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 to 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.
• CANDOR: phase 3 study evaluating the efficacy and safety of DARZALEX for intravenous (IV) use in combination with carfilzomib and dexamethasone (D-Kd) + carfilzomib and dexamethasone (Kd) alone in patients with relapsed or refractory multiple myeloma (RRMM). The most common grade ≥3 treatment-emergent adverse event (TEAE) was thrombocytopenia in both arms (D-Kd, 24.7%; Kd, 16.3%).¹
• CASTOR: phase 3 study evaluating the safety and efficacy of DARZALEX in combination with bortezomib and dexamethasone (D-Vd) + bortezomib and dexamethasone (Vd) alone in patients with RRMM. The most common grade 3/4 hematologic TEAE was thrombocytopenia in both arms (D-Vd, 46.1%; Vd, 32.9%).²
• POLLUX: phase 3 study evaluating the safety and efficacy of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) + lenalidomide and dexamethasone (Rd) alone in patients with RRMM. The most common grade 3/4 hematologic TEAE was neutropenia (D-Rd, 57.6%; Rd, 41.6%).³
• COLUMBA: phase 3 study evaluating the efficacy, pharmacokinetics (PK), and infusion-related reactions (IRRs) of DARZALEX vs DARZALEX FASPRO for subcutaneous (SC) use. The most common grade 3/4 (≥10%) hematologic TEAEs were thrombocytopenia (DARZALEX FASPRO, 14.2%; DARZALEX, 13.6%), anemia (DARZALEX FASPRO, 13.8%; DARZALEX, 15.1%), and neutropenia (DARZALEX FASPRO, 13.1%; DARZALEX, 7.8%).⁴
• APOLLO: phase 3 study evaluating the safety and efficacy of DARZALEX FASPRO in combination with pomalidomide and dexamethasone (D-Pd) + (pomalidomide and dexamethasone) Pd alone in patients with RRMM who received ≥1 prior line of therapy (PL) with both lenalidomide and proteasome inhibitor (PI). The most common grade 3/4 hematologic TEAEs were neutropenia (D-Pd, 69%; Pd, 51%), anemia (D-Pd, 18%; Pd, 22%), thrombocytopenia (D-Pd, 18%; Pd, 18%), leukopenia (D-Pd, 17%; Pd, 5%), lymphopenia (D-Pd, 12%; Pd, 3%), and febrile neutropenia (D-Pd, 9%; Pd, 4%).⁵
• PLEIADES: phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with standard-of-care treatment regimens, specifically, in combination with Rd in patients with RRMM with ≥1 prior line of therapy (≥1PL) and in combination with Kd in patients with RRMM with 1PL.⁶
  • Chari et al (2021)⁷ reported the safety and efficacy results of the D-Rd arm with a median follow-up of 14.7 months. The most common grade 3/4 hematologic TEAEs were neutropenia (49.2%), lymphopenia (10.8%), thrombocytopenia (13.8%), leukopenia (9.2%), and anemia (9.2%).
  • Moreau et al (2020)⁶ presented the primary analysis of the D-Kd arm with a median follow-up of 9.2 months and the updated safety and efficacy results of the D-Rd arm with a median follow-up of 25.7 months. The most common grade 3/4 hematologic TEAEs in the D-Kd and D-Rd arms, respectively, were thrombocytopenia (20%) and neutropenia (55%).
  • Moreau et al (2023)⁸ reported the final results from the D-Kd arm of the PLEIADES and EQUULEUS studies at a median follow-up of 12.4 and 23.7 months, respectively. The most common grade 3/4 hematologic TEAE was thrombocytopenia (19.7%). Results specific to the D-Kd arm of the PLEIADES study have been summarized below.
• Usmani et al (2020)¹⁰ reported the final results from a pooled, post-hoc analysis from the phase 2 DARZALEX monotherapy studies, GEN501 and SIRIUS. In the pooled analysis, the most common grade 3/4 hematologic TEAE was anemia (18%) in the pooled analysis.
• EQUULEUS: phase 1b study evaluating DARZALEX in various standard-of-care regimens in patients with MM.^11,12
  • Chari et al (2017)¹¹ reported safety and tolerability results of the D-Pd arm for patients with RRMM. The most common grade 3/4 hematologic TEAE was neutropenia (77%).
  • Moreau et al (2023)⁸ reported the final results from the D-Kd arm of the PLEIADES and EQUULEUS studies at a median follow-up of 12.4 and 23.7 months, respectively. The most common grade 3/4 TEAE was thrombocytopenia (31.8%). Results specific to the D-Kd arm of the EQUUELUS study have been summarized below.
• GEN503: phase 1/2, dose escalation and dose expansion study assessing the safety and efficacy of DARZALEX in combination with Rd. The most common grade 3/4 hematologic TEAE was neutropenia (84.4%).¹³
• PAVO: phase 1b, dose-finding, proof-of-concept study evaluating the safety, PK, and efficacy of a mixed formulation of daratumumab and recombinant human hyaluronidase PH20 (rHuPH20; daratumumab-MD) and DARZALEX FASPRO in patients with RRMM who have received ≥2 prior therapies.^14-16
  • In part 1, the most common grade 3/4 hematologic TEAE (occurred in >1 patient) was anemia (1200 mg group, 13%; 1800 mg group, 16%), lymphopenia (1200 mg group, 0%; 1800 mg group, 11%), thrombocytopenia (1200 mg group, 13%; 1800 mg group, 7%), and neutropenia (1200 mg group, 13%; 1800 mg group, 7%).¹⁴
  • In part 2, the most common grade 3/4 hematologic TEAE was lymphopenia (20%), thrombocytopenia (8%), anemia (4%), and leukopenia (4%).¹⁵
  • In part 3, the most common grade ≥3 hematologic related TEAEs were lymphopenia (13.3%; n=2) in 3-week corticosteroid taper group, neutropenia (20.0%; n=3) in 2-week corticosteroid taper group, and anemia (16.7%; n=2) in 1-week corticosteroid taper group.¹⁶

