SUMMARY

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• There are no systemically collected data on the management of hematologic events with DARZALEX/DARZALEX FASPRO treatment. Clinical judgement should be exercised when managing hematologic events during DARZALEX/DARZALEX FASPRO-containing treatment regimens.

TRANSPLANT-ELIGIBLE

• CASSIOPEIA: phase 3 study evaluating the safety and efficacy of DARZALEX for intravenous (IV) use in combination with bortezomib, thalidomide and dexamethasone (D-VTd) in transplant eligible patients with previously untreated multiple myeloma (MM).¹
  • Moreau et al (2019)¹ reported results from Part 1 of CASSIOPEIA study. The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (D-VTd, 28%; VTd, 15%), lymphopenia (D-VTd, 17%; VTd, 10%), and thrombocytopenia (D-VTd, 11%; VTd, 7%). The most common serious adverse event (SAE) that occurred in ≥3% of patients was neutropenia (4% in D-VTd arm vs 1% in VTd arm).
  • Moreau et al (2021)² reported results from Part 2 of the CASSIOPEIA study. The most common grade 3/4 hematologic AEs in the DARZALEX monotherapy arm vs observation arm were lymphopenia (n=16 [4%] vs n=8 [2%]), and neutropenia (n=9 [2%] vs n=10 [2%]).
• GRIFFIN: phase 2, 2-part study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in patients with NDMM eligible for high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT).^3-5
  • Part 1: Voorhees et al (2021)⁶ reported the final analysis results of the safety run-in cohort (N=16; all patients received D-VRd) of the GRIFFIN study. The most common grade 3/4 hematologic treatment-emergent adverse events (TEAEs) were neutropenia (43.8%), lymphopenia (31.3%), and thrombocytopenia (25.0%).
  • Part 2: Voorhees et al (2023)⁷ reported the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end of study treatment, died, or withdrew from study participation. In the D-VRd vs bortezomib + lenalidomide + dexamethasone (VRd) arm, the most common (≥10%) grade 3/4 TEAEs were neutropenia (46% vs 23%), lymphopenia (23% in both arms), leukopenia (17% vs 8%), and thrombocytopenia (16% vs 9%).
  • Chari et al (2024)⁸ reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study. At a median follow-up duration of 49.6 months, the most common (>30%) hematologic TEAE reported in the D-VRd vs VRd arm of the safety analysis population separated by age <65 years and ≥65 years was neutropenia ([65.3% vs 38.7%] and [59.3% vs 44.4%], respectively).
• 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 DARZALEX FASPRO in combination with lenalidomide (D-R) in D-VRd group or R in VRd group in patients with NDMM eligible for ASCT.⁹
  • Sonneveld et al (2023)⁹ reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT. The most common grade 3/4 AEs reported in the D-VRd vs VRd arm were neutropenia (62.1% vs 51.0%), thrombocytopenia (29.1% vs 17.3%), and febrile neutropenia (9.4% vs 10.1%).
• MASTER is a phase 2 study (MASTER) evaluating the efficacy and safety of DARZALEX in combination with carfilzomib, lenalidomide, and dexamethasone (D-KRd) induction followed by autologous hematopoietic cell transplantation (AHCT) and minimal residual disease (MRD)-adapted consolidation therapy for patients with NDMM.¹⁰
  • Costa et al (2023)¹⁰ reported the results from the final analysis of the MASTER study (N=123) at a median follow-up of 42.2 months. The most common grade 3 hematologic TEAEs (≥5%) were neutropenia (29%), lymphopenia (15%), anemia (9%), thrombocytopenia (7%), hypophosphatemia (7%), and leukopenia (5%).
• PLEIADES: phase 2 study evaluating the clinical benefit of DARZALEX FASPRO for subcutaneous (SC) use administered in combination with 4 standard-of-care treatment regimens.^11-15 Specifically, with:
  • Chari et al (2021)¹¹ presented updated safety and efficacy results of the D-VRd arm in the PLEIADES study at a median follow-up of 3.9 months (n=67). The most common TEAE (≥5%) was neutropenia (28.4%) in the D-VRd arm.¹¹
• Rodriguez-Otero et al (2024)¹⁶ presented (at the 21^st International Myeloma Society [IMS] Annual Meeting) results from a post hoc analysis of the PERSEUS and GRIFFIN studies that evaluated the efficacy and safety of D-VRd vs VRd in patients aged ≥65 years. There were no new safety concerns observed, and the overall safety profile of patients aged ≥65 years was comparable to the pooled patient population irrespective of age. The most common grade 3/4 hematologic TEAEs reported in patients ≥65 years (pooled PERSEUS and GRIFFIN safety population) included neutropenia/febrile neutropenia (D-VRd, 59.2% vs VRd, 43.0%), and thrombocytopenia (D-VRd, 38.3% vs VRd, 19.3%). The most common serious hematologic TEAEs reported in patients ≥65 years included febrile neutropenia (D-VRd, 6.7% vs VRd, 4.4%).

