Daratumumab, bortezomib, lenalidomide, and dexamethasone for the treatment of multiple myeloma

Abstract

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

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 678,273, filed August 1, 2024; U.S. Provisional Application Serial No. 63 / 725,700, filed November 27, 2024; and Canadian Patent Application No. 3,257,924, filed November 29, 2024, the entire contents of which are incorporated herein by reference.

[0002] sequence list

[0003] This patent application includes a sequence list submitted via EFS-Web, the entire contents of which are incorporated herein by reference. The file, created on July 31, 2025, is named JBI6932WOPCT1 Sequence Listing.xml and is 20 bytes in size. Technical Field

[0004] This disclosure generally relates to methods for treating multiple myeloma, particularly newly diagnosed multiple myeloma. Background Technology

[0005] Induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd), followed by autologous stem cell transplantation (ASCT), VRd consolidation, and lenalidomide (R) maintenance therapy, is the standard of care for newly diagnosed, transplant-eligible patients with multiple myeloma. However, new strategies are needed for patients who are ineligible for transplantation or are not planned for transplantation as initial therapy. The methods disclosed in this invention address these and other important needs. Summary of the Invention

[0006] In some embodiments, this disclosure relates to a method of treating a newly diagnosed multiple myeloma in a subject of need, the method comprising administering to the subject daratumumab or a daratumumab biosimilar in combination with bortezomib, lenalidomide, and dexamethasone.

[0007] In some embodiments, this disclosure relates to a method of treating a newly diagnosed multiple myeloma in a subject of need, the method 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 to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20).

[0008] In some implementations, the subject is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or has had HDC and ASCT delayed. In some implementations, the subject ineligible for HDC and ASCT is 70 years of age or older. In some implementations, the subject ineligible for HDC and ASCT is 18 years of age or older but younger than 70 years of age and has one or more comorbid conditions.

[0009] In some implementations, the method achieves an improved clinical efficacy endpoint in subjects or a reference subject population, relative to the clinical efficacy endpoint achieved in a reference subject population or a reference subject population that has been administered a combination of bortezomib, lenalidomide, and dexamethasone, but not an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar.

[0010] In some implementations, the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD) negative rate, an improved sustained MRD negative rate, an improved complete response (CR) rate or better response rate, improved progression-free survival (PFS), improved overall response rate (ORR), improved overall survival (OS), improved progression-free survival with next-line treatment (PFS2), improved time to response (TTR), or improved duration of response (DOR).

[0011] In some implementations, the improved clinical efficacy endpoint is an improved overall MRD negativity rate. In some implementations, the improved overall MRD negativity rate is at or below 10%. -5 The sensitivity threshold. In some embodiments, the improved overall MRD negative rate is 60.9% relative to 39.4% of the reference subjects or reference subject population. In some embodiments, the improved overall MRD negative rate is an absolute increase of 21.5% relative to the reference subjects or reference subject population. In some embodiments, the improved overall MRD negative rate is at or below 10%. -6 The sensitivity threshold. In some embodiments, the improved sustained MRD negativity rate was 46.2% relative to 27.3% of the reference subjects or reference subject population. In some embodiments, the overall MRD negativity rate was determined before progression of multiple myeloma, after administration of antimyeloma therapy, or both.

[0012] In some implementation schemes, the subjects do not have a high cytogenetic risk.

[0013] In some embodiments, the improved clinical efficacy endpoint is an improved rate of persistent minimal residual disease (MRD) negativity. In other embodiments, the improved rate of persistent MRD negativity lasts for a period of 1 year, 2 years, and / or 3 years. In some embodiments, the improved rate of persistent MRD negativity is at or below 10. -5 The sensitivity threshold. In some implementations, the improved sustained MRD negativity rate was 48.7% relative to 26.3% of the reference subjects or reference subject population.

[0014] In some implementations, the improved sustained MRD negative rate is at or below 10%. -6 The sensitivity threshold.

[0015] In some implementations, the overall MRD negative rate was improved by 32.0% compared to 15.7% of the reference subjects or reference subject population.

[0016] In some implementations, the improved overall MRD negativity rate or the improved sustained MRD negativity rate is assessed by next-generation sequencing.

[0017] In some implementations, improved overall MRD negativity or improved sustained MRD negativity is assessed using bone marrow aspiration samples obtained on day 0, at suspected complete response, and at 12, 18, 24, 30, and 36 months after administration of the drug combination with bortezomib, lenalidomide, and dexamethasone, and annually thereafter in subjects with complete response.

[0018] In some implementations, the improved clinical efficacy endpoint is an improved complete response (CR) rate or better response rate. In some implementations, the improved CR rate or better response rate is 81.2% relative to 61.6% of the reference subjects or reference subject population. In some implementations, the improved CR rate or better response rate is an absolute increase of 19.6% relative to the reference subjects or reference subject population.

[0019] In some implementations, the improved clinical efficacy endpoint is improved strict complete response (sCR). In some implementations, the improved sCR is approximately 65.0% relative to approximately 44.9% of the reference subjects or reference subject population. In some implementations, the improved sCR is an absolute increase of 20.1% relative to the reference subjects or reference subject population.

[0020] In some implementations, the improved clinical efficacy endpoint is improved progression-free survival (PFS). In some implementations, improved PFS is a prolonged period relative to a reference subject or reference subject population. In some implementations, improved PFS is a 43% reduction in the risk of progression or death.

[0021] In some implementations, subjects with improved PFS had a PFS of 10 -6 Sensitivity threshold, 10 -5 It is negative for MRD at or below the sensitivity threshold.

[0022] In some implementations, subjects with improved PFS had a PFS of 10 -6 Sensitivity threshold, 10 -5 The sensitivity threshold or both are below which the MRD is positive.

[0023] In some implementations, the improved PFS is an improvement in median PFS.

[0024] In some implementations, the method achieves an improved median treatment duration relative to the median treatment duration achieved in a reference subject or reference subject population that has been administered a combination of bortezomib, lenalidomide, and dexamethasone without the administration of an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar.

[0025] In some implementations, the median duration of improved treatment was 56.3 months, compared to 34.3 months for the reference subjects or reference subject population.

[0026] In some embodiments, the method achieves an improved median number of treatment cycles compared to the median number of treatment cycles achieved in a reference subject or reference subject population that has received a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab or a daratumumab biosimilar. In other embodiments, the improved median number of treatment cycles is 59 months compared to 37 months in a reference subject or reference subject population.

[0027] In some implementations, the method achieves an equivalent EORTC QLQ-C30 global health status score compared to a reference subject or reference subject population that has been administered a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab.

[0028] In some implementations, subjects have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.

[0029] In some implementations, the subject has a creatinine clearance rate of ≥30 mL / min / 1.73 m2.

[0030] In some implementations, the subjects had stage 3 multiple myeloma according to the International Staging System (ISS).

[0031] In some implementation schemes, the subjects have a high cytogenetic risk.

[0032] 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.

[0033] In some embodiments, at least one of the excipients is histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof.

[0034] In some embodiments, the pharmaceutical composition has a pH of about 5.6, and the pharmaceutical composition comprises: about 1,800 mg of daratumumab or a daratumumab biosimilar; about 30,000 U of rHuPH20; about 10 mM of histidine; about 300 mM of sorbitol; about 0.04% (w / v) PS-20; and about 1 mg / mL of methionine.

[0035] In some embodiments, the pharmaceutical composition has a pH of about 5.6, and the pharmaceutical composition comprises: about 120 mg / mL of daratumumab or a daratumumab biosimilar; about 2,000 U / mL of rHuPH20; about 10 mM of histidine; about 300 mM of sorbitol; about 0.04% (w / v) PS-20; and about 1 mg / mL of methionine.

[0036] In some implementations, daratumumab or a 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.

[0037] In some implementations, the drug composition, bortezomib, lenalidomide, and dexamethasone are administered for one or more 21-day cycles.

[0038] In some implementations, the drug composition bortezomib, lenalidomide, and dexamethasone is administered for eight 21-day cycles.

[0039] In some implementations, ranitumab or daratumumab biosimilars are administered subcutaneously once weekly at a dose of about 1,800 mg during cycles 1 to 2, subcutaneously once every 3 weeks at a dose of about 1,800 mg during cycles 3 to 8, and thereafter subcutaneously once every 4 weeks at a dose of about 1,800 mg until disease progression or unacceptable toxicity.

[0040] In some embodiments, bortezomib is administered subcutaneously at a dose of about 1.3 mg / m² on days 1, 4, 8, and 11. In some embodiments, lenalidomide is administered orally at a dose of about 25 mg on days 1 through 14. In some embodiments, 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 drug composition, lenalidomide, and dexamethasone are administered after eight 21-day cycles and continued for one or more 28-day cycles. In some embodiments, lenalidomide is administered orally at a dose of about 25 mg on days 1 through 21 of 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 one or more 28-day cycles until disease progression. Attached Figure Description

[0041] The invention and the detailed embodiments described below will be further understood when read in conjunction with the accompanying drawings. The drawings illustrate exemplary embodiments of the disclosed methods or uses for the purpose of illustrating them; however, these methods and uses are not limited to the specific embodiments disclosed. In the drawings:

[0042] Figure 1 This is a patient flowchart.

[0043] Figure 2 This is a graph of Kaplan-Meier estimates of progression-free survival for patients in the intention-to-treat population. The final analysis of progression-free survival was performed after 154 disease progression or death events (>90% of the planned 162 events).

[0044] Figure 3This is a graph analyzing progression-free survival in pre-specified subgroups within the intention-to-treat population. The International Staging System (ISS) consists of three phases, with higher phases indicating more severe disease. Stage I: serum β2-microglobulin level less than 3.5 mg / L (300 nmol / L) and albumin level 3.5 g / dL or higher; Stage II: neither Stage I nor Stage III; Stage III: serum β2-microglobulin level 5.5 mg / L or more (≥470 nmol / L). Cytogenetic risk was determined by in situ fluorescence hybridization. High risk was defined as the presence of del(17p), t(4;14), or t(14;16). D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone. NE represents not estimable.

[0045] Figure 4 A is a graph representing the primary endpoint of overall minimal residual disease (MRD) negativity in the intention-to-treat population. Overall MRD negativity was defined as achieving a complete response or better response and MRD negativity (at or below 10) after randomization but before disease progression, subsequent antimyeloma therapy, or both. -5 The proportion of patients with a sensitivity threshold. Figure 4 B indicates a value of 10 or below. -6 An exploratory analysis of the sensitivity threshold of MRD negative rate. Figure 4 C shows the sustained MRD negativity rate in the intention-to-treat population. The sustained MRD negativity rate is defined as achieving a complete or better response and an MRD negativity status (at or below 10) on two separate examinations. -5 The proportion of patients with MRD (sensitivity threshold) who were examined at least one year apart without a positive MRD status during that period. According to the International Myeloma Working Group's MRD assessment guidelines, MRD status is assessed using bone marrow samples and evaluated using next-generation sequencing (clonoSEQ). ® Determined, version 2.0; Adaptive Biotechnologies). Common odds ratios for stratification tables were estimated using the Mantel-Haenszel method. Stratification factors were international staging system disease stage (I, II, III) and age / transplant eligibility (<70 years ineligible, <70 years and delayed transplant, or ≥70 years). An odds ratio >1 indicated an advantage for D-VRd. P-values ​​were calculated using Fisher's Exact Test. D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone. Figure 4DThe sustained MRD negativity rate for years 1, 2, and 3 is shown. This represents the proportion of participants who achieved CR or better response and MRD negativity in two bone marrow assessments at least one year apart, with no tests showing MRD positivity in between. Chi-square estimates were used using common odds ratios. An odds ratio >1 indicates an advantage for DRd. P-values ​​were calculated using Fisher's exact test.

[0046] Figures 5A to 5C It is the overall MRD negativity rate in a pre-specified subgroup within the intention-to-treat population, and the MRD negativity 10. -5 and MRD negative 10 -6 The analysis is presented in a graph. The overall MRD negativity rate was defined as achieving a complete response or better response and MRD negativity (at or below 10%) after randomization but before disease progression, subsequent antimyeloma therapy, or both. -5 The proportion of patients with a sensitivity threshold. 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 / L (300 nmol / L) and albumin level 3.5 g / dL or higher; Stage II: neither Stage I nor Stage III; Stage III: serum β2-microglobulin level 5.5 mg / L or more (≥470 nmol / L). Cytogenetic risk was determined by in situ fluorescence hybridization. High risk was defined as the presence of del(17p), t(4;14), or t(14;16). D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone. Furthermore, all pre-specified subgroup analyses showed consistent treatment efficacy of D-VRd relative to VRd. In the interim PFS analysis (D-VRd 52.5% and VRd 44.7%, odds ratio 1.41 (95% CI: 0.95, 2.10)) and the final PFS analysis (D-VRd 53.5% and VRd 45.7%, odds ratio 1.41 (95% CI: 0.95, 2.10)), the treatment effect of D-VRd relative to VRd in the overall MRD negative rate remained significant and continued to improve.

[0047] Figure 6This is a graph showing the rate of complete response (≥CR) or better in the intention-to-treat population. Tumor response was assessed using a validated computer algorithm according to the International Myeloma Working Group response criteria. A complete response (CR) or strict complete response (sCR) was achieved at any time during the trial. The co-odds ratio for the stratification tables was estimated using the Mantel-Haenszel method. Stratification factors were disease stage (I, II, III) and age / transplant eligibility (<70 years ineligible, <70 years and delayed transplant, or ≥70 years). An odds ratio >1 indicated an advantage for DRd. P-values ​​were calculated using the Cochran–Mantel–Haenszel chi-square test. D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone. VGPR represents very good partial response. PR represents partial response.

[0048] Figure 7 This is a graph showing Kaplan-Meier estimates of overall survival for patients in the intention-to-treat population. D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone.

[0049] Figure 8 This is a plot of Kaplan-Meier estimates of overall survival for patients in the intention-to-treat population, censored for deaths due to COVID-19. Two sensitivity analyses were performed to adjust for the impact of COVID-19 deaths: Figure 8 A redacted deaths caused by COVID-19, and Figure 8 B considers COVID-19 as a competing risk (i.e., COVID-19 deaths are considered competing events, and non-COVID-19 deaths are considered events of interest). D-VRd stands for subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd stands for bortezomib / lenalidomide / dexamethasone.

[0050] Figure 9 This is a Kaplan-Meier estimate of progression-free survival in first-line treatment for patients in the intention-to-treat population. Sensitivity analysis was performed to adjust for the impact of COVID-19 mortality.

[0051] Figure 10 This is a quality of life map of the intended treatment 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. The score ranges from 0 to 100, with higher scores indicating better health status and quality of life.

[0052] Figure 11This is a diagram of the research design provided in Example 1.

[0053] Figure 12 This is a graph representing a pre-planned efficacy analysis. Approximately 360 participants (180 per group) were randomly assigned in a 1:1 ratio to two groups. Participants in group A received VRd alone for eight 21-day cycles, followed by Rd ​​alone until disease progression or unacceptable toxicity. Participants in group B received D-VRd for eight 21-day cycles and continued D-Rd therapy until disease progression or unacceptable toxicity.

[0054] Figure 13 This is a demographic chart of the participants in the study of Example 1. Demographic and baseline characteristics were well balanced between the two treatment groups. The median age was 70 in both groups. Regarding sex, women comprised 43.9% of the VRd group and 55.8% of the D-VRd group.

[0055] Figure 14 This is a chart showing the disease characteristics of participants in the study of Example 1.

[0056] Figure 15 This is a chart showing the treatment regimens of participants in Example 1.

[0057] Figure 16 This is a chart summarizing the exposures of participants in the study of Example 1.

[0058] Figure 17 This is a graph showing the treatment delays, interruptions, and reductions experienced by participants in the study of Example 1.

[0059] Figure 18 It is at 10 -5 A set of graphs showing the primary endpoint at the sensitivity threshold – the overall MRD negative rate.

[0060] Figure 19 It is a set of graphs representing the primary and secondary endpoints – CR rate or better response rate.

[0061] Figure 20 This is a set of graphs representing the primary secondary endpoint – progression-free survival (PFS).

[0062] Figure 21 It is a set of graphs of primary and secondary endpoints (PFS) with censored COVID-19 deaths.

[0063] Figures 22A to 22C It is based on the overall MRD-negative PFS graph (10) -5 and 10 -6 ).

[0064] Figure 23This is a set of graphs showing the primary secondary endpoint – the rate of sustained MRD negativity.

[0065] Figure 24 This is a set of graphs showing the overall survival at the time of the final analysis, along with other secondary endpoints.

[0066] Figure 25 The graph safety analysis set N=392 represents adverse events (AEs) that occurred during treatment.

[0067] Figure 26 This is the figure showing the most frequently reported (>=30%) treatment-related adverse events.

[0068] Figure 27 This is a graph showing COVID-19-related SAEs and deaths.

[0069] Figure 28 This is a graph showing COVID-19-related deaths broken down by country and year.

[0070] Figure 29 A to Figure 29 B is the cumulative MRD negative ≥ CR rate graph, A) is the rate over time (10 -5 A) and B) at a pre-specified time point (10 -5 and 10 -6 The MRD negativity rate was defined as the proportion of patients in the ITT population who achieved both MRD negativity and ≥CR. Patients who were not evaluable, did not achieve ≥CR, or had indeterminate results were considered MRD positive. A window of ±3 months was applied at each time point to complete the bone marrow aspiration.

[0071] Figure 30 Among patients with high cytogenetic risk, those with MRD-negative ≥CR status (10 -5 Kaplan-Meier curves for PFS were used. The MRD negative rate was defined as the proportion of patients achieving MRD negative ≥ CR. Patients who could not be assessed or had indeterminate results were considered MRD positive. High risk was defined as the presence of del(17p), t(4; 14), or t(14; 16), as assessed by FISH testing.

[0072] Figure 31 The Kaplan-Meier curve of PFS in CEPEUS at a median follow-up of 39 months is shown.

[0073] Figure 32 This is a graph showing the MRD negative rate (ITT population). Figure 32 A represents IMWG's weakening level 10. -5 The image; Figure 32 B represents IFM simplified attenuation level 10. -5 The image; Figure 32 C represents IMWG Weakness Level 10. -6 The image; Figure 32 D is IFM simplified attenuation level 10. -6 The graph. The p-value comes from Fisher's exact test.

[0074] Figure 33 This is a graph showing the MRD negative rate (ITT population) for ≥12 months. Figure 33 A represents IMWG's weakening level 10. -5 The image. Figure 33 B represents IFM simplified attenuation level 10. -5 The image. Figure 33 C represents IMWG Weakness Level 10. -6 The image. Figure 33 D is IFM simplified attenuation level 10. -6 The graph shows the p-value, calculated using Fisher's exact test.

[0075] Figure 34 This is a graph of progression-free survival (ITT population). HR and 95% CI are derived from a Cox proportional hazards model, with treatment as the sole explanatory variable. A hazard ratio <1 indicates an advantage for DVRd. P-values ​​are based on an unstratified log-rank test.

[0076] Figure 35 This is a graph showing the rate of MRD negativity for a sustained period of ≥24 months (ITT population). Figure 35 A represents IMWG's weakening level 10. -5 The image. Figure 35 B represents IFM simplified attenuation level 10. -5 The image. Figure 35 C represents IMWG Weakness Level 10. -6 The image. Figure 35 D is IFM simplified attenuation level 10. -6 The graph shows the p-value, calculated using Fisher's exact test.

[0077] Figure 36 It is in ( Figure 36 A) IMWG healthy patients, ( Figure 36 B) IMWG moderately healthy patients, ( Figure 36 C) Non-debilitating IFM patients, and ( Figure 36 D) Plot of ≥CR rates in IFM-debilitated patients, according to treatment group. Mantel-Haenszel estimates of common OR were used. An odds ratio >1 indicated that DVRd had an advantage. P-values ​​were derived from the Cochran-Mantel-Haenszel chi-square test.

[0078] Figure 37This is a graph showing the median PFS with DVRd among patients who are eligible for transplantation and those who are not.

[0079] Figure 38 This is a graph showing the predicted PFS in TE NDMM patients with DVRd.

[0080] Figure 39 This is a graph showing the predicted progression-free survival (PFS) in DVRd TIE NDMM patients. Detailed Implementation

[0081] In this disclosure, unless the context clearly indicates otherwise, the singular forms “a,” “an,” “the,” and “the” include the plural meaning, and references to a specific numerical value include at least that specific value. Thus, for example, a reference to “material” means at least one of such materials, as well as equivalents of that material known to those skilled in the art.

[0082] When a list is provided, unless otherwise indicated, it should be understood that each individual element in the list and each combination of the list is to be understood as a separate implementation. For example, a list of implementations presented as “A, B or C” will be understood to include implementations “A”, “B”, “C”, “A or B”, “A or C”, “B or C”, or “A, B or C”.

[0083] It should be understood that, for clarity, certain features of this disclosure are set forth in the context of individual embodiments, but may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is considered to be combinable with any other embodiment, and such combination is considered another embodiment. Conversely, for brevity, various features of this disclosure are set forth in the context of individual embodiments, but may also be provided individually or in any sub-combination. It should also be noted that the claims may be drafted to exclude any optional elements. Therefore, this statement is intended as a basis for the use of exclusive terms such as “solely,” “only,” etc., or the use of “negative” to define the elements of the claims. Finally, although an embodiment may be described as part of a series of steps or a more general structure, each step may also be considered an independent embodiment in itself.

[0084] certain terms

[0085] All terms used throughout this specification shall have the definitions set forth herein.

[0086] “About” means within the acceptable range of error for a 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. In the context of a particular measurement, result, or implementation, unless otherwise expressly stated in the implementation or elsewhere in the specification, “about” means within one standard deviation or up to 5% (whichever is greater) in accordance with convention in the art.

[0087] "About once a week" is an approximate number and can include once every 7 days ± 2 days, that is, once every 5 days to once every 9 days. Therefore, the dosing frequency of "once a week" can be once every 5 days, once every 6 days, once every 7 days, once every 8 days or once every 9 days.

[0088] "About once every two weeks" is an approximate number and may include once every 14 days ± 2 days, that is, once every 12 days to once every 16 days.

[0089] "About once every three weeks" is an approximate number and may include once every 21 days ± 2 days, that is, once every 19 days to once every 23 days.

[0090] "About once every four weeks" is an approximate number and may include once every 28 days ± 2 days, that is, once every 26 days to once every 30 days.

[0091] "About once every five weeks" is an approximate number and may include once every 35 days ± 2 days, that is, once every 33 days to once every 37 days.

[0092] "About once every six weeks" is an approximate number and may include once every 42 days ± 2 days, that is, once every 40 days to once every 38 days.

[0093] "Approximately twice a week" refers to an approximate number and may include twice a week, for example, the first dose on day 1 of the week and the second dose on day 2, 3, 4, 5, 6 or 7 of the week; the first dose on day 2 of the week and the second dose on day 3, 4, 5, 6 or 7 of the week; the first dose on day 3 of the week and the second dose on day 4, 5, 6 or 7 of the week; the first dose on day 4 of the week and the second dose on day 5, 6 or 7 of the week; the first dose on day 5 of the week and the second dose on day 6 or 7 of the week; the first dose on day 6 of the week and the second dose on day 7 of the week.

[0094] The connecting term "and / or" between multiple listed elements is understood to encompass both individual and combined options. For example, in the case where two elements are connected by "and / or," the first option means applying the first element in the absence of the second element. The second option means applying the second element in the absence of the first element. The third option means applying both the first and second elements together. Any of these options is understood to fall within the meaning and therefore satisfies the requirement of the term "and / or" as used herein. The concurrent applicability of more than one option is also understood to fall within the meaning and therefore satisfies the requirement of the term "and / or".