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 - relapsed AFTER ≥1PL

DARZALEX in Combination with Carfilzomib and Dexamethasone

CANDOR (NCT03158688) is an ongoing, randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-Kd vs Kd in patients with RRMM.^1,17 Usmani et al (2023)¹ reported final analysis of the CANDOR study after a median follow-up of 50 months. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Primary endpoint: progression-free survival (PFS)
• Key secondary endpoints: overall response rate (ORR), minimal residual disease (MRD [10^-5]), and overall survival (OS)

Safety Results - Hematologic Adverse Events

• The most common hematologic TEAEs in the D-Kd vs Kd arms are presented in the Table: Most Common Any Grade (≥20%) and Grade ≥3 (≥5%) Hematologic-Related TEAEs (CANDOR).

DARZALEX in Combination with Bortezomib and Dexamethasone

CASTOR (MMY3004; NCT02136134) is an open-label, randomized, multicenter, active-controlled, phase 3 study which evaluated the safety and efficacy of Vd alone compared to D-Vd in patients with RRMM (N=498).² Sonneveld et al (2022)² reported updated safety and efficacy results of the CASTOR study, after a median follow-up of 72.6 month. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Primary endpoint: PFS
• Secondary endpoints: time to disease progression, overall response, duration of response (DOR), time to response (TTR), very good partial response or better (≥VGPR), OS, and MRD

Safety Results - Hematologic Adverse Events

• The most common hematologic TEAE of any grade in both arms was thrombocytopenia (D-Vd, 59.7%; Vd, 44.3%). A summary of the most common hematologic TEAEs reported in the safety population is provided in the table: Most Common (>15%) or Grade 3/4 (>5%) Hematologic-Related TEAEs (CASTOR).

DARZALEX in Combination with Lenalidomide and Dexamethasone

POLLUX (MMY3003; NCT02076009) is a phase 3, randomized, open-label, active-controlled, multicenter study that evaluated the safety and efficacy of D-Rd and Rd in patients with RRMM (N=569).³ Dimopoulos et al (2023)³ presented the updated safety and efficacy results of the POLLUX study after a median follow-up of 79.7 months. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Primary endpoint: PFS
• Secondary endpoints: time to progression (TTP), ORR, ≥VGPR, rate of complete response or better (≥CR), OS, DOR, MRD, and safety assessments

Safety Results - Hematologic Adverse Events

• Neutropenia was the most common (any grade) TEAE in both arms (D-Rd, 65.4%; Rd, 48.4%). The incidence of the most common any grade and grade 3/4 hematologic-related TEAEs are presented in the table: Most Common Any Grade (>15%) and Grade 3/4 (>5%) Hematologic-Related TEAEs (POLLUX).