TRANSPLANT-INELIGIBLE

• MAIA: phase 3 study evaluating the safety and efficacy of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) compared with lenalidomide and dexamethasone (Rd) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM).^17,18 The most common grade 3/4 (≥20%) hematologic TEAEs were neutropenia (D-Rd, 54.1%; Rd, 37.0%) and anemia (D-Rd, 17.0%; Rd, 21.6%).¹⁹
• ALCYONE: phase 3 study evaluating the safety and efficacy of bortezomib, melphalan, and prednisone (VMP) alone and DARZALEX + VMP (D-VMP) in patients with NDMM who were ineligible for HDT with ASCT.²⁰ The most common grade 3/4 (>15%) hematologic TEAEs were neutropenia (40.5% vs 39.0%), thrombocytopenia (34.7% vs 37.9%), and anemia (18.2% vs 19.8%) in the D-VMP arm vs VMP arm, respectively.²¹
• OCTANS: phase 3 study evaluating the efficacy and safety of D-VMP vs VMP in Asian patients with NDMM who were not eligible for ASCT.²²
  • During cycles 1-9, the most common (≥5%) grade 3/4 hematologic TEAEs were thrombocytopenia (D-VMP, 46.5%; VMP, 45.1%), neutropenia (D-VMP, 39.6%; VMP, 50.7%), leukopenia (D-VMP, 31.3%; VMP, 36.6%), lymphopenia (D-VMP, 30.6%; VMP, 22.5%), and anemia (D-VMP, 24.3%; VMP, 26.8%).
  • Fu et al (2023)²³ reported the final efficacy and safety results of the OCTANS study after an extended median follow-up of 41.2 months in transplant-ineligible Asian patients with NDMM treated with D-VMP vs VMP.
• LYRA: phase 2, single-arm, open-label, multicenter study evaluating the safety and efficacy of DARZALEX in combination with cyclophosphamide, dexamethasone, and bortezomib (CyBorD) for the treatment of MM in patients who have not received previous treatment or have relapsed after receiving only 1 line of treatment.^24,25
  • Yimer et al (2022)^26,27 reported the end-of-study analysis of LYRA. The most common grade 3/4 hematologic AEs reported in patients with NDMM were neutropenia (12.8%) and leukopenia (5.8%).
  • DARZALEX/DARZALEX FASPRO is not approved by the regulatory agencies for use in combination with cyclophosphamide, bortezomib, and dexamethasone for the treatment of MM. Janssen does not recommend the use of DARZALEX/DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• PLEIADES: phase 2 study evaluating the clinical benefit of DARZALEX FASPRO for subcutaneous (SC) use administered in combination with 4 standard-of-care treatment regimens.^11-15 Specifically, with:
  • Chari et al (2021)¹¹ presented updated safety and efficacy results of the PLEIADES study at a median follow-up of 14.3 months for the D-VMP arm (n=67). The most common TEAE (≥5%) was thrombocytopenia (45%) in the D-VMP arm.
• 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).^28,29
  • Badros et al (2024)^29-31 reported primary results from the phase 3 AURIGA study. Slightly higher occurrence rates of grade 3/4 cytopenias (54.2% vs 46.9%) were observed with D-R vs R.
  • Foster et al (2024)³² presented (at the 66^th American Society of Hematology [ASH] Annual Meeting) a post hoc analysis of the phase 3 AURIGA study that evaluated clinically relevant subgroups in patients with NDMM at a median follow-up of 32.3 months. The clinically relevant subgroups included elderly and black patients, patients with high-risk disease per International Staging System (ISS) disease staging, and patients with a high cytogenetic risk per standard, revised, and IMS 2024 high-risk criteria. Maintenance with D-R did not increase grade 3/4 cytopenia rates in patients ≥65 years of age.
  • DARZALEX/DARZALEX FASPRO is not approved by the regulatory agencies for use in combination with lenalidomide as a maintenance treatment for MM. Janssen does not recommend the use of DARZALEX/DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.