[0095] "Antibodies" include immunoglobulin molecules belonging to any class (IgA, IgD, IgE, IgG, and IgM) or subclass (IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4) and containing either a κ (kappa) or λ (lambda) light chain. Antibodies include monoclonal antibodies, including human, humanized, and chimeric monoclonal antibodies. A full-length antibody molecule consists of two heavy chains (HC) and two light chains (LC) linked by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions, called complementarity-determining regions (CDRs), interspersed with framework regions (FRs). Each VH and VL consists of three CDR and four FR segments, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0096] A “biosimilar” (referring to an approved reference product / biologic, i.e., a reference marketed drug) is a biological product that is highly similar to a reference product but has minor differences in clinically inactive components, based on data from studies in which there are no clinically significant differences in safety, purity, and potency between the biosimilar and the reference product: (a) analytical studies demonstrating that the biological product is highly similar to the reference product but has minor differences in clinically inactive components; (b) animal studies (including assessments of toxicity); and / or (c) one or more clinical studies (including assessments of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate the safety, purity, and potency of the reference product under one or more appropriate conditions of use, intended for use, and for which a license to act as a biosimilar is sought. A biosimilar may be an interchangeable product that can replace the reference product at the pharmacy without the intervention of a prescribing healthcare professional. To meet the additional criterion of “interchangeability,” a biosimilar should be expected to produce the same clinical outcomes as the reference product in any given patient, and if the biosimilar is administered to an individual more than once, the risk of reduced safety or efficacy from switching or exchanging between the use of the biosimilar and the reference product is no greater than the risk of using the reference product without such switching or exchanging. The biosimilar utilizes the same mechanism of action for the proposed conditions of use, provided that these mechanisms are known to the reference product. One or more conditions of use specified, recommended, or suggested in the proposed labeling of the biosimilar have previously been approved for use with the reference product. The biosimilar has the same route of administration, dosage form, and / or strength as the reference product, and is manufactured, processed, packaged, or stored in a facility that meets standards designed to ensure that the biosimilar remains safe, pure, and potent. When compared to the reference product, the biosimilar may include minor modifications to the amino acid sequence, such as N-terminal or C-terminal truncation that is not expected to alter the properties of the biosimilar.

[0097] "Cancer" refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, metastasize (spread) to other areas of the patient's body.

[0098] "CD34+" refers to human hematopoietic stem cells that are positive for the CD34 antigen.

[0099] "CD38" refers to human differentiation cluster 38 protein, which is a glycoprotein expressed on immune cells, including plasma cells, natural killer cells, and B and T cell subsets.

[0100] "Clinical efficacy endpoint" or "clinical endpoint" refers to an outcome that indicates a clinically beneficial effect, such as overall minimal residual disease (MRD) negative rate, sustained MRD negative rate, complete response (CR) rate or better response rate, progression-free survival (PFS), overall response rate (ORR), overall survival (OS), progression-free survival with next-line treatment (PFS2), time to response (TTR), or duration of response (DOR).

[0101] "Clinically proven" refers to clinical efficacy results that are sufficient to meet the approval criteria of the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the relevant national regulatory agency. For example, a clinical study may be a well-sized, randomized, double-blind, controlled trial used to clinically confirm the efficacy and / or non-inferiority of a drug.

[0102] Terms such as “together,” “to be administered with,” “to be administered in combination with,” and “in combination with” encompass the administration of two or more therapeutic agents or drugs to a single patient and are intended to include treatment regimens in which these therapeutic agents or drugs are administered via the same or different routes of administration or at the same or different times.

[0103] The complementarity-determining region (CDR) is the antigen-binding site in an antibody. CDRs can 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 descriptions (see Lefranc et al., DevComparat Immunol 27:55-77, 2003). The International Immunogenetics (IMGT) database (http: / / www.imgt.org) provides standardized numbering and definitions for antigen-binding sites.

[0104] "Complete response rate or better response rate" refers to the proportion of patients who achieve a complete response or a near-complete response based on a computerized algorithm according to the International Myeloma Working Group (IMWG) response criteria, during or after study treatment and before the initiation of subsequent antimyeloma therapy.

[0105] The terms “comprising,” “substantially consisting of,” and “consisting of” are intended to imply their accepted meaning in patent terminology; that is, (i) “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open at the end, and does not exclude additional, unlisted elements or method steps; (ii) “consisting of” excludes any element, step, or component not specified in the claims; and (iii) “substantially consisting of” limits the scope of the claims to the specified material or step “and material or step that does not substantially affect the essential and novel features of the invention protected by the claims.” Embodiments described with the phrase “comprising” (or its equivalents) are also provided, as are those described independently with “consisting of” and “substantially consisting of”.

[0106] "Consolidation," "consolidation therapy," or "consolidation period" refers to a short duration of treatment given to a subject after the subject has already received high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT); (i.e., post-HDC and ASCT).

[0107] "Corticosteroids" refer to a class of steroid hormones produced or synthesized in the adrenal cortex, specifically dexamethasone, methylprednisolone, prednisolone, and prednisolone. Dexamethasone is marketed under the brand name DECARON. ® Commercially available.

[0108] A “cycle” refers to a schedule for administering one or more therapeutic agents or drugs, and specifically to the period during which one or more therapeutic agents or drugs are administered to a subject. A cycle may include the number of days during which the drug is administered and rest periods during which the drug is not administered. The length of a cycle can vary and may be, for example, 2 weeks, 3 weeks, 28 days (or 4 weeks), 5 weeks, or 6 weeks.

[0109] "Daratumumab" refers to an antibody that specifically binds to CD38, comprising the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, LCDR3 of SEQ ID NO: 6, the heavy chain variable region (VH) of SEQ ID NO: 7, the light chain variable region (VL) of SEQ ID NO: 8, the heavy chain (HC) of SEQ ID NO: 9, and the light chain (LC) of SEQ ID NO: 10. Daramumumab is marketed under the trade name DARZALEX. ® DARZALEX ® SC and DARZALEX FASPRO ® Sales. DARZALEX® DARZALEX FASPRO ® and DARZALEX ® The SC's packaging insert and label can be found on fda.gov or ema.europa.eu and are incorporated herein by reference.

[0110] "Dosing regimen" refers to information about the amount of therapeutic agent or drug to be taken by the subject and the frequency of taking the therapeutic agent.

[0111] "Dosage" refers to the amount or quantity of a therapeutic agent or drug to be taken each time.

[0112] "Pharmaceutical product" (DP) refers to a finished dosage form containing an active pharmaceutical ingredient (e.g., a pharmaceutical substance), such as a tablet, capsule, or solution, which is usually, but not necessarily, associated with an inactive ingredient.

[0113] "Drug substance" (DS) means any substance or mixture of substances intended for use in the manufacture of a pharmaceutical product, and which, when used in the production of the drug, becomes the active ingredient of the pharmaceutical product. Such substances are intended to provide pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to affect the structure or function of the body.

[0114] "Duration of response" refers to the time between the initial recorded date of the response (partial response (PR) or better) and the date of the first recorded evidence of progressive disease according to the International Myeloma Working Group criteria, or, for patients with a partial response or better as their best response, the date of death due to disease progression (whichever comes first).

[0115] "Effective" means a dose or administration regimen of a therapeutic agent or drug (such as an antibody that specifically binds to CD38) or a combination of therapeutic agents or drugs that provides a therapeutic effect on a given condition and administration regimen in a subject who has received or has received a therapeutic agent or drug or a combination of therapeutic agents or drugs. "Effective" is intended to mean an amount sufficient to reduce and / or prevent clinically significant deficits in a subject's activity, function, and response, or sufficient to result in a clinically significant improvement in the subject's condition.

[0116] "Frontline" or "first-line" therapy refers to the first treatment administered to a subject for a disease such as multiple myeloma.

[0117] "Healthcare professionals" means doctors, nurses, nursing assistants, or anyone who works under the direct supervision of a doctor or nurse, or anyone who works in a hospital or other place where treatment can be provided to a subject.

[0118] "Hyaluronase" refers to an enzyme that degrades hyaluronic acid (EC 3.2.1.35) and reduces the viscosity of hyaluronic acid in the extracellular matrix, thereby increasing tissue permeability. An exemplary hyaluronase is recombinant human hyaluronase PH20 (rHuPH20). rHuPH20 contains the amino acid sequence of SEQ ID NO: 12-16. The enzyme activity of hyaluronases (including rHuPH20) can be defined by units per mL (U / mL) or by the total enzyme activity (U) in a specific formulation. The standard definition of one unit (U) of enzyme activity is the amount of enzyme catalyzing a reaction of 1 nmol of substrate per minute.

[0119] "High-dose chemotherapy" (HDC) or "high-dose therapy" and "autologous stem cell transplantation" (ASCT) refer to treatment of a newly diagnosed multiple myeloma patient who is considered healthy (e.g., the patient is "eligible"). Patients who are not considered candidates for high-dose chemotherapy for stem cell transplantation due to age (≥70 years) or age >18 years to 70 years and the presence of comorbidities (e.g., the patient is "ineligible") or who do not plan to receive high-dose chemotherapy for stem cell transplantation as initial treatment (e.g., the patient is "postponing transplantation") are also considered candidates. An exemplary HDC regimen is a dose of 200 mg / m². 2 Body surface area melphalan (dosage decreases 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, Vol. 9: pp. 123-133, 2018). Cyclophosphamide is marketed under the trade name Cyclostin. ™ Sales. Alkeran is sold under the trade name Alkeran. ® Carmustine is sold under the brand name BiCNU. ® Sales. Etoposide is marketed under the brand name VEPESID. ® Sales. Cytarabine is marketed under the trade name CYTOSAR-U ® Sold under the brand name IDAMYCIN. ® Sales. Thioprene is marketed under the brand name THIOPLEX. ® Lenalidomide is sold under the brand name REVLIMID. ® Sale.

[0120] "High-risk multiple myeloma" refers to multiple myeloma characterized by one or more cytogenetic abnormalities del17p, t(4;14), t(14;20), t(14;16), or del13, or any combination thereof.

[0121] "Induction," "induction therapy," or "induction phase" refers to the first treatment provided for a disease with the aim of reducing the amount of malignant plasma cell burden and improving the depth of response. Induction therapy can be provided before treatment with high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT).

[0122] "Information" refers to reported results from clinical trials, which may be provided in written or electronic form, or orally, or may be available on the Internet.

[0123] An infusion-related reaction (IRR) is any sign or symptom experienced by a subject during administration of a drug or therapeutic agent or during any event that occurs within 24 hours of administration. IRRs are typically classified as grade 1, 2, 3, or 4.

[0124] "Maintenance therapy" refers to treatment given to a disease after a response or optimal response has been achieved, in order to prevent or delay recurrence.

[0125] mg / m 2 "This refers to the drug dosage expressed in milligrams per square meter of body surface area."

[0126] Minimal residual disease (MRD) refers to a small number of clonal multiple myeloma cells remaining in a patient's body after treatment and / or during the response period.

[0127] "MRD negative" or "MRD negative status" refers to a ratio of clonal multiple myeloma cells of 1:1x10 in a bone marrow aspiration sample obtained from the subject. 5 Or lower.

[0128] “MRD negative rate” is defined as achieving a complete or better response after randomization but before disease progression, subsequent antimyeloma therapy, or both, and having an MRD negative status (at or below 10%). –5 Or 10 -6 The proportion of patients with a sensitivity threshold.

[0129] “MRD positive” refers to a patient whose MRD is positive, indeterminate, or negative in all test samples and who has not achieved CR or a better condition.

[0130] Multiple myeloma is a malignant plasma cell disease characterized by the uncontrolled, progressive proliferation of one or more malignant plasma cells. The abnormal proliferation of plasma (myeloma) cells leads to the replacement of normal bone marrow, resulting in hematopoietic tissue dysfunction and bone marrow structural destruction, thus causing disease progression and eventual death.

[0131] "Newly diagnosed" refers to human subjects who have been diagnosed with a disease (such as multiple myeloma, which involves cells that express CD38) but have not yet received treatment.

[0132] "Overall complete response rate or better response rate" refers to the percentage of patients in the intention-to-treat population who achieve a complete or near-complete response at any time during the study period, according to the International Myeloma Working Group criteria. Furthermore, a specific response must have been achieved before initiating subsequent treatment.

[0133] "Overall minimum residual disease negative rate" refers to the percentage of patients in the intention-to-treat population who achieve a minimum residual disease negative result (at or below 1 tumor cell / 10) via bone marrow aspiration. 5 The percentage of patients who achieve a complete response or better response at any time after the randomization date during the study period (the sensitivity threshold for white blood cells). The "sustained MRD negative rate" refers to the percentage of patients in the ITT population who have two consecutive MRD negative results at least 12 months apart without any MRD positive results in between.

[0134] The “Overall Response Rate” (ORR) refers to the proportion of patients who achieve a partial response or better partial response (i.e., partial response, very good partial response, complete response, or strictly complete response) based on a computerized algorithm according to the standards of the International Myeloma Working Group (IMWG) during or after study treatment but before the start of subsequent antimyeloma therapy.

[0135] Overall survival (OS) is defined as the time from the start of treatment to the date of death from any cause. For the purposes 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 from any cause.

[0136] "Percentage w / v" (%w / v) refers to weight in grams per 100 mL.

[0137] "Drug combination" refers to a combination of two or more therapeutic agents or drugs that are administered together or individually.

[0138] "Pharmaceutical composition" refers to a product resulting from the combination of an antibody that specifically binds to CD38 and hyaluronidase in a fixed combination. "Fixed combination" refers to a single pharmaceutical composition containing an anti-CD38 antibody and hyaluronidase, administered simultaneously in a single entity or dose. Pharmaceutical compositions typically contain a pharmaceutically acceptable carrier.

[0139] "Pharmaceutically acceptable carriers" or "excipients" refer to components in a pharmaceutical composition other than the active ingredient that are non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffer solutions, stabilizers, or preservatives.

[0140] A placebo is a substance that has no therapeutic effect.

[0141] "Post-consolidation" refers to the treatment period that ends at the end of the consolidation therapy.

[0142] "Post-induction" refers to the treatment period that ends when the induction therapy is completed.

[0143] When it refers to a composition, dose, dosing regimen, treatment, or method that utilizes a therapeutic agent or medicine (such as an antibody that specifically binds to CD38 or a combination of CD38 and one or more therapeutic agents), "efficacy" means the specific ability or capacity of a product to achieve a given result, as demonstrated by adequately controlled clinical data obtained through appropriate laboratory testing or by administering the product in the intended manner.

[0144] "Progression-free survival" (PFS) refers to the time from the start of treatment to the first detection of disease progression or death from any cause (whichever occurs first). For the purposes of the clinical trials described in this example, PFS is defined as the duration from the date of randomization to disease progression or death (whichever occurs first). Disease progression is determined according to IMWG criteria. Patients who begin subsequent antimyeloma therapy for multiple myeloma without disease progression are censored at the last disease assessment prior to initiating subsequent therapy.

[0145] "Progression-free survival 2" (PFS2) refers to the time from randomization to progression or death (whichever occurs first, for any reason) from the time of randomization to the time of next-line treatment.

[0146] "Progressive disease" (PD), "stable disease" (SD), "partial response" (PR), "very good partial response" (VGPR), "complete response" (CR), and "strict complete response" (sCR) refer to responses to treatment and are understood by those skilled in the art as to design, conduct, or review clinical trials. Response to treatment can be assessed using the International Myeloma Working Group (IMWG) Harmonized Criteria of Response (International Harmonized Criteria of Response Consensus Recommendations) as shown in Table 1.

[0147] "Complete response rate or better response rate" (CR response rate or better response rate) refers to the proportion of subjects who achieve CR or strict complete response (sCR) during or after treatment.

[0148] "Strict complete response rate or better response rate" (sCR rate or better response rate) refers to the proportion of subjects who achieve sCR during or after treatment, which can be measured after induction, transplantation, consolidation, and overall.

[0149] "Reference Drug" or "RLD" can also refer to an approved biological product, such as DARZALEX. ® SC brand name daratumumab or DARZALEX FASPRO ® Biosimilars of daratumumab and hyaluronidase, marketed under trade names, have shown bioequivalence.

[0150] "Reference subjects" or "reference subject population" refers to subjects or groups of subjects with a newly diagnosed multiple myeloma who have received a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. The reference subjects or reference subject population are substantially the same as subjects or groups of subjects treated with daratumumab in combination with bortezomib, lenalidomide, and dexamethasone. Exemplary reference subjects or reference subject populations are those described in Example 1 herein. In some embodiments, the subject population and reference subject population contain at least two subjects. In some embodiments, the number of subjects included in the subject population and reference subject population allows for statistically significant analyses of improvements in safety and / or efficacy.

[0151] "Safety," when referring to a composition, dosage, administration regimen, treatment or method of treatment using a therapeutic agent or drug (such as an antibody that specifically binds to CD38 or a combination of one or more therapeutic agents), means the favorable benefit in the presence of 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 another comparison: the risk ratio.

[0152] "Safe and effective" means, under the Federal Food, Drug, and Cosmetic Act, the amount and / or dosing regimen of a drug (such as an antibody that specifically binds to CD38) or a combination of drugs (such as an antibody that specifically binds to CD38 and a combination of one or more therapeutic agents) that elicits the desired biological or medical response in a subject's biological system without risk exceeding the beneficial effects of such response, compared to the standard of care or another comparable under the revised law (Sections 201–902, 52 Statute, page 1040 and later, revised; 21 USC §§ 321–392) or another comparable, the favorable risk:benefit ratio of the acceptable frequency and / or acceptable severity of treatment-period adverse events (referred to as AEs or TEAEs). Safety is evaluated in laboratory, animal, and human clinical trials to determine the highest tolerated or optimal dose of the drug or combination of drugs required to achieve the desired beneficial effect. Efficacy is evaluated in human clinical trials to determine whether the drug or combination of drugs demonstrates a health benefit superior to placebo or other interventions. A safe and effective drug or combination of drugs is granted marketing authorization by the FDA or other authorities for the intended use.

[0153] Antibodies that "specifically bind to CD38" are those that bind to CD38 with a greater affinity than to other antigens. Typically, this antibody binds to CD38 at a specific equilibrium dissociation constant (K0). D (Approximately 1×10) -8 M or lower, for example, about 1×10 -9 M or lower, approximately 1×10 -10 M or lower, approximately 1×10 -11 M or lower, or approximately 1×10 -12 M or lower, usually K D Compared to its binding to non-specific antigens (such as BSA, casein), K D At least a hundred times lower. K D Standard procedures can be used for measurement. However, antibodies that specifically bind to CD38 may be cross-reactive to other related antigens, such as the same antigens from other species (homologous monkeys) such as cynomolgus monkeys (Macaca fascicularis), chimpanzees (Pan troglodytes), or marmosets (Callithrix jacchus).

[0154] "Subcutaneous" or "subcutaneous treatment" refers to the application of a therapeutic agent under the skin, usually by injection. Application sites can be the side or back of the upper arm, the front of the thigh, or the abdomen.

[0155] "Subject" refers to a human patient. The terms "subject" and "patient" are used interchangeably herein. Those skilled in the art will understand that "patient" may also refer to a patient population. Those skilled in the art will understand that when referring to a median endpoint, such as median progression-free survival, "patient" means a patient population.

[0156] "Stem cell mobilization" refers to the process of stimulating stem cells from the bone marrow space into the bloodstream, making them available for collection.

[0157] "Continuous MRD negative rate ≥1 year" refers to achieving a complete or better reaction and MRD negative status in two separate examinations

[10] -5 Or 10 -6 The proportion of patients who, as specified, were examined at least one year apart, with no MRD positive status during that period.

[0158] "Therapeutic effective dose" refers to the amount that effectively achieves the desired therapeutic outcome at the required dose and time period. Therapeutic effective dose can vary depending on factors such as an individual's disease state, age, sex, and weight, as well as the ability of the therapeutic agent or combination of agents to elicit the desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of agents include, for example, improvements in the patient's overall health, reduction in tumor burden, inhibition or slowing of tumor growth, and / or the absence of metastasis of cancer cells to other parts of the body.

[0159] "Response time" refers to the time between randomization and the first efficacy evaluation, in which the subject has met all criteria for a partial or better response.

[0160] "Time to complete or better response" refers to the time from the randomization date to the date on which a confirmed response (CR) of complete or better response is first recorded for patients with a complete or better response.

[0161] “Treatment” refers to therapeutic treatment. Individuals requiring treatment include subjects diagnosed with a disorder or exhibiting symptoms of a disorder. Treatable subjects also include subjects who are predisposed to or susceptible to developing a disorder, or subjects whose disorder is to be prevented. Beneficial or desired clinical outcomes include symptom reduction, decrease in disease severity, stable (i.e., no worsening) state of the disease, delay or slowing of disease progression, improvement or mitigation of the disease state, disease remission (whether partial or complete), and extended survival compared to the expected survival of a subject who is not receiving treatment or is receiving another form of treatment.

[0162] As used herein, “treatment-associated adverse event” (TEAE) takes its conventional meaning as would be understood by a person skilled in the art of designing, conducting or reviewing clinical trials, and refers to an AE that is considered to be associated with the use of an antibody that specifically binds to CD38 in a situation where the attribute is likely, probable or very likely to occur.

[0163] "Unacceptable adverse events" and "unacceptable adverse reactions" refer to all harms or undesirable results associated with or caused by the administration of the drug composition or therapeutic agent, and such harms or undesirable results are of a severity that the regulatory agency considers unacceptable for the proposed use.

[0164] "Unacceptable toxicity" refers to toxicity associated with or caused by the administration of a pharmaceutical composition or therapeutic agent, and the harm or undesirable outcome is of a severity that a regulatory agency or treating physician deems warranted the discontinuation of the administration of the pharmaceutical composition or therapeutic agent.

[0165] "Very good partial response or better response" (VGPR rate or better response rate) refers to the proportion of subjects who achieve VGPR, complete response (CR), or strict complete response (sCR) during or after treatment.

[0166] Multiple myeloma

[0167] Multiple myeloma causes significant morbidity and mortality. It accounts for approximately 1% of all malignant tumors worldwide and 13% of hematologic cancers. In the European Union and the United States, approximately 50,000 patients are diagnosed with multiple myeloma each year, and 30,000 patients die from it annually.

[0168] Most patients with multiple myeloma produce monoclonal proteins (paraproteins, M proteins, or M fractions), which are immunoglobulins (Ig) or fragments of immunoglobulins that have lost their function (Kyle and Rajkumar, Leukemia 23:3-9, 2009; Palumbo and Anderson, N Engl J Med 364:1046-1060, 2011). Impaired levels of normal immunoglobulins make patients susceptible to infection. The proliferating multiple myeloma cells replace normal bone marrow, leading to dysfunction of normal hematopoietic tissue and destruction of normal bone marrow structure. This is reflected in clinical findings such as anemia, paraproteins in serum or urine, and bone resorption on X-rays that appear as diffuse osteoporosis or lytic lesions (Kyle et al., Mayo Clin Proc, Vol. 78: pp. 21-33, 2003). In addition, hypercalcemia, renal insufficiency or failure, and neurological complications are also common. A small percentage of multiple myeloma patients have the non-secretory type.

[0169] Diagnosis of multiple myeloma

[0170] Subjects with multiple myeloma who meet the CRAB (elevated calcium, renal insufficiency, anemia, and bone abnormalities) criteria and have ≥10% clonal bone marrow plasma cells or biopsy-confirmed bone or extramedullary plasmacytoma, and measurable disease. Measurable disease is defined by any of the following:

[0171] -IgG myeloma: Serum monoclonal paraprotein (M protein) level ≥1.0 g / dL or urine M protein level ≥200 mg / 24 hours; or

[0172] Multiple myeloma with IgA, IgM, IgD, or IgE: serum M protein level ≥0.5 g / dL or urinary M protein level ≥200 mg / 24 hours; or

[0173] - Light chain multiple myeloma with no measurable disease in serum or urine: serum free immunoglobulin light chain ≥10 mg / dL and abnormal serum immunoglobulin kλ free light chain ratio.

[0174] CRAB Standard

[0175] • Hypercalcemia: Serum calcium >0.25 mM / L (>1 mg / dL) above the upper limit of normal [ULN] or >2.75 mM / L (>11 mg / dL)

[0176] • Renal insufficiency: Creatinine clearance <40mL / min or serum creatinine >177µM / L (>2mg / dL).

[0177] • Anemia: Hemoglobin > 2 g / dL (below the lower limit of normal) or hemoglobin < 10 g / dL.

[0178] • Bone lesions: One or more osteolytic lesions visible on bone X-ray, CT, or PET-CT.

