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.
• LYRA: phase 2 study evaluating the safety and efficacy of DARZALEX in combination with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) for the treatment of multiple myeloma (MM) in patients who have not received previous treatment or have relapsed after receiving only 1 line of treatment. Results from both cohorts of patients have been summarized. The most common grade 3/4 hematologic TEAEs were neutropenia (21.4%) and leukopenia (14.3%).⁹
  • DARZALEX/DARZALEX FASPRO is not approved by the regulatory agencies for use in combination with CyBorD 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.
• 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
• TRIMM-2: ongoing, phase 1b, multicohort study evaluating DARZALEX FASPRO regimens in combination with bispecific T-cell redirection antibodies in patients with RRMM.¹⁷
  • Rodriguez-Otero et al (2022)¹⁸ presented the updated results from the TECVAYLI™ SC + DARZALEX FASPRO cohort of the TRIMM-2 study. The most common grade 3/4 (≥20%) hematologic TEAEs were neutropenia (41.5%), anemia (27.7%), and thrombocytopenia (24.6%).
    • DARZALEX FASPRO is not approved by regulatory agencies for use in combination with TECVAYLI 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.
  • Dholaria et al (2023)¹⁹ presented the updated results from the TALVEY™ SC + DARZALEX FASPRO cohorts. The most common grade 3/4 hematologic (≥20%) TEAEs in the TALVEY 0.4 mg/kg SC weekly (QW) + DARZALEX FASPRO vs TALVEY 0.8 mg/kg SC every other week (Q2W) + DARZALEX FASPRO cohorts were lymphopenia (57.1% vs 17.6%), anemia (35.7% vs 25.5%), neutropenia (28.6% vs 27.5%), and thrombocytopenia (28.6% vs 19.6%), respectively.
    • DARZALEX FASPRO is not approved by regulatory agencies for use in combination with TALVEY 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.
• MajesTEC-2 (MMY1004) is an ongoing, phase 1b, multicohort study evaluating TECVAYLI in combination with other anticancer therapies in patients with MM). The most common grade 3/4 (≥10%) hematologic TEAE were neutropenia (78.1%), thrombocytopenia (15.6%), anemia (12.5%), febrile neutropenia (12.5%), and lymphopenia (12.5%).^20,21
  • DARZALEX FASPRO is not approved by regulatory agencies for use in combination with lenalidomide and TECVAYLI 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.
• CARTITUDE-4 (MMY3002) is a phase 3, randomized, open-label study evaluating the efficacy and safety of ciltacabtagene autoleucel (cilta-cel) vs standard care (physician's choice of pomalidomide, bortezomib, and dexamethasone [PVd] or DPd) in adult patients with lenalidomide-refractory MM after 1-3 prior line(s) of therapy (LOT). The most common grade 3/4 AEs (≥15%) were neutropenia (Cilta-cel, 89.9%; standard care, 82.2%), thrombocytopenia (Cilta-cel, 41.3%; standard care, 18.8%), anemia (Cilta-cel, 35.6%; standard care, 14.4%), and lymphopenia (Cilta-cel, 20.7%, standard care, 12.0%).²²

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
• TECVAYLI (teclistamab-cqyv) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.;  https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/TECVAYLI-pi.pdf
• TALVEY (talquetamab-tgvs) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/TALVEY-pi.pdf.
• CARVYKTI (ciltacabtagene autoleucel) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.;  https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf.

CLINICAL DATA - relapsed AFTER ≥1PL

DARZALEX in Combination with Carfilzomib and Dexamethasone

CANDOR (clinicaltrials.gov identifier: 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.^1,23 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; clinicaltrials.gov identifier: 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; clinicaltrials.gov identifier: 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; clinicaltrials.gov identifier: 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).²⁴ 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; clinicaltrials.gov identifier: 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.

DARZALEX in Combination with CyBorD in RMM

LYRA (MMY2012; clinicaltrials.gov identifier: NCT02951819) is a phase 2, single-arm, open-label, multicenter study evaluating the safety and efficacy of DARZALEX when administered in combination with CyBorD for the treatment of MM in patients who have not received previous treatment or have relapsed after receiving only 1 line of treatment.⁹ Yimer et al (2022)⁹ reported the end-of-study results of the LYRA study, with a median follow-up of 35.3 months for the RMM arm. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Primary endpoint: ≥VGPR after 4 induction cycles
• Key secondary endpoints: ORR; time to ≥VGPR, time to ≥partial response (PR), PFS, OS, safety, and tolerability

Safety Results - Hematologic Adverse Events

• Hematologic-related TEAEs are summarized in Table: Most Common Any Grade (≥25%) and Grade 3/4 (≥10%) in the Safety Analysis Set (LYRA).

clinical data - Relapsed/Refractory or Double Refractory

DARZALEX vs DARZALEX FASPRO Non-Inferiority Study

COLUMBA (MMY3012; clinicaltrials.gov identifier: 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; clinicaltrials.gov identifier: 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; clinicaltrials.gov identifier: 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).

