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

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 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: 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: 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: 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 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
  • 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: 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 (40.0% 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.²¹ 
• 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.^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: 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 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: 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.^26,27
  • Badros et al (2024)^27-29 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)³⁰ 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.
• CEPHEUS: 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).^31-33
  • Usmani et al (2025)³³ reported results from the phase 3 CEPHEUS study at a median follow-up of 58.7 months (range, 0.1-64.7). The safety data were consistent with the established safety profile of each individual drug. Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively. Any grade neutropenia occurred in 55.8% vs 39% of patients, any grade thrombocytopenia in 46.7% vs 33.8% of patients, any grade anemia in 37.1% vs 31.8% of patients and any grade lymphopenia in 18.3% vs 17.4% of patients from the D-VRd vs VRd arm, respectively. Serious hematologic TEAEs (≥2%) in the D-VRd arm were anemia (3%), febrile neutropenia (2%), and thrombocytopenia (2%).
  • Zweegman et al (2025)³⁴ 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 51 (41.1%) vs 36 (27.3%) of patients in IMWG fit subgroup; 36 (49.3%) vs 22 (34.9%) of patients in IMWG intermediate fitness subgroup; 60 (42.9%) vs 47 (30.1%) in IFM nonfrail subgroup; 27 (47.4%) vs 11 (28.2%) in IFM frail subgroup, in D-VRd vs VRd arms respectively. Thrombocytopenia occurred in 27 (21.8%) vs 27 (20.5%) in IMWG fit subgroup; 29 (39.7%) vs 12 (19.0%) in IMWG intermediate fitness subgroup; 32 (22.9%) vs 31 (19.9%) in IFM nonfrail subgroup; 24 (42.1%) vs 8 (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 - Newly Diagnosed multiple myeloma - transplant-eligible

DARZALEX in Combination with Bortezomib, Thalidomide, and Dexamethasone

CASSIOPEIA (MMY3006; 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.

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; 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)³⁵ 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.

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 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 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)^8,36 reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study.

Results - Safety - 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).

DARZALEX FASPRO in Combination With Bortezomib, Lenalidomide, and Dexamethasone

PERSEUS (MMY3014; NCT03710603) is an ongoing, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-VRd vs VRd induction and consolidation followed by maintenance with D-R in 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.

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; 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.

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 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.

Results - Safety - Hematologic Events

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

CLINICAL DATA - NEWLY DIAGNOSED MULTIPLE MYELOMA - TRANSPLANT-INELIGIBLE

DARZALEX in Combination with Lenalidomide and Dexamethasone

MAIA (MMY3008; 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 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).
• 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.

DARZALEX in Combination with Bortezomib, Melphalan, and Prednisone

ALCYONE (MMY3007; 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 (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.

Results - Safety - 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).

DARZALEX in Combination with Cyclophosphamide, Bortezomib, and Dexamethasone

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 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.

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; 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.

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; 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.^26-28 Badros et al (2024)^27,28 reported primary results from the phase 3 AURIGA study.

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.²⁷
  • 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)³⁰ 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.³⁰ 
  • 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.

CEPHEUS (MMY3019; NCT03652064) is an ongoing, randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-VRd vs VRd in patients with NDMM who are TIE or for whom transplant is not planned as initial therapy (transplant deferred).^31-33 Usmani et al (2025)³³ reported results from the phase 3 CEPHEUS study.

Results - Safety - Hematologic events

• The safety data were consistent with the established safety profile of each individual drug.³³ Hematologic TEAEs in the safety population are summarized in Table: Hematologic TEAEs in the Safety Population.

• Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively. A summary of the serious hematologic TEAEs is presented in Table: Serious Hematologic TEAEs (≥2%) in the Safety Population

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 09 May 2025. 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.