates were 41.1% with DVRd and 27.3% with VRd in fit patients and were 49.3% and 34.9%, respectively, in intermediate-fitness patients. In IFM frailty subgroups, respective rates were 42.9% and 30.1% in nonfrail patients and in frail patients were 47.4% and 28.2%. In IMWG frailty subgroups, rates of peripheral sensory neuropathy of any grade were 57.3% (grade 2, 28.2%; grade 3 or 4, 8.9%) and 62.1% (grade 2, 40.2%; grade 3 or 4, 6.8%), respectively, with DVRd and VRd in fit patients and were 53.4% (grade 234.2%; grade 3 or 4, 6.8%) and 58.7% (grade 2, 27.0%; grade 3 or 4, 11.1%) in intermediate-fitness patients (Table 8). In IFM frailty subgroups, peripheral sensory neuropathy rates were 55.7% (grade 2: 29.3%; grade 3 or 4, 8.6%) with DVRd and 66.0% with VRd (grade 2: 39.1%; grade 3 or 4, 9.0%) in nonfrail patients and were 56.1% (grade 2: 33.3%; grade 3 or 4, 7.0%) and 41.0% (grade 2: 23.1%; grade 3 or 4, 5.1%) in frail patients (Table 9).

[0391] In both treatment arms, the incidence of serious TEAEs was higher in frailer patients than in fitter patients. In IMWG frailty subgroups, rates were 70.2% with DVRd and 60.6% with VRd in fit patients and were a respective 75.3% and 81.0% in intermediate-fitness patients. In IFM frailty subgroups, rates were 69.3% with DVRd and 62.8% with VRd in nonfrail patients and 78.9% and 84.6% in frail patients. The most common serious TEAEs across treatment arms and frailty subgroups were infections, most commonly pneumonia or COVID-19. In IMWG frailty subgroups, rates of serious infections in fit patients were 35.5% with DVRd arm and 32.6% with VRd; respective rates in intermediate-fitness patients were 46.6% and 41.3%. In IFM frailty subgroups, rates of serious infections in nonfrail patients were 36.4% with DVRd and 30.8% with VRd and in frail patients were 47.4% and 53.8%.

[0392] Across frailty subgroups, TEAEs led to discontinuation of all study drugs at lower rates with DVRd (5.7–12.3%) than with VRd (13.6–20.6%). Rates of bortezomib discontinuation due to TEAEs were similar with DVRd and VRd in the fitter subgroups (IMWG fit: 14.5% with DVRd and 15.2% with VRd; IFM nonfrail: 12.9% and 14.1%, respectively) and were lower with DVRd in the frailer subgroups (IMWG intermediate fitness: 9.6% and 19.0%; IFM frail: 12.4% and 25.6%). Across frailty subgroups, rates ofbortezomib discontinuation due to peripheral sensory neuropathy were lower with DVRd than with VRd.

[0393] In IMWG frailty subgroups, grade 5 non-COVID-19 TEAEs in fit patients occurred in 10.5% of the DVRd arm and 6.1% of the VRd arm and in a respective 11.0% and 11.1% of intermediate-fitness patients. Grade 5 COVID-19 TEAEs occurred in 4.0% and 3.0% of fit patients and 9.6% and 3.2% of intermediate-fitness patients. In IFM frailty subgroups, grade 5 non-COVID TEAEs occurred in 10.0% and 5.1% of nonfrail patients, respectively, and in 12.3% and 17.9% of frail patients. Grade 5 COVID-19 TEAEs occurred in 6.4% and 2.6% of nonfrail patients and 5.3% and 5.1% of frail patients.