CLINICAL DATA – RELAPSED/REFRACTORY – In Combination with bISPECIFIC aNTIBODY

DARZALEX FASPRO in Combination with TECVAYLI (TRIMM-2 Study)

TRIMM-2 (MMY1002; clinicaltrials.gov identifier: NCT04108195) is an ongoing, phase 1b, 2-part, multicohort, open-label study evaluating DARZALEX FASPRO in combination with bispecific T-cell redirection antibodies (TECVAYLI and TALVEY) in patients with RRMM who had received ≥3PL.¹⁷ Rodriguez-Otero et al (2022)¹⁸ presented the updated results from the TECVAYLI SC + DARZALEX FASPRO cohort of the TRIMM-2 study. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Eligible patients on TECVAYLI were administered step-up dosing with full doses of 1.5 mg/kg SC weekly, 3 mg/kg SC every other week, or 3 mg/kg SC weekly.
• Primary outcomes:
  • Part 1: Identify the recommended phase 2 dose (RP2D) for each treatment combination.
  • Part 2: safety and tolerability at the selected RP2D of each treatment combination.
  • Antitumor activity, PK, and pharmacodynamics (PD).
• Secondary outcomes: serum concentrations, biomarker assessments, anti-drug antibody assessments, ORR, clinical benefit rate (defined as ORR + minimal response) assessed per 2016 International Myeloma Working Group (IMWG) criteria, TTR, and DOR.

Safety Results - Hematologic Adverse Events

• The most common hematologic TEAEs occurring in ≥20% of patients are summarized in Table: Any Grade or Grade 3/4 Hematologic-Related TEAEs (TRIMM-2; TECVAYLI + DARZALEX FASPRO Cohort).

DARZALEX FASPRO in Combination with TALVEY (TRIMM-2 Study)

Dholaria et al (2023)¹⁹ presented the updated efficacy and safety results of the TALVEY SC (QW) + DARZALEX FASPRO cohort at a median follow-up of 16.8 months and TALVEY SC (Q2W) + DARZALEX FASPRO cohort at median follow-up of 15.0 months. Safety results related to hematologic events have been summarized below.

Study Design/Methods

• Patients who were on TALVEY were administered step-up doses within 1 week prior to full dose. Patients were administered 0.4 mg/kg SC (QW; n=14) or
  0.8 mg/kg SC (Q2W; n=51). Premedications (glucocorticoid, antihistamine, antipyretic) were administered during the step-up doses and 1^st full dose of TALVEY.
• Key Study Objectives:
  • Part 1: identify RP2Ds for each treatment combination
  • Part 2: safety of each combination at the selected RP2D
  • PK, PD, antitumor activity

Safety Results - Hematologic Adverse Events

• Among 80.0% of patients who reported grade 3/4 AEs, 60.0% were hematologic in nature. Cytopenias occurred generally during step-up and cycle 1/2 doses only and resolved in most patients.
• Grade 3/4 neutropenia was reported in <30% of patients in both cohorts.
• The most common hematologic TEAEs occurring in ≥20% of patients are summarized in Table: Any Grade or Grade 3/4 Hematologic-Related TEAEs (TRIMM-2; TALVEY + DARZALEX FASPRO Cohort).

DARZALEX FASPRO in Combination with TECVAYLI and Lenalidomide (MajesTEC-2 Study; Cohort E)

MajesTEC-2 (MMY1004; clinicaltrials.gov identifier: NCT04722146) is an ongoing, phase 1b, multicohort study evaluating the safety and efficacy of TECVAYLI in combination with other anticancer treatments in patients with MM. ^20,21 Searle et al (2022)²⁰ presented initial results from cohort E that evaluated the safety and efficacy of TECVAYLI + DARZALEX FASPRO + lenalidomide in 32 patients with MM and 1-3 prior lines of treatments, including a PI and an immunomodulatory drug.

Study Design/Methods

• Primary endpoints: safety, dose-limiting toxicities, and laboratory abnormalities.
• Key Secondary endpoints: ORR assessed per IMWG 2016 criteria, ≥VGPR (per IMWG 2016 criteria), ≥CR (per IMWG 2016 criteria), stringent complete response (sCR), DOR, TTR, and anti-drug antibodies to TECVAYLI, DARZALEX FASPRO.

Safety Results - Hematologic Adverse Events

• The incidence of hematologic AEs is presented in Table: Any Grade (≥25%) and/or Grade 3/4 (≥10%) Hematologic AEs (MajesTEC-2 [Cohort E]).

Cilta-cel vs Standard Care (Physician's Choice of PVd or DPd) - CARTITUDE-4 Study

CARTITUDE-4 (MMY3002; clinicaltrials.gov identifier: NCT04181827) is an ongoing, phase 3, randomized, open-label study evaluating the efficacy and safety of cilta-cel versus standard care (physician's choice of PVd or DPd) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.²² San-Miguel et al (2023)²² reported efficacy and safety results from the interim analysis of this study.

Study Design/Methods

• Patients were randomized 1:1 into one of two arms to receive cilta-cel or standard care (PVd or DPd).
• After undergoing apheresis, patients received ≥1 cycle of bridging therapy (physicians’ choice) with PVd or DPd (number of cycles was based on clinical status and cilta-cel manufacturing time).
• Primary endpoint: PFS
• Key Secondary endpoint: ≥CR, ORR, overall MRD-negativity rate, OS, patient reported outcomes, safety, and PK.

Safety Results - Hematologic Adverse Events

• The most common hematologic AEs occurring in ≥15% of patients are summarized in Table: Any Grade and/or Grade 3/4 Hematologic-Related AEs (CARTITUDE-4).
• The most common hematologic malignancies are summarized in Table: Second Primary Malignancies (CARTITUDE-4).
• The incidence of prolonged (>60 days) grade 3/4 cytopenias in patients who received cilta-cel as study treatment (n=176) was 10.8% for thrombocytopenia, 10.2% for lymphopenia, 10.2 % for neutropenia and 1.1% for anemia.²²

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 31 May 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.