[0179] The response to treatment can be assessed using the International Myeloma Working Group (IMWG) Unified Criteria of Response (International Unified Criteria of Response Consensus Recommendations) as shown in Table 1.

[0180] Table 1 .

[0181]

[0182]

[0183] Treatment methods and uses

[0184] This disclosure provides a method for treating a newly diagnosed multiple myeloma in a subject of need, the method 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 to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase. In some aspects, the pharmaceutical composition comprises an antibody that specifically binds to CD38 (particularly daratumumab or a daratumumab biosimilar) and hyaluronidase (particularly recombinant human hyaluronidase).

[0185] In one aspect, the use of a pharmaceutical composition for manufacturing a medicine for treating a newly diagnosed multiple myeloma in a subject of need is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar.

[0186] In one aspect, the use of a pharmaceutical composition for manufacturing a medicament for treating a newly diagnosed multiple myeloma in a subject of need is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase.

[0187] In one aspect, a pharmaceutical composition is provided for treating a newly diagnosed multiple myeloma in a subject of need, 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 to CD38, particularly daratumumab or a daratumumab biosimilar.

[0188] In one aspect, a pharmaceutical composition is provided for treating a newly diagnosed multiple myeloma in a subject of need, 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 to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase.

[0189] For each of the treatment methods described herein, it should be understood that the treatment method may also be defined as a method of preparing a medicament for treating the indicated condition, or as a pharmaceutical composition in combination with bortezomib, lenalidomide and dexamethasone for treating the indicated condition.

[0190] In some implementations, the subject is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or has had HDC and ASCT delayed. In some implementations, the subject ineligible for HDC and ASCT is 70 years of age or older. In some implementations, the subject ineligible for HDC and ASCT is 18 years of age or older but younger than 70 years of age and has one or more comorbid conditions.

[0191] In some implementations, the method achieves a clinical efficacy endpoint of improvement in subjects, relative to a clinical efficacy endpoint achieved in a reference subject or reference subject population, who have been administered a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab.

[0192] In some implementations, the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD) negative rate, an improved sustained MRD negative rate, an improved complete response (CR) rate or better response rate, improved progression-free survival (PFS), improved overall response rate (ORR), improved overall survival (OS), improved progression-free survival with next-line treatment (PFS2), improved time to response (TTR), or improved duration of response (DOR).

[0193] In some implementations, the improved clinical efficacy endpoint is an improved overall MRD negativity rate. In some implementations, the improved overall MRD negativity rate is at or below 10%. -5The sensitivity threshold. In some embodiments, the improved overall MRD negative rate is 60.9%. In some embodiments, the overall MRD negative rate for the reference subject or reference subject population is 39.4%. In some embodiments, the improved overall MRD negative rate represents an absolute increase of 21.5% relative to the reference subject or reference subject population.

[0194] In some implementations, the improved overall MRD negative rate is at or below 10%. -6 The sensitivity threshold is determined. In some embodiments, the improved overall MRD negativity rate is 46.2%. In some embodiments, the overall MRD negativity rate for the reference subjects or the reference subject population is 27.3%. In some embodiments, the overall MRD negativity rate is determined before progression of multiple myeloma, after administration of antimyeloma therapy, or both.

[0195] In some implementation schemes, the subjects do not have a high cytogenetic risk.

[0196] In some embodiments, the improved clinical efficacy endpoint is an improved rate of persistent minimal residual disease (MRD) negativity. In other embodiments, the improved rate of persistent MRD negativity lasts for a period of 1 year, 2 years, and / or 3 years. In some embodiments, the improved rate of persistent MRD negativity is at or below 10. -5 The sensitivity threshold. In some implementations, the improved sustained MRD negativity rate was 48.7% relative to 26.3% of the reference subjects or reference subject population.

[0197] In some implementations, the improved sustained MRD negative rate is at or below 10%. -6 The sensitivity threshold.

[0198] In some implementations, the improved overall MRD negativity rate or the improved sustained MRD negativity rate is assessed by next-generation sequencing.

[0199] In some implementations, improved overall MRD negativity or improved sustained MRD negativity is assessed using bone marrow aspiration samples obtained on day 0, at suspected complete response, and at 12, 18, 24, 30, and 36 months after administration of the drug combination with bortezomib, lenalidomide, and dexamethasone, and annually thereafter in subjects with complete response.

[0200] In some implementations, the improved clinical efficacy endpoint is an improved complete response (CR) rate or better response rate. In some implementations, the improved CR rate or better response rate is 81.2%. In some implementations, the CR rate or better response rate for the reference subjects or reference subject population is 61.6%. In some implementations, the improved CR rate or better response rate represents an absolute increase of 19.6% relative to the reference subjects or reference subject population.

[0201] In some implementations, the improved clinical efficacy endpoint is improved strict complete response (sCR). In some implementations, the improved sCR is approximately 65.0% relative to approximately 44.9% of the reference subjects or reference subject population. In some implementations, the improved sCR is an absolute increase of 20.1% relative to the reference subjects or reference subject population.

[0202] In some implementations, the improved clinical efficacy endpoint is improved progression-free survival (PFS). In some implementations, improved PFS is a prolonged period relative to a reference subject or reference subject population. In some implementations, improved PFS is a 43% reduction in the risk of progression or death.

[0203] In some implementations, subjects with improved PFS had a PFS of 10 -6 Sensitivity threshold, 10 -5 It is negative for MRD at or below the sensitivity threshold.

[0204] In some implementations, subjects with improved PFS had a PFS of 10 -6 Sensitivity threshold, 10 -5 The sensitivity threshold or both are below which the MRD is positive.

[0205] In some implementations, the improved PFS is an improvement in median PFS.

[0206] In some implementations, the method achieves an improved median treatment duration relative to the median treatment duration achieved in a reference subject or reference subject population that has been administered a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab.

[0207] In some implementations, the median duration of improved treatment is 56.3 months. In some implementations, the median duration of treatment for the reference subjects or reference subject population is 34.3 months.

[0208] In some embodiments, the method achieves an improved median number of treatment cycles compared to the median number of treatment cycles achieved in a reference subject or reference subject population that has received a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In another embodiment, the improved median number of treatment cycles is 59 months. In yet another embodiment, the median number of treatment cycles in a reference subject or reference subject population is 37 months.

[0209] In some implementations, the method achieves an equivalent EORTC QLQ-C30 global health status score compared to a reference subject or reference subject population that has been administered a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab.

[0210] In some implementations, subjects have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.

[0211] In some implementations, the subject has a creatinine clearance rate of ≥30 mL / min / 1.73 m2.

[0212] In some implementations, the subjects had stage 3 multiple myeloma according to the International Staging System (ISS).

[0213] In some implementation schemes, the subjects have a high cytogenetic risk.

[0214] In some implementations, daratumumab or a daratumumab biosimilar is administered subcutaneously at a dose of approximately 1,800 mg, and bortezomib at approximately 1.3 mg / m². 2 The dosage is administered subcutaneously, 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 a daratumumab biosimilar is administered subcutaneously at a dose of about 1,800 mg, and bortezomib at a dose of about 1.3 mg / m². 2 The dosage is administered subcutaneously, 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 a daratumumab biosimilar is administered subcutaneously at a dose of about 1,800 mg, and bortezomib at a dose of about 1.3 mg / m². 2 Lenalidomide is administered subcutaneously at a dose of approximately 25 mg orally, and dexamethasone is administered orally or intravenously at a dose of approximately 40 mg.

[0215] In some implementations, the drug composition, bortezomib, lenalidomide, and dexamethasone are administered for one or more 21-day cycles.

[0216] In some implementations, the drug composition bortezomib, lenalidomide, and dexamethasone is administered for eight 21-day cycles.

[0217] In some implementations, ranitumab or daratumumab biosimilars are administered subcutaneously once weekly at a dose of about 1,800 mg during cycles 1 to 2, subcutaneously once every 3 weeks at a dose of about 1,800 mg during cycles 3 to 8, and thereafter subcutaneously once every 4 weeks at a dose of about 1,800 mg until disease progression or unacceptable toxicity.

[0218] In some embodiments, lenalidomide is administered orally at a dose of about 25 mg on days 1 through 14. In some embodiments, 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 drug composition, lenalidomide, and dexamethasone are administered after eight 21-day cycles and continued for one or more 28-day cycles. In some embodiments, lenalidomide is administered orally at a dose of about 25 mg on days 1 through 21 of 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 one or more 28-day cycles until disease progression.

[0219] This disclosure further provides a method for improving the MRD negativity rate in subjects or subject populations with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of: administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38 (particularly daratumumab or a daratumumab biosimilar) and hyaluronidase (particularly recombinant human hyaluronidase). In some embodiments, the improvement in the MRD negativity rate is relative to the MRD negativity rate of a reference subject population with newly diagnosed multiple myeloma who has been treated with bortezomib, lenalidomide, and dexamethasone but not with the pharmaceutical composition. In some embodiments, the improvement in the MRD negativity rate is relative to the MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some embodiments, the MRD negativity rate is the overall rate. In some embodiments, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0220] In one aspect, the use of a pharmaceutical composition for manufacturing a medicament for improving the MRD negativity rate in a subject or subject population suffering from newly diagnosed multiple myeloma is provided, wherein the pharmaceutical composition is administered or to be administered in combination with bortezomib, lenalidomide, and dexamethasone to the subject or subject population, and wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the MRD negativity rate is relative to the MRD negativity rate of a reference subject population suffering from newly diagnosed multiple myeloma who has been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some embodiments, the improvement in the MRD negativity rate is relative to the MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some embodiments, the MRD negativity rate is the overall rate. In some embodiments, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0221] In one aspect, a pharmaceutical composition is provided for improving the MRD negativity rate in a subject or subject population with newly diagnosed multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or subject population in combination with bortezomib, lenalidomide, and dexamethasone, and wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the MRD negativity rate is relative to the MRD negativity rate of a reference subject population with newly diagnosed multiple myeloma who has been administered bortezomib, lenalidomide, and dexamethasone but not the pharmaceutical composition. In some embodiments, the improvement in the MRD negativity rate is relative to the MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some embodiments, the MRD negativity rate is the overall rate. In some embodiments, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0222] This disclosure further provides a method for improving the overall MRD negativity rate in subjects or subject populations with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the overall MRD negativity rate is relative to the overall MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in the overall MRD negativity rate is relative to the overall MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0223] In one aspect, the use of a pharmaceutical composition for manufacturing a medicament for improving the overall MRD negativity rate in subjects or a population of subjects with newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the overall MRD negativity rate is relative to the overall MRD negativity rate of a reference population of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in the overall MRD negativity rate is relative to the overall MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0224] In one aspect, a pharmaceutical composition is provided for improving the overall MRD negativity rate in subjects or a subject population 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the overall MRD negativity rate is relative to the overall MRD negativity rate of a reference population of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in the overall MRD negativity rate is relative to the overall MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0225] This disclosure further provides a method for improving the sustained MRD negativity rate in subjects or subject populations with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of: administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the sustained MRD negativity rate is relative to the sustained MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with bortezomib, lenalidomide, and dexamethasone but not with the pharmaceutical composition. In some implementations, the improvement in the sustained MRD negativity rate is defined relative to the sustained MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have received a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0226] In one aspect, the use of a pharmaceutical composition for manufacturing a medicament for improving the sustained MRD negativity rate in subjects or subject populations suffering from newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the sustained MRD negativity rate is relative to the sustained MRD negativity rate of a reference population of subjects suffering from newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in the sustained MRD negativity rate is defined relative to the sustained MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have received a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0227] In one aspect, a pharmaceutical composition is provided for improving the sustained MRD negativity rate in subjects or subject populations 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the sustained MRD negativity rate is relative to the sustained MRD negativity rate of a reference population of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in the sustained MRD negativity rate is defined relative to the sustained MRD negativity rate of a reference group of subjects with newly diagnosed multiple myeloma who have received a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0228] This disclosure further provides a method for improving the complete response (CR) rate or better response rate in subjects or subject populations with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of: administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the complete response (CR) rate or better response rate is relative to the CR rate or better response rate of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in CR rate or better response rate is relative to the CR rate or better response rate of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0229] In one aspect, the use of a pharmaceutical composition for manufacturing a medicament for improving the complete response (CR) rate or better response rate in subjects or subject populations suffering from newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the complete response (CR) rate or better response rate is relative to the CR rate or better response rate of a reference population of subjects suffering from newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in CR rate or better response rate is relative to the CR rate or better response rate of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0230] In one aspect, a pharmaceutical composition is provided for improving the complete response (CR) rate or better response rate in subjects or a subject population suffering from 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in the complete response (CR) rate or better response rate is relative to the CR rate or better response rate of a reference population of subjects suffering from newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in CR rate or better response rate is relative to the CR rate or better response rate of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0231] This disclosure further provides a method for improving progression-free survival (PFS) in subjects or subject populations with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of: administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in PFS is relative to the PFS of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in PFS is relative to the PFS of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0232] In one aspect, the use of a pharmaceutical composition for manufacturing a medicine for improving progression-free survival (PFS) in subjects or subject populations suffering from newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in PFS is relative to the PFS of a reference population of subjects suffering from newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in PFS is relative to the PFS of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0233] In one aspect, a pharmaceutical composition is provided for improving progression-free survival (PFS) in a subject or subject population 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in PFS is relative to the PFS of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in PFS is relative to the PFS of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0234] This disclosure further provides a method for improving the overall response rate (ORR) of subjects or subject populations with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in ORR is relative to the ORR of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in ORR is relative to the ORR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0235] In one aspect, the use of a pharmaceutical composition for manufacturing a medicament for improving the overall response rate (ORR) of a subject or subject population suffering from newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in ORR is relative to the ORR of a reference population of subjects suffering from newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in ORR is relative to the ORR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0236] In one aspect, a pharmaceutical composition is provided for improving the overall response rate (ORR) of a subject or subject population suffering from 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in ORR is relative to the ORR of a reference population of subjects suffering from newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in ORR is relative to the ORR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0237] This disclosure further provides a method for improving overall survival (OS) in subjects or subject populations with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in OS is relative to the OS of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in overall survival (OS) is relative to the OS of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0238] In one aspect, the use of a pharmaceutical composition for manufacturing a medicament for improving the overall survival (OS) of a subject or subject population suffering from newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in OS is relative to the OS of a reference group of subjects suffering from newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in overall survival (OS) is relative to the OS of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0239] In one aspect, a pharmaceutical composition is provided for improving overall survival (OS) in a subject or subject population 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in OS is relative to the OS of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some embodiments, the improvement in OS is relative to the OS of a reference group of subjects with newly diagnosed multiple myeloma who have been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In some implementations, the subject is not eligible for HDC and ASCT or has had HDC and ASCT delayed.

[0240] This disclosure further provides a method for improving progression-free survival (PFS2) of a subject or subject population receiving next-line therapy for newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of: administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in PFS2 is relative to the PFS2 of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in PFS2 is relative to the PFS2 of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0241] In one aspect, the use of a pharmaceutical composition for manufacturing a medicine for improving progression-free survival (PFS2) as a next-line therapy for subjects or subject populations with newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in PFS2 is relative to the PFS2 of a reference population of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in PFS2 is relative to the PFS2 of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0242] In one aspect, a pharmaceutical composition is provided for improving progression-free survival (PFS2) of a subject or subject population receiving next-line therapy for 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in PFS2 is relative to the PFS2 of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in PFS2 is relative to the PFS2 of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0243] This disclosure further provides a method for improving the time to response (TTR) of a subject or subject population with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in TTR is relative to the TTR of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in TTR is relative to the TTR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0244] In one aspect, the use of a pharmaceutical composition for manufacturing a medicament for improving the time-to-response (TTR) of a subject or subject population suffering from newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in TTR is relative to the TTR of a reference population of subjects suffering from newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in TTR is relative to the TTR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0245] In one aspect, a pharmaceutical composition is provided for improving the time to response (TTR) of a subject or subject population 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in TTR is relative to the TTR of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some embodiments, the improvement in TTR is relative to the TTR of a reference group of subjects with newly diagnosed multiple myeloma who have been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In some implementations, the subject is not eligible for HDC and ASCT or has had HDC and ASCT delayed.

[0246] This disclosure further provides a method for improving the duration of response (DOR) in subjects or subject populations with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in DOR is relative to the DOR of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in DOR is relative to the DOR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0247] In one aspect, the use of a pharmaceutical composition for manufacturing a medicament for improving the duration of response (DOR) in a subject or subject population suffering from newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in DOR is relative to the DOR of a reference group of subjects suffering from newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in DOR is relative to the DOR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0248] In one aspect, a pharmaceutical composition is provided for improving the duration of response (DOR) in a subject or subject population 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in DOR is relative to the DOR of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some embodiments, the improvement in DOR is relative to the DOR of a reference group of subjects with newly diagnosed multiple myeloma who have been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In some implementations, the subject is not eligible for HDC and ASCT or has had HDC and ASCT delayed.

[0249] This disclosure further provides a method for improving the sCR (short-term complete response) of a subject or subject population with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of: administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in sCR is relative to the sCR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in sCR is relative to the sCR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab. In some implementations, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0250] In one aspect, the use of a pharmaceutical composition for manufacturing a medicine for improving the sCR of a subject or subject population suffering from newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in sCR is relative to the sCR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some embodiments, the improvement in sCR is relative to the sCR of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In some embodiments, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0251] In one aspect, a pharmaceutical composition is provided for improving the sCR (short-term complete response) of a subject or subject population 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in sCR is relative to the sCR of a reference group of subjects with newly diagnosed multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some embodiments, the improvement in sCR is relative to the sCR of a reference group of subjects with newly diagnosed multiple myeloma who have been administered a combination of bortezomib, lenalidomide, and dexamethasone without daratumumab. In some implementations, the subject is not eligible for HDC and ASCT or has had HDC and ASCT delayed.

[0252] This disclosure further provides a method for achieving an improved median duration of treatment in subjects or subject populations with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of: administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in median duration of treatment is relative to the median duration of treatment in a reference subject population with newly diagnosed multiple myeloma who has been treated with bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in median treatment duration is relative to the median treatment duration of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with bortezomib, lenalidomide, and dexamethasone but not daratumumab. In some implementations, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0253] In one aspect, the use of a pharmaceutical composition for manufacturing a medicine for achieving an improved median duration of treatment in a subject or subject population with a newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in median treatment duration is relative to the median treatment duration of a reference subject population with newly diagnosed multiple myeloma who have received bortezomib, lenalidomide, and dexamethasone but not the pharmaceutical composition. In some embodiments, the improvement in median treatment duration is relative to the median treatment duration of a reference subject population with newly diagnosed multiple myeloma who have received bortezomib, lenalidomide, and dexamethasone but not daratumumab. In some embodiments, the subject is ineligible for HDC and ASCT or has had HDC and ASCT delayed.

[0254] In one aspect, a pharmaceutical composition is provided for achieving an improved median duration of treatment in a subject or subject population 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in median duration of treatment is relative to the median duration of treatment in a reference subject population with newly diagnosed multiple myeloma who has been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in median treatment duration is relative to the median treatment duration of a reference group of subjects with newly diagnosed multiple myeloma who have been treated with bortezomib, lenalidomide, and dexamethasone but not daratumumab. In some implementations, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0255] This disclosure further provides a method for achieving an improved median number of treatment cycles in subjects or subject populations with newly diagnosed multiple myeloma, the method comprising, consisting of, or substantially consisting of: administering to the subject or subject population a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in median number of treatment cycles is relative to the median number of treatment cycles in a reference subject population with newly diagnosed multiple myeloma who has been treated with bortezomib, lenalidomide, and dexamethasone but not with the pharmaceutical composition. In some implementations, the improvement in median treatment cycles is relative to the median treatment cycle count of a reference group of subjects with newly diagnosed multiple myeloma who have received bortezomib, lenalidomide, and dexamethasone but not daratumumab. In some implementations, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0256] In one aspect, the use of a pharmaceutical composition for manufacturing a medicament for achieving an improved median number of treatment cycles in a subject or subject population with newly diagnosed multiple myeloma is provided, 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in median number of treatment cycles is relative to the median number of treatment cycles in a reference subject population with newly diagnosed multiple myeloma who has been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in median treatment cycles is relative to the median treatment cycle count of a reference group of subjects with newly diagnosed multiple myeloma who have received bortezomib, lenalidomide, and dexamethasone but not daratumumab. In some implementations, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0257] In one aspect, a pharmaceutical composition is provided for achieving an improved median number of treatment cycles in a subject or subject population 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 to CD38, particularly daratumumab or a daratumumab biosimilar. In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20). In some embodiments, the improvement in median number of treatment cycles is relative to the median number of treatment cycles in a reference subject population with newly diagnosed multiple myeloma who has been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In some implementations, the improvement in median treatment cycles is relative to the median treatment cycle count of a reference group of subjects with newly diagnosed multiple myeloma who have received bortezomib, lenalidomide, and dexamethasone but not daratumumab. In some implementations, subjects are ineligible for HDC and ASCT or have had their HDC and ASCT delayed.

[0258] In any of the disclosed embodiments in which the improvement is mentioned, the improvement may be relative to a reference patient or reference patient population with a newly diagnosed multiple myeloma who has been given bortezomib, lenalidomide, and dexamethasone instead of a pharmaceutical composition of bortezomib, lenalidomide, and dexamethasone with an antibody that specifically binds to CD38 (especially daratumumab or a daratumumab biosimilar) or a pharmaceutical composition containing an antibody that specifically binds to CD38 (especially daratumumab or a daratumumab biosimilar) and hyaluronidase (especially recombinant human hyaluronidase (rHuPH20)).

[0259] This disclosure also provides a method for treating a subject with a newly diagnosed multiple myeloma, the method comprising administering to the subject a combination therapy containing an antibody that specifically binds to CD38 (particularly daratumumab, or a daratumumab biosimilar, bortezomib, lenalidomide, and dexamethasone). In some embodiments, daratumumab or a daratumumab biosimilar is present in the form of a pharmaceutical composition formulated with hyaluronidase (particularly recombinant human hyaluronidase (rHuPH20)).

[0260] This disclosure also provides a method for treating a subject with a newly diagnosed multiple myeloma, the method comprising administering to the subject a combination therapy containing an antibody that specifically binds to CD38 (particularly daratumumab, or a daratumumab biosimilar, bortezomib, lenalidomide, and dexamethasone).

[0261] This disclosure also provides a method for treating a subject with a newly diagnosed multiple myeloma, the method comprising administering to the subject a combination therapy containing an antibody that specifically binds to CD38 (particularly daratumumab, bortezomib, lenalidomide, and dexamethasone), wherein the method achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is administered a combination of bortezomib, lenalidomide, and dexamethasone.

[0262] This disclosure also provides a method for treating a subject with a newly diagnosed multiple myeloma who is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), the method comprising administering to or providing to the subject an antibody that specifically binds to CD38 (particularly 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 compared to the clinical efficacy endpoint achieved when the subject is administered the combination of bortezomib, lenalidomide, and dexamethasone.

[0263] In some implementations, subjects with newly diagnosed multiple myeloma are ineligible for autologous stem cell transplantation (ASCT) and high-dose chemotherapy (HDC). In some implementations, subjects are ineligible for autologous stem cell transplantation (ASCT). In some implementations, subjects with newly diagnosed multiple myeloma are ineligible for high-dose chemotherapy (HDC). In some implementations, transplantation is not planned as the subject's initial therapy (transplantation delay).

[0264] MRD status can be assessed from bone marrow aspirated samples using next-generation sequencing (NGS), for example, of immunoglobulin heavy and light chains. ClonoSEQ is available from Adaptive Biotechnologies. ® The updated, analytically validated version (Revision 2) can be used for the detection, quantification, and analysis of MRD.

[0265] Pharmaceutical Composition

[0266] In some embodiments, the pharmaceutical composition comprises about 1,800 mg of daratumumab and about 30,000 U of hyaluronidase. In some embodiments, the pharmaceutical composition comprises about 1,800 mg of a daratumumab biosimilar and about 30,000 U of hyaluronidase. In other embodiments, the pharmaceutical composition comprises about 120 mg / mL of daratumumab and about 2,000 U / mL of hyaluronidase. In other embodiments, the pharmaceutical composition comprises about 120 mg / mL of a daratumumab biosimilar and about 2,000 U / mL of hyaluronidase.