[0394] In conclusion, the benefit of DVRd versus VRd across frailty subgroups supports DVRd as a new standard of care for patients aged ≤ 80 years with transplant- ineligible or transplant-deferred NDMM who can tolerate bortezomib, and who are fit or of intermediate fitness per IMWG criteria or nonfrail or frail per IFM criteria. These findings, along with frailty subgroup analyses of MAIA, help to inform the choice of daratumumab quadruplet therapy or triplet therapy in patients with NDMM who do not receive frontline transplant, with the ability to tailor the regimen based on bortezomib eligibility and treatment goals. EXAMPLE 4: Modeling Long-Term Progression-Free Survival in Transplant-Eligible And Transplant-Ineligible Newly Diagnosed Multiple Myeloma Treated With Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone

[0395] Quadruplet therapy consisting of daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) plus DR maintenance therapy showed superior efficacy to VRd with R maintenance in patients with transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM) in the PERSEUS trial. Similarly, the CEPHEUS trial showed superiority of DVRd over VRd in transplant-ineligible (TIE) or transplant-deferred patients with NDMM. In the DVRd arms of both trials (intent to treat [ITT]), median progression-free survival (PFS) had not been reached at median follow-up of 47.5 months (mo; PERSEUS) and 58.7 mo (CEPHEUS); in the VRd arms, median PFS was not reached in PERSEUS and was 52.6 mo in CEPHEUS. With the availability of DVRd to treat both TE and TIE patients, and treatment guidelines focusing on these 2 groups, this analysis aimed to extrapolate PFS data from the PERSEUS trial (ITT) and the TIE subgroup of CEPHEUS to estimate long-term outcomes of DVRd in the frontline setting to help inform clinical decision making.

[0396] Following UK National Institute for Health and Clinical Excellence (NICE) guidance on survival data extrapolation, 7 parametric distributions were fitted to model PFS data: exponential, Weibull, gamma, Gompertz, log-logistic, log-normal, and generalized gamma. Individual parametric curves were fit for the DVRd and VRd groups. Longterm extrapolations were capped by UK general population data for 2020–2022 on disease-specific and all-cause mortality, utilizing the median age of the population and the proportion of male patients in the cohort at the initiation of treatment (per NICE guidance). PFS projections begin at the median age of the population.

[0397] In PERSEUS, 709 TE patients were randomized (DVRd, n=355; VRd, n=354), with median age 60 years and 59% male. In CEPHEUS, 289 TIE patients were randomized (DVRd, n=144; VRd, n=145), with median age 72 years and 51% male. Observed Kaplan Meier estimates of PFS at 48 mo in TE patients in PERSEUS were 84.3% vs 67.7% in the DVRd and VRd groups, respectively; for TIE patients in CEPHEUS, they were 72.3% vs 52.3% (FIG.37). Based on PFS modeling in the PERSEUS TE population, the range of estimated median PFS across all distributions was 158–255 mo (13.2–21.2 years) for the DVRd group and 76–119 mo (6.3–9.9 years) for the VRd group. The exponential distribution (best fit), gave PFS estimates of 205 vs 87 mo (17.1 vs 7.3 years) for DVRd and VRd, respectively (FIG.38). For the CEPHEUS TIE population, the range of estimated median PFS across distributions was 96–118 mo (8.0–9.8 years) for the DVRd group and 52– 54 mo (4.34.5 years) for the VRd group, with the exponential distribution (best fit) giving estimates of 100 vs 53 mo (8.3 vs 4.4 years) for DVRd and VRd, respectively (FIG.39).

[0398] Across all 7 distributions, PFS projections were significantly longer with DVRd than VRd in both TE and TIE patients with NDMM. As expected, projected PFS with DVRd was longer for TE patients (205 mo from baseline age of 60 years) than TIE patients (100 mo from age 72 years). These extrapolations provide supportive projections beyond the observed PFS data, helping to inform treatment decisions and reinforcing the benefit of DVRd with a daratumumab-containing maintenance regimen in all patients with NDMM. EXAMPLE 4: Highlights of Prescribing Information

[0399] DARZALEX FASPRO®is a combination of daratumumab, a CD38-directed cytolytic antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of adult patients with:• multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant. DOSAGE AND ADMINISTRATION Important Dosing Information

[0400] DARZALEX FASPRO®is for subcutaneous use only. Administer medications before and after administration of DARZALEX FASPRO®to minimize administration- related reactions. Type and screen patients prior to starting DARZALEX FASPRO®. Recommended Dosage for Multiple Myeloma

