SUMMARY

• DARZALEX for intravenous (IV) use is not approved by the regulatory agencies for use in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of multiple myeloma (MM).
• DARZALEX FASPRO is approved for MM in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant.
• Janssen does not recommend the use of DARZALEX or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• This response includes information on high-risk subgroups from studies that include patients with newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM).
• PERSEUS is an ongoing, phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) vs VRd induction and consolidation followed by maintenance with lenalidomide and daratumumab (D-R) in DVRd group or lenalidomide (R) in VRd group in patients with NDMM eligible for autologous stem cell transplant (ASCT).¹
  • Dimopoulos et al (2024)² presented an expanded sub-group analysis of PERSEUS clinical outcomes (progression-free survival [PFS], overall minimal residual disease [MRD] negativity, and sustained MRD negativity) based on the presence of high-risk cytogenetic abnormalities (HRCAs), including gain(1q21) and amp(1q21). At a median follow-up of 47.5 months, hazard ratio (HR) point estimates for PFS favored D-VRd vs VRd for revised standard (HR, 0.29; 95% confidence interval [CI], 0.15-0.56; P=0.0001) and revised high cytogenetic risk (HR, 0.53; 95% CI, 0.35-0.81; P=0.0027).
  • Dimopoulos et al (2024)³ presented an expanded subgroup analysis of PERSEUS clinical outcomes (PFS, overall MRD-negativity, and sustained MRD-negativity) based on the second revised International Staging System (R2-ISS) and the presence of HRCAs, including gain(1q21) and amp(1q21). At a median follow-up of 47.5 months, HR point estimates for PFS favored D-VRd vs VRd for revised standard risk (HR, 0.29; 95% CI, 0.15-0.56; P=0.0001) and revised high risk (HR, 0.53; 95% CI, 0.35-0.81; P=0.0027). D-VRd increased PFS irrespective of the R2-ISS disease stage with a pronounced effect for R2-ISS stages II (HR, 0.29; 95% CI, 0.14-0.57) and III (HR, 0.46; 95% CI, 0.29-0.75). The overall and sustained (≥12 months) MRD-negativity (at 10^-5 and 10^-6 threshold) with ≥CR rates based on the R2-ISS disease stage favored D-VRd followed by D-R maintenance over VRd followed by R maintenance.
  • Bertamini et al (2024)⁴ presented results from the PERSEUS study that highlighted the significance of circulating tumor cells (CTCs) as a biomarker in transplant-eligible NDMM patients. D-VRd vs VRd improved PFS in patients with high cytogenetic risk and low CTC levels. However, there was no improvement in outcomes for patients with high cytogenetic risk combined with high CTC levels.
• CEPHEUS is a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) or VRd in patients with NDMM who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred). The trial has enrolled 395 patients in 13 countries.^5-7
  • Usmani et al (2025)⁷ reported results from the phase 3 CEPHEUS study at a median follow-up of 58.7 months (range, 0.1-64.7). The treatment effect on the overall MRD-negativity rate remained consistent across the predefined subgroups and is summarized in Table: Prespecified Subgroup Analysis of Overall MRD-Negativity Rates (ISS Staging and Cytogenetic Risk). Similarly, the treatment effect on PFS remained consistent across the predefined subgroups and is summarized in Table: PFS in Prespecified Subgroups (ISS Staging and Cytogenetic Risk).
• AURIGA is an ongoing, open-label, active-controlled, multicenter, randomized phase 3 study evaluating the conversion rate to MRD-negativity after maintenance treatment with DARZALEX FASPRO in combination with lenalidomide (D-R) vs R alone in patients with NDMM who are anti-cluster of differentiation (CD) 38 naïve, have a very good partial response or better (≥VGPR), and are MRD-positive following ASCT after standard-of-care induction/consolidation. A total of 200 patients were randomized (D-R, n=99; R, n=101).^8-10
  • Badros et al (2024)^8,9,11 reported primary results from the phase 3 AURIGA study. Efficacy data by key subgroups is noted in Table: Subgroup Analysis (ISS Staging, Cytogenetic Risk, and Revised Cytogenetic Risk at Diagnosis) of MRD-Negativity (10^- 5) Conversion Rate From Baseline to 12 Months of Maintenance Treatment in the ITT Population.⁸
  • Foster et al (2024)¹² presented a post hoc analysis of the phase 3 AURIGA study that evaluated clinically relevant subgroups at a median follow-up of 32.3 months. The clinically relevant subgroups included elderly and Black patients; patients with high-risk disease per the International Staging System (ISS) disease staging; and patients with high cytogenetic risk per standard, revised, and IMS 2024 high-risk criteria. The subgroup analysis of MRD-negativity (10^-5 sensitivity) conversion rates by 12 months of maintenance appeared to consistently favor D-R vs lenalidomide (R) maintenance alone, regardless of age, race, ISS disease stage, or response upon study entry. D-R vs R maintenance improved MRD-negativity (10^-5 sensitivity) conversion rates by 12 months in patients with ultra high-risk disease, standard-risk disease, and patients with modified IMS 2024 high-risk disease. D-R vs R maintenance showed a PFS benefit across various definitions of high cytogenetic risk, in addition to patients with standard-risk disease and regardless of the number of HRCAs. D-R vs R maintenance improved PFS among patients with gain/amp(1q21), irrespective of other HRCAs (HR, 0.46; 95% CI, 0.13-1.59).
• MAIA is a phase 3 study that evaluated the safety and efficacy of DARZALEX + lenalidomide and dexamethasone (D-Rd) compared to Rd alone in transplant-ineligible NDMM patients.¹³
  • Kumar et al (2022)¹⁴ presented updated efficacy and safety results (median follow-up, 64.5 months), including updated overall survival (OS) results (median follow-up, 73.6 months) from MAIA. Efficacy data by key subgroups is noted in Table: OS in ISS Staging and Cytogenetic Risk Subgroups (MAIA).
  • Moreau et al (2025)¹⁵ reported the efficacy and safety results in clinically important subgroups of patients from the MAIA study, including ISS stage III disease and cytogenetic risk. Efficacy data by key subgroups are noted in Tables: PFS in the ISS Stage III and Cytogenetic Risk Subgroups (ITT Population; MAIA), ORR in the ISS Stage III and Cytogenetic Risk Subgroups (ITT Population; MAIA), MRD-Negativity (10^-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups (ITT Population; MAIA), and Sustained MRD-Negativity Rates in the ISS Stage and Cytogenetic Risk Subgroups Lasting ≥12 months (ITT Population; MAIA).
• ALCYONE is a phase 3 study which assessed the safety and efficacy of bortezomib, melphalan, and prednisone (VMP) alone and DARZALEX + VMP (D-VMP) in patients with NDMM who were ineligible for high-dose therapy (HDT) with ASCT.¹⁶
  • Mateos et al (2022)¹⁷ presented updated efficacy and safety results from ALCYONE at a median follow-up of 78.8 months. Efficacy data by cytogenetic risk status are noted in Table: OS in ISS Staging and Cytogenetic Risk Subgroups (ALCYONE).¹⁷
