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 infections with DARZALEX/DARZALEX FASPRO treatment. Clinical judgement should be exercised when managing infections during DARZALEX/DARZALEX FASPRO containing treatment regimens.
• CASTOR: phase 3 study evaluating the safety and efficacy of bortezomib and dexamethasone (Vd) alone and DARZALEX for intravenous (IV) use in combination with Vd (D-Vd).^1,2 The most common infection-related any grade treatment-related adverse event (TEAE) was upper respiratory tract infection (URTI; D-Vd, 37.0%; Vd, 18.1%) (TEAE; any grade).²
• CANDOR: phase 3 study evaluating the efficacy and safety of DARZALEX in combination with carfilzomib and dexamethasone (D-Kd) vs carfilzomib and dexamethasone (Kd) in patients with RRMM.³ The most common infection-related any grade TEAE was URTI (D-Kd, 34.1%; Kd, 24.2%).⁴
• POLLUX: phase 3 study evaluating the safety and efficacy of lenalidomide and dexamethasone (Rd) vs DARZALEX in combination with Rd (D-Rd).^5,6 In the D-Rd vs Rd arm, grade 3/4 infections were reported in 44.5% vs 28.1% patients. The most common infection-related TEAE (any grade) was URTI (D-Rd, 44.2%; Rd, 28.1%).⁶
• Usmani et al (2020)⁷ reported the final results from a pooled, post-hoc analysis from the phase 2 DARZALEX monotherapy studies, GEN501 and SIRIUS. Most URTIs were reported as grade 1/2 (22%, n=32) in this pooled analysis.
• EQUULEUS: phase 1b study evaluating DARZALEX in various standard-of-care regimens in patients with multiple myeloma (MM) and those who received prior treatment.^8,9
  • Chari et al (2017)⁸ reported safety and tolerability results of the DARZALEX in combination with pomalidomide and dexamethasone (D-Pd) arm for patients with RRMM. The most common infection-related TEAE (any grade) was URTI (D-Pd, 28%).
  • Moreau et al (2023)⁹ 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 infection-related TEAE (any grade) was URTI (D-Kd, 44.7%). Results specific to the D-Kd arm of the EQUULEUS study have been summarized below.
• GEN503: phase 1/2, dose escalation and dose expansion study assessing the safety and efficacy of DARZALEX with Rd. URTI (D-Rd, 25%) was the most common infection-related TEAE (any grade).¹⁰
• COLUMBA: phase 3 study evaluating the efficacy, pharmacokinetics (PK), and infusion-related reactions (IRRs) of DARZALEX vs DARZALEX FASPRO for subcutaneous (SC) use.^11,12 URTI (DARZALEX, 11.6%; DARZALEX FASPRO, 16.9%) was the most common infection-related TEAE (any grade). ¹²
• APOLLO: phase 3 study evaluating the safety and efficacy of daratumumab in combination with pomalidomide and dexamethasone (Pd) vs Pd alone in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a proteasome inhibitor.^13,14 The most common infection-related TEAE (any grade) was URTI (D-Pd, 24.8%; Pd, 16%).¹⁴
• PLEIADES: phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with 4 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.^9,15
  • Moreau et al (2020)¹⁵ 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. Pneumonia was the most common infection-related TEAE (D-Kd, 3%; D-Rd, 15%).
  • Moreau et al (2023)⁹ 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 infection-related TEAE (any grade) was nasopharyngitis (D-Kd, 25.8%). 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 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 infection-related TEAE (any grade) was URTI (50%) in the relapsed multiple myeloma (RMM) arm.^16,17
  • 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.
• 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.¹⁸
  • All-grade infection-related TEAE was URTI in part 1 (1200 mg group, 38%; 1800 mg group, 24%) and part 2 (DARZALEX FASPRO, 8%).¹⁸
  • In the updated results from part 2, the most common all-grade infection-related TEAEs was nasopharyngitis (24%).¹⁹
  • In the updated results from part 3, the most common all-grade infection-related TEAE was URTI (3-week corticosteroid taper group, 40.0%; 2-week corticosteroid taper group, 20.0%; 1week corticosteroid taper group, 8.3%).²⁰
• TRIMM-2 is an ongoing, phase 1b, multicohort study evaluating DARZALEX FASPRO regimens in combination with bispecific T-cell redirection antibodies in patients with RRMM.²¹
  • Rodriguez-Otero et al (2022)²² presented the updated results from the TECVAYLI™ SC + DARZALEX FASPRO cohort of the TRIMM-2 study. Infections were reported in 44 (67.7%) patients, of which 27.7% were grade 3/4.
    • 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)²³ presented the updated results from the TALVEY™ SC + DARZALEX FASPRO cohort of the TRIMM-2 study. The most common any grade infection-related adverse event 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 was coronavirus disease 2019 ([COVID-19], 28.6% vs 23.5%).
    • 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.^24,25 The most common any grade infection-related TEAE was COVID-19 (37.5%).²⁴
  • 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 D-Pd) in adult patients with lenalidomide-refractory MM after 1-3 prior line(s) of therapy (LOT). The most common all-grade infection-related adverse event (AE) was URTI (cilta-cel, 18.8%; standard care, 26.0%).²⁶