PRODUCT LABELING

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

CLINICAL DATA - Newly Diagnosed multiple myeloma - transplant-eligible

DARZALEX in Combination with Bortezomib, Thalidomide, and Dexamethasone

CASSIOPEIA (MMY3006; clinicaltrials.gov identifier: NCT02541383) is an ongoing, open-label, 2-arm, multicenter, phase 3 study evaluating the safety and efficacy of D-VTd in patients with previously untreated MM who are eligible for high dose chemotherapy and ASCT.¹ Moreau et al (2019)¹ reported the results from Part 1 of this study (induction treatment). Moreau et al (2021)² reported results from Part 2 of this study (maintenance treatment). Safety results related to hematologic events in Part 1 and Part 2 have been summarized below.

Study Design/Methods

• Part 1: Patients randomized to 1 of 2 treatment arms (each cycle is 4 weeks):
  • Arm A: Up to 4 cycles of bortezomib, thalidomide, and dexamethasone (VTd) induction therapy followed by ASCT, followed by 2 cycles of VTd consolidation.
  • Arm B: Up to 4 cycles of D-VTd induction therapy, followed by ASCT, followed by 2 cycles of D-VTd consolidation.
• Part 2: Responders rerandomized to 1 of 2 treatment arms:
  • Arm A: Observation.
  • Arm B: DARZALEX 16 mg/kg maintenance therapy every 8 weeks (Q8W) for 2 years
• Primary Endpoint: Part 1: stringent complete response (sCR) after consolidation therapy assessed at 100 days after ASCT (or immediately after consolidation if >100 days); Part 2: progression-free survival (PFS) after maintenance therapy.
• Secondary endpoints: Part 1: PFS, time to progression (TTP), proportion of post ASCT/consolidation MRD, proportion of post-induction sCR, PFS after next line of therapy (PFS2), overall survival (OS); Part 2: TTP from second randomization, rate of complete response (CR) or better, MRD-negativity rates (in patients with ≥CR at a threshold of 10^-5 by next-generation sequencing [NGS]), PFS2, overall response rate (ORR), and OS from second randomization.

Results - Safety - Hematologic Events in Part 1

• Hematologic events are presented in Table: Most Common Hematologic Adverse Events During Treatment in the Safety Population (CASSIOPEIA Part 1 Study).
• The most common SAE that occurred in ≥3% of patients was neutropenia (4% in D-VTd arm vs 1% in VTd arm).

Results - Safety - Hematologic Events in Part 2

• Hematologic events are presented in Table: Most Common Hematologic Adverse Events During Treatment/Observation in Maintenance-Specific Safety Population (CASSIOPEIA Part 2 Study).

DARZALEX in Combination with Bortezomib, Lenalidomide and Dexamethasone

GRIFFIN (MMY2004; clinicaltrials.gov identifier: NCT02874742) is an ongoing, 2-part, randomized, active-controlled, phase 2 US study evaluating the safety and efficacy of DARZALEX in combination with VRd in patients with NDMM eligible for HDT and ASCT.^3-5 Voorhees et al (2021)⁶ reported the final analysis of the safety run-in cohort of the GRIFFIN study. Sborov et al (2022)³³ presented the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end of study treatment. Safety results specific to hematologic events are summarized below.