• Jakubowiak et al (2022)¹⁸ conducted a pooled analysis of patient-level data from the MAIA and ALCYONE studies, analyzing PFS and best response in transplant-ineligible patients with NDMM and HRCAs. The median PFS was 21.2 months in the pooled DARZALEX cohort vs 19.3 months in the pooled control cohort (adjusted HR, 0.59; 95% CI, 0.41-0.85; P=0.0046), representing a 41% reduction in risk of disease progression or death. Complete response or better (≥CR) was achieved in 41.6% (n=42) of patients in the pooled DARZALEX cohort vs 22.5% (n=20) of patients in the pooled control cohort (adjusted odds ratio [OR], 2.63; 95% CI, 1.34-5.16; P=0.0051).
• CASSIOPEIA is a 2-part, phase 3 study evaluating the safety and efficacy of DARZALEX + bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant eligible patients with NDMM.¹⁹
  • Moreau et al (2021)²⁰ reported results from Part 2 of the CASSIOPEIA study. Efficacy data by key subgroups is noted in Table: PFS in the Prespecified ISS and Cytogenetic Risk Subgroups (CASSIOPEIA Part 2).
• GRIFFIN is a phase 2, 2-part study evaluating the safety and efficacy of DARZALEX when administered in combination with VRd (D-VRd) in patients with NDMM eligible for HDT and ASCT.^21-23
  • Chari et al (2024)^24,25 reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study, including ISS stage III disease and cytogenetic risk. Efficacy data by key subgroups are noted in Tables: Final Analysis of MRD-Negativity (10^-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN), Final Analysis of sCR in the ISS Stage III and Cytogenetic Subgroups (GRIFFIN), Final Analysis of MRD-negativity (10^-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups with a Best Response of ≥CR (GRIFFIN), and Final Analysis of PFS in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN).
• MASTER evaluated the efficacy and safety of DARZALEX + carfilzomib + lenalidomide + dexamethasone (D-KRd) induction followed by autologous hematopoietic cell transplantation (AHCT) and MRD-adapted consolidation therapy in patients with NDMM.²⁶
  • Costa et al (2023)²⁶ reported the results from the final analysis of the MASTER study at a median follow-up of 42.2 months. The overall MRDnegative remission rate (next-generation sequencing [NGS]; <10⁵ threshold) in MRD-evaluable patients at any point in treatment was 81%. The 3-year PFS rate was 88% for patients with standard-risk (0 HRCAs), 79% for patients with high-risk (1 HRCA), and 50% for patients with ultra high-risk (≥2 HRCAs) cytogenetic abnormalities. The 3-year OS rate was 94% (95% CI, 88-98) for patients with 0 HRCA, 92% (95% CI, 86-96) for patients with 1 HRCA, and 75% (95% CI, 63-85) for patients with ≥2 HRCAs.
  • Costa et al (2023)²⁷ reported additional details on PFS and OS for different study populations and at difference timepoints according to MRD status.
• Callander et al (2024)²⁸ reported the results of a post hoc analysis evaluating the clinical efficacy of DARZALEX-based quadruplet therapies, including D-KRd and D-VRd, in transplant-eligible patients with NDMM and HRCAs from the MASTER and GRIFFIN studies, respectively. In the MASTER study, in patients with 0, 1, and ≥2 HRCAs, respectively, ≥CR was achieved by 90.6%, 89.1%, and 70.8% of patients; the estimated 24-month PFS rate was 92.4%, 95.7%, and 65.5%; and MRD-negativity (10⁵) was reported in 80%, 86.4%, and 83.3% of patients. In the GRIFFIN study, in patients with 0, 1, and ≥2 HRCAs, respectively, ≥CR was achieved by 90.9%, 78.8%, and 61.5% of patients; the 24-month PFS rate was 96.7%, 93.8%, and 64.2%; and MRD-negativity (10^-5) was reported in 76.1%, 55.9%, and 61.5% of patients. The total number of deaths reported in MASTER and GRIFFIN studies were 3 and 8, respectively.
• CASTOR is a phase 3 study assessing the safety and efficacy of bortezomib and dexamethasone (Vd) alone and DARZALEX + Vd (D-Vd) in patients with RRMM.²⁹
  • Sonneveld et al (2022)³⁰ reported updated efficacy and safety results from CASTOR at a median follow-up of 72.6 months. Efficacy data by key subgroups is noted in the Table: OS in ISS Staging and Cytogenetic Risk Pre-Specified Subgroups (ITT Population; CASTOR).
  • Weisel et al (2020)³¹ reported the updated efficacy and safety data based on cytogenetic risk status of DVd from CASTOR in patients with RRMM. Overall response rate (ORR), very good partial response or better (≥VGPR), and ≥CR were higher with D-Vd vs Vd, regardless of cytogenetic risk status. Efficacy data for cytogenetic risk subgroups are noted in Table: Response and MRD-negative Rates in Patients with Standard and High Cytogenetic Risk (CASTOR).
• POLLUX is a phase 3 study assessing the safety and efficacy of Rd vs D-Rd in patients with RRMM.³²
  • Dimopoulos et al (2022)³³ presented updated efficacy and safety results from POLLUX at a median follow-up of 79.7 months. Efficacy data by key subgroups is noted in Table: OS in ISS Staging and Cytogenetic Risk Pre-Specified Subgroups (ITT Population; POLLUX).
  • Kaufman et al (2020)³⁴ presented updated efficacy and safety data based cytogenetic risk status of D-Rd from POLLUX in patients with RRMM. Among patients with high cytogenetic risk, PFS was prolonged with D-Rd vs Rd in MRD-positive patients (median, 20.3 months vs 8.3 months; HR, 0.49; 95% CI, 0.23-1.03; P=0.0567); median PFS with D-Rd in MRD-negative patients was not estimable (NE). MRD-negativity rates were higher with D-Rd vs Rd, regardless of cytogenetic risk.
• Mateos et al (2022)³⁵ presented the results of a post hoc subgroup analysis of the phase 3 CASTOR and POLLUX studies, evaluating the efficacy of D-Vd vs Vd alone (CASTOR) and D-Rd vs Rd alone (POLLUX) in patients with RRMM. In the pooled intent-to-treat (ITT) population of CASTOR and POLLUX, PFS benefit of the DARZALEX (median, 20.3 months) vs control (median, 7.3 months) arm was observed (HR, 0.45; 95% CI, 0.31-0.65) and OS benefit of the DARZALEX (median, 40 months) vs control (median, 23.6 months) arm was observed (HR, 0.68; 95% CI, 0.47-1) in patients with high cytogenetic risk.
• CANDOR is a phase 3 study evaluating the safety and efficacy of D-Kd vs carfilzomib and dexamethasone in patients with RRMM.^36,37
  • Usmani et al (2023)³⁸ reported the final efficacy and safety results of the CANDOR study after a median follow-up of approximately 50 months. The HR for OS favored the D-Kd arm across prespecified subgroups including ISS stage and cytogenetic risk status and is presented in the Table: OS in Pre-specified ISS Staging and Cytogenetic Risk Subgroups (CANDOR).
• APOLLO is a phase 2 study evaluating the safety of pomalidomide + lenalidomide (Pd) vs DARZALEX FASPRO + Pd (D-Pd) in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a proteasome inhibitor (PI).^39,40
  • Sonneveld et al (2021)⁴¹ presented updated efficacy and safety data at a median follow-up of 30.7 months. PFS favored D-Pd vs Pd across subgroups, including ISS stage and cytogenetic risk status and is presented in the Table: PFS in the ISS Staging and Cytogenetic Profile Subgroups (APOLLO).
  • Dimopoulos et al (2022)⁴² presented final OS results and updated safety data at a median follow-up of 39.6 months. The updated analysis did not discuss cytogenetic risk status and the citation is listed in the reference below.
• Other relevant literature has been identified in addition to the data summarized above.^43-48 