[0401] The recommended dose of DARZALEX FASPRO®is 1,800 mg / 30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3-5 minutes. Table 8 provide the recommended dosing schedule when DARZALEX FASPRO®is administered as part of a combination therapy. In Combination with Bortezomib, Lenalidomide, and Dexamethasone (DARZALEX FASPRO-VRd) for Patients Who Are Ineligible for ASCT

[0402] Use the dosing schedule in Table 8 when DARZALEX FASPRO®is administered in combination with bortezomib, lenalidomide, and dexamethasone (3-week cycle) for treatment of newly diagnosed multiple myeloma patients who are ineligible for ASCT. Table 10: DARZALEX FASPRO®dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (3-week cycle) Weeks Schedule Weeks 1 to 6 weekly (total of 6 doses) Weeks 7 to 24aevery three weeks (total of 6 doses) Week 25 onwards until disease every four weeks progressionbaFirst dose of the every-3-week dosing schedule is given at Week 7 b First dose of the every-4-week dosing schedule is given at Week 25

[0403] When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs. Administration

[0404] If a dose of DARZALEX FASPRO® is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval. Recommended Concomitant Medications Pre-medication

[0405] Administer the following pre-medications 1-3 hours before each dose of DARZALEX FASPRO®: • Acetaminophen 650 to 1,000 mg orally • Diphenhydramine 25 to 50 mg (or equivalent) orally or intravenously • Corticosteroid (long- or intermediate-acting) Monotherapy

[0406] Administer methylprednisolone 100 mg (or equivalent) orally or intravenously. Consider reducing the dose of methylprednisolone to 60 mg (or equivalent) following the second dose of DARZALEX FASPRO®. In Combination

[0407] Administer dexamethasone 20 mg (or equivalent) orally or intravenously prior to every DARZALEX FASPRO®administration.

[0408] When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX FASPRO®administration days.

[0409] Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX FASPRO®administration days when patients have received dexamethasone (or equivalent) as a pre-medication. Post-medication

[0410] Administer the following post-medications: Monotherapy

[0411] Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long- acting corticosteroid) orally for 2 days starting the day after the administration of DARZALEX FASPRO®. In Combination

[0412] Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after administration of DARZALEX FASPRO®.

[0413] If a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the administration of DARZALEX FASPRO®, additional corticosteroids may not be needed.

[0414] If the patient does not experience a major systemic administration-related reaction after the first 3 doses of DARZALEX FASPRO®, consider discontinuing the administration of corticosteroids (excluding any background regimen-specific corticosteroid).

[0415] For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 doses of DARZALEX FASPRO®, consider discontinuing these additional post- medications, if the patient does not experience a major systemic administration-related reaction. Prophylaxis for Herpes Zoster Reactivation

[0416] Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX FASPRO®and continue for 3 months following the end of treatment. Dosage Modifications for Adverse Reactions

[0417] No dose reductions of DARZALEX FASPRO®are recommended. Consider withholding DARZALEX FASPRO®to allow recovery of blood cell counts in the event of myelosuppression. Preparation and Administration

[0418] DARZALEX FASPRO®should be administered by a healthcare provider.

[0419] To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is DARZALEX FASPRO®for subcutaneous use. Do not administer DARZALEX FASPRO®intravenously. DARZALEX FASPRO®is ready to use. Preparation

[0420] Remove the DARZALEX FASPRO®vial from refrigerated storage [2°C to 8°C (36°F to 46°F)] and equilibrate to ambient temperature [15°C to 30°C (59°F to 86°F)]. Store the unpunctured vial at ambient temperature and ambient light for a maximum of 24 hours. Keep out of direct sunlight. Do not shake.

[0001] Withdraw 15 mL from the vial into a syringe.

[0421] DARZALEX FASPRO®is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles. Use the product immediately.

[0422] After the solution of DARZALEX FASPRO®is withdrawn into the syringe, replace the transfer needle with a syringe closing cap. Label the syringe appropriately toinclude the route of administration per institutional standards. Label the syringe with the peel- off label.

[0423] To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection.

[0424] Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if opaque particles, discoloration or other foreign particles are present. Storage

[0425] If the syringe containing DARZALEX FASPRO®is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours and / or at room temperature at 15°C to 25°C (59°F to 77°F) for up to 12 hours under ambient light.