[0267] Many suitable hyaluronidases are known according to this disclosure. Preferred enzymes are human hyaluronidases, such as soluble human PH20 hyaluronidase, preferably a recombinant human hyaluronidase product referred to as rHuPH20. The amino acid sequence of soluble human PH20 hyaluronidase includes soluble human PH20 known as rHuPH20 and available under CAS Registry No. 757971-58-7. In some embodiments, rHuPH20 is Hylenex. ® Soluble human PH20 hyaluronidase is described in International Patent Publication WO2004 / 078140 and U.S. Patent 7,767,429, the entire contents of which are incorporated herein by reference. In some embodiments, the soluble hyaluronidase comprises those whose sequences are shown in any of SEQ ID NO: 12-16. When expressed in cells, the soluble PH20 hyaluronidase comprises a signaling sequence for transport in cells. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase is SEQ ID NO: 13, namely residues 36-482 of wild-type human hyaluronidase. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 14. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 15. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase rHuPH20 comprises SEQ ID NO: 16. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 12. In some embodiments, when expressed in cells, the soluble PH20 hyaluronidase comprises a mixture of substances that may contain any one or more of SEQ ID NO: 12 to SEQ ID NO: 16 in varying abundances. The average molecular weight is 61 kDa.

[0268] rHuPH20 refers to a composition produced when expressed in cells such as CHO cells. Because of the heterogeneity at the C-terminus when produced in culture medium, products named rHuPH20 comprise a mixture of substances that may contain any or more of the polypeptides of SEQ ID NO: 12-16 in varying abundances, as well as some shorter polypeptides. Typically, rHuPH20 is produced in cells that promote proper N-glycosylation to maintain viability, such as CHO cells, e.g., DG44 CHO cells.

[0269] In other embodiments, the pharmaceutical composition has a pH of about 5.6, and 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 yet another embodiment, the pharmaceutical composition has a pH of about 5.6, and 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.

[0270] In some embodiments, the pharmaceutical composition comprises about 1,800 mg of an antibody that specifically binds to CD38, including HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; and about 30,000 U of rHuPH20.

[0271] In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of an antibody that specifically binds to CD38, including HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; and about 2,000 U / mL rHuPH20.

[0272] In some embodiments, the pharmaceutical composition comprises one or more excipients.

[0273] In some embodiments, one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof.

[0274] In some embodiments, the pharmaceutical composition comprises:

[0275] a) Histidine between approximately 5 mM and approximately 15 mM;

[0276] b) Sorbitol, with concentrations between approximately 100 mM and 300 mM;

[0277] c) PS-20 between approximately 0.01% w / v and approximately 0.04% w / v;

[0278] d) Methionine between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0279] In some embodiments, the pharmaceutical composition contains about 10 mM histidine.

[0280] In some embodiments, the pharmaceutical composition contains about 300 mM sorbitol.

[0281] In some embodiments, the pharmaceutical composition contains about 0.04% (w / v) PS-20.

[0282] In some embodiments, the pharmaceutical composition contains about 1 mg / mL of methionine.

[0283] In some embodiments, the pharmaceutical composition comprises: about 1,800 mg of an antibody that specifically binds to CD38, comprising HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; about 30,000 U of rHuPH20; about 10 mM of histidine; about 300 mM of sorbitol; about 0.04% (w / v) PS-20; and about 1 mg / mL of methionine at a pH of about 5.6.

[0284] In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of an antibody that specifically binds to CD38, comprising HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; about 2,000 U / mL 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.

[0285] The pharmaceutical compositions disclosed herein may optionally include additional or alternative pharmaceutically acceptable carriers, such as physiologically compatible solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents and absorption delay agents, such as salts, buffers, antioxidants, sugars, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifiers, or combinations thereof.

[0286] Exemplary buffers that can be used include acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffer, HEPPSO, and HEPES.

[0287] Exemplary antioxidants that may be used include ascorbic acid, methionine, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, lecithin, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, and tartaric acid.

[0288] Exemplary amino acids that may be used are histidine, isoleucine, methionine, glycine, arginine, lysine, L-leucine, trileucine, alanine, glutamic acid, L-threonine, and 2-phenylalanine.

[0289] Exemplary surfactants that can be used include polysorbates (e.g., polysorbate-20 or polysorbate-80); polyoxamers (e.g., poloxamer 188); Triton; sodium octyl glycoside; lauryl-, tetradecyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, tetradecyl-, linoleyl-, or stearyl-sarcosine; linoleyl-, tetradecyl-, or cetyl-betaine; lauroylaminopropyl-, cocoylaminopropyl-, linoleylaminopropyl-, myristoylaminopropyl-, palmitopropyl-, or isostearylaminopropyl-betaine (e.g., lauroylaminopropyl); myristoylaminopropyl-, palmitopropyl-, or isostearylaminopropyl-dimethylamine; sodium methylcocoyl taurate, or disodium methyloleylenyl taurate; and Monaqua ™ Series (MonaIndustries, Inc., Paterson, NJ), polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol (e.g., Pluronics) ™ (e.g., PF68).

[0290] Exemplary preservatives that may be used are phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkyl esters of p-hydroxybenzoic acid (methyl ester, ethyl ester, propyl ester, butyl ester, etc.), alkylbenzyl dimethyl ammonium chloride, benzyl ethoxy ammonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof.

[0291] Exemplary sugars that can be used include monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, and non-reducing sugars such as glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerol, glucan, erythritol, glycerol, arabinitol, sylitol, sorbitol, mannitol, melibiose, pinetriose, raffinose, mannitol, stachyose, maltose, lactulose, maltitol, maltitol, maltitol, lactitol, and isomaltulose.

[0292] Exemplary salts that can be used are acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, etc., and those derived from non-toxic organic acids, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium, etc., and those derived from non-toxic organic amines, such as N,N′-dibenzylethylenediamine, N-methylglucosamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, etc. An exemplary salt is sodium chloride.

[0293] In some embodiments, the pharmaceutical composition is at a pH of 5.0 to 6.0.

[0294] In some embodiments, the pharmaceutical composition is at a pH of 5.3 to 5.8.

[0295] In some embodiments, the pharmaceutical composition is at pH 5.5.

[0296] In some implementations, the pharmaceutical composition is at pH 5.6.

[0297] In some implementations, the antibody that specifically binds to CD38 comprises the heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of SEQ ID NO: 8.

[0298] In some implementations, the antibody that specifically binds to CD38 is an IgG1 isotype.

[0299] An exemplary IgG1 constant domain sequence comprises the amino acid sequence of SEQ ID NO: 11. Variations exist within the IgG1 constant domain (e.g., well-known allotypes) at positions 214, 356, 358, 422, 431, 435, or 436 (residue numbering according to EU designation) (see, for example, IMGT Web Resources; IMGT Library (IG and TR); Proteins and Alleles; Allotypes). Antibodies that specifically bind to CD38 can be any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0300] In some implementations, the antibody that specifically binds to CD38 comprises the heavy chain (HC) of SEQ ID NO: 9 and the light chain (LC) of SEQ ID NO: 10.

[0301] In some implementations, the antibody that specifically binds to CD38 is daratumumab.

[0302] In some implementations, the antibody that specifically binds to CD38 is a daratumumab biosimilar.

[0303] In some implementations, the antibody that specifically binds to CD38 is daratumumab, marketed under the brand name DARZALEX. ® Biosimilars.

[0304] Application method

[0305] In some embodiments, a pharmaceutical composition comprising an antibody that specifically binds to CD38 and rHuPH20 is administered once weekly at a dose of about 1,800 mg daratumumab or a daratumumab biosimilar and 30,000 U rHuPH20. In some embodiments, a pharmaceutical composition comprising an antibody that specifically binds to CD38 and rHuPH20 is administered once every two weeks at a dose of about 1,800 mg daratumumab or a daratumumab biosimilar and 30,000 U rHuPH20. In some embodiments, a pharmaceutical composition comprising an antibody that specifically binds to CD38 and rHuPH20 is administered once every three weeks at a dose of about 1,800 mg daratumumab or a daratumumab biosimilar and 30,000 U rHuPH20. In some implementations, a pharmaceutical composition comprising an antibody that specifically binds to CD38 and rHuPH20 is administered once every four weeks at a dose of about 1,800 mg of daratumumab or a daratumumab biosimilar and 30,000 U of rHuPH20.

[0306] The pharmaceutical composition disclosed herein is administered by subcutaneous application.

[0307] The pharmaceutical composition, comprising an antibody that specifically binds to CD38 and rHuPH20, is administered subcutaneously.

[0308] The pharmaceutical composition disclosed herein can 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.

[0309] In some embodiments, the pharmaceutical composition of this disclosure is administered subcutaneously to the abdominal area.

[0310] Subcutaneous administration can be achieved using devices. These devices can be syringes, drug-loaded syringes, auto-injectors (disposable or reusable), pen syringes, patch injectors, wearable syringes, or walk-on syringe infusion pumps with subcutaneous infusion sets.

[0311] The pharmaceutical composition disclosed herein can be administered over a period of about 1 minute to about 60 minutes.

[0312] In some implementations, daratumumab or a daratumumab biosimilar is administered subcutaneously at a dose of approximately 1,800 mg, and bortezomib at approximately 1.3 mg / m². 2 Lenalidomide is administered subcutaneously at a dose of about 25 mg orally, and dexamethasone is administered orally or intravenously at a dose of about 20 mg to about 40 mg.

[0313] In some implementations, the drug composition, bortezomib, lenalidomide, and dexamethasone are administered for one or more 21-day cycles.

[0314] In some implementations, the drug composition bortezomib, lenalidomide, and dexamethasone is administered for eight 21-day cycles.

[0315] In some implementations, ranitumab or daratumumab biosimilars are administered subcutaneously once weekly at a dose of about 1,800 mg during cycles 1 to 2, subcutaneously once every 3 weeks at a dose of about 1,800 mg during cycles 3 to 8, and thereafter subcutaneously once every 4 weeks at a dose of about 1,800 mg until disease progression or unacceptable toxicity.

[0316] In some implementations, bortezomib is administered at approximately 1.3 mg / m². 2The dosage is administered twice weekly. In other embodiments, bortezomib is administered subcutaneously. In other embodiments, bortezomib is administered intravenously. In some embodiments, bortezomib is administered at approximately 1.3 mg / m². 2 The dosage was administered subcutaneously on days 1, 4, 8, and 11.

[0317] In some embodiments, lenalidomide is administered at a dose of about 25 mg daily. In other embodiments, lenalidomide is administered at a dose of about 10 mg daily. In other embodiments, lenalidomide is administered at a dose of about 10 mg daily during the maintenance phase. After three 28-day maintenance therapy cycles, if well tolerated, the lenalidomide dose may be increased to 15 mg daily. In some embodiments, if a daily lenalidomide dose is missed, it may be administered if <12 hours have elapsed since it was supposed to be taken. If the next dose is scheduled to be taken within 12 hours, the missed lenalidomide dose should be skipped. In some embodiments, lenalidomide is administered as a single daily dose at approximately the same time. In some embodiments, lenalidomide may be taken with or without food. In some embodiments, lenalidomide is administered orally. In some embodiments, lenalidomide is administered orally at a dose of about 25 mg from day 1 to day 14.

[0318] In some embodiments, dexamethasone is administered daily at a dose of about 20 mg to about 40 mg. In some embodiments, dexamethasone is administered daily at a dose of about 20 mg. In some embodiments, dexamethasone is administered daily at a dose of about 40 mg. In other embodiments, dexamethasone is administered orally. In other embodiments, dexamethasone is administered intravenously. On days when dexamethasone is administered with the pharmaceutical composition, dexamethasone is administered orally or intravenously at a dose of 40 mg, 1 hour to 3 hours before administration of the pharmaceutical composition. On days when the pharmaceutical composition is not administered, dexamethasone is administered orally. In some embodiments, dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12.

[0319] In some embodiments, the pharmaceutical composition, lenalidomide, and dexamethasone are administered after eight 21-day cycles and continued for one or more 28-day cycles. In some embodiments, lenalidomide is administered orally at a dose of about 25 mg on days 1 through 21 of 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 one or more 28-day cycles until disease progression.

[0320] The dosage of bortezomib, lenalidomide, and dexamethasone can be reduced, or the treatment regimen can be modified to manage study drug-related toxicities. Subjects who need to discontinue treatment with any component of the study therapy (daratumumab or a daratumumab biosimilar, bortezomib, lenalidomide, or dexamethasone) may continue treatment with other components.

[0321] In some implementations, the pharmaceutical composition, bortezomib, lenalidomide, and dexamethasone are administered in one or more 21-day cycles.

[0322] In some embodiments, the pharmaceutical composition is administered weekly in the first and second 21-day cycles, every three weeks in the third, fourth, fifth, sixth, seventh, and eighth 21-day cycles, and every four weeks thereafter in any subsequent 21-day cycles.

[0323] In other embodiments, bortezomib is administered at approximately 1.3 mg / m². 2 The dosage was administered on days 1, 4, 8, and 11, and continued for cycles 1-8.

[0324] In other embodiments, lenalidomide is administered at a dose of about 25 mg on days 1 through 14 for cycles 1 through 8, and at a dose of 25 mg on days 1 through 21 in any subsequent 28-day cycles. 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 through 8, and at a dose of about 40 mg on days 1, 8, 15, and 22 in any subsequent 28-day cycles.

[0325] Implementation Plan

[0326] Implementation Plan Part 1

[0327] The present invention provides the following non-limiting embodiments:

[0328] 1) A method of treating a newly diagnosed multiple myeloma in a subject in need, the method 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 to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20).

[0329] 1a) The method according to embodiment 1, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20).

[0330] 2) The method described in implementation scheme 1 or 1a, wherein the subject is not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or has delayed HDC and ASCT.

[0331] 3) The method described in Implementation Scheme 2, wherein subjects who are not eligible for HDC and ASCT are 70 years of age or older.

[0332] 4) The method described in Implementation Scheme 2, wherein subjects who are not eligible for HDC and ASCT are 18 years of age or older and less than 70 years of age and have one or more comorbid conditions.

[0333] 5) The method according to any one of the foregoing embodiments, wherein the method achieves a clinical efficacy endpoint of improvement in subjects relative to a clinical efficacy endpoint achieved in a reference subject or reference subject population, wherein the reference subject or reference subject population has been administered a combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0334] 6) The method according to implementation plan 5, wherein the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD) negative rate, an improved sustained MRD negative rate, an improved complete response (CR) rate or better response rate, an improved progression-free survival (PFS), an improved overall response rate (ORR), an improved overall survival (OS), an improved progression-free survival with next-line treatment (PFS2), an improved time to response (TTR), or an improved duration of response (DOR).

[0335] 7) The method according to implementation plan 6, wherein the improved clinical efficacy endpoint is the improved overall MRD negative rate.

[0336] 8) The method according to embodiment 7, wherein the improved overall MRD negative rate is at or below 10%. -5 The sensitivity threshold.

[0337] 9) The method according to implementation plan 8, wherein the overall MRD negative rate is 60.9% relative to 39.4% of the reference subjects or reference subject population.

[0338] 10) The method according to implementation plan 8, wherein the improvement in the overall MRD negative rate is an absolute increase of 21.5% relative to the reference subjects or the reference subject population.

[0339] 11) The method according to embodiment 7, wherein the improved overall MRD negative rate is at or below 10 -6 The sensitivity threshold.

[0340] 12) The method according to implementation scheme 11, wherein the improved overall MRD negative rate is 46.2% relative to 27.3% of the reference subjects or reference subject population.

[0341] 13) The method according to any one of embodiments 7-12, wherein the overall MRD negative rate is determined before the progression of multiple myeloma, after administration of antimyeloma therapy, or both.

[0342] 14) The method according to any one of embodiments 7-13, wherein the subject does not have a high cytogenetic risk.

[0343] 15) The method according to implementation plan 6, wherein the improved clinical efficacy endpoint is an improved rate of negative persistent minimal residual disease (MRD).

[0344] 16) The method according to implementation plan 15, wherein the improved sustained MRD negative rate lasts for a period of 1 year, 2 years and / or 3 years.

[0345] 17) The method according to embodiment 15 or 16, wherein the improved sustained MRD negative rate is at or below 10 -5 The sensitivity threshold.

[0346] 18) The method according to implementation plan 17, wherein the improved sustained MRD negative rate is 48.7% relative to 26.3% of the reference subjects or reference subject population.

[0347] 19) The method according to embodiment 15 or 16, wherein the improved sustained MRD negative rate is at or below 10 -6 The sensitivity threshold.

[0348] 20) The method according to implementation plan 19, wherein the improved overall MRD negative rate is 32.0% relative to 15.7% of the reference subjects or reference subject population.

[0349] 21) The method according to any one of embodiments 6-20, wherein the improved overall MRD negative rate or the improved sustained MRD negative rate is assessed by next-generation sequencing.

[0350] 22) The method according to any one of embodiments 6-21, wherein improved overall MRD negativity or improved sustained MRD negativity is assessed using bone marrow aspiration samples obtained on day 0, at suspected complete response, and at 12, 18, 24, 30, and 36 months after administration of the drug composition in combination with bortezomib, lenalidomide, and dexamethasone, and thereafter annually in subjects with complete response.

[0351] 23) The method according to implementation plan 6, wherein the improved clinical efficacy endpoint is an improved complete response (CR) rate or a better response rate.

[0352] 24) The method according to implementation plan 23, wherein the improved CR rate or better response rate is 81.2% relative to 61.6% of the reference subjects or reference subject population.

[0353] 25) The method according to implementation scheme 23 or 24, wherein the improvement in CR rate or better response rate is an absolute increase of 19.6% relative to the reference subject or reference subject population.

[0354] 26) The method according to implementation plan 6, wherein the improved clinical efficacy endpoint is improved progression-free survival (PFS).

[0355] 27) The method according to implementation scheme 26, wherein the improved PFS is prolonged relative to the reference subject or reference subject population.

[0356] 28) The method according to implementation scheme 26 or 27, wherein the improved PFS is a 43% reduction in the risk of progression or death.

[0357] 29) The method according to any one of embodiments 26-28, wherein the subject with improved PFS is within 10 -6 Sensitivity threshold, 10 -5 It is negative for MRD at or below the sensitivity threshold.

[0358] 30) The method according to any one of embodiments 26-28, wherein the subject with improved PFS is within 10 -6 Sensitivity threshold, 10 -5 The sensitivity threshold or both are below which the MRD is positive.

[0359] 31) The method according to any one of embodiments 26-30, wherein the improved PFS is an improvement of the median PFS.

[0360] 32) The method according to any one of the foregoing embodiments, wherein the method achieves an improved median treatment duration relative to the median treatment duration achieved in a reference subject or reference subject population that has been administered a combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0361] 33) The method according to implementation plan 32, wherein the median duration of treatment for the improvement is 56.3 months relative to 34.3 months for the reference subjects or the reference subject population.

[0362] 34) The method according to any one of the embodiments, wherein the method achieves an improved median number of treatment cycles relative to the median number of treatment cycles achieved in a reference subject or reference subject population that has been administered a combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0363] 35) The method according to implementation plan 34, wherein the median number of treatment cycles for this improvement is 59 months relative to 37 months for the reference subjects or the reference subject population.

[0364] 36) The method according to any one of the foregoing embodiments, wherein the method achieves an equivalent EORTC QLQ-C30 global health status score relative to the EORTC QLQ-C30 global health status score achieved in a reference subject or reference subject population, the reference subject or reference subject population having been administered a combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0365] 37) The method according to any one of the preceding embodiments, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.

[0366] 38) The method according to any one of the foregoing embodiments, wherein the subject has a creatinine clearance rate of ≥30 mL / min / 1.73 m2.

[0367] 39) The method according to any one of the foregoing embodiments, wherein the subject has stage 3 multiple myeloma according to the International Staging System (ISS).

[0368] 40) The method according to any one of the foregoing embodiments, wherein the subject has a high cytogenetic risk.

[0369] 41) The method according to any one of the foregoing embodiments, wherein the pharmaceutical composition comprises 1,800 mg of daratumumab or a daratumumab biosimilar, and about 30,000 U rHuPH20.

[0370] 42) The method according to embodiment 41, wherein the pharmaceutical composition comprises about 120 mg / mL of daratumumab or a daratumumab biosimilar, and about 2,000 U / mL rHuPH20.

[0371] 43) The method according to any one of the foregoing embodiments, wherein the pharmaceutical composition comprises one or more excipients.

[0372] 44) The method according to embodiment 43, wherein at least one of the excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0373] 45) The method according to any one of the foregoing embodiments, wherein the pH of the pharmaceutical composition is 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 of histidine; about 300 mM of sorbitol; about 0.04% (w / v) PS-20; and about 1 mg / mL of methionine.

[0374] 46) The method according to any one of the foregoing embodiments, wherein the pH of the pharmaceutical composition is about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL daratumumab or a daratumumab biosimilar; about 2,000 U / mL rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04% (w / v) PS-20; and about 1 mg / mL methionine.

[0375] 47) The method according to any one of the foregoing 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.

[0376] 48) The method according to any one of the foregoing embodiments, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles.

[0377] 49) The method according to embodiment 48, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for eight 21-day cycles.

[0378] 50) The method according to embodiment 49, wherein ranitumab or daratumumab biosimilar is administered subcutaneously once weekly at a dose of about 1,800 mg during cycles 1 to 2, subcutaneously once every 3 weeks at a dose of about 1,800 mg during cycles 3 to 8, and thereafter subcutaneously once every 4 weeks at a dose of about 1,800 mg until disease progression or unacceptable toxicity.

[0379] 51) The method according to embodiment 49, wherein bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2 on days 1, 4, 8 and 11.

[0380] 52) The method according to embodiment 49, wherein lenalidomide is administered orally at a dose of about 25 mg from day 1 to day 14.

[0381] 53) The method according to embodiment 49, wherein dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12.

[0382] 54) The method according to embodiment 49, wherein after the eight 21-day cycles, the pharmaceutical composition, lenalidomide and dexamethasone are administered and continued for one or more 28-day cycles.

[0383] 55) The method according to embodiment 54, wherein lenalidomide is administered orally at a dose of about 25 mg on days 1 to 21 of 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 one or more 28-day cycles until disease progression.

[0384] 56) The method according to any one of the foregoing embodiments, wherein the improved clinical efficacy endpoint is improved strict complete response (sCR).

[0385] 57) The method according to implementation plan 56, wherein the improved sCR is approximately 65.0% relative to approximately 44.9% of the reference subjects or reference subject population.

[0386] 58) The method according to implementation plan 56 or 57, wherein the improved sCR is an absolute increase of approximately 20.1% relative to the reference subject or reference subject population.

[0387] 59) A method of treating a newly diagnosed multiple myeloma in a subject in need, the method comprising administering to the subject daratumumab or a daratumumab biosimilar in combination with bortezomib, lenalidomide and dexamethasone.

[0388] 60) The method according to implementation plan 59, wherein the subject is not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or has delayed HDC and ASCT.

[0389] Implementation Plan Part 2

[0390] 1) Use of the pharmaceutical composition for manufacturing a medicine for treating a newly diagnosed multiple myeloma in a subject in need, the use including administering to the subject the pharmaceutical composition in combination with bortezomib, lenalidomide and dexamethasone, wherein the pharmaceutical composition contains an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar.

[0391] 1a) The use according to embodiment 1, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20).

[0392] 2) For use as described in implementation scheme 1 or 1a, where the subject is not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or has had HDC and ASCT delayed.

[0393] 3) For the purpose described in Implementation Scheme 2, subjects who are not eligible for HDC and ASCT are 70 years of age or older.

[0394] 4) For the purpose described in Implementation Scheme 2, subjects who are not eligible for HDC and ASCT are 18 years of age or older and less than 70 years of age and have one or more comorbid conditions.