DARZALEX FASPRO in Combination with Pomalidomide and Dexamethasone

APOLLO (MMY3013; NCT03180736) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of D-Pd vs Pd in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a PI (N=304).¹⁸ Dimopoulos et al (2023)⁵ presented the final OS and updated safety analysis of the APOLLO study at a median follow-up of 39.6 months. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Primary endpoint: PFS
• Secondary endpoints: ORR, ≥VGPR rate, ≥CR rate, MRD-negativity rate, OS, TTR, DOR, time to next therapy, safety, health-related quality of life outcomes, PK analysis of daratumumab, and daratumumab immunogenicity

Safety Results - Hematologic Adverse Events

• The most common any grade and grade 3/4 hematologic-related TEAEs are presented in Table: Summary of Most Common Hematologic-Related TEAEs (APOLLO).

DARZALEX FASPRO in Combination with 4 Standard-of-Care Regimens

PLEIADES (MMY2040; NCT03412565) is an ongoing, phase 2, non-randomized, open-label, multicenter study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various treatment regimens in patients with MM. Chari et al (2021)⁷ presented the safety and efficacy results of the D-Rd arm from the PLEIADES study at a median follow-up of 14.7 months. Moreau et al (2020)⁶ presented the primary analysis of the D-Kd arm with a median follow-up of 9.2 months and the updated safety and efficacy results of the D-Rd arm with a median follow-up of 25.7 months. Moreau et al (2023)⁸ reported the final results from the D-Kd arm of the PLEIADES and EQUULEUS studies. Safety results related to hematologic events specific to D-Kd and D-Rd arms have been summarized below.

Study Design/Methods

• RRMM:
  • D-Rd for patients with RRMM with ≥1PL (n=65)
  • D-Kd in patients with RRMM with 1PL (n=60)
• Primary endpoint: ORR
• Key secondary endpoints: maximum observed serum concentrations (C_max) and minimum observed serum concentrations (C_min) of daratumumab, immunogenicity, IRR rate, CR, DOR, MRD-negativity rate, and ≥VGPR

Safety Results - Hematologic Adverse Events - D-Rd Arm

• The most common grade 3/4 hematologic TEAEs in the D-Rd arm are summarized in Table: The Most Common Grade 3/4 (≥5%) Hematologic-Related TEAEs (PLEIADES) in the D-Rd Arm.

Moreau et al (2020)⁶ presented the primary analysis of the D-Kd arm with a median follow-up of 9.2 months and the updated safety and efficacy results of the D-Rd arm with a median follow-up of 25.7 months.

Safety Results - Hematologic Adverse Events - D-Kd and D-Rd Arms

• The most common grade 3/4 hematologic TEAE in the D-Kd and D-Rd arms were thrombocytopenia (20%) and neutropenia (55%).
• A summary of the hematologic-related TEAEs reported in each cohort is presented in the table: Most Common (≥5% in any arm) Hematologic-Related Grade 3/4 TEAEs (PLEIADES) in the D-Kd and D-Rd Arms.

Moreau et al (2023)⁸ reported the final results from the D-Kd arm of the PLEIADES and EQUULEUS studies. Results specific to the D-Kd arm of the PLEIADES study have been summarized below.

Safety Results - Hematologic Adverse Events - D-Kd (Final Results)

• A summary of the hematologic-related TEAEs reported in each cohort is presented in the table: Most Common Any Grade (≥25%) and Grade 3/4 (≥5%) TEAEs (PLEIADES) in the D-Kd Arm.

clinical data - Relapsed/Refractory or Double Refractory

DARZALEX vs DARZALEX FASPRO Non-Inferiority Study

COLUMBA (MMY3012; NCT03277105) is an ongoing, phase 3, randomized, open-label, multicenter, non-inferiority study evaluating the efficacy, PK, and IRRs of DARZALEX vs DARZALEX FASPRO in patients with RRMM. Usmani et al (2022)⁴ reported final analysis of efficacy and safety results of the COLUMBA study after a median follow-up of 29.3 months. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Co-primary endpoints: ORR and maximum serum pre-dose daratumumab concentration on cycle 3 day 1 (C_trough)
• Secondary endpoints: IRR rates, PFS, ≥VGPR, ≥CR, time to next therapy, OS, patient-reported satisfaction with therapy, DOR, and TTR