[0426] Discard if storage time exceeds these limits.

[0427] If stored in the refrigerator, allow the solution to come to room temperature before administration. Administration

[0428] Inject 15 mL of DARZALEX FASPRO®into the subcutaneous tissue of the abdomen approximately 3 inches [7.5 cm] to the right or left of the navel over approximately 3-5 minutes. No data are available on performing the injection at other sites of the body.

[0002] Rotate injection sites for successive injections.

[0429] Never inject DARZALEX FASPRO®into areas where the skin is red, bruised, tender, hard or areas where there are scars.

[0430] Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

[0431] During treatment with DARZALEX FASPRO®, do not administer other medications for subcutaneous use at the same site as DARZALEX FASPRO®. DOSAGE FORMS AND STRENGTHS

[0432] Injection: 1,800 mg daratumumab and 30,000 units hyaluronidase per 15 mL (120 mg and 2,000 units / mL) colorless to yellow and clear to opalescent solution in a single- dose vial. CONTRAINDICATIONS

[0433] DARZALEX FASPRO®is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation. WARNINGS AND PRECAUTIONS Hypersensitivity and Other Administration Reactions

[0434] Both systemic administration-related reactions, including severe or life- threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO®. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO®. DRUG INTERACTIONS Effects of Daratumumab on Laboratory Tests Interference with Indirect Antiglobulin Tests (Indirect Coombs Test)

[0435] Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs.

[0436] If an emergency transfusion is required, administer non-cross-matched ABO / RhD-compatible RBCs per local blood bank practices. Interference with Serum Protein Electrophoresis and Immunofixation Tests

[0437] Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In DARZALEX FASPRO®-treated patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary

[0438] DARZALEX FASPRO® can cause fetal harm when administered to a pregnant woman. The assessment of associated risks with daratumumab products is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on the use of DARZALEX FASPRO® in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted.

[0439] The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

[0440] The combination of DARZALEX FASPRO® and lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide and pomalidomide may cause birth defects and death of the unborn child. Lenalidomide, thalidomide and pomalidomide are only available through a REMS program. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy. Clinical Considerations Fetal / Neonatal Adverse Reactions

[0441] Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX FASPRO® may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed. Data Animal Data

[0442] DARZALEX FASPRO® for subcutaneous injection contains daratumumab and hyaluronidase. Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. Data from studies using CD38 knockout animal models also suggest the involvement of CD38 in the regulation of humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs).

[0443] No systemic exposure of hyaluronidase was detected in monkeys given 22,000 U / kg subcutaneously (12 times higher than the human dose) and there were no effects on embryo-fetal development in pregnant mice given 330,000 U / kg hyaluronidase subcutaneously daily during organogenesis, which is 45 times higher than the human dose.

[0444] There were no effects on pre- and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 990,000 U / kg hyaluronidase subcutaneously, which is 134 times higher than the human doses. Lactation Risk Summary

[0445] There is no data on the presence of daratumumab and hyaluronidase in human milk, the effects on the breastfed child, or the effects on milk production. Maternal immunoglobulin G is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. Because of the potential for serious adverse reactions in the breastfed child when DARZALEX FASPRO® is administered with lenalidomide, thalidomide or pomalidomide, advise women not to breastfeed during treatment with DARZALEX FASPRO®. Refer to lenalidomide, thalidomide or pomalidomide prescribing information for additional information. Data Animal Data

[0446] No systemic exposure of hyaluronidase was detected in monkeys given 22,000 U / kg subcutaneously (12 times higher than the human dose) and there were no effects on post-natal development through sexual maturity in offspring of mice treated daily during lactation with 990,000 U / kg hyaluronidase subcutaneously, which is 134 times higher than the human doses. Females and Males of Reproductive Potential

[0447] DARZALEX FASPRO® can cause fetal harm when administered to a pregnant woman. Pregnancy Testing

[0448] With the combination of DARZALEX FASPRO® with lenalidomide, thalidomide or pomalidomide, refer to the lenalidomide, thalidomide or pomalidomidelabeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential. Contraception