PRODUCT LABELING

• DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf
• DARZALEX FASPRO (daratumumab and hyaluronidase) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf
  
  
  

CLINICAL studies - nDMM

DARZALEX FASPRO in Combination With Bortezomib, Lenalidomide, and Dexamethasone

PERSEUS (MMY3014; NCT03710603) is an ongoing, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-VRd vs VRd induction and consolidation followed by maintenance with D-R in DVRd group or lenalidomide in VRd arm in patients with NDMM eligible for ASCT. Sonneveld et al (2023)¹ reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT. Dimopoulos et al (2024)² presented an expanded analysis of PERSEUS clinical outcomes (PFS, overall MRD negativity, and sustained MRD negativity) based on the presence of HRCAs, including gain(1q21) and amp(1q21). The results of the expanded analysis are presented below. Dimopoulos et al (2024)³ presented (at the 21^st IMS Annual Meeting) an expanded subgroup analysis of PERSEUS clinical outcomes (PFS, overall MRD-negativity, and sustained MRD-negativity) based on R2-ISS and the presence of HRCAs, including gain(1q21) and amp(1q21).

Study Design/Methods

• A total of 709 patients were randomized 1:1 to into D-VRd (n=355) vs VRd (n=354) arm.¹
  • Stratification was done based on the ISS disease stage (I, II, or III) and standard or high cytogenetic risk (defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16]).¹
• Primary endpoint: PFS.¹
• Key secondary endpoints: Overall ≥CR, overall MRD-negativity, and OS.¹
• Other secondary endpoints: ORR, ≥VGPR, stringent complete response (sCR), duration of MRD-negativity.¹

Results

Patient Characteristics

• A total of 709 patients were randomized (D-VRd, n=355; VRd, n=354) in this study. Patient demographics and baseline characteristics are summarized in Table: Demographics and Baseline Clinical Characteristics of the High-Risk ITT Population.
• The median follow-up was 47.5 months.²

• Across all cytogenetic risk subgroups, PFS was favored for D-VRd followed by D-R maintenance vs VRd followed by R maintenance and is summarized in Table: Cytogenetic Risk Subgroup Analysis of PFS in the ITT Population.²
  • HR point estimates for PFS favored D-VRd vs VRd for revised standard (HR, 0.29; 95% CI, 0.15-0.56; P=0.0001) and revised high cytogenetic risk (HR, 0.53; 95% CI, 0.35-0.81; P=0.0027).^2,3
  • Irrespective of other HRCAs, HR point estimates for PFS also favored D-VRd vs VRd in patients with the presence of gain(1q21), amp(1q21), and gain(1q21) or amp(1q21).²
• D-VRd increased PFS irrespective of the R2-ISS disease stage with a pronounced effect for R2-ISS stages II and III and is summarized in Table: Subgroup Analysis of PFS Based on R2-ISS Disease Stage.³
• Regardless of high-risk cytogenetic markers, a subgroup analysis of overall and sustained (≥12 months) MRD negativity (at 10^-5 and 10^-6) ≥CR rates based on cytogenetic risk markers favored treatment with D-VRd followed by D-R maintenance over VRd followed by R maintenance and is summarized in Table: Subgroup Analysis of MRD Negativity.