[0395] 5) The use according to any one of the foregoing embodiments, wherein the use achieves a clinical efficacy endpoint of improvement in subjects relative to a clinical efficacy endpoint achieved in a reference subject or reference subject population, said reference subject or reference subject population having been administered a combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0396] 6) According to the use described in Implementation Scheme 5, wherein the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD) negative rate, an improved sustained MRD negative rate, an improved complete response (CR) rate or better response rate, an improved progression-free survival (PFS), an improved overall response rate (ORR), an improved overall survival (OS), an improved progression-free survival with next-line treatment (PFS2), an improved time to response (TTR), or an improved duration of response (DOR).

[0397] 7) The use as described in Implementation Scheme 6, wherein the improved clinical efficacy endpoint is the improved overall MRD negative rate.

[0398] 8) As described in Implementation Scheme 7, wherein the improved overall MRD negative rate is at or below 10%. -5 The sensitivity threshold.

[0399] 9) The method according to implementation plan 8, wherein the overall MRD negative rate is 60.9% relative to 39.4% of the reference subjects or reference subject population.

[0400] 10) The method according to implementation plan 8, wherein the improvement in the overall MRD negative rate is an absolute increase of 21.5% relative to the reference subjects or the reference subject population.

[0401] 11) According to the use described in Implementation Scheme 7, wherein the improved overall MRD negative rate is at or below 10 -6 The sensitivity threshold.

[0402] 12) According to the use described in Implementation Scheme 11, the improved overall MRD negative rate is 46.2% relative to 27.3% of the reference subjects or reference subject population.

[0403] 13) The use according to any one of embodiments 7-12, wherein the overall MRD negative rate is determined before the progression of multiple myeloma, after administration of antimyeloma therapy, or both.

[0404] 14) The use according to any one of the implementation schemes 7-13, wherein the subject does not have a high cytogenetic risk.

[0405] 15) The use according to implementation plan 6, wherein the improved clinical efficacy endpoint is an improved rate of negative persistent minimal residual disease (MRD).

[0406] 16) The use as described in Implementation Scheme 15, wherein the improved sustained MRD negative rate lasts for a period of 1 year, 2 years and / or 3 years.

[0407] 17) The use according to embodiment 15 or 16, wherein the improved sustained MRD negative rate is at or below 10%. -5 The sensitivity threshold.

[0408] 18) According to the use described in Implementation Scheme 17, the improved sustained MRD negative rate was 48.7% relative to 26.3% of the reference subjects or reference subject population.

[0409] 19) The use according to embodiment 15 or 16, wherein the improved sustained MRD negative rate is at or below 10%. -6 The sensitivity threshold.

[0410] 20) According to the use described in Implementation Scheme 19, the improved overall MRD negative rate is 32.0% relative to 15.7% of the reference subjects or reference subject population.

[0411] 21) The use according to any one of embodiments 6-20, wherein the improved overall MRD negative rate or the improved sustained MRD negative rate is assessed by next-generation sequencing.

[0412] 22) Use according to any one of embodiments 6-21, wherein the improved overall MRD negative rate or improved sustained MRD negative rate is assessed in bone marrow aspiration fluid samples obtained in subjects with a complete response on day 0, at 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 thereafter annually.

[0413] 23) The use according to the implementation plan 6, wherein the improved clinical efficacy endpoint is an improved complete response (CR) rate or a better response rate.

[0414] 24) According to the use described in implementation scheme 23, the improved CR rate or better response rate is 81.2% relative to 61.6% of the reference subjects or reference subject population.

[0415] 25) The use according to embodiment 23 or 24, wherein the improved CR rate or better response rate is an absolute increase of 19.6% relative to the reference subject or reference subject population.

[0416] 26) The method according to implementation plan 6, wherein the improved clinical efficacy endpoint is improved progression-free survival (PFS).

[0417] 27) The use as described in implementation scheme 26, wherein the improved PFS is prolonged relative to the reference subject or reference subject population.

[0418] 28) The use according to implementation scheme 26 or 27, wherein the improved PFS is a 43% reduction in the risk of progression or death.

[0419] 29) Use according to any one of embodiments 26-28, wherein the subject with improved PFS is within 10 -6 Sensitivity threshold, 10 -5 It is negative for MRD at or below the sensitivity threshold.

[0420] 30) Use according to any one of embodiments 26-28, wherein the subject with improved PFS is within 10 -6 Sensitivity threshold, 10 -5 The sensitivity threshold or both are below which the MRD is positive.

[0421] 31) The use according to any one of embodiments 26-30, wherein the improved PFS is an improvement of the median PFS.

[0422] 32) The use according to any one of the foregoing embodiments, wherein the use achieves an improved median treatment duration relative to the median treatment duration achieved in a reference subject or reference subject population that has been administered a combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0423] 33) According to the use described in implementation scheme 32, the median duration of treatment for this improvement is 56.3 months relative to 34.3 months for the reference subjects or the reference subject population.

[0424] 34) The use according to any one of the embodiments, wherein the use achieves an improved median number of treatment cycles relative to the median number of treatment cycles achieved in a reference subject or reference subject population that has been administered a combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0425] 35) According to the use described in implementation scheme 34, the median number of treatment cycles for this improvement is 59 months relative to 37 months for the reference subjects or the reference subject population.

[0426] 36) The use according to any one of the foregoing embodiments, wherein the use achieves an equivalent EORTC QLQ-C30 global health status score relative to the EORTC QLQ-C30 global health status score achieved in a reference subject or reference subject population, the reference subject or reference subject population having been administered a combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0427] 37) The use according to any one of the preceding embodiments, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.

[0428] 38) The use according to any one of the foregoing embodiments, wherein the subject has a creatinine clearance rate of ≥30 mL / min / 1.73 m2.

[0429] 39) The use according to any one of the foregoing embodiments, wherein the subject has stage 3 multiple myeloma according to the International Staging System (ISS).

[0430] 40) The use according to any one of the foregoing embodiments, wherein the subject has a high cytogenetic risk.

[0431] 41) The use according to any one of the foregoing embodiments, wherein the pharmaceutical composition comprises 1,800 mg of daratumumab or a daratumumab biosimilar, and about 30,000 U rHuPH20.

[0432] 42) The use according to embodiment 41, wherein the pharmaceutical composition comprises about 120 mg / mL of daratumumab or a daratumumab biosimilar, and about 2,000 U / mL rHuPH20.

[0433] 43) The use according to any one of the foregoing embodiments, wherein the pharmaceutical composition comprises one or more excipients.

[0434] 44) According to the use described in embodiment 43, at least one of the excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0435] 45) The use according to any one of the foregoing embodiments, wherein the pH of the pharmaceutical composition is 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 of histidine; about 300 mM of sorbitol; about 0.04% (w / v) PS-20; and about 1 mg / mL of methionine.

[0436] 46) The use according to any one of the foregoing embodiments, wherein the pH of the pharmaceutical composition is about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL daratumumab or a daratumumab biosimilar; about 2,000 U / mL rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04% (w / v) PS-20; and about 1 mg / mL methionine.

[0437] 47) Use according to any one of the foregoing 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.

[0438] 48) The use according to any one of the foregoing embodiments, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles.

[0439] 49) The use according to claim 48, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for eight 21-day cycles.

[0440] 50) According to the use described in embodiment 49, wherein ranitumab or daratumumab biosimilar is administered subcutaneously once weekly at a dose of about 1,800 mg during cycles 1 to 2, subcutaneously once every 3 weeks at a dose of about 1,800 mg during cycles 3 to 8, and thereafter subcutaneously once every 4 weeks at a dose of about 1,800 mg until disease progression or unacceptable toxicity.

[0441] 51) The use according to embodiment 49, wherein bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2 on days 1, 4, 8 and 11.

[0442] 52) The use according to embodiment 49, wherein lenalidomide is administered orally at a dose of about 25 mg from day 1 to day 14.

[0443] 53) The use according to embodiment 49, wherein dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12.

[0444] 54) The use according to embodiment 49, wherein after the eight 21-day cycles, the pharmaceutical composition, lenalidomide and dexamethasone are administered for one or more 28-day cycles.

[0445] 55) The use according to embodiment 54, wherein lenalidomide is administered orally at a dose of about 25 mg on days 1 to 21 of 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 one or more 28-day cycles until disease progression.

[0446] 56) The use according to any one of the foregoing embodiments, wherein the improved clinical efficacy endpoint is improved strict complete response (sCR).

[0447] 57) According to the use described in implementation scheme 56, the improved sCR is about 65.0% relative to about 44.9% of the reference subjects or the reference subject population.

[0448] 58) The use according to embodiment 56 or 57, wherein the improved sCR is an absolute increase of approximately 20.1% relative to the reference subject or reference subject population.

[0449] 59) Use of a pharmaceutical composition for the manufacture of a medicine for the treatment of a newly diagnosed multiple myeloma in a subject of need, the use comprising administering to the subject daratumumab or a daratumumab biosimilar in combination with bortezomib, lenalidomide and dexamethasone.

[0450] 60) The use as described in implementation scheme 59, wherein the subject is not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or has delayed HDC and ASCT.

[0451] Implementation Plan Part 3

[0452] 1) A pharmaceutical composition for treating a newly diagnosed multiple myeloma in a subject of need, comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide and dexamethasone, wherein the pharmaceutical composition contains an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar.

[0453] 1a) The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition comprises an antibody that specifically binds to CD38, particularly daratumumab or a daratumumab biosimilar, and hyaluronidase, particularly recombinant human hyaluronidase (rHuPH20).

[0454] 2) The pharmaceutical composition according to implementation scheme 1 or 1a, wherein the subject is not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or has delayed HDC and ASCT.

[0455] 3) The pharmaceutical composition according to embodiment 2, wherein the subject who does not qualify for HDC and ASCT is 70 years of age or older.

[0456] 4) The pharmaceutical composition according to embodiment 2, wherein the subject who does not qualify for HDC and ASCT is 18 years or older and less than 70 years old and has one or more comorbid conditions.

[0457] 5) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the administration achieves a clinical efficacy endpoint of improvement in the subject relative to a clinical efficacy endpoint achieved in a reference subject or reference subject population, wherein the reference subject or reference subject population has been administered the combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0458] 6) The pharmaceutical composition according to embodiment 5, wherein the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD) negative rate, an improved sustained MRD negative rate, an improved complete response (CR) rate or better response rate, improved progression-free survival (PFS), improved overall response rate (ORR), improved overall survival (OS), improved progression-free survival with next-line treatment (PFS2), improved time to response (TTR), or improved duration of response (DOR).

[0459] 7) The pharmaceutical composition according to embodiment 6, wherein the improved clinical efficacy endpoint is an improved overall MRD negative rate.

[0460] 8) The pharmaceutical composition according to embodiment 7, wherein the improved overall MRD negative rate is at or below 10%. -5 The sensitivity threshold.

[0461] 9) The pharmaceutical composition according to embodiment 8, wherein the improved overall MRD negative rate is 60.9% relative to 39.4% of the reference subjects or reference subject population.

[0462] 10) The pharmaceutical composition according to embodiment 8, wherein the improvement in the overall MRD negative rate is an absolute increase of 21.5% relative to the reference subject or reference subject population.

[0463] 11) The pharmaceutical composition according to embodiment 7, wherein the improved overall MRD negative rate is at or below 10%. -6 The sensitivity threshold.

[0464] 12) The pharmaceutical composition according to embodiment 11, wherein the improved overall MRD negative rate is 46.2% relative to 27.3% of the reference subjects or reference subject population.

[0465] 13) The pharmaceutical composition according to any one of embodiments 7-12, wherein the overall MRD negative rate is determined before the progression of multiple myeloma, after administration of antimyeloma therapy, or both.

[0466] 14) The pharmaceutical composition according to any one of embodiments 7-13, wherein the subject does not have a high cytogenetic risk.

[0467] 15) The pharmaceutical composition according to embodiment 6, wherein the improved clinical efficacy endpoint is an improved rate of negative persistent minimal residual disease (MRD).

[0468] 16) The pharmaceutical composition according to embodiment 15, wherein the improved sustained MRD negative rate lasts for a period of 1 year, 2 years and / or 3 years.

[0469] 17) The pharmaceutical composition according to embodiment 15 or 16, wherein the improved sustained MRD negative rate is at or below 10 -5 The sensitivity threshold.

[0470] 18) The pharmaceutical composition according to embodiment 17, wherein the improved sustained MRD negative rate is 48.7% relative to 26.3% of the reference subjects or reference subject population.

[0471] 19) The pharmaceutical composition according to embodiment 15 or 16, wherein the improved sustained MRD negative rate is at or below 10 -6 The sensitivity threshold.

[0472] 20) The pharmaceutical composition according to embodiment 19, wherein the improved overall MRD negative rate is 32.0% relative to 15.7% of the reference subjects or reference subject population.

[0473] 21) The pharmaceutical composition according to any one of embodiments 6-20, wherein the improved overall MRD negative rate or the improved sustained MRD negative rate is assessed by next-generation sequencing.

[0474] 22) The pharmaceutical composition according to any one of embodiments 6-21, wherein the improved overall MRD negative rate or improved sustained MRD negative rate is assessed by using bone marrow aspiration fluid samples obtained in subjects with a complete response on day 0, at 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 thereafter annually.

[0475] 23) The pharmaceutical composition according to embodiment 6, wherein the improved clinical efficacy endpoint is an improved complete response (CR) rate or a better response rate.

[0476] 24) The pharmaceutical composition according to embodiment 23, wherein the improved CR rate or better response rate is 81.2% relative to 61.6% of the reference subject or reference subject population.

[0477] 25) The pharmaceutical composition according to embodiment 23 or 24, wherein the improved CR rate or better response rate is an absolute increase of 19.6% relative to the reference subject or reference subject population.

[0478] 26) The pharmaceutical composition according to embodiment 6, wherein the improved clinical efficacy endpoint is improved progression-free survival (PFS).

[0479] 27) The pharmaceutical composition according to embodiment 26, wherein the improved PFS prolongation is relative to the reference subject or reference subject population.

[0480] 28) The pharmaceutical composition according to embodiment 26 or 27, wherein the improved PFS is a 43% reduction in the risk of progression or death.

[0481] 29) The pharmaceutical composition according to any one of embodiments 26-28, wherein the subject with improved PFS is within 10 -6 Sensitivity threshold, 10 -5 It is negative for MRD at or below the sensitivity threshold.

[0482] 30) The pharmaceutical composition according to any one of embodiments 26-28, wherein the subject with improved PFS is within 10 -6 Sensitivity threshold, 10 -5 The sensitivity threshold or both are below which the MRD is positive.

[0483] 31) The pharmaceutical composition according to any one of embodiments 26-30, wherein the improved PFS is an improvement in median PFS.

[0484] 32) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the administration achieves an improved median treatment duration relative to the median treatment duration achieved in a reference subject or reference subject population that has been administered the combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0485] 33) The pharmaceutical composition according to embodiment 32, wherein the median duration of treatment for the improvement is 56.3 months relative to 34.3 months for a reference subject or reference subject population.

[0486] 34) The pharmaceutical composition according to any one of the embodiments, wherein the administration achieves an improved median number of treatment cycles relative to the median number of treatment cycles achieved in a reference subject or reference subject population that has been administered the combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0487] 35) The pharmaceutical composition according to embodiment 34, wherein the median number of treatment cycles for the improvement is 59 months relative to 37 months for a reference subject or reference subject population.

[0488] 36) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the administration achieves an equivalent EORTCQLQ-C30 global health status score relative to the EORTC QLQ-C30 global health status score achieved in a reference subject or reference subject population, wherein the reference subject or reference subject population has been administered a combination of bortezomib, lenalidomide and dexamethasone, but not daratumumab.

[0489] 37) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.

[0490] 38) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the subject has a creatinine clearance rate of ≥30 mL / min / 1.73 m2.

[0491] 39) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the subject has stage 3 multiple myeloma according to the International Staging System (ISS).

[0492] 40) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the subject has a high cytogenetic risk.

[0493] 41) A pharmaceutical composition according to any one of the foregoing embodiments, wherein the pharmaceutical composition comprises 1,800 mg of daratumumab or a daratumumab biosimilar, and about 30,000 U rHuPH20.

[0494] 42) The pharmaceutical composition according to embodiment 41, wherein the pharmaceutical composition comprises about 120 mg / mL of daratumumab or a daratumumab biosimilar, and about 2,000 U / mL rHuPH20.

[0495] 43) A pharmaceutical composition according to any one of the foregoing embodiments, wherein the pharmaceutical composition comprises one or more excipients.

[0496] 44) The pharmaceutical composition according to embodiment 43, wherein at least one of the excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0497] 45) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the pH of the pharmaceutical composition is 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 of histidine; about 300 mM of sorbitol; about 0.04% (w / v) PS-20; and about 1 mg / mL of methionine.

[0498] 46) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the pH of the pharmaceutical composition is about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg of daratumumab or a daratumumab biosimilar; about 2,000 U / mL of rHuPH20; about 10 mM of histidine; about 300 mM of sorbitol; about 0.04% (w / v) PS-20; and about 1 mg / mL of methionine.

[0499] 47) The pharmaceutical composition according to any one of the foregoing 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.

[0500] 48) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 21-day cycles.

[0501] 49) The pharmaceutical composition according to embodiment 48, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for eight 21-day cycles.

[0502] 50) The pharmaceutical composition according to embodiment 49, wherein ranitumab or daratumumab biosimilar is administered subcutaneously once weekly at a dose of about 1,800 mg during cycles 1 to 2, subcutaneously once every 3 weeks at a dose of about 1,800 mg during cycles 3 to 8, and thereafter subcutaneously once every 4 weeks at a dose of about 1,800 mg until disease progression or unacceptable toxicity.

[0503] 51) The pharmaceutical composition according to embodiment 49, wherein bortezomib is administered subcutaneously at a dose of about 1.3 mg / m2 on days 1, 4, 8 and 11.

[0504] 52) The pharmaceutical composition according to embodiment 49, wherein lenalidomide is administered orally at a dose of about 25 mg from day 1 to day 14.

[0505] 53) The pharmaceutical composition according to embodiment 49, wherein dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12.

[0506] 54) The pharmaceutical composition according to embodiment 49, wherein after the eight 21-day cycles, the pharmaceutical composition, lenalidomide and dexamethasone are administered for one or more 28-day cycles.

[0507] 55) The pharmaceutical composition according to embodiment 54, wherein lenalidomide is administered orally at a dose of about 25 mg on days 1 to 21 of 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 one or more 28-day cycles until disease progression.

[0508] 56) The pharmaceutical composition according to any one of the foregoing embodiments, wherein the improved clinical efficacy endpoint is improved strict complete response (sCR).

[0509] 57) The pharmaceutical composition according to embodiment 56, wherein the improved sCR is about 65.0% relative to about 44.9% of the reference subjects or reference subject population.

[0510] 58) The pharmaceutical composition according to embodiment 56 or 57, wherein the improved sCR is an absolute increase of about 20.1% relative to the reference subject or reference subject population.

[0511] 59) A pharmaceutical composition for treating a newly diagnosed multiple myeloma in a subject of need, comprising administering to the subject daratumumab or a daratumumab biosimilar in combination with bortezomib, lenalidomide and dexamethasone.

[0512] 60) The pharmaceutical composition according to embodiment 59, wherein the subject is not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or has delayed HDC and ASCT.

[0513] Example

[0514] The embodiments and implementations described herein are for illustrative purposes only and are intended to suggest to those skilled in the art various modifications or variations to be considered, which are included within the spirit and scope of this application and within the scope of the appended claims.

[0515] Example 1: Daramumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma

[0516] This article provides an analysis of efficacy and safety data from the CEPEUS study of subcutaneous daratumumab in combination with bortezomib / lenalidomide / dexamethasone (VRd) versus VRd alone in patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for transplantation or who do not intend to receive transplantation as initial therapy.

[0517] introduce :

[0518] Daremumab is a human IgGκ monoclonal antibody targeting CD38, acting directly on tumors and possessing an immunomodulatory mechanism of action. In this phase 3 CEPEUS study, daratumumab plus VRd (D-VRd) was evaluated as a quadruple therapy in patients with newly diagnosed multiple myeloma who were ineligible for transplantation (TIE) or who were not planned for transplantation as initial therapy (TIE or transplant delay). This article reports observations from the final progression-free survival analysis of CEPEUS.

[0519] Research Design :

[0520] This study was a randomized, open-label, multicenter phase 3 trial that recruited patients at 92 sites in 13 countries. The protocol was approved at each site by an independent ethics committee or institutional review committee.

[0521] patient

[0522] Recruited patients have a newly diagnosed multiple myeloma and are not considered candidates for high-dose chemotherapy and stem cell transplantation due to age (≥70 years), or are older than 18 to 70 years and have comorbidities that may adversely affect tolerance to high-dose chemotherapy, in which stem cell transplantation is the initial treatment (transplantation delay).

[0523] The patient had an Eastern Oncology Collaboration Group performance status of 0 to 2, and a blood glucose level of 1.0 × 10⁻⁶. 9 An absolute neutrophil count of 7.5 g / dL or higher (granule colony-stimulating factor [G-CSF] is permitted), a hemoglobin level of 7.5 g / dL or higher (no prior red blood cell transfusion within 7 days prior to laboratory testing; recombinant human erythropoietin is permitted), and 70 × 10⁶ mmol / L or higher are also required. 9 A platelet count of 50 × 10⁹ / L or higher (if <50% of the nucleated cells in the bone marrow are plasma cells; otherwise, a platelet count >50 × 10⁹ / L). 9Calculated creatinine clearance of 30 mL / min or higher, corrected serum calcium level of 13.5 mg / dL or lower (≤3.4 mmol / L) or free ionized calcium level of 6.5 mg / dL or less (≤1.6 mmol / L), aspartate and alanine aminotransferase levels of 2.5 times or less of the upper limit of normal, and total bilirubin level of 1.5 times or less of the upper limit of normal. Exclude patients with the following conditions: a frailty index ≥2 according to the Geriatric Assessment of Multiple Myeloma score; prior therapy for multiple myeloma other than short-term corticosteroids; previous or concurrent aggressive malignancy (other than multiple myeloma) within 5 years of randomization; grade 2 or higher peripheral neuropathy or neuropathic pain (according to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], 5th edition); focal radiotherapy within 14 days of randomization; plasma ablation within 28 days of randomization; clinical signs of multiple myeloma involving the meninges; chronic obstructive pulmonary disease with a forced expiratory volume in one second (FEV1) <50% of the predicted normal value; or moderate or severe persistent asthma or currently uncontrolled asthma within the past 2 years.

[0524] Selection criteria

[0525] 1. Newly diagnosed patients who are not considered candidates for high-dose chemotherapy and stem cell transplantation (SCT) for the following reasons: age ≥70 years or age 18 to 70 years, presence of comorbidities that may adversely affect tolerance to high-dose chemotherapy and SCT, or refusal of high-dose chemotherapy and SCT as initial treatment.

[0526] 2. Diagnosis of multiple myeloma according to IMWG criteria: ≥10% monoclonal plasma cells in the bone marrow or presence of biopsy-confirmed plasmacytoma, and the recorded multiple myeloma meeting at least one of the CRAB (calcium, kidney, anemia, bone) criteria or biomarker criteria for malignancy:

[0527] CRAB Standard :

[0528] a. Hypercalcemia: Serum calcium >0.25 mmol / L (>1 mg / dL) above the upper limit of normal (ULN) or >2.75 mmol / L (>11 mg / dL)

[0529] b. Renal insufficiency: Creatinine clearance <40 mL / min or serum creatinine >177 μmol / L (>2 mg / dL)

[0530] c. Anemia: Hemoglobin >2 g / dL (below the lower limit of normal) or hemoglobin <10 g / dL

[0531] d. Bone lesions: One or more osteolytic lesions visible on bone radiography, computed tomography (CT), or positron emission tomography (PET)-CT.