[0449] Advise females of reproductive potential to use effective contraception during treatment with DARZALEX FASPRO® and for 3 months after the last dose. Additionally, refer to the lenalidomide, thalidomide or pomalidomide labeling for additional recommendations for contraception. Pediatric Use

[0450] Safety and effectiveness of DARZALEX FASPRO® in pediatric patients have not been established. CLINICAL STUDIES In Combination with Bortezomib, Lenalidomide and Dexamethasone in Patients Who Are Ineligible for ASCT

[0451] The efficacy of DARZALEX FASPRO®with bortezomib, lenalidomide and dexamethasone (DARZALEX FASPRO®-VRd) versus bortezomib, lenalidomide and dexamethasone (VRd) was evaluated in CEPHEUS (NCT03652064), an open-label, randomized, active-controlled trial in patients with newly diagnosed multiple myeloma who were ineligible for ASCT or refused ASCT as initial therapy.

[0452] Patients received DARZALEX FASPRO®1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 6, once every three weeks from weeks 7 to 24, and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg / m2body surface area twice weekly for two weeks (days 1, 4, 8, and 11) of each 21- day cycle. Lenalidomide was administered orally at 25 mg daily on Days 1-14 of Cycles 1-8. Dexamethasone was administered orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of Cycles 1-8. On the days of DARZALEX FASPRO®injection, the dexamethasone dose was administered orally or intravenously as a pre-injection medication.

[0453] The effectiveness of DARZALEX FASPRO®-VRd has not been established in patients who refused ASCT as initial therapy.

[0454] The major efficacy outcome measures were overall minimal residual disease (MRD) negativity rate and progression-free survival (PFS) by independent review committee (IRC) based on IMWG response criteria.

[0455] A total of 395 patients were randomized: 197 to the DARZALEX FASPRO®- VRd arm and 198 to the VRd arm. The median age was 70 years (range: 31 to 80); 50% were male and 81% were White, 5% were Black or African American, and 6% were Asian. Thirty- four percent had ISS Stage I, 38% had ISS Stage II, and 28% had ISS Stage III disease. High- risk cytogenetics (presence of del(17p), t(4;14), t(14,16)) were present in 13% of patients.

[0456] The trial demonstrated a statistically significant improvement in overall MRD negativity rate, PFS, CR or better rate, and sustained MRD negativity rate, as shown in Table 11. Table 11: Efficacy Outcomes from CEPHEUSa,bDARZALEX FASPRO®VRd -VRd (N=197) (N=198) PFS based on IRC n (%)c46 (23.4%) 68 (34.3%) Median, months with 95% CI NR (NE, NE) NR (NE, NE) Hazard ratio with 95% CId0.60 (0.41, 0.88) p-valuee0.0078 MRD negativity rate n (%)f,g103 (52.3%) 69 (34.8%) p-valuei0.0005 Overall CR or better (sCR+CR) n (%)f150 (76.1%) 116 (58.6%) p-valueh0.0002 MRD negativity rate in patients with CR or betterf,iNumber of patients with CR or better n=150 n=116 MRD negativity rate n (%) 103 (68.7%) 69 (59.5%) 95% CI (%)j(60.6%, 76.0%) (50.0%, 68.5%) Sustained MRD negativity rate n (%)c,k84 (42.6%) 50 (25.3%) p-valuel0.0003 Overall response (sCR+CR+VGPR+PR) n(%)m191 (97.0%) 185 (93.4%) Stringent Complete Response (sCR) 128 (65.0%) 89 (44.9%) Complete response (CR) 32 (16.2%) 33 (16.7%) Very good partial response (VGPR) 23 (11.7%) 49 (24.7%) Partial response (PR) 8 (4.1%) 14 (7.1%)VRd = bortezomib-lenalidomide-dexamethasone; PFS = progression-free survival; MRD = minimal residual disease; CI = confidence interval; NR = not reached; NE = not evaluable a Based on intent-to-treat population unless otherwise noted. b The hierarchical testing order in the CEPHEUS study was overall MRD negativity rate followed by CR or better rate, PFS, and sustained MRD negativity rate. c Interim analysis: Median follow-up of 39 months (cut-off date 08 September 2022). d Hazard ratio and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable and stratified with ISS staging (I, II, III), and age / transplant eligibility (<70 years ineligible, or <70 years and refusal to transplant, or ≥70 years) as randomized. A hazard ratio <1 indicates an advantage for D-VRd. e p-value is based on the log-rank test stratified with ISS staging (I, II, III), and age / transplant eligibility (<70 years ineligible, or <70 years and refusal to transplant, or ≥70 years) as randomized. f Primary analysis: Median follow-up of 22 months (cut-off date 08 April 2021). g Patients achieved both MRD negativity (threshold of 10-5) and CR or better. All MRD testing was performed with a next-generation sequencing assay (clonoSEQ). h p-value from Cochran Mantel-Haenszel Chi-Squared test. i Patients achieving MRD negativity (threshold of 10-5) among only patients achieving a response of CR or better. j Exact 95% confidence interval. k Sustained MRD negativity is defined as confirmed MRD negative status at two examinations at least 1 year apart without MRD positive status in between. l p-value from Fisher’s exact test. m Final analysis: Median follow-up of 59 months (cut-off date 07 May 2024). HOW SUPPLIED / STORAGE AND HANDLING