Significance of CTC as a Biomarker in Transplant-Eligible NDMM Patients - Results From the PERSEUS Study

Bertamini et al (2024)⁴ presented results from the PERSEUS study that highlighted the significance of CTC as a biomarker in transplant-eligible NDMM patients.

Results

Patient Characteristics

• The CTC testing was performed at screening in 451 patients from the PERSEUS study (D-VRd, 231/355 [65.1%] vs VRd, 220/354 [62.1%] patients). The baseline patient characteristics were balanced between the treatment groups and are summarized in Table: Baseline Characteristics in Patients From the PERSEUS Study - CTC Subgroup.

Efficacy

• D-VRd vs VRd improved PFS in patients with high cytogenetic risk and low CTC levels. However, there was no improvement in the outcomes for patients with high cytogenetic risk combined with high CTC levels.⁴ The prognostic impact of CTC and other risk factors on PFS is presented in Table: Prognostic Impact of CTC and Other Risk Factors on PFS.
  • D-VRd vs VRd significantly improved PFS in patients with both high and low CTC levels (P<0.0001).⁴

DARZALEX FASPRO in Combination with Bortezomib, Lenalidomide, and Dexamethasone

CEPHEUS (MMY3019; NCT03652064) is an ongoing, randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-VRd vs VRd in patients with NDMM who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred).^5-7 Usmani et al (2025)⁷ reported results from the phase 3 CEPHEUS study.

Study Design/Methods

• The trial has enrolled 395 patients from 13 different countries including the United States.^5,6
• Primary endpoint: Overall MRD-negativity (≥CR) rate at 10^-5 sensitivity threshold.^5,6
• Key secondary endpoints: PFS, ORR, ≥VGPR, ≥CR, PFS2, OS, and sustained MRD-negativity (10^-5) rate at ≥12 months.^5,6

Results

Patient Characteristics

• A total of 395 patients were randomized into the D-VRd (n=197) and VRd (n=198) arms.⁷ 
• The baseline demographics and clinical characteristics of the ITT population are presented in Table: Baseline Demographics and Clinical Characteristics of the High-Risk ITT Population.
• The median follow-up was 58.7 months (range, 0.1-64.7).⁷ 

Efficacy

• The treatment effect on the overall MRD-negativity rate remained consistent across the predefined subgroups and is summarized in Table: Prespecified Subgroup Analysis of Overall MRD-Negativity Rates (ISS Staging and Cytogenic Risk).
• The treatment effect on PFS remained consistent across the predefined subgroups and is summarized in Table: PFS in Prespecified Subgroups (ISS Staging and Cytogenic Risk).

Safety

• The safety data were consistent with the established safety profile of each individual drug.⁷
  • Overall, deaths were reported in 51 vs 60 patients from the D-VRd vs VRd arm, respectively.
  • Grade 5 non-COVID-related TEAEs occurred in 10.7% vs 7.7% of patients from the D-VRd vs VRd arm, respectively.
  • Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%).
  • Most grade 5 TEAEs occurred after the discontinuation of bortezomib (cycle 8) in both arms (D-VRd, 13%; VRd, 9%). When adjusted for treatment exposure, the rate of grade 5 TEAEs was similar between the two arms (D-VRd, 0.39 per 100 patient-months; VRd, 0.31 per 100 patient-months).

DARZALEX FASPRO in Combination with Lenalidomide

AURIGA (MMY3021; NCT03901963) is an ongoing, open-label, active-controlled, multicenter, randomized, phase 3 study evaluating the conversion rate to MRDnegativity after maintenance treatment with DR vs lenalidomide alone in patients with NDMM who are anti-CD 38 naïve, have ≥VGPR, and are MRD positive after ASCT.^8-10 Badros et al (2024)^8,9 reported primary results from the phase 3 AURIGA study.

Study Design/Methods

• The trial enrolled 200 patients from the United States and Canada.⁸
• Patients underwent 1:1 randomization to receive D-R (n=99) or R alone (n=101) across 28-day cycles.^8,10
  • D-R: DARZALEX FASPRO 1800 mg SC QW in cycles 1-2, Q2W in cycles 3-6, Q4W in cycles 7+.
  • R: Lenalidomide 10 mg PO once a dayon days 1-28.
• The treatment regimen continued until unacceptable toxicity, disease progression, consent withdrawal, or for a maximum of 36 cycles.⁸
• Primary endpoint: MRD-negativity conversion rate from baseline by 12 months.⁸
  • MRD was assessed at 12, 18, 24, and 36 months.
  • If lenalidomide is well tolerated, the dose may be increased to 15 mg daily after cycle 3, at the investigator’s discretion.
• Key secondary endpoints: Safety, PFS, overall MRD-negativity conversion rate, sustained MRD-negativity rate (≥6 months), response rates including CR/sCR as assessed by International Myeloma Working Group 2016 criteria, duration of ≥CR, OS, HRQoL changes based on patient reported outcomes.⁸

Results

Patient Characteristics

• A total of 200 patients were randomized into the D-R maintenance (n=99) and R alone maintenance (n=101) arms.⁸
• The median duration of treatment was 30.7 (range, 0.7-37.5) months vs 20.6
  (range, 0-37.7) months in the D-R vs R arm, respectively.⁸
• The baseline demographics and disease characteristics of the ITT population are presented in Table: Baseline Demographics and Disease Characteristics of the High-Risk ITT Population.⁸
• The median follow-up was 32.3 months.⁸
• Patients in the D-R vs R arm received a median of 33 (range, 1-36) vs 21.5
  (range, 1-36) maintenance cycles, respectively.⁸
• Overall, 85 of 96 (88.5%) vs 77 of 98 (78.6%) patients in the D-R vs R arm completed ≥12 maintenance cycles, respectively.⁸

