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 (MMY3014) is an ongoing, open-label, multicenter, randomized, 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 (at the European Hematology Association [EHA] Hybrid Congress) 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 (at the 21^st International Myeloma Society [IMS] Annual Meeting) 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 (at the 66^th American Society of Hematology [ASH] Annual Meeting) 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 (MMY3019) 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 (MMY3021) 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 (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 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 (at the 64th ASH Annual Meeting and Exposition) 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 (2022)¹⁵ presented (at the 64th ASH Annual Meeting and Exposition) 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 (at the 64th Annual Meeting and Exposition) 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).
• OCTANS is a phase 3, multicenter, randomized, active-controlled, open-label study evaluating the efficacy and safety of D-VMP vs VMP alone in Asian patients with NDMM ineligible for high-dose chemotherapy with ASCT.^19,20
  • Hou et al (2021)²¹ presented (at the 63rd ASH Annual Meeting & Exposition) clinical benefit results in patient subgroups within the pooled population of Asian patients from the OCTANS study and global patients from the ALCYONE study with NDMM ineligible for ASCT. Among patients with high cytogenetic risk, although median PFS improved with D-VMP (19.5 months) vs VMP (18.1 months), PFS benefit was less pronounced than that observed for patients with standard cytogenetic risk (median PFS: D-VMP, not reached [NR]; VMP, 17.4 months).
  • Fu et al (2023)²² evaluated PFS by MRD status in a pooled population of Asian and global patients from the OCTANS and ALCYONE studies. In a pooled analysis of OCTANS and ALCYONE, D-VMP vs VMP alone was associated with prolonged PFS across most of the high-risk subgroups evaluated. PFS in the high-risk subgroups of the OCTANS and ALCYONE studies is noted in Table: PFS by High-Risk Subgroups in Pooled Data from the OCTANS and ALCYONE Studies.
• 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.²³ Moreau et al (2021)²⁴ 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). Sonneveld et al (2019)²⁵ presented a subgroup analysis of patients with high-risk NDMM in Part 1 of the CASSIOPEIA study based on cytogenetic risk status and ISS stage. Efficacy data from the subgroup analyses of the study are presented in Table: Post-consolidation Response and MRD Status for High-Risk Patients (CASSIOPEIA Part 1).
• 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.^26-28 Chari et al (2024)^29,30 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 (ClinicalTrials.gov identifier: NCT03224507) 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.³¹ Costa et al (2023)³¹ 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)³² reported additional details on PFS and OS for different study populations and at difference timepoints according to MRD status.
• Callander et al (2024)³³ 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.³⁴ Sonneveld et al (2022)³⁵ 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)³⁶ 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.³⁷ Dimopoulos et al (2022)³⁸ presented (at the 3^rd Annual Meeting of the EMN) 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)³⁹ presented updated efficacy and safety data based cytogenetic risk status of DRd 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 as noted in Table: Response and MRD-negativity Rates in Patients with Standard and High Cytogenetic Risk (POLLUX).
• Mateos et al (2022)⁴⁰ presented (at the 19th IMS Annual Meeting) 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 (n=312) vs carfilzomib and dexamethasone (Kd, n=154) in patients with RRMM.^41,42 Usmani et al (2023)⁴³ 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).^44,45 Sonneveld et al (2021)⁴⁶ presented (at the 63rd ASH Annual Meeting & Exposition) 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)⁴⁷ presented (at 64th ASH Annual Meeting and Exposition) 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.
• Giri et al (2020)⁴⁸ conducted a systematic review and meta-analysis of 6 randomized clinical studies which evaluated the efficacy relative to DARZALEX in combination with backbone MM regimens for patients with newly diagnosed or relapsed/refractory high-risk multiple myeloma (HRMM). The percentage of patients with HRMM ranged from 15% to 33% in the included studies. The analysis reported an improved PFS associated with the addition of DARZALEX to various backbone MM regimens in patients with relapsed/refractory HRMM (pooled HR, 0.15; 95% CI, 0.30-0.67; P<0.001) and newly diagnosed HRMM (pooled HR, 0.67; 95% CI, 0.4-0.95; P=0.02).

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; clinicaltrials.gov identifier: 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 (at the 66^th ASH Annual Meeting) 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; clinicaltrials.gov identifier: 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; clinicaltrials.gov identifier: 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) 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.

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 (2022)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
  • Cytogenetic risk
    • 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 (≥20%) grade 3/4 TEAEs were neutropenia (D-Rd, 62.4%; Rd, 41.5%), lymphopenia (D-Rd, 21%; Rd, 12.6%), anemia (DRd, 20.4%; Rd, 25.2%), and pneumonia (D-Rd, 20.4%; Rd, 14.5%).
• 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%.

Pooled Analysis of MAIA and ALCYONE Studies

Jakubowiak et al (2022)¹⁸ reported the results of a pooled analysis of patient-level data of transplant-ineligible patients with NDMM and high cytogenetic risk from the MAIA and ALCYONE studies.

Study Design/Methods

• Patients with baseline high-risk cytogenetics [del(17p), t(4;14), or t(14;16)] were included.
• Primary endpoint: PFS
• Secondary endpoint: ORR, best response, ≥VGPR, MRD-negative CR

Results

Patient Characteristics

• Overall, 101 patients (D-Rd [MAIA], n=48; DARZALEX + bortezomib + melphalan + prednisone arm [D-VMP; ALCYONE], n=53) were included in the pooled DARZALEX cohort and 89 patients (Rd [MAIA], n=44; VMP [ALCYONE], n=45) were included in the pooled control cohort.
• The combined median follow-up duration of both the trials was 43.7 months (MAIA, 47.9 months; ALCYONE, 40.1 months).
• In the pooled DARZALEX and control cohorts, the median duration of treatment was 19.9 and 12 months, respectively.
• Baseline characteristics of patients within the MAIA and ALCYONE studies are summarized in Table: Key Baseline Characteristics in MAIA and ALCYONE.

Efficacy

• 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.
  • After adjusting for age differences, the pooled HR for PFS was 0.59 (95% CI, 0.410.85; P=0.0044).
  • In the subgroup of patients with del(17p) at baseline (pooled DARZALEX, n=54; pooled control, n=56) the adjusted HR for PFS was 0.63 (95% CI, 0.39-1.03; P=0.0659).
  • In the individual studies, the adjusted HRs for PFS were 0.73 (95% CI, 0.46-1.14) in the ALCYONE study and 0.57 (95% CI, 0.33-1) in the MAIA study. See Table: HRs for PFS in Patient with High-Risk Cytogenetics (MAIA and ALYCONE).
• The 36-month PFS rate was 41.3% in the pooled DARZALEX cohort vs 19.9% in the pooled control cohort.

• The median time to ≥CR was 9.3 months (range, 3.5-34.5) in the pooled DARZALEX cohort vs 7.1 months (range, 2.3-43.8) in the pooled control cohort. See Table: Response Rates Among ASCT-Ineligible High-Risk NDMM Patients from MAIA and ALYCONE.
• In the pooled DARZALEX vs control cohorts, the median PFS was NR vs 31 months in patients achieving ≥CR and 16.4 months vs 15.6 months in patients not achieving CR.