Study Design/Methods

• Part 1 of the study (safety run-in phase) consisted of an induction phase (cycles 1-4; 21-day cycles), followed by ASCT and a consolidation phase (cycles 5-6; 21-day cycles) that was initiated 60-100 days after ASCT, and a maintenance phase (cycles 7-32; 28-day cycles) thereafter.
  • From the induction phase through the consolidation phase, patients received:
    • DARZALEX 16 mg/kg IV weekly in cycles 1-4 and every 3 weeks in cycles 5-6.
    • Lenalidomide 25 mg orally (PO) on days 1-14.
    • Bortezomib 1.3 mg/m² SC on days 1, 4, 8, and 11.
    • Dexamethasone 40 mg PO weekly (20 mg PO on days 1, 2, 8, 9, 15, and 16).
  • During the maintenance phase, patients received:
    • DARZALEX 16 mg/kg IV every 4 weeks (Q4W) or (Q8W).
    • Lenalidomide 10 mg PO daily on days 1-21, then 15 mg PO daily beginning cycle 10 (if no tolerability issues).
    • Dexamethasone 20 mg PO (Q8W) on days 1, 2, 8, 9, 15, and 16.
  • One interim safety analysis was performed for the safety run-in patients after being treated for ≥4 cycles or discontinued from the study.
• In part 2 of the study, following successful completion of the safety run-in phase, patients were randomized 1:1 to an induction phase (D-VRd or VRd [cycles 1-4; 21-day cycles]), followed by ASCT, a consolidation phase (D-VRd or VRd [cycles 5-6; 21-day cycles]), and a maintenance phase (DARZALEX + lenalidomide or lenalidomide monotherapy [cycles 7-32; 28-day cycles]), following the same dosing as part 1, with or without DARZALEX.
• Primary endpoints: sCR (by the end of post-ASCT consolidation).
• Secondary endpoints: MRD (10^-5 via NGS), CR, ORR, very good partial response (VGPR) or better, duration of response (DOR), time to CR or sCR, PFS, and OS.

Voorhees et al (2021)⁶ reported the final analysis of the safety run-in cohort of the GRIFFIN study.

Results - Safety - Hematologic Events in Part 1

• The most common grade 3/4 hematologic TEAEs reported at a median follow-up duration of 40.8 months (range, 20.6-43.0) after patients completed D-VRd treatment and after 24 months of D-R maintenance therapy are summarized in Table: Most Common Grade 3/4 Hematologic TEAEs (GRIFFIN, Part 1).

Voorhees et al (2023)⁷ reported the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end-of-study treatment, died, or withdrew from study participation.

Results - Safety - Hematologic Events in Part 2

• The most common hematologic TEAEs reported in the safety population after a median follow-up duration of 49.6 months are summarized in Table: Most Common Hematologic TEAEs (GRIFFIN, Part 2).

Final Analysis in Clinically Relevant Subgroups

Chari et al (2024)^8,34 reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study.

Study Design/Methods

• This final analysis was conducted after all patients completed ≥1 year of follow-up after concluding study treatment, died, or withdrew.

Results

Safety

• At a median follow-up duration of 49.6 months, a summary of the most common (>30%) hematologic TEAEs in the safety analysis population separated by age <65 years and ≥65 years is provided in Table: Most Common (>30%) Any Grade Hematologic TEAEs by Age (<65 years and ≥65 year).

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 the D-VRd group or R in the VRd group in patients with NDMM eligible for ASCT. Sonneveld et al (2023)⁹ reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT.

Study Design/Methods

• A total of 709 patients were randomized 1:1 to into D-VRd (n=355) vs VRd (n=354) arm.
  • 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]).
• Dosing:
  • Induction and consolidation: Total duration of induction and consolidation treatment was 6 cycles. Each cycle was 28 days.
    • D-VRd:
      • DARZALEX FASPRO- 1800 mg once weekly (QW) in cycles 1-2 and every 2 weeks (Q2W) in cycles 3-4
      • SC bortezomib- 1.3 mg/m² on days 1, 4, 8, and 11 of each cycle
      • PO lenalidomide- 25 mg on days 1-21 of each cycle
      • PO/IV dexamethasone- 40 mg on days 1-4 and days 9-12 of each cycle
    • VRd:
      • SC bortezomib- 1.3 mg/m² on days 1, 4, 8, and 11 of each cycle
      • PO lenalidomide- 25 mg daily on days 1-21 of each cycle
      • PO/IV dexamethasone- 40 mg on days 1-4 and days 9-12 of each cycle
  • Maintenance: Total duration of maintenance (≥24 months) was cycle 7 until progressive disease. Each cycle was 28 days.
    • D-VRd:
      • DARZALEX FASPRO- 1800 mg SC Q4W
      • PO lenalidomide-10 mg until PD or unacceptable toxicity
      • Patients who achieved sustained MRD for 12 months after ≥24 months of maintenance discontinued DARZALEX FASPRO, but continued PO lenalidomide until PD or unacceptable toxicity. Once they experienced loss of MRD-negativity or CR, they restarted DARZALEX FASPRO
      • Patients who did not achieve sustained MRD for 12 months after ≥24 months of maintenance continued DARZALEX FASPRO and PO lenalidomide
    • VRd:
      • PO lenalidomide-10 mg daily until PD or unacceptable toxicity
• Primary endpoint: PFS.
• Key secondary endpoints: Overall ≥CR, overall MRD-negativity, and OS.
• Other secondary endpoints: ORR, ≥VGPR, sCR, duration of MRD-negativity.