Safety Results - Hematologic Adverse Events

• Safety profiles were similar and consistent with the primary analysis. Any grade TEAEs occurred in 91.5% (n=238) vs 93% (n=240) and grade 3/4 occurred in 50.8% (n=132) vs 52.7% (n=136) of patients in the DARZALEX FASPRO vs DARZALEX arms, respectively. See Table: Most Common Any Grade (≥10%) and Grade 3/4 (≥5%) Hematologic-Related TEAEs in the Safety-Evaluable Population (COLUMBA).
• The overall incidence of serious TEAE was 31.9% vs 34.5% in the DARZALEX FASPRO vs DARZALEX arms.
• Treatment modifications due to any grade TEAEs occurred in 30% (n=78) vs 32.6% (n=84) in the DARZALEX FASPRO vs DARZALEX arms, respectively.
• With the longer follow-up, the rates of any grade and grade 3/4 TEAEs across all body weight subgroups (≤65 Kg, >65-85 kg, and >85 kg) were similar to the overall population. See Table: Most Common Grade 3/4 (≥5%) Hematologic-Related TEAEs Across Body Weight Subgroups (COLUMBA).
  • In ≤65 kg subgroup, incidence of neutropenia was higher in the DARZALEX FASPRO vs DARZALEX arms for any grade TEAEs (25.8% vs 14.1%) and grade 3/4 TEAEs (20.4% vs 8.7%), respectively.

DARZALEX Monotherapy in Patients with Heavily Pretreated RRMM

Usmani et al (2020)¹⁰ reported a pooled, post-hoc final analysis of the SIRIUS and GEN501 studies after a median follow-up of 36.6 months (interquartile range [IQR], 34.5-38.24) in patients with RRMM (N=148).

• GEN501 (clinicaltrials.gov identifier: NCT00574288) was an open-label, phase 1/2, international, multicenter, dose escalation and expansion study in patients with MM who were refractory to ≥2PL, including a PI or an immunomodulatory drug, or who had relapsed.
• SIRIUS (MMY2002; clinicaltrials.gov identifier: NCT01985126) was on open-label, phase 2, international, multicenter study in patients with MM who were double refractory or had received ≥3PL, including a PI or an immunomodulatory drug.

Safety Results - Hematologic Adverse Events

• Most common hematologic specific TEAEs (N=148) are presented in the table: Most Common Hematologic-Related TEAEs in ≥10% Combined from GEN501 Part 2 and SIRIUS.

DARZALEX in Combination with Various Backbone Treatment Regimens.

EQUULEUS (MMY1001; NCT01998971) is a phase 1b, open label, non-randomized, multicenter study evaluating the safety, tolerability, and dose regimen of DARZALEX in combination with various backbone treatment regimens for the treatment of patients with MM. Chari et al (2017)¹¹ reported safety and tolerability results of the D-Pd arm with a median follow-up of 13.1 months in patients with RRMM. Moreau et al (2023)⁸ reported the final results from the D-Kd arm of the PLEIADES and EQUULEUS studies at a median follow-up of 12.4 and 23.7 months, respectively. Safety results related to hematologic events specific to D-Pd and D-Kd arms have been summarized below.

Study Design/Methods

• Primary endpoint: safety
• Secondary endpoints: ORR and MRD by next-generation sequencing

Safety Results - Hematologic Adverse Events - D-Pd arm

• Hematologic specific TEAEs occurring in >25% patients are presented in the table: Most Common (>25%) Hematologic-Related TEAEs in the D-Pd arm (EQUULEUS).
• Most common (>5%) grade 3/4 hematologic-related TEAEs reported were neutropenia (77%), anemia (28%), leukopenia (24%), thrombocytopenia (19%), lymphopenia (14%), and febrile neutropenia (8%).
  • Most of the grade 3/4 neutropenia AEs were reported within 2 months of receiving the 1^st daratumumab dose administration. At enrollment of the study, 44% of patients had pre-existing grade 1/2 neutropenia.
  • No discontinuations due to neutropenia or febrile neutropenia were reported.
• Febrile neutropenia (5%) and anemia (3%) were reported among the most common (>2 patients) serious TEAEs.