Efficacy

• Subgroup analyses of MRD-negativity (10^-5 sensitivity) conversion rates at 12 months appeared to consistently favor D-R over R across most clinically relevant subgroups, including patients with a standard or high cytogenetic risk and older patients; the results are summarized in Table: Subgroup Analysis of MRD-Negativity (10^-5) Conversion Rate From Baseline to 12 Months of Maintenance Treatment in the High-Risk ITT Population.⁸

Safety

• Slightly higher occurrence rates of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were observed with D-R vs R.⁸
• Serious AEs were reported in 30.2% vs 22.4% of patients in the D-R vs R arm, respectively.⁸
• Any TEAEs occurred in 99% of patients in both the D-R and R arms.⁸
  • Grade 3/4 TEAEs occurred in 74% and 67.3% of patients in the D-R and R arms, respectively.
• During the analysis, 32 of 96 (33.3%) vs 47 of 98 (48%) patients in the D-R vs R arm, respectively, discontinued ≥1 component of the study treatment.⁸

Clinically Relevant Subgroup Analysis - Phase 3 AURIGA Study

Foster et al (2024)¹²  presented (at the 66^th ASH Annual Meeting) a post hoc analysis of the phase 3 AURIGA study that evaluated clinically relevant subgroups at a median follow-up of 32.3 months. The clinically relevant subgroups included elderly and Black patients; patients with high-risk disease per ISS disease staging; and patients with high cytogenetic risk per standard, revised, and IMS 2024 high-risk criteria.

Results

Demographics and Disease Characteristics

• A total of 200 patients were randomized into the D-R maintenance (n=99) vs R alone maintenance (n=101) groups.¹² 
• The median follow-up was 32.3 months.¹² 
• The demographics and disease characteristics of the ITT population are presented in Table: Demographics and Disease Characteristics of the ITT Population.

Efficacy

• A subgroup analysis of MRD-negativity (10^-5 sensitivity) conversion rates by 12 months of maintenance showed improvement for D-R vs R regardless of age, race, ISS disease stage, or response upon study entry.¹² The results are summarized in Table: Subgroup Analysis of MRD-negativity (10^-5 Sensitivity) Conversion Rate^a from Baseline to 12 Months of Maintenance Treatment.
• D-R vs R improved MRD-negativity (10^-5 sensitivity) conversion rates by 12 months of maintenance in patients with ultra-high-risk disease and standard-risk disease.¹² The results are summarized in Table: Subgroup Analysis of MRD-negativity (10^-5 Sensitivity) Conversion Rate^a from Baseline to 12 Months of Maintenance Treatment by Risk Status.
• D-R vs R improved MRD-negative (10^-5 sensitivity) conversion rate by 12 months of maintenance, among patients with modified IMS 2024 high-risk disease.¹² The results are summarized in Table: Subgroup Analysis of MRD-negativity (10^-5 Sensitivity) Conversion Rate from Baseline to 12 Months of Maintenance Treatment by Modified IMS 2024 Criteria.
• D-R vs R maintenance showed a PFS benefit across various definitions of high cytogenetic risk, in addition to patients with standard-risk disease. The HR and 95% CI values presented below are derived from a Cox proportional hazards model with treatment as the sole explanatory variable. A HR <1 indicates an advantage for D-R maintenance.¹² 
  • Standard criteria: High-risk cytogenetics was defined as ≥1 abnormality including del(17p), t(4;14), or t(14;16).
    • Standard-risk: HR, 0.59; 95% CI, 0.23-1.49.
    • High-risk: HR, 0.60; 95% CI, 0.21-1.70.
  • Revised criteria: Revised high-risk cytogenetics was defined as ≥1 abnormality including del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21).
    • Revised standard-risk: HR, 0.69; 95% CI, 0.24-1.95.
    • Revised high-risk: HR, 0.53; 95% CI, 0.21-1.31.
  • Modified IMS 2024 criteria: High risk per the modified IMS 2024 criteria was defined as the presence of ≥20% del(17p); or the association of ≥2 of the following: t(4;14) or t(14;16) or t(14;20); gain/amp(1q21); or del(1p32). In the AURIGA study, data were not available on TP53 mutations, baseline ß2M, and creatinine levels and differentiation between monoallelic versus biallelic del(1p32).
    • Modified IMS 2024 standard-risk: HR, 0.42; 95% CI, 0.16-1.07.
    • Modified IMS 2024 high-risk: HR, 0.45; 95% CI, 0.13-1.53.
• D-R vs R maintenance demonstrated a PFS benefit regardless of the number of HRCAs. The HRCA numbers presented below were defined as number of abnormalities from del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21). Cytogenetic results at diagnosis (based on case report forms collected data from local laboratories) were used in the analysis. The HR and 95% CI were derived from a Cox proportional hazards model with treatment as the sole explanatory variable. A HR <1 indicates an advantage for D-R maintenance.¹²
  • 0 HRCAs: HR, 0.69; 95% CI, 0.24-1.95.
  • 1 HRCAs: HR, 0.36; 95% CI, 0.09-1.45.
  • ≥2 HRCAs: HR, 0.61; 95% CI, 0.17-2.25.
• D-R vs R maintenance improved PFS among patients with gain/amp(1q21), irrespective of other HRCAs (HR, 0.46; 95% CI, 0.13-1.59).¹²

DARZALEX in Combination with Lenalidomide and Dexamethasone

MAIA (MMY3008; NCT02252172) is an international, phase 3, randomized, open-label, active-controlled, multicenter study that evaluated the efficacy and safety of combination of D-Rd vs Rd in patients with NDMM not eligible for high-dose chemotherapy and ASCT (N=737).¹³ Kumar et al (2022)¹⁴ presented the results of the updated efficacy and safety analysis (median follow-up, 64.5 months), including updated OS results (median follow-up, 73.6 months), of the MAIA study in patients with NDMM who were ineligible for high-dose chemotherapy and ASCT. Results in the high-risk cytogenetic subgroup are summarized below. Moreau et al (2025)¹⁵ presented the efficacy and safety results in clinically important subgroups of patients from the MAIA study.