Results - Safety - Hematologic Events

• The most common grade 3/4 AEs recorded in the D-VRd vs VRd group were neutropenia (62.1% vs 51.0%), thrombocytopenia (29.1% vs 17.3%), and febrile neutropenia (9.4% vs 10.1%). See Table: Most Common Hematologic AEs During Treatment in the Safety Population.
• Serious hematologic AEs in the safety population are summarized in Table: Serious Hematologic AEs in the Safety Population.

DARZALEX FASPRO in Combination with Bortezomib, Lenalidomide and Dexamethasone

PLEIADES (MMY2040; clinicaltrials.gov identifier: NCT03412565) is an ongoing, non-randomized, open-label, multicenter, phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various 4 standard-of-care treatment regimens in patients with MM.^11-15 Specifically with:

• Transplant-eligible NDMM: D-VRd for patients with transplant-eligible NDMM (n=67).
• Transplant-ineligible NDMM: DARZALEX FASPRO in combination with VMP for patients with transplant-ineligible NDMM (n=67).
• Relapsed refractory multiple myeloma (RRMM):
  • DARZALEX FASPRO in combination with Rd for patients with RRMM with ≥1 prior line of therapy (n=65).
  • DKd in patients with RRMM with 1 prior line of therapy (n=60).

Chari et al (2021)¹¹ presented updated safety and efficacy results of the D-VRd arm in the PLEIADES study at a median follow-up of 3.9 months. Safety results related to hematologic AEs reported in the D-VRd arm have been summarized below.

Study Design/Methods

• Patients with transplant-eligible NDMM were included in the D-VRd arm and received 4 cycles of the following induction treatment (21 days/cycle):
  • DARZALEX FASPRO 1800 mg SC QW during cycles 1-3 and on day 1 of cycle 4
  • Bortezomib 1.3 mg/m² SC on days 1, 4, 8, and 11 during cycles 1-4
  • Lenalidomide 25 mg PO on days 1-14 during cycles 1-4
  • Dexamethasone 20 mg PO/IV on days 1, 2, 8, 9, 15, and 16 of cycles 1-4
• Primary endpoints: ≥VGPR after the 4 induction cycles for the D-VRd arm
• Key secondary endpoints: maximum observed serum concentrations (C_max) and minimum observed serum concentrations (C_min) of daratumumab, immunogenicity, percentage of participants with infusion-related reactions (IRR), ≥CR, DOR, MRD-negativity rate and ≥VGPR for the D-VMP arm, ORR for the D-VRd arm.

Results - Safety - Hematologic Events in the D-VRd Arm

• Hematologic events are presented in Table: Most Common Hematologic TEAEs (≥5% in D-VRd cohort, PLEIADES Study).

DARZALEX in Combination with Carfilzomib, Lenalidomide, and Dexamethasone

MASTER is a phase 2 study (MASTER) evaluating the efficacy and safety of DARZALEX in combination with D-KRd induction followed by AHCT and MRD-adapted consolidation therapy for patients with NDMM.¹⁰ Costa et al (2023)¹⁰ reported the results from the final analysis of the MASTER study at a median follow-up of 42.2 months. Results from the final analysis are reported below.

Study Design/Methods

• Key eligibility criteria: Patients of any age group with NDMM with measurable disease, with Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2, who had measurable renal function (CrCl ≥40 mL/min) and were either untreated or had received up to 1 cycle of bortezomib, cyclophosphamide, and dexamethasone (VCd) were included. Patients with a concomitant or recent malignancy, or significant cardiopulmonary disease were excluded.
• Primary endpoint: Rate of MRD-negative responses (<10^-5) by NGS (clonoSEQ^®).
• Secondary endpoints: Toxicity of D-KRd, rates and kinetics of MRD resurgence upon treatment discontinuation, PFS, and OS.
• Exploratory endpoints: PFS and OS for patients who transitioned to MRD-surveillance (MRD-SURE) and were monitored off therapy.
• Enrichment for patients with HRCA was planned during recruitment.

Results - Safety - Hematologic Events

• The most common hematologic TEAEs reported in the MASTER study are presented in Table: Most Common Hematologic TEAEs (MASTER).