[0532] Biomarkers of malignant tumors

[0533] a. Percentage of clonal bone marrow plasma cells ≥ 60%

[0534] b. Participation: Non-participating serum-free light chain (FLC) ratio ≥100

[0535] c. >1 focal lesion in magnetic resonance imaging (MRI) studies

[0536] 3. Must have a measurable disease assessed by a central laboratory, defined by any of the following:

[0537] a. Multiple myeloma with IgG, IgA, IgM, IgD, or IgE: serum monoclonal paraprotein (M protein) level ≥1.0 g / dL or urinary M protein level ≥200 mg / 24 hours; or

[0538] b. Light chain multiple myeloma with no measurable disease in serum or urine: serum Ig FLC ≥10 mg / dL and abnormal serum Ig k-λ FLC ratio.

[0539] 4. ECOG performance status score is 0, 1, or 2.

[0540] 5. During the screening phase, clinical laboratory values ​​meeting the following criteria:

[0541] a. Hemoglobin > 7.5 g / dL (mmol / L) (no prior RBC infusion within 7 days prior to laboratory testing; recombinant human erythropoietin is permitted).

[0542] b. Absolute neutrophil count (ANC) > 1.0 x 10⁹ / L (granulocyte colony-stimulating factor [G-CSF] is permitted);

[0543] c. For subjects whose bone marrow nucleated cells are plasma cells, the platelet count should be >70 x10⁹ / L; otherwise, the platelet count should be >50 ×10⁹ / L (transfusion is not allowed within 7 days).

[0544] d. Aspartate aminotransferase (AST) ≤ 2.5 x ULN;

[0545] e. Alanine aminotransferase (ALT) ≤ 2.5 × ULN;

[0546] f. Total bilirubin ≤1.5 x ULN, except for subjects with congenital bilirubinemia such as Gilbert's syndrome (direct bilirubin ≤2.0 x ULN);

[0547] g. Estimated creatinine clearance (CrCl) ≥ 30 mL / min. Creatinine clearance can be calculated using the Cockcroft-Gault formula 9, eGFR, or CKD-epi formula. Alternatively, creatinine clearance can be calculated for overweight or underweight subjects by measuring CrCl from a 24-hour urine collection. If the Cockcroft-Gault formula is used and the body mass index (BMI) ≥ 30 kg / m², corrected weight should be used in the calculation.

[0548] h. Corrected serum calcium ≤13.5 mg / dL (≤3.4 mM / L); or free ionized calcium ≤6.5 mg / dL (≤1.6 mM / L)

[0549] 6. Female subjects of reproductive potential must commit to abstaining from heterosexual intercourse or using two reliable methods of contraception simultaneously, such as heterosexual intercourse, throughout the entire risk period associated with the study drug, during the treatment period, at any interruption of dosing, and for 3 months after any component of the treatment regimen following the last dose. Such contraception must include one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [contraceptive pill, injection, hormonal patch, vaginal ring, or implant], or partner vasectomy) and an additional effective method of contraception (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must be initiated 4 weeks prior to dosing. Even with a history of infertility, reliable contraception is required unless due to hysterectomy or bilateral oophorectomy.

[0550] 7. During screening, women of childbearing age must have negative results in two serum or urine pregnancy tests, the first within 10 to 14 days before administration and the second within 24 hours before administration.

[0551] 8. Women must agree not to donate eggs (ovaries, oocytes) for assisted reproductive purposes during the study period and for a period of 3 months after receiving any component of the final dose of the treatment regimen.

[0552] 9. In cases where the female is of reproductive potential, sexually active male subjects of reproductive potential must always use latex or synthetic condoms during the study and for 3 months after discontinuation of study treatment (even after successful vasectomy).

[0553] 10. Male subjects with reproductive potential are not allowed to donate sperm during the study or for 3 months after the last dose of study treatment.

[0554] 11. An informed consent form (ICF) must be signed, or their legal representative must sign, indicating that he or she understands the purpose of the study and the required procedures and is willing to participate in the study.

[0555] 12. Able to comply with the prohibitions and restrictions stipulated in the plan.

[0556] Exclusion criteria

[0557] 1. According to the geriatric assessment score for multiple myeloma, the frailty index is ≥2.

[0558] 2. Prior therapy for multiple myeloma other than short-term corticosteroids (not exceeding 40 mg of dexamethasone or equivalent daily, totaling 160 mg of dexamethasone or equivalent).

[0559] 3. Subjects must have a history of or concurrent invasive malignancy (excluding multiple myeloma) within 5 years of the randomization date (exceptions include adequately treated basal cell carcinoma and squamous cell carcinoma of the skin, cervical or breast carcinoma in situ, or other non-invasive lesions that, in the investigator's opinion and in agreement with the sponsor's medical monitor, are cured and have a minimal risk of recurrence within 3 years).

[0560] 4. Peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by the National Cancer Institute-Common Terminology Guidelines for Adverse Events (NCI-CTCA) 5th edition.

[0561] 5. Localized radiotherapy within 14 days of randomization, except for palliative radiotherapy for symptomatic pain management. Even in cases of symptom relief management, radiotherapy for measurable extramedullary plasmacytoma is not permitted within 14 days prior to randomization.

[0562] 6. Had plasma ablation within 28 days of randomization.

[0563] 7. Clinical signs of meningeal involvement in multiple myeloma.

[0564] 8. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in one second (FEV1) <50% of the predicted normal value. (Subjects suspected of having COPD need to be tested for FEV1).

[0565] 9. Moderate or severe persistent asthma, any type of uncontrolled asthma, within the past 2 years. (The study allows participants with controlled intermittent asthma or controlled mild persistent asthma.)

[0566] 10. Subjects:

[0567] a. Known to be seropositive for human immunodeficiency virus (HIV).

[0568] b. Hepatitis B serological positivity (defined as a positive test for hepatitis B surface antigen [HBsAg]). Subjects whose infection has been resolved (i.e., HBsAg negative but positive for hepatitis B core antigen [anti-HBc] and / or positive for hepatitis B surface antigen antibody [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) to measure hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. Exceptions: Subjects with serological findings suggesting HBV vaccination (anti-HBs positivity is the only serological marker) and those with a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR.

[0569] c. Known to be seropositive for hepatitis C virus (HCV; positive for anti-HCV antibody or positive for HCV-RNA quantification), except in cases of sustained virological response (SVR), which is defined as viremia at least 12 weeks after completion of antiviral therapy.

[0570] 11. Comorbid medical or psychiatric conditions or illnesses that may interfere with research procedures or results or that the investigator believes may pose a risk to the recruited personnel in the study (such as, but not limited to, systemic amyloidosis, POEMS, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative lung disease).

[0571] 12. Having clinically significant heart disease, including: a myocardial infarction within 6 months prior to signing the ICF, or an unstable or uncontrolled condition / symptom related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association class III-IV); uncontrolled arrhythmias or clinically significant ECG abnormalities; screening showing a 12-lead ECG with a baseline QT interval >470 ms, as corrected by the Frederica formula (QTcF).

[0572] 13. The patient received a strong CYP3A4 inducer within 5 half-lives prior to randomization.

[0573] 14. Hypersensitivity, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies, or human proteins or their excipients (see Investigator's Handbook), or sensitivity to products of mammalian origin or lenalidomide.

[0574] Research on treatment

[0575] 395 newly diagnosed multiple myeloma patients who were ineligible for transplantation or whose transplantation was delayed 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 daralimumab weekly in cycles 1–2, every 3 weeks in cycles 3–8, and every 4 weeks thereafter, until disease progression. The primary endpoint was the overall minimal residual disease (MRD) negativity rate (10-10). –5 ).

[0576] Patients were randomly assigned (1:1) to D-VRd or VRd using an interactive network response system. Randomization was stratified by disease stage (I, II, or III) of the International Staging System (ISS) and age / transplant eligibility (<70 years old ineligible, <70 years old and delayed transplant, or ≥70 years old).

[0577] All patients received eight 21-day cycles of VRd, consisting of subcutaneous bortezomib (1.3 mg / m² body surface area on days 1, 4, 8, and 11), oral lenalidomide (25 mg on days 1 through 14), and oral or intravenous dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12). Bortezomib was then discontinued according to the protocol, and patients continued to receive a 28-day cycle of Rd, consisting of oral lenalidomide (25 mg on days 1 through 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, which is combined with recombinant human hyaluronidase PH20 [2,000 U / mL]) every week in cycles 1 to 2, every 3 weeks in cycles 3 to 8, and every 4 weeks in cycle 9+. ® Drug delivery technology, co-formulated by Halozyme, Inc., San Diego, CA, USA). Treatment continued until progression or unacceptable toxicity. The primary endpoint was the MRD negativity rate (10). –5 (Assessed by next-generation sequencing), defined as patients achieving ³CR and MRD negativity.

[0578] Before and after drug administration

[0579] To reduce 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 mg to 1000 mg), antihistamines (intravenous or oral diphenhydramine 25 mg to 50 mg or equivalent) and oral montelukast (10 mg, recommended on day 1 of cycle 1) for up to 24 hours prior to daratumumab injection.

[0580] Patients with FEV1 <80% who have mild asthma or chronic obstructive pulmonary disease can receive post-injection medications, including antihistamines, short-acting β2-adrenergic receptor agonists (such as salbutamol), and control medications for lung disease (e.g., inhaled corticosteroids ± long-acting β2-adrenergic receptor agonists for asthma patients or long-acting bronchodilators [such as tiotropium bromide or salmeterol] ± inhaled corticosteroids for chronic obstructive pulmonary disease patients).

[0581] Endpoint and Assessment

[0582] The primary endpoint was the overall minimal residual disease (MRD) negativity rate, defined as achieving a complete or better response and having an MRD negativity status (at or below 10) after randomization but before disease progression, subsequent antimyeloma therapy, or both. -5 The proportion of patients (within the sensitivity threshold). The primary secondary endpoints were the rate of complete response or better response at ≥12 months, progression-free survival, and sustained MRD negativity.

[0583] MRD-positive patients include those whose all test samples are found to be MRD-positive or indeterminate, or those who are MRD-negative but do not have a CR or better response. For patients missing MRD samples, whose baseline MRD could not be calibrated, or other samples that could not be evaluated, the MRD status is considered MRD-positive.

[0584] A complete response rate or better response rate was defined as the proportion of patients who achieved a complete or near-complete response based on a computerized algorithm according to the International Myeloma Working Group (IMWG) response criteria, during or after study treatment and before initiation of subsequent antimyeloma therapy. (Raykumar SV, Harousseau JL, Durie B, et al., Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 117:4691-4695.)

[0585] Progression-free survival was defined as the duration from the date of randomization to disease progression or death, whichever occurred first. Disease progression was determined according to the IMWG criteria. Patients who started subsequent antimyeloma therapy for multiple myeloma without disease progression were censored at their last disease assessment before starting subsequent therapy. Patients who withdrew informed consent before disease progression were censored at their last disease assessment. Patients lost to follow-up were censored at their last disease assessment before loss to follow-up. Patients who were still alive and had not experienced disease progression at the analysis cutoff date were censored at their last disease assessment. Patients without any post-baseline disease assessment were censored at the randomization date.

[0586] The sustained MRD negativity rate was defined as achieving a complete response or better response and MRD negativity (10) with no MRD positivity in between, at least one year apart between two examinations (and both examinations should be performed before disease progression, before subsequent antimyeloma therapy, or both). -5 The proportion of patients with ).

[0587] Overall response rate was defined as the proportion of patients who achieved a partial or better response (i.e., partial response, very good partial response, complete response, or strictly complete response) during or after study treatment but before the start of subsequent antimyeloma therapy, based on a computerized algorithm according to the standards of the International Myeloma Working Group (IMWG).

[0588] Overall survival was defined as the time from the randomization date to the date the patient died from any cause. Lost-to-follow-up subjects were censored at the time of loss. Patients who died after consenting to withdraw were considered to have an overall survival event. If a patient was alive or their survival status was unknown at the analysis cutoff date, the patient's data were censored on the last date the patient was known to be alive.

[0589] Progression-free survival (PFS2) for next-line treatment is defined as the time from randomization to progression or death (for any reason) on next-line treatment, whichever occurs first. Disease progression is based on investigator judgment. Subjects still alive and who have not progressed on next-line treatment will be censored on the last follow-up date. During the study, patients who withdrew consent or were lost to follow-up on the last date of disease assessment prior to any subsequent antimyeloma therapy will be censored. Patients who did not have any baseline follow-up at randomization will also be censored.

[0590] 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 consists of 30 items and generates five function scales (physical function, role function, emotional function, cognitive function, and social function) within a one-week recall period, one global health status scale, three symptom scales (fatigue, nausea and vomiting, and pain) and six single items (dyspnea, insomnia, decreased appetite, constipation, diarrhea, and financial difficulties).

[0591] result :

[0592] Patients and treatment

[0593] A total of 395 patients were recruited, with 197 and 198 assigned to D-VRd and VRd, respectively. Recruitment by country is summarized in Table S1. Demographic and baseline characteristics were generally balanced between groups (Table 2). The median patient age was 70.0 years (range, 31 to 80 years); 28.1% had ISS stage III disease, and 13.2% had a 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 and 7.1% for VRd; 36.0% and 42.4% had an ECOG score of 0, respectively.

[0594] Table 2. Demographic and clinical characteristics of the intention-to-treat population at baseline . *

[0595]

[0596] D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone.

[0597] *The intention-to-treat population is defined as all patients who underwent randomization.

[0598] † Race is reported according to the patient.

[0599] ‡ The Eastern Cooperative Oncology Group (ECOG) performance status score ranges from 0 to 5, where 0 indicates no symptoms and a higher score indicates greater disability.

[0600] § Including IgD, IgM, IgE, and biclonal antibodies.

[0601] ¶ The International Staging System (ISS) classifies diseases based on a combination of serum β2-microglobulin and albumin levels. Higher stages indicate more severe disease.

[0602] || Cellular genetic risk was determined using in situ fluorescence hybridization. High risk was defined as the presence of del(17p), t(4;14), or t(14;16).

[0603] **Uncertainty includes patients with missing or unevaluable samples.

[0604] Of the randomized patients, 392 patients (197 with D-VRd and 195 with VRd) received at least one dose of the designated treatment. Figure 1 At the clinical cutoff point for the final progression-free survival analysis (May 7, 2024), 102 patients (51.8%) in the D-VRd group and 67 patients (34.4%) in the VRd group maintained treatment. The most common reason for treatment discontinuation was progressive disease (D-VRd, 13.7%; VRd, 26.2%).

[0605] Compared to VRd, D-VRd had a median duration of treatment 22 months longer (56.3 months vs. 34.3 months) (Table 3). D-VRd also had a longer median number of treatment cycles compared to VRd (59 [range, 1 to 71] vs. 37 [range, 1 to 70]). The relative dose intensities were similar between the treatment groups (Table 3).

[0606] Table 3. Treatment duration and relative dose intensity in the safety population* . †

[0607]

[0608] D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone. NA indicates not applicable.

[0609] *Dose intensity is defined as the ratio of the total administered dose to the total planned dose.

[0610] † The safety population includes all patients who received at least one dose of the study treatment.

[0611] effect

[0612] With a median follow-up of 58.7 months (range, 0.1–64.7), the overall MRD negative rate of D-VRd relative to VRd (MRD negative status with complete or better response)

[10] -5 The percentage of positive cases was significantly higher (60.9% vs. 39.4%; odds ratio, 2.37; 95% CI, 1.58–3.55; P < 0.0001). Figure 4 A). Apart from patients with high cytogenetic risk, in all pre-specified subgroups, the overall MRD negativity rate and MRD negativity rate of D-VRd were significantly lower than those of VRd in 10... -5 and 10 -6 The next consistent higher ( Figures 5A to 5C Compared to VRd, D-VRd has a MRD negative rate of 10%. -6 The odds ratio was also higher (46.2% vs. 27.3%; odds ratio, 2.24; 95% CI, 1.48–3.40; P = 0.0001). Figure 4 B). Compared with VRd, D-VRd had a significantly higher rate of sustained MRD negativity (≥12 months) (48.7% vs. 26.3%; odds ratio, 2.63; 95% CI, 1.73–4.00; P<0.0001). Figure 4 C). Compared to VRd, D-VRd nearly doubled the rate of persistent MRD negativity in years 1, 2, and 3. Figure 4D ).

[0613] In a small subgroup of patients with high cytogenetic risk, the treatment effect of D-VRd was less pronounced (D-VRd, n=25; VRd, n=27); however, it is noteworthy that the overall MRD negativity rate (10) was high in patients with high cytogenetic risk treated with VRd. -5 The rate was unexpectedly high, significantly higher than in the VRd ITT group (55.6% vs. 39.4%). Furthermore, patients at high cytogenetic risk who received D-VRd had a shorter median treatment duration (27 cycles vs. 35.5 cycles), primarily due to earlier treatment discontinuation, resulting in a higher proportion of missing post-baseline MRD values ​​in the high cytogenetic risk D-VRd group (n=6 [24.0%]) compared to the VRd group (n=4 [14.8%]). Twice as many patients in the high cytogenetic risk D-VRd group (n=6 [24.0%]) discontinued treatment before their first post-baseline MRD sample compared to the VRd group (n=3 [11.1%]), implying fewer patients in the high cytogenetic risk D-VRd group had the opportunity to achieve an MRD-negative test. In any case, in 10 -5 In patients with high cytogenetic risk who achieved MRD negativity below the threshold (D-VRd, 48.0% [12 / 25]; VRd, 55.6% [15 / 27]), a trend was observed for the beneficial effect of D-VRd on PFS relative to VRd (HR, 0.33; 95% CI, 0.07–1.57). Figure 30 ).

[0614] In the D-VRd group, 63 patients (32.0%) and in the VRd group, 91 patients (46.0%) experienced disease progression or death. Compared with VRd, D-VRd significantly improved progression-free survival, with a hazard ratio of 0.57 (95% CI, 0.41–0.79; P = 0.0005). Figure 2 Compared to VRd's 52.6 months, D-VRd did not reach median progression-free survival; the 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). In all pre-specified subgroups including patients with high cytogenetic risk, D-VRd showed superior progression-free survival compared to VRd (…). Figure 3 ).

[0615] Compared with VRd, D-VRd had a significantly higher complete response rate or better response rate (81.2% vs. 61.6%; odds ratio, 2.73; 95% CI, 1.71–4.34; P<0.0001). Figure 6 Additional reaction data are shown in Table 4.

[0616] Compared to VRd, the overall survival risk tends to favor D-VRd (hazard ratio, 0.85; 95% CI, 0.58–1.24); Figure 7 Overall survival is premature and follow-up is ongoing. Of the 51 patients in the D-VRd group and 60 patients in the VRd group, 24 died due to COVID-19 (21.6% of all deaths in the study; 15 in D-VRd and 9 in VRd), with 21 occurring during the peak of the global pandemic deaths in 2020 and 2021, only 3 in 2022 (with the availability of a COVID-19 vaccine), and no deaths in 2023 or 2024. Significant regional variation exists, with 54.2% of all COVID-19 deaths occurring in Brazil and 16.7% in Poland. Two sensitivity analyses of overall survival adjusted for the impact of COVID-19 death showed that D-VRd was more effective than VRd: similar adverse events leading to compound discontinuation were reported in participants who censored any death due to COVID-19 (hazard ratio, 0.69; 95% CI, 0.45–1.05) and treated COVID-19 death as a competing risk (hazard ratio for non-COVID mortality, 0.67; 95% CI, 0.44–1.03).

[0617] Progression-free survival data for next-line treatments are not yet mature; the hazard ratio also favors D-VRd compared to VRd (hazard ratio, 0.78; 95% CI, 0.54-1.14). Figure 9 Sensitivity analysis of progression-free survival with next-line treatment, censored for deaths due to COVID-19, supports further improvements in D-VRd (hazard ratio, 0.60; 95% CI, 0.40–0.93). Figure 8 Compared to the D-VRd group (3 out of 22 patients [13.6%]), the VRd group had a higher proportion of patients receiving the first follow-up treatment based on anti-CD38 (39 out of 65 patients [60.0%]).

[0618] The scores on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status dimension improved over time in both groups, with no adverse effect from the addition of daratumumab. Figure 10 ).

[0619] Table 4. Summary of response rates in the intention-to-treat group . *

[0620]

[0621] D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone.

[0622] * Response rate at any time during the study. Response was assessed based on the International Myeloma Working Group response criteria.

[0623] † The p-value was calculated using the stratified Cochran-Mantel-Haenszel chi-square test.

[0624] Security

[0625] The most common adverse events of any grade (≥20% of patients in any group) and the most common grade 3 or 4 adverse events (≥10% of patients in any 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%, respectively). 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%, respectively; and grade 3 or 4 peripheral neuropathy occurred in 11.2% and 10.8%, respectively.

[0626] Table 5. Most common adverse events during treatment in the safety group . *

[0627]

[0628] D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone. NA indicates not applicable.

[0629] *The safety population includes patients who received at least one dose of the study treatment. Lists are adverse events of any grade reported in at least 20% of patients in either treatment group and grade 3 or 4 adverse events reported in at least 10% of patients in either treatment group.

[0630] † Level 3.

[0631] 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 rates of study drug discontinuation due to adverse events were 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% of patients in the VRd group (7.7% non-COVID-related and 3.1% COVID-related). In both groups, most Grade 5 events occurred after discontinuation of bortezomib (cycle 8) (13% D-VRd vs. 9% VRd). Addition of daratumumab had virtually no effect on the relative dose intensity of VRd. When adjusted for treatment exposure, the rate of Grade 5 adverse events was comparable between the groups (D-VRd, 0.39 / 100 patient-months; VRd, 0.31 / 100 patient-months).

[0632] Table 6. Serious adverse events in the safe population . *

[0633]

[0634] D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone.

[0635] *The safety population includes patients who received at least one dose of the study treatment.

[0636] Secondary 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).

[0637] Table 7. Summary of the second primary malignancy in the safety group . *

[0638]

[0639] D-VRd represents subcutaneous daralimumab plus bortezomib / lenalidomide / dexamethasone. VRd represents bortezomib / lenalidomide / dexamethasone.

[0640] *The safety population includes patients who received at least one dose of the study treatment.

[0641] Discussion and Conclusion :

[0642] Results from the final progression-free survival analysis of this CEPEUS (median follow-up of 58.7 months) showed that, in patients with newly diagnosed multiple myeloma who were ineligible for transplantation or whose transplantation was delayed, adding daratumumab to VRd significantly improved clinical outcomes, including overall MRD negativity and progression-free survival, compared to VRd alone. The deeper response to D-VRd translated into superior progression-free survival, with a significantly reduced risk of disease progression or death by 43%. While overall survival data are immature, they show a positive trend favoring D-VRd. Further sensitivity analyses, adjusted for the effects of COVID-19, provided stronger evidence for the therapeutic efficacy in overall survival.

[0643] Pre-specified subgroup analyses showed that, except for patients with high cytogenetic risk, the overall MRD negativity rate was consistently higher with D-VRd in all subgroups. In all pre-specified subgroups including patients with high cytogenetic risk, D-VRd demonstrated superior progression-free survival compared to VRd. In patients with high-risk cytogenetic disease, progression-free survival was not significant at this clinical cutoff, suggesting the need for longer follow-up in this small, difficult-to-treat patient population.

[0644] Because triple therapy such as D-VRd is the primary treatment for patients ineligible for transplantation, it is important to observe the tolerability of adding bortezomib to the D-VRd regimen. In the phase 3 ALCYONE study, adding daratumumab to bortezomib, melphalan, and prednisone did not increase overall toxicity compared to triple therapy alone, and the 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 in the D-VRd group compared to VRd, and the incidence of grade 3 or 4 peripheral neuropathy was similar across 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 a higher number of grade 5 COVID-19 events. Since most grade 5 adverse events occur after bortezomib discontinuation, the higher incidence of grade 5 adverse events in the D-VRd group likely reflects prolonged treatment exposure rather than increased toxicity from quadruple therapy. When adjusted for exposure by taking into account the additional treatments received in the D-VRd group over the past two years, the rate of grade 5 adverse events was comparable across groups. The incidence of a second primary malignancy was numerically lower in the D-VRd group.