Study Design/Methods

• Primary endpoint: PFS
• Secondary endpoints: ≥CR rate, ≥VGPR rate, duration of response (DOR), MRD-negativity rate (10^-5) via NGS, ORR, OS, PFS on subsequent line of therapy (PFS2), sCR, time to next (2nd-line) treatment, time to response (TTR), time to progression (TTP), and safety
• Cytogenetic analysis: efficacy in the subgroup of patients with a high-risk cytogenic profile (defined by del17p, t[14;16], or t[4;14] abnormality [or a combination of these] on FISH or karyotype analysis)

Results

Efficacy

• At a median follow-up of 73.6 months, the median OS in the D-Rd vs Rd arm was NR vs 64.1 months (HR, 0.65; 95% CI, 0.52-0.80; P<0.0001).
  • The 60-month OS rate in the D-Rd vs Rd arm was 66.7% vs 53.7%. Among patients with high-risk cytogenetic profile, median OS was 55.6 months vs 42.5 months in the D-Rd vs Rd arm, respectively (HR, 0.65; 95% CI, 0.39-1.06). See Table: OS in ISS Staging and Cytogenetic Risk Subgroups (MAIA).

Safety

• No new safety concerns were reported with the longer follow-up.
• Grade 3/4 TEAEs occurring in ≥20% of patients in the D-Rd vs Rd arm were neutropenia (54.1% vs 37%) and anemia (17% vs 21.6%).
• The most common serious TEAE in both arms was pneumonia (D-Rd, 18.7%; Rd, 10.7%).
• The rate of treatment discontinuation due TEAEs in the D-Rd vs Rd arm was 14.6% vs 23.8%.

Analysis of Clinically Important Subgroups from the MAIA Study

Moreau et al (2025)¹⁵ presented the efficacy and safety results in clinically important subgroups of patients from the MAIA study.

Study Design/Methods

• Efficacy outcomes (PFS, ORR, and MRD-negativity) were analyzed in ISS stage III and cytogenetic risk based on the following patient characteristics:
  • ISS stage III disease
  • Revised ISS stage III disease
  • Cytogenetic risk
    • Presence of HRCAs (t[4;14], t[14;16], and/or del[17p]) or a high serum lactate dehydrogenase level
    • Standard cytogenetic risk (0 of the following HRCAs: t[4;14], t[14;16], and del[17p])
    • High cytogenetic risk (≥1 of the following HRCAs: t[4;14], t[14;16], and del[17p])
    • Revised standard cytogenetic risk (0 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], and amp[1q21])
    • Revised high cytogenetic risk (≥1 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], and amp[1q21])
    • Gain(1q21) (3 copies of chromosome 1q21, with or without other HRCAs)
    • Amp(1q21) (≥4 copies of chromosome 1q21, with or without other HRCAs)
    • Gain(1q21) or amp(1q21) (3 or ≥4 copies of chromosome 1q21, with or without other HRCAs)
    • 1 HRCA (only 1 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], or amp[1q21])
    • Two or more HRCAs (≥2 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], and amp[1q21])
    • Isolated gain(1q21) (3 copies of chromosome 1q21, without any other HRCAs)
    • Isolated amp(1q21) (≥4 copies of chromosome 1q21, without any other HRCAs)
    • Isolated gain(1q21) or amp(1q21) (3 or ≥4 copies of chromosome 1q21, without any other HRCAs)
    • Gain(1q21) or amp(1q21) plus ≥1 HRCA (3 or ≥4 copies of chromosome 1q21, plus ≥1 of the following HRCAs: t[4;14], t[14;16], del[17p], and t[14;20])

Results

Patient Characteristics

• Overall, 737 patients (D-Rd, 368; Rd, 369) were included in the ITT population.
• The median duration of follow-up was 64.5 months.

Efficacy

• The PFS duration was longer in the D-Rd vs Rd arm in the patient subgroup of ISS stage III and cytogenetic risk. See Table: PFS in the ISS Stage III and Cytogenetic Risk Subgroups (ITT Population; MAIA).
  • PFS was improved in the D-Rd vs Rd arm among patients with the following characteristics:
    • Revised standard cytogenetic risk (HR, 0.50; 95% CI, 0.37-0.66; P<0.0001)
    • 1 HRCA (HR, 0.55; 95% CI, 0.40-0.76; P=0.0003)
    • Isolated gain(1q21) (HR, 0.36; 95% CI, 0.19-0.67; P=0.0008)
    • Isolated amp(1q21) (HR, 0.78; 95% CI, 0.50-1.22; P=0.2764)
  • PFS was similar in the D-Rd and Rd arms among patients with ≥2 HRCAs (HR, 0.92 95% CI, 0.40-2.10; P=0.8477).
• A more favorable result was reported in the D-Rd vs Rd arm for the following endpoints in the ISS stage III and cytogenetic risk subgroups:
  • ORR (See Table: ORR in the ISS Stage III and Cytogenetic Risk Subgroups [ITT Population; MAIA]).
  • MRD-negativity (10^-5) rate (See Table: MRD-Negativity (10^-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups [ITT Population; MAIA]).
  • Sustained MRD-negativity (10^-5) lasting ≥12 months (See Table: Sustained MRD-Negativity Rates in the ISS Stage and Cytogenetic Risk Subgroups Lasting ≥12 months [ITT Population; MAIA]).