DARZALEX FASPRO in Combination with Bortezomib, Lenalidomide, and Dexamethasone

Rodriguez-Otero et al (2024)¹⁶ presented (at the 21^st IMS Annual Meeting) results from a post hoc analysis of the PERSEUS and GRIFFIN studies that evaluated the efficacy and safety of D-VRd vs VRd in 237 patients aged ≥65 years.

Results - Safety - Hematologic Events

• The most common Grade 3/4 and serious hematologic TEAEs are presented in Table: Summary of TEAEs in Patients Aged ≥65 Years and All Patients Irrespective of Age in the Pooled PERSEUS/GRIFFIN Safety Population.

CLINICAL DATA - NEWLY DIAGNOSED MULTIPLE MYELOMA - TRANSPLANT-INELIGIBLE

DARZALEX in Combination with Lenalidomide and Dexamethasone

MAIA (MMY3008; clinicaltrials.gov identifier: NCT02252172) is an international, phase 3, randomized, open-label, active-controlled, multicenter study in patients with NDMM not eligible for high dose chemotherapy and ASCT (N=737).^17,18 Kumar et al (2022)¹⁹ reported the updated safety and efficacy results of the MAIA study at a median follow-up of 64.5 months. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Patients were randomized 1:1 to D-Rd (n=368) or Rd (n=369) and received 28-day cycles of the following treatment until PD or unacceptable safety event:
  • Rd arm:
    • Lenalidomide 25 mg PO daily on days 1-21 until PD (10 mg daily if creatinine clearance [CrCl] is between 30 and 50 mL/min).
    • Dexamethasone: 40 mg PO or IV weekly on days 1, 8, 15, and 22, until PD
      (20 mg weekly in patients >75 years of age or with a body mass index [BMI] <18.5 kg/m²).
  • D-Rd arm:
    • DARZALEX 16 mg/kg IV weekly during cycles 1-2, Q2W during cycles 3-6, then Q4W during cycle 7+. Following a protocol amendment (2020), patients in the D-Rd arm were given the option to switch from DARZALEX IV to DARZALEX FASPRO for SC use. DARZALEX FASPRO was to be administered at a fixed dose of 1800 mg SC over 3-5 minutes in the abdominal SC tissue Q4W.
    • Same dosage and schedule of lenalidomide and dexamethasone as the Rd arm.
• Primary endpoint: PFS
• Secondary endpoints: ≥CR rate, DOR, ≥VGPR rate, MRD-negativity rate, ORR, OS, PFS2, sCR, time to next (2nd-line) treatment, time to response, time to progression, and safety.

Results - Safety - Hematologic Events

• The most common any-grade (≥30%) and grade 3/4 (≥20%) hematologic events reported at a median follow-up duration of 64.5 months are presented in Table: Most Common Any-Grade (≥30%) and Grade 3/4 (≥20%) Hematologic TEAEs (MAIA Study).

DARZALEX in Combination with Bortezomib, Melphalan, and Prednisone

ALCYONE (MMY3007; clinicaltrials.gov identifier: NCT02195479) is a multicenter, randomized, open-label, active-controlled, phase 3 study evaluating the safety and efficacy of D-VMP compared with VMP alone for the treatment of NDMM in patients (N=706) who were ineligible for high-dose chemotherapy with ASCT.²⁰ Mateos et al (2022)²¹ presented an updated efficacy and safety analysis of the ALCYONE study at a median follow-up of almost 7 years (78.8 months). Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Patients were randomly assigned 1:1 to receive either VMP alone or D-VMP as follows (randomization was stratified according to disease stage [I, II, or III], geographic region [Europe vs other], and age [<75 vs ≥75 years]):
  • VMP: up to 9 cycles (42 days/cycle) of:
    • Bortezomib 1.3 mg/m² SC twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and QW on weeks 1, 2, 4, and 5 of cycles 2-9
    • Melphalan 9 mg/m² PO once daily on days 1-4 of each cycle
    • Prednisone 60 mg/m² PO once daily on days 1-4 of each cycle
  • D-VMP: Up to 9 cycles (42 days/cycle) of VMP as described above plus:
    • DARZALEX 16 mg/kg IV QW in cycle 1, once every 3 weeks in cycles 2-9, and Q4W thereafter until there was disease progression or unacceptable toxicity
    • Patients in this arm also received dexamethasone 20 mg PO or IV and other pre-infusion medications (approximately 1 hour before DARZALEX infusion) for management of infusion reactions. On day 1 of each cycle, the dexamethasone 20 mg dose was substituted for the prednisone dose in the VMP regimen.
• Primary Endpoint: PFS
• Secondary Endpoints: ≥CR rate, ≥VGPR rate, MRD-negativity (10^-5), ORR, and median OS.