[0457] DARZALEX FASPRO®(daratumumab and hyaluronidase-fihj) injection is a sterile, preservative- free, colorless to yellow, and clear to opalescent solution for subcutaneous use supplied as individually packaged single-dose vials providing 1,800 mg of daratumumab and 30,000 units of hyaluronidase per 15 mL (NDC 57894-503-01).

[0458] Store DARZALEX FASPRO® vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) in the original carton to protect from light. Do not freeze or shake.Table 12: Sequence Listing Amino Acid Sequence SEQ ID NO:HCDR1 SFAMS1HCDR2 AISGSGGGTYYADSVKG2HCDR3 DKILWFGEPVFDY3LCDR1 RASQSVSSYLA4LCDR2 DASNRAT5LCDR3 QQRSNWPPT6EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGK VH GLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSL 7 RAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP VL RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQ 8 RSNWPPTFGQGTKVEIK EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGK GLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSL RAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK HC RVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE 9 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAP RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQ LC RSNWPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL 10 LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL IgG1 MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE constant QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS 11 domain KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRI NATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDK AKKDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNR SIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLR PNHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLW rHuPH20 NESTALYPSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPL 12 PVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLS IMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVC IRKNWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSE KFYCSCYSTLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMET EEP LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRI NATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDK AKKDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNR SIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLR PNHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLW rHuPH20 NESTALYPSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPL 13 variant 1 PVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLS IMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVC IRKNWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSE KFYCSCYSTLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMET EEPQIFYLNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRI NATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDK AKKDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNR SIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLR PNHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLW rHuPH20 NESTALYPSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPL 14 variant 2 PVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLS IMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVC IRKNWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSE KFYCSCYSTLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMET EEPQIF LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRI NATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDK AKKDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNR SIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLR PNHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLW rHuPH20 NESTALYPSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPL 15 variant 3 PVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLS IMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVC IRKNWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSE KFYCSCYSTLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMET EEPQI LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRI NATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDK AKKDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNR SIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLR PNHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLW rHuPH20 NESTALYPSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPL variant 4 16 PVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLS IMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVC IRKNWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSE KFYCSCYSTLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMET EEPQ