Safety (Patients Aged ≥75 Years)

• Among patients aged ≥75 years, grade 3/4 TEAEs were reported in 95.5% vs 95% patients in the D-Rd vs Rd arm.
  • The most common (≥10%) grade 3/4 TEAEs are summarized in Table: Most Common (≥10%) Grade 3/4 TEAEs Among Patients Aged ≥75 Years in the Safety Population.
• Serious TEAEs were reported in 80.9% vs 79.2% of patients in the D-Rd vs Rd arm, the most common of which was pneumonia (D-Rd, 19.7%; Rd, 12.6%).
• TEAEs led to treatment discontinuation in 15.3% vs 27.7% of patients in the D-Rd vs Rd arm.
• TEAEs resulting in death were reported in 11.5% vs 13.2% of patients in the D-Rd vs Rd arm.

DARZALEX in Combination with Bortezomib, Melphalan, and Prednisone

ALCYONE (MMY3007) was a phase 3, multicenter, randomized, open-label, active-controlled study that assessed the safety and efficacy of VMP alone and D-VMP in patients with NDMM who were ineligible for HDT with ASCT.¹⁶ Mateos et al (2022)¹⁷ presented updated analysis of the ALCYONE study that evaluated the efficacy and safety of D-VMP vs VMP in patients with NDMM who were ineligible for high-dose chemotherapy and ASCT. Results in the high-risk cytogenetic subgroup are summarized below.

Study Design/Methods

• Primary endpoint: PFS
• Key secondary endpoints: CR rate, ORR, OS, safety
• Cytogenetic analysis: efficacy in the subgroup of patients with a high-risk cytogenic profile (defined by del17p, t[14;16], or t[4;14] abnormality [or a combination of these] on FISH or karyotype analysis)

Results

Patient Characteristics

• A total of 98 patients (D-VMP, n=53; VMP, n=45) were classified as high cytogenetic risk and 518 patients (D-VMP, n=261; VMP, n=257) were classified as standard cytogenetic risk.

Efficacy

• Median duration of follow-up was 78.8 months.
• In the D-VMP vs VMP arm, the median OS was 82.7 vs 53.6 months (HR, 0.64; 95% CI, 0.52-0.79; P<0.0001) and the 72-month OS rate was 55.7% vs 39.7%.
  • Among patients with high cytogenetic profile, median OS was 46.2 months vs 39.5 months in the D-VMP vs VMP arm, respectively (HR, 0.85; 95% CI, 0.52-1.38). See Table: OS in ISS Staging and Cytogenetic Risk Subgroups (ALCYONE).

Safety

• In the D-VMP vs VMP arm, grade 3/4 TEAEs were reported in 82.9% vs 77.4% of patients, and grade 3/4 infections were reported in 30.3% vs 15% of patients.
• Grade 3/4 TEAEs occurring in ≥20% of patients in the D-VMP vs VMP arm were neutropenia (40.5% vs 39%) and thrombocytopenia (34.7% vs 37.9%).
• The most common serious TEAE in both treatment arms was pneumonia (D-VMP, 14.7%; VMP, 3.7%).
• The rate of treatment discontinuation due to TEAEs in the D-VMP vs VMP arm was 9% vs 9.3%.

DARZALEX in Combination with Bortezomib, Thalidomide and Dexamethasone

CASSIOPEIA (MMY3006) is an ongoing, open-label, 2-arm, multicenter, phase 3 study evaluating the safety and efficacy of D-VTd in patients with NDMM who are eligible for high dose chemotherapy and ASCT.¹⁹ Moreau et al (2021)²⁰ reported the results from Part 2 of the CASSIOPEIA study (maintenance treatment). Results in the high-risk cytogenetic subgroup are summarized below.

Study Design/Methods

• Part 2: Responders (patients who completed consolidation and achieved partial response or better [≥PR]) were rerandomized to 1 of 2 treatment groups:
  • Arm A: DARZALEX 16 mg/kg maintenance therapy every 8 weeks for 2 years
  • Arm B: Observation
• Primary endpoint: Part 2: PFS after second randomization
• Secondary endpoints: Part 2: TTP from second randomization, rates of ≥CR, MRD-negativity rates (in patients with ≥CR at a threshold of 10^-5 by NGS), PFS2, ORR, and OS from second randomization

Results

Baseline Characteristics

• Key baseline patient demographics and disease characteristics are summarized in Table: Key Baseline Demographics and Disease Characteristics after Second Randomization (CASSIOPEIA Part 2).
• In Part 2, 886 patients with ≥PR in Part 1 underwent second 1:1 randomization: DARZALEX monotherapy, n=442 patients vs observation (no maintenance) group, n=444.

Efficacy

• After a median follow-up of 35.4 months (interquartile range [IQR], 30.2-39.9), median PFS from second randomization was NR (95% CI, not evaluable) in the DARZALEX monotherapy group vs 46.7 months (95% CI, 40-NE) in the observation group (HR, 0.53; 95% CI, 0.42-0.68; P<0.0001).
  • The DARZALEX monotherapy group experienced 108 PFS events, while the observation group experienced 173 events.
  • The PFS benefit of the DARZALEX monotherapy group vs the observation group was consistent across most prespecified subgroups, except for patients with ISS stage III disease, patients with creatinine clearance ≤90 mL/min, and those who received VTd as a part of induction, ASCT, and consolidation treatment group, as presented in Table: PFS in the Prespecified ISS and Cytogenetic Risk Subgroups (CASSIOPEIA Part 2).
• After a median follow-up of 44.5 months (IQR, 38.9-49.1), an updated analysis was performed from first randomization (Part 1 CASSIOPEIA study) of patients in the D-VTd group vs VTd group.
  • The median PFS was NR (95% CI, NE-NE) in the D-VTd group vs 51.5 months (95% CI, 46.3-NE) in the VTd group (HR, 0.58; 95% CI, 0.47-0.72; P<0.0001).
  • The median OS was NR for patients in the D-VTd group vs VTd group (41 [8%] deaths of patients in D-VTd group vs 73 [13%] deaths in VTd group; HR, 0.54; 95% CI, 0.37-0.79).