Results - Safety - Hematologic Events

• Hematologic events reported at a median follow-up duration of 78.8 months are presented in Table: Most Common Any-Grade (≥10%) and Grade 3/4 (≥5%) Hematologic TEAEs (ALCYONE Study).

DARZALEX in Combination with Bortezomib, Melphalan, and Prednisone in Asian Patients

OCTANS (MMY3011; clinicaltrials.gov identifier: NCT03217812) is a multicenter, randomized, open-label, active-controlled, phase 3 study evaluating the efficacy and safety of D-VMP vs VMP in Asian patients with NDMM who were not eligible for ASCT.²² Fu et al (2023)²² reported the pre-specified primary results of the OCTANS study. Safety results related to the hematologic events have been summarized below.

Study Design/Methods

• Patients were randomized 1:2 to receive D-VMP or VMP (42 days/cycle).
  • Patients in the D-VMP arm received:
    • DARZALEX 16 mg/kg IV QW during cycle 1, once every 3 weeks during cycles 2 through 9, and Q4W thereafter until PD or unacceptable toxicity
    • Bortezomib 1.3 mg/m² twice weekly during weeks 1, 2, 4, and 5 of cycle 1 and QW during weeks 1, 2, 4, and 5 of cycles 2 to 9
    • Melphalan 9 mg/m² PO once daily on days 1 to 4 of each cycle
    • Prednisone 60 mg/m² PO once daily on days 1 to 4 of each cycle
  • Patients in the VMP arm received the same dose of bortezomib, melphalan, and prednisone as the D-VMP arm.
• Primary endpoint: rate of ≥VGPR²³
• Key secondary endpoints: PFS, ORR, sCR rate, CR rate, time to response, DOR, OS, time to next treatment²³

Results - Safety - Hematologic Events

• Hematologic events reported at a median follow-up of 12.3 months (range, 0-29.3) are summarized in Table: Most Common Any-Grade (≥20%) and Grade 3/4 (≥5%) Hematologic TEAEs in the Safety Population (OCTANS Study).
• During Cycles 1-9, thrombocytopenia was reported as the most common (≥5% of patients in both arms) hematologic SAE (D-VMP, 6.9%; VMP, 7.0%).

Fu et al (2023)²³ reported the final efficacy and safety results of the OCTANS study after an extended median follow-up of 41.2 months in transplant-ineligible Asian patients with NDMM treated with D-VMP vs VMP.

Results - Safety - Hematologic Events

• The most common any-grade and grade 3/4 TEAEs are summarized in Table: Most Common Any-Grade (≥20%) and Grade 3/4 (≥10%) TEAEs in the Safety Population (Extended Follow-up).

Most Common Any-Grade (≥20%) and Grade 3/4 (≥10%) TEAEs in the Safety Population (Extended Follow-up)²³

DARZALEX in Combination with Cyclophosphamide, Bortezomib, and Dexamethasone

LYRA (clinicaltrials.gov identifier: NCT02951819) is a phase 2, single-arm, open-label, multicenter study evaluating the safety and efficacy of DARZALEX in combination with CyBorD for the treatment of MM in patients who had not received previous treatment or had relapsed after receiving only 1 line of treatment.^24,25 Yimer et al (2022)²⁶ reported the end-of-study analysis results of the LYRA study. Safety results specific to hematologic events reported in patients with NDMM are summarized below.