[0645] Prior to this study, results from previous research established D-Rd as the standard of care for ineligible transplant patients, with a median overall survival of 7.5 years and consistent beneficial effects across age, health, and risk status subgroups. It is important to note that all patients recruited in previous studies were ineligible for transplantation, the cohort included frail patients, and there were no upper or lower age limits (approximately 19% were ≥80 years old). However, this study recruited ineligible patients and those with delayed transplantation, excluded frail patients, and had no patients >80 years of age. While the beneficial effects on progression-free survival observed in previous studies are impressive, especially considering the inclusion of frail and elderly patients, quadruple therapy with D-VRd offers the opportunity to improve depth of response and prolong progression-free survival. With the advent of this study, physicians are increasingly able to tailor daratumumab-based first-line combination therapies based on patient age, frailty, and other patient-related and disease-related risk factors. It is important to balance the greater depth of response and longer progression-free survival achievable with quadruple D-VRd therapy with the improved tolerability offered by triple D-Rd therapy. The final decision may be based on the individual patient’s overall treatment goals and perceived tolerance to bortezomib addition.

[0646] Due to differences in patient populations and trial designs, crossover trial comparisons should be interpreted with caution, but contextual consideration of findings can be helpful. Overall, the MRD negativity rate in ALCYONE and MAIA was lower than that observed in CEPEUS (10). –5 The percentages were: D-VMP, 28%; D-Rd, 32.1%; D-VRd, 60.9%, respectively, demonstrating the beneficial effect of D-VRd quadruple therapy in ineligible or delayed transplant patients who could tolerate D-VRd. However, despite the lack of head-to-head comparative trials, these different MRD rates are likely due to inherent differences in study eligibility and patient characteristics (median age for ineligibility in ALCYONE and MAIA was 71 years [range, 40 to 93 years] and 73 years [45 to 90 years], respectively, compared to 70 years [31 to 80 years] for ineligibility / delayed transplant in CEPEUS). The phase 3 IMROZ study evaluated intravenous isatuximab plus VRd in ineligible transplant patients with newly diagnosed multiple myeloma, relative to VRd alone. This study's patient population included ineligible and delayed transplant patients and represented a more real-world population. The median age in this study (70 years) was similar to that in IMROZ (72 years), and a similar proportion of patients had a high cytogenetic risk (13.2% vs. 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). The VMRD negativity rate (55.5% vs. 40.9%; P = 0.003) and the complete response or better response rate (74.7% vs. 64.1%; P = 0.01) were higher with isatuximab plus VRd compared to VRd alone.23 As expected, the incidence of grade 5 adverse events was higher with quadruple therapy compared to triple therapy (approximately twice as high in both studies). There are differences in the timing of study recruitment, with this study starting later than the start of the COVID-19 pandemic (December 2018 compared to IMROZ's December 2017), implying that more patients may still be under study treatment and at risk during the pandemic. It is also noteworthy that IMROZ did not recruit any patients from Brazil, yet over half of the COVID-related deaths in this study occurred in Brazil.

[0647] Recent reports also describe the use of quadruple therapy in transplant-eligible populations. A previous phase 3 study demonstrated significant and clinically meaningful benefits in progression-free survival (hazard ratio, 0.42; P<0.001), complete or better response rate (87.9% vs. 70.1%; P<0.001), and MRD negativity rate (75.2% vs. 47.5%; P<0.001) in the case of D-VRd induction / consolidation followed by daratumumab-lenalidomide maintenance, compared to VRd induction / consolidation and lenalidomide maintenance alone. In summary, these data from this study, combined with results from previous studies, further demonstrate the important role of daratumumab-based triple and quadruple therapies in deepening and prolonging responses in all patients across the first-line treatment spectrum. Many elderly patients with newly diagnosed multiple myeloma may not receive subsequent treatment, highlighting the importance of selecting the most effective regimen in a first-line setting. First-line quadruple D-VRd therapy offers an opportunity to further deepen responses and improve clinical outcomes.

[0648] In summary, with nearly 5 years of follow-up, results from this study demonstrated that, in patients with newly diagnosed multiple myeloma who were ineligible for transplantation or whose transplantation was delayed, adding daratumumab to VRd significantly increased depth of response compared to VRd alone, including overall MRD negativity rate, complete response rate or better response rate, and sustained MRD negativity rate, which translated into significantly improved progression-free survival. Furthermore, the results further enhance the validity of using 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 previous Phase 3 studies, demonstrate the consistent beneficial effects of quadruple therapy with daratumumab plus VRd compared to triple VRd therapy, and support D-VRd quadruple therapy as a new standard of care for newly diagnosed multiple myeloma, regardless of transplant eligibility.

[0649] Example 2: Daramumumab plus bortezomib and lenalidomide in patients with newly diagnosed multiple myeloma Amine and dexamethasone (D-VRd): Subgroup analysis of ineligible transplant patients in the phase 3 CEPEUS study

[0650] D-VRd is the standard of care for newly diagnosed multiple myeloma (NDMM) patients who are eligible for transplantation. In CEPEUS (NCT03652064), D-VRd, compared with VRd, improved minimal residual disease (MRD) negativity and progression-free survival (PFS) in NDMM patients who were ineligible for transplantation (TIE) or whose transplantation was delayed. Because transplantation delay is uncommon in many regions, a post-hoc analysis of the efficacy of D-VRd in TIE patients only is reported.

[0651] Materials and methods :

[0652] CEPEUS recruits patients with TIE or delayed transplantation who have NDMM, an ECOG performance status of 0–2, and an International Myeloma Working Group (IMWG) frailty score of 0–1. Patients who provide informed consent are randomly assigned 1:1 to D-VRd or VRd. The primary endpoint is the overall MRD negativity rate (10). –5 Thresholds include complete response or better response [≥CR]); secondary endpoints include PFS and persistent MRD negativity (confirmed MRD negativity for ≥12 months, with no MRD positivity).

[0653] result :

[0654] Of the 395 patients, 289 were TIE (D-VRd, n=144; VRd, n=145). Baseline characteristics were generally balanced between treatment groups. In TIE, the median age was older (72 years vs. 70 years) compared to the intention-to-treat group, and the percentage of moderately healthy patients was higher according to IMWG criteria (41.2% vs. 35.2%). In TIE patients, the 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); the MRD negativity rate under 10⁻⁶ was 45.8% vs. 26.9% (OR, 2.28 [95% CI, 1.40–3.73]; P=0.001). The sustained MRD negative rate (10-5) was 46.5%, compared to 27.6% (OR, 2.27 [95% CI, 1.39-3.70]; P = 0.0010). The overall ≥CR rate was 80.6%, compared to 61.4% (OR, 2.73 [95% CI, 1.71-4.34]; P < 0.0001). During a median follow-up of 58.7 months, D-VRd did not achieve median PFS, compared to 49.6 months for VRd (54-month ratio: 69.0% vs. 48.0%; hazard ratio [HR], 0.51 [95% CI, 0.35-0.74]; P = 0.0003). In TIE patients who achieved MRD negativity (10⁻⁵; D-VRd, n=87; VRd, n=57), median PFS was not achieved in either treatment group (54-month rate: 79.5% for D-VRd vs. 70.6% for VRd; HR, 0.62, [95% CI, 0.33–1.17]; P=0.1382). In TIE patients who maintained MRD positivity (10⁻⁵; D-VRd, n=57; VRd, n=88), median PFS was not achieved with D-VRd, which was 34.5 months compared to VRd (54-month rate: 51.0% vs. 30.2%; HR, 0.62, [95% CI, 0.38–1.02]; P=0.0569). Overall survival was favorable for D-VRd compared to 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 efficacy was consistent across subgroups. Safety results were consistent with the known safety profiles of subcutaneous daralimumab and VRd.

[0655] In patients with CEPEUS TIE, the ≥CR rate was 80.6%, and the overall MRD negative rate (10 −5The efficacy rate was 60.4% and the 12-month MRD negativity rate was 46.5%, all strongly supporting the superiority of D-VRd over VRd. Furthermore, 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.

[0656] Example 3: Weakness subgroup analysis of CEPEUS

[0657] Patients ineligible for transplantation under both MAIA and CEPEUS are generally considered ineligible for autologous stem cell transplantation due to age or comorbidities. These two factors are also criteria for classifying frailty, and increased frailty is a predictor of increased risk of disease progression and death in patients with multiple myeloma (MM). Notably, poorer outcomes in frail patients are associated with higher rates of non-hematologic adverse events and treatment discontinuation observed in this population. Therefore, criteria for assessing frailty are crucial for guiding treatment decisions that balance efficacy with increased toxicity risks in frail patients. Several indices have been developed to measure frailty in MM patients. The two most commonly used indices are the International Myeloma Working Group (IMWG) Frailty Index recommended by the European Myeloma Network and the Simplified Frailty Index of the Inter-French-Speaking Myeloma (IFM). Both indices incorporate the patient’s age and number of comorbidities, but they differ in that the IMWG index incorporates functional status (Katz Activities of Daily Living (ADL) and Lawton Instrumental Activities of Daily Living (IADL), which assess the ability to perform daily activities such as self-care and home management) using patient-reported assessments, while the IFM Simplified Frailty Index uses the Eastern Cooperative Oncology Group (ECOG) performance status.

[0658] A post-hoc analysis of MAIA data using the IFM Simplified Frailty Scale identified approximately 50% of study participants as frail and demonstrated a beneficial effect on progression-free survival (PFS) relative to RD in the case of DRd, regardless of baseline frailty status. CEPEUS excluded patients who were frail according to the IMWG criteria but did not exclude those classified as frail according to the IFM criteria. Therefore, subgroup analyses of CEPEUS are presented, comparing DVRd relative to VRd in the frail subgroup based on protocol-defined IMWG frailty status at baseline, as well as a post-hoc analysis based on the IFM Simplified Frailty Scale.

[0659] A total of 395 patients were randomly assigned to either DVRd (n=197) or VRd (n=198) in CEPHEUS; the median follow-up (range) was 58.7 (0.1–64.7) months. On the IMWG Frailty Scale, 256 patients were classified as healthy (DVRd, n=124; VRd, n=132), and 139 patients were classified as moderately healthy (DVRd, n=73; VRd, n=66). On the IFM Simplified Frailty Scale, 297 patients were non-frail (DVRd, n=140; VRd, n=157), and 98 patients were frail (DVRd, n=57; VRd, n=41). Baseline demographics and disease characteristics were generally similar across the treatment groups in the overall frailty subgroup, except that a higher proportion of the frailty subgroup had ISS stage III disease and, as expected, were older and had poorer ECOG performance status.

[0660]

[0661]

[0662]

[0663]

[0664] Overall, 392 patients (DVRd: n=197; DVRd, n=195) received at least one dose of study treatment. In the frailty subgroup, the median duration of treatment was longer in the DVRd case than in the VRd case, but shorter in the healthier patients than in the frailty patients. In the IMWG frailty subgroup, the median (range) duration of treatment was 57.1 months (0.3–64.6) in the healthy subgroup and 40.1 months (0.5–63.8) in the VRd case, while in the moderately healthy subgroup, the median (range) duration of treatment was 45.8 months (0.1–63.7) in the DVRd case and 32.4 months (0.5–62.4) in the VRd case. In the simplified frailty subgroup of IFM, the median duration of treatment was 57.1 months (0.1–64.6) in the non-frailty subgroup and 36.2 months (0.5–63.8) in the VRd subgroup, while the median duration of treatment was 44.7 months (0.5–63.7 months) in the DVRd subgroup and 25.7 months (0.5–62.4 months) in the VRd subgroup.

[0665] In the weakened subgroup, in 10 -5 and 10 -6At the threshold, the overall MRD negative rate with ≥CR was consistently higher in the case of DVRd compared to VRd. Figure 32 In the IMWG debilitated subgroup, the overall MRD negative rate with ≥CR was 44.7% in healthy patients compared to 44.7% in those with VRd, compared to 10% in those with DVRd. -5 The prevalence was 63.7% (P = 0.0026) in moderately healthy patients, compared to 28.8% in moderately healthy patients, and 56.2% (P = 0.0019) in healthy patients. -6 In the IMWG frail subgroup, the overall MRD negative rate with ≥CR was 46.8% in the DVRd case, compared to 31.8% in the VRd case (P=0.0153), and 45.2% in moderately healthy patients, compared to 18.2% (P = 0.0010). In non-frail patients, the overall MRD negative rate with ≥CR was 42.0% in the VRd case, compared to 42.0% in the DVRd case (P = 10). -5 The prevalence was 63.6% (P = 0.0003), and among frail patients, it was 54.4% (P = 0.0148) compared to 29.3% (P = 0.0148) in 10... -6 The corresponding rates were 47.9% in non-asthenic patients versus 29.3% (P=0.0012) and 42.1% in asthenic patients versus 19.5% (P=0.0283).

[0666] In 10 -5 and 10 -6 Below the threshold, in the entire frailty subgroup, a higher proportion of patients with DVRd had persistently negative MRD compared to VRd. In the IMWG frailty subgroup, at 10 -5 Below the threshold, in healthy patients, the rate of sustained MRD negativity for ≥12 months was 50.0% in the case of DVRd, compared to 31.1% in the case of VRd (P=0.0023), and in moderately healthy patients, it was 47.9% (P=0.0006), compared to 19.7% in the case of DVRd. Figure 33 A). In 10 -6 Below the threshold, in healthy patients, these rates were 34.7% in DVRd, compared to 18.2% in VRd (P=0.0029), and in moderately healthy patients, they were 32.9% compared to 12.1% (P=0.0045). Figure 33 B). In the IFM simplified weakened subgroup, at 10 -5At the threshold, 52.1% of non-frail patients in the DVRd condition maintained a negative MRD for ≥12 months, compared to 30.6% in the VRd condition (P = 0.0002), and among frail patients, the figure was 42.1% compared to 14.6% (P = 0.0040), and in 10... -6 At the threshold, the percentage of non-frail patients was 36.4% vs. 17.2% (P = 0.0002), and the percentage of frail patients was 28.1% vs. 12.2% (P = 0.0808). In the IMWG and IFM frail subgroups, at both thresholds, the rate of sustained MRD negativity for ≥24 months was also higher in the DVRd case compared to the VRd case. Figure 35 ).

[0667] In the IMWG frailty subgroup, DVRd improved PFS compared to VRd. In healthy patients, median PFS was not achieved with DVRd at 60.6 months compared to VRd (HR, 0.59; 95% CI: 0.39–0.91; P = 0.0149), and in moderately healthy patients, median PFS was not achieved at 38.7 months compared to VRd (HR, 0.56; 95% CI: 0.34–0.91; P = 0.0189). Figure 34 A). Similarly, in the simplified frailty subgroup of IFM, DVRd improved PFS compared to VRd. In non-frail patients, median PFS was not achieved in DVRd at 60.6 months compared to VRd (HR, 0.58; 95% CI: 0.39–0.86; P = 0.0054), and in frail patients, median PFS was not achieved at 31.7 months compared to VRd (HR, 0.51; 95% CI: 0.28–0.93; P = 0.0242). Figure 34 B).

[0668] In all weakened subgroups, the proportion of ≥CR was higher in the case of DVRd compared to VRd. Figure 36 In the IMWG frailty subgroup, the proportion of patients achieving ≥CR was 68.9% in the healthy subgroup compared to 68.9% in the VRd subgroup and 86.3% in the DVRd subgroup (P=0.0009), and 72.6% vs 47.0% in the moderately healthy subgroup (P=0.0021). In the IFM simplified frailty subgroup, the corresponding rates were 85.7% vs 65.0% in non-frail patients (P<0.0001) and 70.2% vs 48.8% in frail patients (P=0.0329).

[0669] Compared with healthier patients (i.e., healthy in IMWG and non-frail in IFM), frail patients (i.e., moderately healthy in IMWG and frail in IFM) had worse health-related quality of life (lower scores) at baseline as assessed on the EORTC QLQ-C30 Global Health Status Dimension. In both treatment groups, scores in the healthier subgroup remained close to baseline; in the frail subgroup, scores improved (increased) over time and became comparable to those in the healthier subgroup.

[0670] The most common treatment-emergent adverse events (TEAEs) are shown in Tables 8 (IMWG frailty subgroup) and 9 (IFM simplified frailty subgroup). The rates of Grade 3 or 4 TEAEs were higher in both treatment groups in the less healthy IMWG subgroup (healthy: 89.5% in DVRd and 84.1% in VRd; moderately healthy: 97.3% in DVRd and 88.9% in VRd) and in the more frail IFM subgroup (non-frail: 90.0% in DVRd and 84.6% in VRd; frail: 98.2% in DVRd and 89.7% in VRd). Neutropenia was the most common Grade 3 or 4 TEAE across all subgroups in both treatment groups. In the IMWG frailty subgroup, the rates of grade 3 or 4 neutropenia were 41.1% in healthy patients with DVRd and 27.3% in VRd, compared to 49.3% and 34.9% in moderately healthy patients, respectively. In the IFM frailty subgroup, the corresponding rates were 42.9% and 30.1% in non-frail patients, and 47.4% and 28.2% in frail patients, respectively. In the IMWG frailty subgroup, the 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%) in healthy patients with DVRd and VRd, respectively, and 53.4% ​​(grade 2, 34.2%; grade 3 or 4, 6.8%) and 58.7% (grade 2, 27.0%; grade 3 or 4, 11.1%) in moderately healthy patients, respectively (Table 8). In the IFM frailty subgroup, the peripheral sensory neuropathy rate was 55.7% (grade 2: 29.3%; grade 3 or 4, 8.6%) in non-frail patients with DVRd, 66.0% (grade 2: 39.1%; grade 3 or 4, 9.0%) in VRd, and 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).

[0671] The incidence of serious TEAEs was higher in frail patients than in healthy patients in both treatment groups. In the IMWG frail subgroup, these rates were 70.2% in healthy patients with DVRd and 60.6% in VRd, compared to 75.3% and 81.0% in moderately healthy patients, respectively. In the IFM frail subgroup, these rates were 69.3% in non-frail patients with DVRd and 62.8% in VRd, compared to 78.9% and 84.6% in frail patients, respectively. The most common serious TEAEs in both treatment and frail subgroups were infections, most commonly pneumonia or COVID-19. In the IMWG frail subgroup, the rate of severe infection was 35.5% in healthy patients with DVRd and 32.6% in VRd; the corresponding rates were 46.6% and 41.3% in moderately healthy patients, respectively. In the IFM debilitated subgroup, the rate of severe infection was 36.4% in non-debilitated patients with DVRd, 30.8% in VRd, and 47.4% and 53.8% in debilitated patients, respectively.

[0672] In the frail subgroup, the rate of all study drug discontinuation due to TEAE was lower in the DVRd subgroup (5.7% to 12.3%) compared to the VRd subgroup (13.6% to 20.6%). In the healthier subgroup, the rates of bortezomib discontinuation due to TEAE were similar in both the DVRd and VRd subgroups (IMWG healthy: 14.5% in the DVRd subgroup and 15.2% in the VRd subgroup; IFM non-frail: 12.9% and 14.1%, respectively), and lower in the frail subgroup in the DVRd subgroup (IMWG moderately healthy: 9.6% and 19.0%; IFM frail: 12.4% and 25.6%). In the frail subgroup, the median rate of bortezomib discontinuation due to peripheral sensory neuropathy was lower in the DVRd subgroup compared to the VRd subgroup.

[0673] In the IMWG frailty subgroup, Grade 5 non-COVID-19 TEAEs occurred in 10.5% of healthy patients in the DVRd group and 6.1% in the VRd group, and correspondingly in 11.0% and 11.1% of moderately healthy patients. Grade 5 COVID-19 TEAEs occurred in 4.0% and 3.0% of healthy patients and 9.6% and 3.2% of moderately healthy patients. In the IFM frailty subgroup, Grade 5 non-COVID-19 TEAEs occurred in 10.0% and 5.1% of non-frail patients, and in 12.3% and 17.9% of frail patients. Grade 5 COVID-19 TEAEs occurred in 6.4% and 2.6% of non-frail patients and 5.3% and 5.1% of frail patients.

[0674] In summary, the beneficial effects of DVRd in the frail subgroup, compared to VRd, support DVRd as a new standard of care for patients ≤80 years of age with NDMM who are ineligible for transplantation or whose transplantation is delayed, can tolerate bortezomib, and are healthy or moderately healthy according to IMWG criteria or non-frail or frail according to IFM criteria. These findings, along with the frail subgroup analysis from MAIA, help inform patients with NDMM who have not received first-line transplantation about the option of daratumumab quadruple or triple therapy, allowing for customized regimens based on bortezomib eligibility and treatment goals.

[0675] Example 4: Transplant-eligible patients treated with daratumumab, bortezomib, lenalidomide, and dexamethasone Modeling long-term progression-free survival in newly diagnosed multiple myeloma patients who are ineligible for transplantation.

[0676] In the PERSEUS trial, quadruple therapy consisting of daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) plus DR maintenance therapy showed superior efficacy to VRd with R maintenance in newly diagnosed multiple myeloma (NDMM) patients with ineligible for transplantation (TE). Similarly, the CEPEUS trial demonstrated the superiority of DVRd over VRd in NDMM patients with ineligible for transplantation (TIE) or delayed transplantation. In the DVRd group (intent-to-treat [ITT]) of both trials, median progression-free survival (PFS) was not achieved at median follow-up of 47.5 months (PERSEUS) and 58.7 months (CEPEUS); in the VRd group, median PFS was not achieved in PERSEUS and was 52.6 months in CEPEUS. Since DVRd can be used to treat both TE and TIE in patients, and treatment guidelines focus on these two groups, this analysis aims to extrapolate PFS data from the TIE subgroups of the PERSEUS trial (ITT) and CEPHALUS to estimate the long-term outcomes of DVRd in a frontline setting, thereby helping to inform clinical decisions.

[0677] Following the UK National Institute for Health and Clinical Excellence (NICE) guidelines on extrapolation of survival data, seven parameter distributions were fitted to the model's PFS data: exponential, Weibull, γ, Gompertz, log-logic, log-normal, and generalized γ. Curves for each parameter were fitted to the DVRd and VRd groups. Long-term extrapolation was performed using UK general population data on disease-specific and all-cause mortality from 2020–2022, capped by the median age of the population at treatment initiation and the proportion of male patients in the cohort (according to NICE guidelines). PFS prediction began at the median age of the population.

[0678] In PERSEUS, 709 patients with TE were randomized (DVRd, n=355; VRd, n=354), with a median age of 60 years and 59% male. In CEPHEUS, 289 patients with TIE were randomized (DVRd, n=144; VRd, n=145), with a median age of 72 years and 51% male. In PERSEUS, the Kaplan-Meier estimates of PFS observed at 48 months in TE patients were 84.3% vs. 67.7% in the DVRd and VRd groups, respectively; for TIE patients in CEPHALUS, they were 72.3% vs. 52.3%. Figure 37 Based on PFS modeling in the PERSEUS TE population, the estimated median PFS range across all distributions is 158–255 months (13.2–21.2 years) for the DVRd group and 76–119 months (6.3–9.9 years) for the VRd group. The exponential distribution (best fit) yields PFS estimates of 205 months versus 87 months (17.1 years versus 7.3 years) for both DVRd and VRd. Figure 38 For the CEPHEUS TIE population, the estimated median PFS range in the distribution is 96–118 months (8.0–9.8 years) for the DVRd group and 52–54 months (4.3–4.5 years) for the VRd group. For both DVRd and VRd, the exponential distribution (best fit) is 100 months versus 53 months (8.3 years versus 4.4 years), respectively. Figure 39 ).

[0679] In all seven distributions, in patients with NDMM who underwent TE and TIE, the predicted PFS was significantly longer in the DVRd case compared to VRd. As expected, the predicted PFS in TE patients was longer in the DVRd case (205 months from baseline age of 60 years) compared to TIE patients (100 months from age 72). These extrapolations provide supporting predictions beyond the observed PFS data, helping to inform treatment decisions and enhance the beneficial effects of DVRd with daratumumab-containing maintenance regimens in all NDMM patients.

[0680] Example 4: Key Points of Prescription Information

[0681] DARZALEX FASPRO ® It is a combination of daratumumab, CD38-directed cytolytic antibody, and hyaluronidase and endoglucosidase, which is indicated for the treatment of the following adult patients:

[0682] • In combination with bortezomib, thalidomide, and dexamethasone, it is used for newly diagnosed multiple myeloma patients who are ineligible for autologous stem cell transplantation.