Claims

What is claimed: 1) A method of treating newly diagnosed multiple myeloma in a subject in need thereof comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises daratumumab, or a daratumumab biosimilar, and wherein the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT. 2) The method of claim 1, wherein the pharmaceutical composition comprises daratumumab, or a daratumumab biosimilar, and a hyaluronidase. 3) The method of claim 2, wherein the hyaluronidase is a recombinant human hyaluronidase or rHuPH20. 4) The method of any one of the claims 1-3, wherein the subject who is ineligible for HDC and ASCT is greater than or equal to 70 years of age. 5) The method of any one of the claims 1-4, wherein the subject who is ineligible for HDC and ASCT is greater than or equal to 18 and less than 70 years of age and has one or more comorbid conditions. 6) The method of any one of the claims 1-5, wherein the method achieves an improved clinical efficacy endpoint of the subject relative to a clinical efficacy endpoint achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 7) The method of claim 6, wherein the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD)-negativity rate, an improved sustained MRD-negativity rate, an improved complete response (CR) or better rate, an improved progression-free survival (PFS), an improved overall response rate (ORR), an improved overall survival (OS), an improved progression-freesurvival on next line of therapy (PFS2), an improved time to response (TTR), or an improved duration of response (DOR). 8) The method of claim 7, wherein the improved clinical efficacy endpoint is an improved overall MRD-negativity rate. 9) The method of claim 8, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10-5. 10) The method of claim 9, wherein the improved overall MRD-negativity rate is 60.9% relative to 39.4% for the reference subject or the reference population of subjects. 11) The method of claim 10, wherein the improved overall MRD-negativity rate is an absolute increase of 21.5% relative to the reference subject or the reference population of subjects. 12) The method of claim 11, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10-6. 13) The method of claim 12, wherein the improved overall MRD-negativity rate is 46.2% relative to 27.3% for the reference subject or the reference population of subjects. 14) The method of any one of claims 8-13, wherein the overall MRD-negativity rate is determined prior to a progression of the multiple myeloma, subsequent to administration of an antimyeloma therapy, or both. 15) The method of any one of claims 8-14 wherein the subject does not have high cytogenetic risk. 16) The method of claim 7, wherein the improved clinical efficacy endpoint is an improved sustained minimal residual disease (MRD)-negativity rate. 17) The method of claim 16, wherein the improved sustained MRD-negativity rate is for a period of 1 year, 2 years, and / or 3 years.18) The method of claim 16 or 17, wherein the improved sustained MRD-negativity rate is at or below a sensitivity threshold of 10-5. 19) The method of claim 18, wherein the improved sustained MRD-negativity rate is 48.7% relative to 26.3% for the reference subject or the reference population of subjects . 20) The method of claim 16 or 17, wherein the improved sustained MRD-negativity rate is at or below a sensitivity threshold of 10-6. 21) The method of claim 20, wherein the improved sustained MRD-negativity rate is 32.0% relative to 15.7% for the reference subject or the reference population of subjects. 22) The method of any one of claims 7-21, wherein the improved overall MRD- negativity rate or the improved sustained MRD-negativity rate is evaluated by next-generation sequencing. 23) The method of any one of claims 7-22, wherein the improved overall MRD- negativity rate or the improved sustained MRD-negativity rate is evaluated using bone marrow aspirate samples obtained at day 0, at the time of suspected complete response, and at 12, 18, 24, 30, and 36 months after administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, and yearly thereafter in subjects with a complete response. 24) The method of claim 7, wherein the improved clinical efficacy endpoint is an improved complete response (CR) or better rate. 25) The method of claim 24, wherein the improved CR or better rate is 81.2% relative to 61.6% for the reference subject or the reference population of subjects. 26) The method of claim 24 or 25, wherein the improved CR or better rate is an absolute increase of 19.6% relative to the reference subject or the reference population of subjects.27) The method of claim 7, wherein the improved clinical efficacy endpoint is an improved progression-free survival (PFS). 28) The method of claim 27, wherein the improved PFS is prolonged relative to the reference subject or the reference population of subjects. 29) The method of claim 27 or 28, wherein the improved PFS is a 43% reduction of risk of progression or death. 30) The method of any one of claims 27-28, wherein the subjects with improved PFS are negative for MRD at a sensitivity threshold of 10-6, 10-5, or both. 31) The method of any one of claims 27-28, wherein the subjects with improved PFS are positive for MRD at a sensitivity threshold of 10-6, 10-5, or both. 32) The method of any one of claims 27-31, wherein the improved PFS is an improvement in median PFS. 33) The method of any one of the preceding claims, wherein the method achieves an improved median treatment duration relative to a median treatment duration achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 34) The method of claim 33, wherein the improved median treatment duration is 56.3 months relative to 34.3 months for the reference subject or the reference population of subjects. 