Safety

• Any TEAEs occurred in 95% (n=420) of patients in the DARZALEX monotherapy group vs 89% (n=394) in the observation group.
• Grade ≥3 TEAEs occurred in 28% (n=122) of patients in the DARZALEX monotherapy group (who received at least 1 dose) vs 24% (n=108) in the observation group.
• Serious AEs that occurred in >1% of patients in the DARZALEX monotherapy vs observation groups were pneumonia (n=11 [3%] vs n=7 [2%]) and lung infection (n=6 [1%] vs n=7 [2%], respectively.
• Two AEs led to death in the DARZALEX monotherapy group (septic shock and natural killer-cell lymphoblastic lymphoma, n=1 each); both were treatment-related.

DARZALEX with Bortezomib, Lenalidomide, and Dexamethasone

Final Subgroup Analysis From GRIFFIN

GRIFFIN (MMY2004; NCT02874742) is a 2-part, phase 2, randomized, active-controlled US study evaluating the safety and efficacy of DARZALEX in combination with VRd in patients with NDMM eligible for HDT and ASCT.^21-23 Chari et al (2024)^24,25 reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study, including ISS stage III disease and cytogenetic risk (median follow-up, 49.6 months).

Study Design/Methods

• Of note, the data presented utilized the abbreviation “RVd”, which has been replaced with “VRd” in the summary below to remain consistent throughout this scientific response.
• This final analysis was conducted after all patients completed ≥1 year of follow-up after concluding study treatment, died, or withdrew.
• Primary endpoint: sCR (by end of post-ASCT consolidation)
• Secondary endpoints: MRD (10^-5 via NGS), CR, ORR, ≥VGPR
• Cytogenetic risk was assessed by FISH; high-risk was defined as the presence of del17p, t(4;14), or t(14;16)

Results

Efficacy

• MRD-negativity (10^-5) rates favored the D-VRd vs VRd arm in the patient subgroup of ISS stage III and cytogenetic risk. See Table: Final Analysis of MRD-Negativity (10^-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN).
• A final analysis of sCR rates were higher for D-VRd vs VRd for most subgroups, including the patient subgroup of ISS stage III and cytogenetic risk. See Table: Final Analysis of sCR in the ISS Stage III and Cytogenetic Subgroups (GRIFFIN).
• MRD-negativity (10^-5) rates favored the D-VRd vs VRd arm in the patient subgroup of ISS stage III and cytogenetic risk among patients who achieved a best response ≥CR by the end of the study. See Table: Final Analysis of MRD-negativity (10^-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups with a Best Response of ≥CR (GRIFFIN).  
• D-VRd was associated with higher rates of sustained MRD-negativity (10^-5) lasting ≥12 in the patient subgroup of ISS stage III and cytogenetic risk. See Table: Final Analysis of Rates of Sustained MRD-negativity (10^-5) lasting ≥12 months in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN).
  • No patients who achieved sustained MRD-negativity (10^-5) lasting ≥12 months developed PD.
• Among MRD-evaluable patients who achieved MRD-negativity (10^-5) at any time, 2 (both with ≥2 HRCAs) patients in the D-VRd arm and 5 (0 HRCA, n=2; 1 HRCA, n=3) patients in the VRd arm developed PD.
  • Two patients from the D-VRd arm and 3 patients from the VRd arm, who initially achieved MRD-negativity, developed PD after they became MRD positive again. The remaining 2 patients from the VRd arm developed PD while they continued to be MRD negative; however, MRD was not evaluated around the time of PD.
• At a median follow-up of 49.6 months, the HR point estimates for PFS among ISS stage III disease and cytogenetic risk subgroups favored the D-VRd vs VRd arm, except for patients with ≥2 HRCAs. See Table: Final Analysis of PFS in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN).
  • Median PFS was not reached for either treatment group among patients with 0 HRCA, and the PFS HR was 0.39 (95% CI, 0.10-1.51) for D-VRd vs VRd.
  • Median PFS was not reached for D-VRd and was 47.9 months for VRd among patients with 1 HRCA, and the PFS HR was 0.19 (95% CI, 0.05-0.75) for D-VRd vs VRd.
  • Median PFS was 33.9 months for D-VRd and was not reached for VRd among patients with ≥2 HRCAs, (HR, 1.65; 95% CI, 0.30-9.18).
  • PFS was not reached for D-VRd and was 47.9 months for VRd among patients with gain/amp(1q21), with or without HRCAs, and the PFS HR was 0.42 (95% CI, 0.14-1.27) for D-VRd vs VRd.
• Within the functionally high-risk subgroup of patients with a best response of <VGPR by the end of induction, more D-VRd vs VRd patients had revised high cytogenetic risk and 1 HRCA at baseline, and similar proportions had ≥2 HRCAs.
  • Revised high risk: 48.3% (n=14/29) vs 32.6% (n=14/43), D-VRd vs VRd respectively.
  • 1 HRCA: 37.9% (n=11/29) vs 23.3% (n=10/43), D-VRd vs VRd respectively.
  • ≥2 HRCAs: 10.3% (n=3/29) vs 9.3% (n=4/43), D-VRD vs VRd respectively.
• Among patients who did not achieve MRD-negativity (10^-5)by the end of consolidation, the proportion of patients with revised high cytogenetic risk, 1 HRCA, and ≥2 HRCAs was higher for D-VRd vs VRd at baseline.
  • Revised high risk: 52.1% (n=25/48) vs 34.2% (n=26/76), D-VRd vs VRd respectively.
  • 1 HRCA: 39.6% (n=19/48) vs 25% (n=19/76), D-VRd vs VRd respectively.
  • ≥2 HRCAs: 12.5% (n=6/48) vs 9.2% (n=7/76), D-VRd vs VRd respectively.