DARZALEX + DARZALEX FASPRO - Hematologic Events in Patients with Newly Diagnosed Multiple Myeloma

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 systematically 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.
• Johnson & Johnson does not recommend the use of DARZALEX/DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.

Transplant-Eligible Newly Diagnosed Multiple Myeloma

• CASSIOPEIA is a 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
  • Part 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).
  • Part 2: 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 (4% vs 2%), and neutropenia (2% vs 2%).
• GRIFFIN is a phase 2, 2-part study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in patients with newly diagnosed multiple myeloma (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 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 is a phase 3 study evaluating the efficacy and safety of D-VRd vs VRd induction and consolidation followed by maintenance with DARZALEX FASPRO in combination with lenalidomide (D-R) in D-VRd group or lenalidomide (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 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 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 is a 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
  • 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 reported 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 Newly Diagnosed Multiple Myeloma

• MAIA is a 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 NDMM.^17,18
  • Facon et al (2025)¹⁹ reported the updated efficacy and safety results from the MAIA study at a long-term median follow-up of 64.5 months. The most common any grade (≥30%) hematologic TEAEs were neutropenia (D-Rd, 61.5%; Rd, 45.5%) and anemia (D-Rd, 42.3%; Rd, 41.1%). 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%).
• ALCYONE is a 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
  • Mateos et al (2025)²¹ reported an updated efficacy and safety analysis of the ALCYONE study at a median follow-up of 86.7 months. The most common grade 3/4 (>15%) hematologic TEAEs were neutropenia (40.0% vs 39.0%), thrombocytopenia (35.0% vs 38.0%), and anemia (18.0% vs 20.0%) in the D-VMP arm vs VMP arm, respectively. 
• LYRA is a phase 2 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.^22,23
  • Yimer et al (2022)^24,25 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%).
• PLEIADES is a phase 2 study evaluating the clinical benefit of DARZALEX FASPRO for SC use administered in combination with 4 standard-of-care treatment regimens.^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 (n=67). The most common TEAE (≥5%) was thrombocytopenia (45%) in the D-VMP arm.
• AURIGA is a phase 3 study evaluating the conversion rate to MRD-negativity after maintenance treatment with 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.²⁶
  • Anderson et al (2025)²⁷ presented the updated efficacy and safety results from the phase 3 AURIGA study at 24 months from the start of maintenance therapy, with a median follow-up of 40.3 months. The most common grade 3/4 hematologic TEAEs observed in the D-R vs R arm were neutropenia (49.0% vs 45.9%, respectively), leukopenia (10.4% vs 7.1%, respectively), and lymphopenia (10.4% vs 6.1%, respectively). No new safety concerns were identified with the addition of DARZALEX FASPRO to R maintenance.
  • Foster et al (2024)²⁸ presented 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.
• CEPHEUS is a phase 3 study evaluating the efficacy and safety of 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).²⁹
  • Usmani et al (2026)³⁰ presented the efficacy and safety results of the TIE population of the CEPHEUS study at a median follow-up of 76 months. The most common grade 3/4 hematologic TEAEs were neutropenia (D-VRd, 45.1%; VRd, 33.1%), thrombocytopenia (D-VRd, 30.6%; VRd, 23.2%), and anemia (D-VRd, 11.1%; VRd, 9.9%).
  • Zweegman et al (2025)³¹ presented a subgroup analysis to assess efficacy and safety outcomes from the CEPHEUS study based on frailty status in patients with NDMM who were TIE or transplant deferred. Safety profiles were generally consistent with the established profiles of DARZALEX FASPRO and VRd across frailty subgroups. Grade 3/4 hematologic TEAEs included neutropenia and thrombocytopenia. Neutropenia occurred in 41.1% vs 36 27.3% of patients in International Myeloma Working Group (IMWG) fit subgroup; 49.3% vs 22 34.9% of patients in IMWG intermediate fitness subgroup; 42.9% vs 30.1% in Intergroupe Francophone du Myélome (IFM) nonfrail subgroup; 47.4% vs 28.2% in IFM frail subgroup, in D-VRd vs VRd arms respectively. Thrombocytopenia occurred in 21.8% vs 20.5% in IMWG fit subgroup; 39.7% vs 19.0% in IMWG intermediate fitness subgroup; 22.9% vs 19.9% in IFM nonfrail subgroup; 42.1% vs 20.5% in IFM frail subgroup, in D-VRd vs VRd arms respectively.