[0683] Dosage and administration

[0684] Important Dosage Information

[0685] DARZALEX FASPRO ® For subcutaneous use only. When applying DARZALEX FASPRO... ® Administer the drug before and after administration to minimize administration-related reactions. At the start of DARZALEX FASPRO ® Previously, patients were classified and screened.

[0686] Recommended dose for multiple myeloma

[0687] DARZALEX FASPRO ® The recommended dose is 1,800 mg / 30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes. Table 8 provides information on the use of DARZALEX FASPRO. ® Recommended dosing schedule when used as part of a combination therapy.

[0688] Combined with bortezomib, lenalidomide and dexamethasone (DARZALEX FASPRO-VRd) for use in patients who do not meet ASCT requirements Qualified patients

[0689] When DARZALEX FASPRO ® When used in combination with bortezomib, lenalidomide and dexamethasone (3-week cycle) to treat newly diagnosed patients with multiple myeloma who do not qualify for ASCT, use the dosing schedule in Table 8.

[0690]

[0691] When DARZALEX FASPRO is administered as part of a combination therapy, refer to the prescribing information for the dosage recommendations of the other medications.

[0692] application

[0693] If you miss a dose of DARZALEX FASPRO ® If the dosage is correct, administer that dosage as soon as possible and adjust the dosing schedule accordingly to maintain the dosing interval.

[0694] Recommended combination therapy

[0695] Pre-medication

[0696] In each DARZALEX FASPRO ®Administer the following pre-treatment medications 1 to 3 hours prior to the main medication:

[0697] • Acetaminophen 650mg to 1,000mg, orally

[0698] • Diphenhydramine 25 mg to 50 mg (or equivalent), orally or intravenously

[0699] • Corticosteroids (long-acting or intermediate-acting)

[0700] Monotherapy

[0701] Administer methylprednisolone 100 mg (or equivalent) orally or intravenously. Consider a second dose of DARZALEX FASPRO. ® The dose of methylprednisolone was then reduced to 60 mg (or equivalent).

[0702] combination

[0703] In each DARZALEX FASPRO ® Prior to administration, administer 20 mg of dexamethasone (or equivalent) orally or intravenously.

[0704] When dexamethasone is the background regimen specific corticosteroid, the dexamethasone dose as part of the background regimen will be at DARZALEX FASPRO ® It is used as a pre-treatment medication on the day of application.

[0705] When patients have already received dexamethasone (or equivalent) as pre-treatment, at DARZALEX FASPRO ® Do not administer background regimen on the day of administration - specific corticosteroids (e.g., prednisone).

[0706] Post-medication

[0707] The following medications should be used after administration:

[0708] Monotherapy

[0709] From the application of DARZALEX FASPRO ® Starting the day after that, administer 20 mg of methylprednisolone orally (or an equivalent dose of a medium- or long-acting corticosteroid) for 2 days.

[0710] combination

[0711] Consider using DARZALEX FASPRO ® Starting the following day, methylprednisolone was administered orally at a dose of 20 mg or less (or an equivalent dose of a medium- or long-acting corticosteroid).

[0712] If DARZALEX FASPRO is applied ® If the background regimen of a specific corticosteroid (such as dexamethasone or prednisone) is administered on the following day, additional corticosteroids may not be necessary.

[0713] If the first 3 doses of DARZALEX FASPRO ® If the patient does not experience major systemic administration-related reactions, discontinuation of corticosteroids should be considered (excluding any background regimen-specific corticosteroids).

[0714] For patients with a history of chronic obstructive pulmonary disease (COPD), consider prescribing short-acting and long-acting bronchodilators, as well as inhaled corticosteroids. In the first four doses of DARZALEX FASPRO... ® Subsequently, if the patient does not experience major systemic administration-related reactions, discontinuation of these additional post-treatment medications should be considered.

[0715] Prevention of shingles reactivation

[0716] At the beginning of DARZALEX FASPRO ® Antiviral prophylaxis should begin within one week after treatment to prevent shingles reactivation and should continue for three months after treatment ends.

[0717] Dosage modification for adverse reactions

[0718] It is not recommended to reduce DARZALEX FASPRO ® The dosage. Consider discontinuing DARZALEX FASPRO. ® This allows for the restoration of blood cell counts in cases of bone marrow suppression.

[0719] Preparation and application

[0720] DARZALEX FASPRO ® It should be administered by a healthcare provider.

[0721] To prevent medication errors, check the vial label to ensure that the prepared and administered medication is DARZALEX FASPRO for subcutaneous use. ® Do not administer DARZALEX FASPRO intravenously. ® DARZALEX FASPRO ® It is ready to use.

[0722] preparation

[0723] Remove DARZALEX FASPRO from refrigerated storage.® Vials [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 unpunctured vials at ambient temperature and light for up to 24 hours. Avoid direct sunlight. Do not shake.

[0724] Draw 15mL from the vial into the syringe.

[0725] DARZALEX FASPRO ® Compatible with: polypropylene or polyethylene syringe materials; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer needles and injection needles. Use the product immediately.

[0726] In DARZALEX FASPRO ® After the solution is drawn into the syringe, replace the transfer needle with the syringe cap. Properly label the syringe to include the administration route according to the institution's standards. Label the syringe with the peel-off label.

[0727] To avoid needle clogging, connect the subcutaneous injection needle or subcutaneous infusion set to the syringe immediately before injection.

[0728] Provided the solution and container allow, visually inspect the parenteral drug product for particulate matter and discoloration before application. Do not use if opaque particles, discoloration, or other foreign matter are present.

[0729] storage device

[0730] If not used immediately, it contains DARZALEX FASPRO ® The syringes are to be refrigerated at 2°C to 8°C (36°F to 46°F) under ambient light for up to 24 hours and / or stored at room temperature at 15°C to 25°C (59°F to 77°F) for up to 12 hours.

[0731] If the storage time exceeds these limits, it will be discarded.

[0732] If stored in a refrigerator, allow the solution to reach room temperature before application.

[0733] application

[0734] Add 15 mL of DARZALEX FASPRO ® The injection is administered over approximately 3 to 5 minutes into the subcutaneous tissue of the abdomen, about 3 inches [7.5 cm] to the right or left of the navel. No data is available regarding injections at other sites on the body.

[0735] Continuous injection is performed by rotating the injection site.

[0736] Do not use DARZALEX FASPRO ® Injected into areas of skin that are red, bruised, tender, hard, or have scars.

[0737] If the patient experiences pain, pause or slow the delivery rate. If pausing or slowing the delivery rate does not alleviate the pain, a second injection site can be selected on the opposite side of the abdomen to deliver the remaining dose.

[0738] Using DARZALEX FASPRO ® Do not use DARZALEX FASPRO during treatment. ® Other subcutaneous medications were applied to the same site.

[0739] Dosage form and specifications

[0740] Injection: 1,800 mg daratumumab and 30,000 units of hyaluronidase / 15 mL (120 mg and 2,000 units / mL) in a single-dose vial, colorless to yellow, clear to milky white solution.

[0741] Taboo

[0742] DARZALEX FASPRO ® This medication is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any component of the formulation.

[0743] Warnings and precautions

[0744] Hypersensitivity reactions and other application reactions

[0745] In DARZALEX FASPRO ® In cases of systemic administration, reactions may occur, including severe or life-threatening reactions, as well as local injection site reactions. Reactions involving products containing daralimumab (including DARZALEX FASPRO) have been reported. ® () a fatal reaction.

[0746] Drug Interactions

[0747] The impact of daratumumab on laboratory testing

[0748] Interference with the indirect antiglobulin test (indirect Coombs test)

[0749] Daremumab binds to CD38 on RBCs and interferes with compatibility tests, including antibody screening and cross-matching. Methods to mitigate daratumumab interference include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or genotyping. Because the Kell blood group system is also sensitive to DTT treatment, K-negative units are supplied after excluding or identifying alloantibodies using DTT-treated RBCs.

[0750] If an emergency transfusion is required, non-cross-matched ABO / RhD compatible RBCs should be administered according to local blood bank practices.

[0751] Interference with serum protein electrophoresis and immunofixation assays

[0752] Daremumab can be detected in serum protein electrophoresis (SPE) and immunofixation (IFE) assays, which are used to monitor disease monoclonal immunoglobulins (M proteins). In patients with IgGκ myeloma protein, false-positive results can occur in both SPE and IFE assays, affecting the initial assessment of complete response according to the International Myeloma Working Group (IMWG) criteria. In patients with suspected daratumumab interference and a consistently very good partial response, as determined by DARZALEX FASPRO... ® In treated patients, the use of an FDA-approved daratumumab-specific IFE assay should be considered to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, in order to help determine a complete response.

[0753] Special population medication

[0754] pregnancy

[0755] Risk Overview

[0756] When administered to pregnant women, DARZALEX FASPRO ® It may cause harm to the fetus. The risk assessment associated with daratumumab products is based on the mechanism of action and data from CD38 knockout animal models of the target antigen (see Data). Regarding the use of DARZALEX FASPRO in pregnant women... ® The data cannot be used to assess the risk of major birth defects, miscarriage, or adverse maternal and infant outcomes associated with the drug. Animal reproductive toxicity studies have not yet been conducted.

[0757] The estimated background risk of major birth defects and miscarriage in the target population is unclear. All pregnancies carry a background risk of birth defects, miscarriage, or other adverse outcomes. In the general U.S. population, the clinically accepted estimated background risks of major birth defects and miscarriage during pregnancy are 2% to 4% and 15% to 20%, respectively.

[0758] DARZALEX FASPRO ® Combinations with lenalidomide, thalidomide, or pomalidomide are contraindicated in pregnant women because lenalidomide, thalidomide, and pomalidomide may cause birth defects and unborn fetal death. Lenalidomide, thalidomide, and pomalidomide are only available through the REMS procedure. For information on lenalidomide, thalidomide, or pomalidomide use during pregnancy, refer to the prescribing information for lenalidomide, thalidomide, or pomalidomide.

[0759] Clinical precautions

[0760] Adverse reactions in fetuses / newborns

[0761] Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX FASPRO... ® It can lead to depletion of fetal CD38-positive immune cells and decreased bone density. Live vaccination should be postponed for newborns and infants exposed to daratumumab in utero until hematological evaluation is completed.

[0762] data

[0763] Animal data

[0764] DARZALEX FASPRO for subcutaneous injection ® It contains daratumumab and hyaluronidase. Mice genetically modified to eliminate all CD38 expression (CD38 knockout mice) have reduced bone density at birth, which recovers by 5 months of age. Data from studies using CD38 knockout animal models also indicate that CD38 is involved in the regulation of humoral immune responses (mice), fetal-maternal immune tolerance (mice), and early embryonic development (frogs).

[0765] No systemic exposure to hyaluronidase was detected in monkeys given subcutaneously at 22,000 U / kg (12 times higher than the human dose), and there was no effect on embryonic fetal development in pregnant mice given subcutaneously daily at 330,000 U / kg hyaluronidase (45 times higher than the human dose) during organogenesis.

[0766] The treatment of mouse offspring subcutaneously with 990,000 U / kg hyaluronidase (134 times higher than the human dose) daily from implantation to lactation had no effect on prenatal and postnatal development to sexual maturity.

[0767] Breastfeeding

[0768] Risk Overview

[0769] There is no data on the presence of daralimumab and hyaluronidase in human milk, their effects on breastfed infants, or their impact on milk yield. Maternal immunoglobulin G is known to be present in human milk. Published data indicate that antibodies in breast milk do not enter the circulatory system of newborns and infants in large quantities. Due to the presence of DARZALEX FASPRO... ® Serious adverse reactions may occur in breastfed children when used with lenalidomide, thalidomide, or pomalidomide; therefore, women are advised to use DARZALEX FASPRO with caution. ® Do not breastfeed during treatment. Refer to lenalidomide, thalidomide, or pomalidomide prescription information for additional information.

[0770] data

[0771] Animal data

[0772] No systemic exposure to hyaluronidase was detected in monkeys that were subcutaneously administered 22,000 U / kg (12 times higher than the human dose), and it had no effect on postnatal development to sexual maturity in mouse offspring that were subcutaneously treated daily during lactation with 990,000 U / kg hyaluronidase (134 times higher than the human dose).

[0773] Women and men with fertility potential

[0774] When administered to pregnant women, DARZALEX FASPRO ® It may harm the fetus.

[0775] Pregnancy test

[0776] In DARZALEX FASPRO ® When used in combination with lenalidomide, thalidomide, or pomalidomide, refer to the label of lenalidomide, thalidomide, or pomalidomide required for pregnancy testing before initiating treatment in women of reproductive potential.

[0777] contraception

[0778] It is recommended that women of childbearing age use DARZALEX FASPRO ® Use effective contraception during treatment and for 3 months after the last dose. Also, please refer to the label of lenalidomide, thalidomide, or pomalidomide for more contraceptive advice.

[0779] Pediatric use

[0780] DARZALEX FASPRO ® Its safety and efficacy in pediatric patients have not been established.

[0781] Clinical research

[0782] In patients ineligible for ASCT transplantation, in combination with bortezomib, lenalidomide, and dexamethasone

[0783] DARZALEX FASPRO was evaluated in CEPHEUS (NCT03652064) in patients with newly diagnosed multiple myeloma who were ineligible for ASCT or refused ASCT as initial therapy. ® With bortezomib, lenalidomide and dexamethasone (DARZALEX FASPRO) ® CEPEUS is an open-label, randomized, active-controlled trial comparing the efficacy of bortezomib, lenalidomide, and dexamethasone (VRd) to VRd.

[0784] Patients received subcutaneous DARZALEX FASPRO once a week from week 1 to week 6, once every three weeks from week 7 to week 24, and once every four weeks starting from week 25. ® 1800 mg / 30,000 units, until disease progression or unacceptable toxicity. Bortezomib at 1.3 mg / m². 2 The body surface area dose is administered subcutaneously twice weekly for two weeks of each 21-day cycle (days 1, 4, 8, and 11). Lenalidomide is administered orally at a dose of 25 mg daily from day 1 to day 14 of cycles 1-8. Dexamethasone is administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1-8. (DARZALEX FASPRO) ® On the day of injection, administer the prescribed dose of dexamethasone orally or intravenously as a pre-injection medication.

[0785] DARZALEX FASPRO ® The effectiveness of VRd in patients who refuse ASCT as initial therapy has not been confirmed.

[0786] The primary efficacy outcome measures were the overall minimal residual disease (MRD) negative rate and progression-free survival (PFS) based on the IMWG response criteria by an independent review committee (IRC).

[0787] A total of 395 patients were randomly assigned: 197 entered the DARZALEX FASPRO ®-VRd group, and 198 patients were enrolled in the VRd group. 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. 34% of patients had ISS stage I disease, 38% had ISS stage II disease, and 28% had ISS stage III disease. High-risk cytogenetic patterns (presence of del(17p), t(4;14), t(14,16)) were present in 13% of patients.

[0788] The trial demonstrated statistically significant improvements in overall MRD negative rate, PFS, CR rate or better response rate, and sustained MRD negative rate, as shown in Table 11.

[0789]

[0790]

[0791] How to supply / store and handle

[0792] DARZALEX FASPRO ® (Daratumumab and Hyaluronidase-fihj) injection is a sterile, preservative-free, colorless to yellow and clear to milky white solution for subcutaneous use, provided in individually packaged single-dose vials, each 15 mL providing 1,800 mg of daratumumab and 30,000 units of hyaluronidase (NDC 57894-503-01).

[0793] DARZALEX FASPRO ® Store the vials in their original cardboard box in a refrigerator at 2°C to 8°C (36°F to 46°F) to protect them from light. Do not freeze or shake.

[0794]

[0795]

[0796]

Claims

1. A method for treating a newly diagnosed multiple myeloma in a subject in need, the method 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 transplantation (ASCT) or has had HDC and ASCT delayed.

2. The method according to claim 1, wherein the pharmaceutical composition comprises daratumumab or a daratumumab biosimilar, and hyaluronidase.

3. The method according to claim 2, wherein the hyaluronidase is recombinant human hyaluronidase or rHuPH20.

4. The method according to any one of claims 1-3, wherein the subject who is not eligible for HDC and ASCT is 70 years of age or older.

5. The method according to any one of claims 1-4, wherein the subject who is not eligible for HDC and ASCT is 18 years of age or older and less than 70 years of age, and has one or more comorbid conditions.

6. The method according to any one of claims 1-5, wherein the method achieves an improved clinical efficacy endpoint for the subject relative to a clinical efficacy endpoint achieved in a reference subject or reference subject population, the reference subject or reference subject population having been administered a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab.

7. The method of claim 6, wherein the improved clinical efficacy endpoint is an improved overall minimal residual disease (MRD) negative rate, an improved sustained MRD negative rate, an improved complete response (CR) rate or better response rate, improved progression-free survival (PFS), an improved overall response rate (ORR), an improved overall survival (OS), an improved progression-free survival with next-line treatment (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 negative rate.

9. The method of claim 8, wherein the improved overall MRD negative rate is at or below 10%. -5 The sensitivity threshold.

10. The method of claim 9, wherein the improved overall MRD negative rate is 60.9% relative to 39.4% of the reference subjects or the reference subject population.

11. The method of claim 10, wherein the improved overall MRD negative rate represents an absolute increase of 21.5% relative to the reference subject or the reference subject population.

12. The method of claim 11, wherein the improved overall MRD negative rate is at or below 10%. -6 The sensitivity threshold.

13. The method of claim 12, wherein the improved overall MRD negative rate is 46.2% relative to 27.3% of the reference subjects or the reference subject population.

14. The method according to any one of claims 8-13, wherein the overall MRD negative rate is determined before progression of multiple myeloma, after administration of antimyeloma therapy, or both.

15. The method according to any one of claims 8-14, wherein the subject does not have a high cytogenetic risk.

16. The method of claim 7, wherein the improved clinical efficacy endpoint is an improved rate of negative persistent minimal residual disease (MRD).

17. The method of claim 16, wherein the improved sustained MRD negative rate lasts 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 negative rate is at or below 10%. -5 The sensitivity threshold.

19. The method of claim 18, wherein the improved sustained MRD negative rate is 48.7% relative to 26.3% of the reference subjects or the reference subject population.

20. The method of claim 16 or 17, wherein the improved sustained MRD negative rate is at or below 10%. -6 The sensitivity threshold.

21. The method of claim 20, wherein the improved sustained MRD negative rate is 32.0% relative to 15.7% of the reference subjects or the reference subject population.

22. The method according to any one of claims 7-21, wherein the improved overall MRD negative rate or the improved sustained MRD negative rate is assessed by next-generation sequencing.

23. The method according to any one of claims 7-22, wherein the improved overall MRD negativity rate or the improved sustained MRD negativity rate is assessed using bone marrow aspiration samples obtained on day 0, at 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 thereafter annually in subjects with complete response.

24. The method of claim 7, wherein the improved clinical efficacy endpoint is an improved complete response (CR) rate or a better response rate.

25. The method of claim 24, wherein the improved CR rate or better response rate is 81.2% relative to 61.6% of the reference subject or the reference subject population.

26. The method of claim 24 or 25, wherein the improved CR rate or better response rate is an absolute increase of 19.6% relative to the reference subject or the reference subject population.

27. The method of claim 7, wherein the improved clinical efficacy endpoint is 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 subject population.

29. The method of claim 27 or 28, wherein the improved PFS is a 43% reduction in the risk of progression or death.

30. The method according to any one of claims 27-28, wherein the subject with improved PFS is within 10 -6 Sensitivity threshold, 10 -5 It is negative for MRD at or below the sensitivity threshold.

31. The method according to any one of claims 27-28, wherein the subject with improved PFS is within 10 -6 Sensitivity threshold, 10 -5 The sensitivity threshold or both are below which the MRD is positive.

32. The method according to any one of claims 27-31, wherein the improved PFS is an improvement in median PFS.

33. The method according to any one of the preceding claims, wherein the method achieves an improved median treatment duration relative to the median treatment duration achieved in a reference subject or reference subject population who have been administered a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab.

34. The method of claim 33, wherein the median duration of the improved treatment is 56.3 months relative to 34.3 months for the reference subject or the reference subject population.

35. The method according to any one of claims 1-34, wherein the method achieves an improved median number of treatment cycles relative to the median number of treatment cycles achieved in a reference subject or reference subject population who have been administered a combination of bortezomib, lenalidomide, and dexamethasone, but not 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 subject population.

37. The method according to any one of claims 1-36, wherein the method achieves an equivalent EORTC QLQ-C30 global health status score relative to an EORTC QLQ-C30 global health status score achieved in a reference subject or reference subject population, the reference subject or reference subject population having been administered a combination of bortezomib, lenalidomide, and dexamethasone, but not daratumumab.

38. The method according to 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 according to any one of claims 1-38, wherein the subject has a concentration of ≥30 mL / min / 1.73 m 2 Creatinine clearance rate.

40. The method according to any one of claims 1-39, wherein the subject has stage 3 multiple myeloma according to the International Staging System (ISS).

41. The method according to any one of claims 1-40, wherein the subject has a high cytogenetic risk.

42. The method according to any one of claims 2-41, wherein the pharmaceutical composition comprises about 1800 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 2000 U / mL rHuPH20.

44. The method according to any one of claims 1-43, wherein the pharmaceutical composition comprises one or more excipients.

45. The method of claim 44, wherein at least one of the excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

46. ​​The method according to any one of claims 2-45, wherein the pH of the pharmaceutical composition is about 5.6, and wherein the pharmaceutical composition comprises: about 1800 mg of daratumumab or a daratumumab biosimilar; about 30,000 U of rHuPH20; about 10 mM of histidine; about 300 mM of sorbitol; about 0.04% (w / v) PS-20; and about 1 mg / mL of methionine.

47. The method according to any one of claims 2-46, wherein the pH of the pharmaceutical composition is about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL daratumumab or a daratumumab biosimilar; about 2,000 U / mL 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 according to any one of claims 1-47, wherein daratumumab or a daratumumab biosimilar is administered subcutaneously at a dose of about 1,800 mg, and bortezomib is administered at a dose of about 1.3 mg / m². 2 Lenalidomide is administered subcutaneously at a dose of about 25 mg orally, and dexamethasone is administered orally or intravenously at a dose of about 20 mg to about 40 mg.

49. The method according to any one of 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 according to any one of claims 48-50, wherein daratumumab or a daratumumab biosimilar is administered subcutaneously once weekly at a dose of about 1,800 mg during cycles 1 to 2, subcutaneously once every 3 weeks at a dose of about 1,800 mg during cycles 3 to 8, and thereafter subcutaneously once every 4 weeks at a dose of about 1,800 mg until disease progression or unacceptable toxicity.

52. The method according to any one of claims 48-51, wherein the bortezomib is at about 1.3 mg / m³ 2 The dosage was administered subcutaneously on days 1, 4, 8, and 11.

53. The method according to any one of claims 48-52, wherein the lenalidomide is administered orally at a dose of about 25 mg from day 1 to day 14.

54. The method according to any one of 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 according to any one of claims 48-55, wherein after the eight 21-day cycles, the pharmaceutical composition, lenalidomide, and dexamethasone are administered for one or more 28-day cycles.

56. The method of claim 55, wherein the lenalidomide is administered orally at a dose of about 25 mg on days 1 to 21 of the one or more 28-day cycles, and the 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 according to any one of claims 1-56, wherein the improved clinical efficacy endpoint is improved strict complete response (sCR).

58. The method of claim 57, wherein the improved sCR is about 65.0% relative to about 44.9% of the reference subject or the reference subject population.

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 subject population.

60. A pharmaceutical composition for treating a newly diagnosed multiple myeloma in a subject in need, comprising administering the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone to the subject, 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 transplantation (ASCT) or has had HDC and ASCT delayed.

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 manufacturing a medicine for treating a newly diagnosed multiple myeloma in a subject of need, comprising administering to said subject a pharmaceutical composition in combination with bortezomib, lenalidomide and dexamethasone, wherein said pharmaceutical composition comprises daratumumab or a daratumumab biosimilar, and wherein said subject is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or has delayed HDC and ASCT.

63. The use according to claim 62, wherein the pharmaceutical composition comprises daratumumab or a daratumumab biosimilar, and hyaluronidase.

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