Safety Results - Hematologic Adverse Events - D-Kd arm (Final Results)

• The most common hematologic-related TEAEs are presented in the table: Most Common Any grade (>25%) and Grade 3/4 (≥5%) Hematologic-Related TEAEs in the D-Kd arm (EQUULEUS).

DARZALEX Dose Escalation, Dose Expansion Study in Combination with Rd

Plesner et al (2019)¹³ reported final results from GEN503, a dose-escalation and dose-expansion study assessing the safety and efficacy of D-Rd in patients with RRMM. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Phase 1/2, open-label, multicenter, dose escalation (Part 1) and dose expansion (Part 2) study.
• Primary endpoint: ORR
• Secondary endpoints: TTP, DOR, PFS, and OS

Safety Results - Hematologic Adverse Events

Safety

• TEAEs occurring in ≥25% patients are presented in the table: Most Common (≥25%) Hematologic-Related TEAEs in Part 2 of GEN503 Study.

DARZALEX FASPRO Dose-Finding Study

PAVO (MMY1004; NCT02519452) is an ongoing, phase 1b, open-label, multicenter, dose-finding, proof-of-concept study evaluating the safety, PK, and efficacy of daratumumab-MD and DARZALEX FASPRO in patients with RRMM who have received ≥2 lines of prior therapy. Chari et al (2017)¹⁴ presented results from the part 1 and part 2 of the PAVO study. San-Miguel et al (2021)¹⁵ published results from the part 2 of the PAVO study. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• The study had 2 parts: daratumumab-MD (1200 mg and 1800 mg) was used in part 1, and a second generation premixed concentrated coformulation of daratumumab and rHuPH20 (DARZALEX FASPRO) was used in part 2.¹⁴
• Primary endpoints: C_trough of daratumumab at cycle 3 day 1; safety
• Key secondary endpoints: CR; ORR; DOR; and TTR

Safety Results - Hematologic Adverse Events - Part 1 and Part 2

• Part 1: The median duration of follow-up for was 5.2 months (range, 1.6-13.9) in the 1200 mg group, and 8.3 months (range, 1.8-19.5) in the 1800 mg group.
• Part 2: The median duration of follow-up was 4.6 months (range, 2.4-5.5).
• For information regarding hematologic-related TEAEs, see Tables: All-Grade and Grade 3/4 Hematologic-Related TEAEs - Part 1 and Part 2 (PAVO).

Updated Analysis of the Part 2 of the PAVO Study

San-Miguel et al (2021)¹⁵ published updated results from the part 2 of the PAVO study. Safety results related to infections have been summarized below.

Safety Results - Infection-Related - Part 2 (updated)

• The median duration of follow-up for part 2 was 14.2 months (range, 2.4-18.5).
• For information regarding hematologic-related TEAEs, see Table: All-Grade and Grade 3/4 Hematologic-Related TEAEs - Updated Results from Part 2 (PAVO).

Evaluation of Pre- and Post-Dose Corticosteroid Tapering in Part 3 of the PAVO Study

Nahi et al (2023)¹⁶ published the updated safety and efficacy results from part 3 of the PAVO study, which was conducted to evaluate the safety of tapering off pre- and post-dose corticosteroids during DARZALEX FASPRO administration. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Patients received either a 1, 2, or 3-week corticosteroid tapering schedule.
• Primary Endpoint: safety of pre- and post-dose steroid tapering
• Secondary Endpoints: ORR and CR

Safety Results - Hematologic Adverse Events - Part 3

• The median duration of follow-up was 9.2 months (range, 1.9-25.5) for the 3-week corticosteroid taper group, 11.1 months (range, 1.7-24.0) for the 2-week corticosteroid taper group, and 8.3 months (range, 0.4-13.1) for the 1-week corticosteroid taper group.
• TEAEs led to death in 2 patients in the 3-week corticosteroid taper group, of which 1 was due to complications from diffuse large B-cell lymphoma and 3 patients in the 1-week corticosteroid taper group, of which 1 was due to pulmonary embolism (grade 5).
• The most common hematologic related grade ≥3 TEAEs were lymphopenia (13.3%; n=2) in 3-week corticosteroid taper group, neutropenia (20.0%; n=3) in 2-week corticosteroid taper group, and anemia (16.7%; n=2) in 1-week corticosteroid taper group as presented in Table: Most Common Hematologic-Related TEAEs - Part 3 (PAVO).

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 13 June 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.