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 -  transplant-eligible NDMM

Phase 3 Study of DARZALEX in Combination with VTd in Previously Untreated MM

CASSIOPEIA (MMY3006; NCT02541383) is a phase 3, open-label, 2-arm, multicenter 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

Primary Analysis of Part 1 of the CASSIOPEIA Study

Moreau et al (2019)¹ reported the results from Part 1 of this study at a median follow-up of 18.8 months (range, 0.0-32.2). Results specific to hematologic events are summarized below.

Safety Results - Hematologic Events in Part 1

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

Primary Analysis of Part 2 of the CASSIOPEIA Study

Moreau et al (2021)² reported results from Part 2 of this study (maintenance treatment). Safety results related to hematologic events have been summarized below.

Safety Results - 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).²

Phase 2 Study of DARZALEX in Combination with VRd in TE NDMM

GRIFFIN (MMY2004; NCT02874742) is a 2-part, phase 2, randomized, active-controlled study evaluating the safety and efficacy of DARZALEX in combination with VRd in patients with NDMM eligible for HDT and ASCT.^3-5

Final Analysis of Part 1 (Safety Run-in Phase) of the GRIFFIN Study

Voorhees et al (2021)⁶ reported the final analysis of the safety run-in cohort of the GRIFFIN study. Results specific to hematologic events are summarized below.

Safety Results - Hematologic Events in Part 1

• The most common grade 3/4 hematologic TEAEs reported at a median follow-up 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).⁶

Final Analysis of Part 2 9Randomized Phase) of the GRIFFIN Study

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 specific to hematologic events are summarized below.

Safety Results - Hematologic Events in Part 2

• The most common hematologic TEAEs reported in the safety population after a median follow-up of 49.6 months are summarized in Table: Most Common Hematologic TEAEs (GRIFFIN; Part 2).³²

Final Analysis of  Clinically Relevant Subgroups of the GRIFFIN Study

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

Safety Results - Hematologic Events

• At a median follow-up 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).⁸

Phase 3 Study of DARZALEX FASPRO in Combination with VRd in TE NDMM

PERSEUS (MMY3014; NCT03710603) is a phase 3, randomized, open-label, multicenter 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.⁹

Primary Analysis of the PERSEUS Study

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.

Safety Results - 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.⁹

• SAEs occurred in 57.0% vs 49.3% of patients in the D-VRd vs VRd arms, respectively. The most common hematologic serious AEs (occurring in ≥2% of patients in either group) were³³: 
  • Febrile neutropenia: 4.6% (D-VRd) vs 4.6% (VRd) 

Phase 2 Study of DARZALEX FASPRO in Combination with Various Treatment Regimens

PLEIADES (MMY2040; NCT03412565) is a phase 2, non-randomized, open-label, multicenter 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

Updated Analysis of the PLEIADES Study: D-VRd Arm

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.

Safety Results - Hematologic Events in the D-VRd Arm

• Hematologic events are presented in Table: Most Common Hematologic TEAEs (≥5% in D-VRd cohort, PLEIADES Study).¹¹

Phase 2 Study of DARZALEX in Combination with KRd in TE NDMM

MASTER is a phase 2 study 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

Final Analysis of the GRIFFIN Study

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 specific to hematologic events are summarized below.