Study Design/Methods

• Patients received 4-8 cycles (28 days per cycle) of the following induction treatment²⁴:
  • DARZALEX: 16 mg/kg IV
    • Cycle 1: 8 mg/kg IV on days 1 and 2, followed by 16 mg/kg weekly
    • Cycle 2: weekly
    • Cycles 3-6: Q2W
    • Cycles 7-8: Q4W
  • Bortezomib: 1.5 mg/m² SC weekly on days 1, 8, and 15 in all cycles
  • Cyclophosphamide: 300 mg/m² PO weekly on days 1, 8, 15, and 22 in all cycles
  • Dexamethasone: 40 mg
    • Cycle 1: 20 mg IV on days 1 and 2, followed by 40 mg weekly
    • Cycles 2-8: 40 mg IV/PO weekly
• After the induction phase, all patients received up to 12 cycles (28 days per cycle) of the following maintenance treatment²⁴:
  • DARZALEX: 16 mg/kg IV Q4W
  • Dexamethasone: 12 mg IV/PO on DARZALEX dosing days
• Patients underwent HDT and ASCT at the discretion of the investigator after the induction phase.²⁶
• Primary endpoint: ≥VGPR after 4 induction cycles²⁶
• Key secondary endpoints: ORR, time to ≥VGPR, time to ≥PR, PFS, OS, safety, and tolerability²⁶

Results - Safety - Hematologic Events

• The most common hematologic TEAEs reported in patients with NDMM at a median follow-up of 35.7 months are summarized in Table: Most Common Hematologic TEAEs of Any Grade (≥25%) or Grade 3/4 (≥10%) in the Safety Analysis Set (LYRA).

DARZALEX FASPRO in Combination with Bortezomib, Melphalan and Dexamethasone

PLEIADES (MMY2040; clinicaltrials.gov identifier: NCT03412565) is an ongoing, non-randomized, open-label, multicenter, phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various treatment regimens in patients with MM.^11-15 Chari et al (2021)¹¹ presented updated safety and efficacy results of the PLEIADES study at a median follow-up of 14.3 months for the D-VMP arm. Safety results related to hematologic AEs reported in the D-VMP arm have been summarized below.

Study Design/Methods

• Patients with transplant-ineligible NDMM were included in the D-VMP arm and received 42-day cycles of the following treatment until PD:
  • DARZALEX FASPRO 1800 mg SC QW during cycle 1, on days 1 and 22 during cycles 2-9, and on day 1 during cycle 10
  • Bortezomib 1.3 mg/m² SC on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycle 1 and on days 1, 8, 22, and 29 during cycles 2-9
  • Melphalan 9 mg/m² PO on days 1-4 during cycles 1-9
  • Prednisone 60 mg/m² PO on days 1-4 during cycles 1-9
• Primary endpoints: ORR for the D-VMP arm
• Key secondary endpoints: maximum observed serum concentrations (C_max) and minimum observed serum concentrations (C_min) of daratumumab, immunogenicity, percentage of participants with IRR, ≥CR rate, DOR, MRD-negativity rate and ≥VGPR for the D-VMP arm.

Results - Safety - Hematologic Events in the D-VMP arm

• Hematologic events are presented in Table: Summary of Hematologic TEAEs in the D-VMP Arm (PLEIADES Study).

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 MRD-negativity after maintenance treatment with D-R vs lenalidomide alone in patients with NDMM who are anti-CD 38 naïve, have ≥VGPR, and are MRD positive after ASCT.^28-30 Badros et al (2024)^29,30 reported primary results from the phase 3 AURIGA study.

Study Design/Methods

• The trial enrolled 200 patients from the United States and Canada.²⁹
• Patients underwent 1:1 randomization to receive D-R maintenance (n=99) or R alone maintenance (n=101) across 28-day cycles.^28,29
  • 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.²⁹
• Primary endpoint: MRD-negativity conversion rate from baseline to 12 months.²⁹
  • 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.
• 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.²⁹

Results - Safety - Hematological AEs

• The most common hematologic AEs in the safety population are summarized in Table: Most Common Hematologic AEs in the Safety Population.²⁹
  • 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.

Foster et al (2024)³² presented (at the 66^th ASH Annual Meeting) a post hoc analysis of the phase 3 AURIGA study that evaluated clinically relevant subgroups in patients with NDMM at a median follow-up of 32.3 months.

Results - Safety - Hematological AEs

• D-R maintenance did not increase grade 3/4 cytopenia rates in patients ≥65 years of age.³² 
  • Hematological safety results according to age for patients with ≥1 TEAE are summarized in Table: Hematological Safety Results Based on Age for Patients with ≥1 TEAE.
  • Hematological safety results according to race for patients with ≥1 TEAE are summarized in Table: Hematological Safety Results Based on Race for Patients with ≥1 TEAE.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 18 December 2024. For streamlining purposes, retrospective-analyses, systematic reviews, review articles, and case reports have been excluded.

In response to your specific request, summarized in this response is the relevant data from company-sponsored studies pertaining to this topic.