35) The method of any one of claims 1-34, wherein the method achieves an improved median number of treatment cycles relative to a median number of treatment cycles achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab.36) The method of claim 35, wherein the improved median number of treatment cycles is 59 months relative to 37 months for the reference subject or the reference population of subjects. 37) The method of any one of claims 1-36, wherein the method achieves a comparable EORTC QLQ-C30 global health status domain score relative to a EORTC QLQ- C30 global health status domain score achieved in a reference subject or a reference population of subjects, said reference subject or reference population of subjects having been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. 38) The method of any one of claims 1-37, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2. 39) The method of any one of the claims 1-38, wherein the subject has creatinine clearance of ≥30 mL / min / 1.73 m2. 40) The method of any one of the claims 1-39, wherein the subject has stage 3 multiple myeloma according to the International Staging System (ISS). 41) The method of any one of the claims 1-40, wherein the subject has high cytogenetic risk. 42) The method of any one of claims 2-41, wherein the pharmaceutical composition comprises about 1,800 mg of daratumumab, or a daratumumab biosimilar, and about 30,000 U rHuPH20. 43) The method of claim 42, wherein the pharmaceutical composition comprises about 120 mg / mL of daratumumab, or a daratumumab biosimilar, and about 2,000 U / mL rHuPH20. 44) The method of any one of the claims 1-43, wherein the pharmaceutical composition comprises one or more excipients. 45) The method of claim 44, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.46) The method of any one of claims 2-45, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. 47) The method of any one of claims 2-46, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of daratumumab, or a daratumumab biosimilar; about 2,000 U / mL of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. 48) The method of any one of the claims 1-47, wherein daratumumab or daratumumab biosimilar is administered subcutaneously at a dose of about 1,800 mg, bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2, lenalidomide is administered orally at a dose of about 25 mg, and dexamethasone is administered orally or intravenously at a dose of about 20 mg to about 40 mg. 49) The method of any one of the claims 1-48, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles. 50) The method of claim 49, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for eight 21-day cycles. 51) The method of any one of the claims 48-50, wherein daratumumab or daratumumab biosimilar is administered subcutaneously at a dose of about 1,800 mg once a week in cycles 1 through 2, about 1,800 mg once a week every 3 weeks in cycles 3 through 8, and about 1,800 mg once a week every 4 weeks thereafter until disease progression or unacceptable toxicity. 52) The method of any one of the claims 48-51, wherein the bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2on days 1, 4, 8 and 11.53) The method of any one of the claims 48-52, wherein the lenalidomide is administered orally at a dose of about 25 mg on days 1-14. 54) The method of any one of the claims 48-53, wherein the dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. 55) The method of any one of the claims 48-55, wherein the pharmaceutical composition, lenalidomide and dexamethasone are administered for one or more 28-day cycles following the eight 21-day cycles. 56) The method of claim 55, wherein the lenalidomide is administered orally at a dose of about 25 mg on days 1-21 of the one or more 28-day cycles and dexamethasone is administered orally or intravenously at a dose of about 40 mg on days 1, 8, 15 and 22 of the one or more 28-day cycles until disease progression. 57) The method of any one of the claims 1-56, wherein the improved clinical efficacy endpoint is an improved stringent complete response (sCR). 58) The method of claim 57, wherein the improved sCR is about 65.0% relative to about 44.9% for the reference subject or the reference population of subjects. 59) The method of claim 57 or 58, wherein the improved sCR is an absolute increase of about 20.1% relative to the reference subject or the reference population of subjects. 60) A pharmaceutical composition for use in the treatment of newly diagnosed multiple myeloma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises daratumumab, or a daratumumab biosimilar, and wherein the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT.61) The pharmaceutical composition of claim 60, wherein the pharmaceutical composition comprises daratumumab, or a daratumumab biosimilar, and hyaluronidase. 62) Use of a pharmaceutical composition for the manufacture of a medicament for treating newly diagnosed multiple myeloma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises daratumumab, or a daratumumab biosimilar, and wherein the subject is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) or has deferred HDC and ASCT. 63) The use of claim 62, wherein the pharmaceutical composition comprises daratumumab, or a daratumumab biosimilar, and hyaluronidase.

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