Results - Safety - Hematologic Events

• The most common hematologic TEAEs reported in the MASTER study are presented in Table: Most Common Hematologic TEAEs (MASTER).¹⁰

CLINICAL DATA - TRANSPLANT-INELIGIBLE NDMM

Phase 3 Study of DARZALEX in Combination with Rd in TIE NDMM

MAIA (MMY3008; NCT02252172) is a 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

Updated Efficacy and Safety Analysis of the MAIA Study

Facon et al (2025)¹⁹ reported the updated efficacy and safety results from the MAIA study at a long-term median follow-up of 64.5 months. Safety results related to hematologic events have been summarized below.

Results - Safety - Hematologic Events

• The most common any-grade (≥30%) and grade 3/4 (≥20%) hematologic TEAEs reported at a median follow-up of 64.5 months are presented in Table: Most Common Any-Grade (≥30%) and Grade 3/4 (≥20%) Hematologic TEAEs (MAIA Study).¹⁹
• The most common any-grade (≥30%) and grade 3/4 (≥20%) hematologic TEAEs Among patients aged ≥75 years and ≥80 years in the safety population are presented in Table: Most Common Any-Grade and Grade 3/4 TEAEs Among Patients Aged ≥75 Years and ≥80 Years in the Safety Population.³⁴

DARZALEX in Combination with Bortezomib, Melphalan, and Prednisone

ALCYONE (MMY3007; NCT02195479) is a phase 3, randomized, open-label, active-controlled, multicenter 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

Updated Efficacy and Safety Analysis of the ALCYONE Study

Mateos et al (2025)²¹ reported an updated efficacy and safety analysis of the ALCYONE study at a median follow-up of 86.7 months. Safety results related to hematologic events have been summarized below.

Safety Results - Hematologic Events

• Hematologic events reported at a median follow-up of 86.7 months are presented in Table: Most Common Any-Grade (≥10%) and Grade 3/4 (≥5%) Hematologic TEAEs (ALCYONE Study).²¹

Phase 2 Study of DARZALEX in Combination with CyBorD in MM

LYRA (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.^22,23

Final Analysis of the LYRA Study

Yimer et al (2022)²⁴ 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.

Safety Results - 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).^24,25

Phase 2 Study of DARZALEX FASPRO in Combination with Various Treatment Regimens

PLEIADES (MMY2040; 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

Updated Analysis of the PLEAIDES Study: D-VMP Arm

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.

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).¹¹

Phase 3 Study of 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 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.²⁶

Updated Efficacy and Safety Analysis of the AURIGA Study

Anderson et al (2025)²⁷ presented the updated efficacy and safety results from the study at 24 months from the start of maintenance therapy, with a median follow-up of 40.3 months. Safety results related to hematologic events have been summarized below.

Safety Results - Hematologic Events

• The most common grade 3/4 hematologic TEAEs in the safety population are summarized in Table: Most Common Hematologic TEAEs (≥5% in Any Arm).²⁷
• No new safety concerns were identified with the addition of DARZALEX FASPRO to R maintenance.²⁷

Post Hoc Analysis of Clinically Relevant Subgroups of the AURIGA Study

Foster et al (2024)²⁸ presented 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.

Safety Results - Hematologic Events

• D-R maintenance did not increase grade 3/4 cytopenia rates in patients ≥65 years of age.²⁸ 
  • 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.²⁸
  • 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.²⁸

Phase 3 Study of DARZALEX FASPRO in Combination with VRd in TIE NDMM

CEPHEUS (MMY3019; NCT03652064) is a phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of D-VRd vs VRd in patients with NDMM who are TIE or for whom transplant is not planned as initial therapy (transplant deferred).²⁹

Final Analysis of TIE Patients in the CEPHEUS Study

Usmani et al (2026)³⁰ reported the final analysis of TIE patients in the CEPHEUS study at a median follow-up of 76 months.

Safety Results - Hematologic Events

• Grade 3/4 TEAEs occurred in 93.8% of patients in the D-VRd arm vs 88.7% in the VRd arm. Hematologic events are summarized in Table: Hematologic Safety Summary (CEPHEUS; TIE Subgroup).³⁰

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 02 June 2026. 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.