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 ≥1 PRIOR THERAPY

DARZALEX in Combination with Bortezomib and Dexamethasone

CASTOR (MMY3004; clinicaltrials.gov identifier: NCT02136134) is a phase 3 study which evaluated the safety and efficacy of Vd alone compared to D-Vd in patients with RRMM (N=498).^1,2 Sonneveld et al (2023)² published the updated safety and efficacy results at a median follow-up of 72.6 months. Safety results related to infections have been summarized below.

Study Design/Methods

• Primary endpoint: progression-free survival (PFS)
• Secondary endpoints: time to disease progression, overall response rate (ORR), duration of response (DOR), time to response (TTR), very good partial response or better (≥VGPR), overall survival (OS), and minimal residual disease (MRD)-negativity

Safety Results - Infection-Related

• Infection-related TEAEs are summarized in Table: Any Grade or Grade 3/4 Infection-Related TEAEs (CASTOR).
• The most common serious TEAE was pneumonia (D-Vd, 10.7%; Vd, 10.1%).
• Treatment discontinuation due to infections was reported in 7 (2.9%) patients in the D-Vd arm and 5 (2.1%) patients in the Vd arm.
• Pneumonia was reported as the most frequent TEAE (0.8% in both arms) with an outcome of death in the D-Vd arm.
• Three deaths occurred due to COVID-19 disease (D-Vd, n=1; Vd, n=2).

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.^3,4 Usmani et al (2023)⁴ reported final analysis of the CANDOR study after a median follow-up of 50 months. Safety results related to infections have been summarized below.

Study Design/Methods

• Primary endpoint: PFS
• Key secondary endpoints: ORR, MRD (10^-5), and OS

Safety Results - Infection-Related

• The most common infection-related TEAEs are presented in Table: Most Common Any Grade (≥20%) and Grade ≥3 (≥5%) Infection-Related TEAEs and TEAEs of Interest (CANDOR).
• Grade ≥3 TEAEs occurred in 273 (89%) vs 120 (78%) patients in the D-Kd vs Kd arm, with the most common infection-related TEAE in both groups being pneumonia.
• Grade ≥3 infections and infestations occurred in 46% (n=142) vs 32% (n=49) patients in the D-Kd vs Kd arm and led to carfilzomib discontinuation in 22% (n=69) vs 20% (n=30) patients.
• Fatal TEAEs occurred in 35 (11%) vs 9 (6%) patients in the D-Kd vs Kd arm; the most common fatal TEAE was infection (D-Kd, n=21 [7%]; Kd, n=5 [3%]). See Table: Infection-Related Fatal TEAEs.
• Three patients reported treatment-related fatal AEs related to infection in the D-Kd arm only (Acinetobacter infection, pneumonia, and sepsis [n=1 each]). Fatal infection rates were 7% (n=21) vs 3% (n=5) in the DKd vs Kd arm; correspondingly, when adjusted for exposure, fatal infection rates were 3.5 vs 2.55 per 100 patient-years.
• TEAEs related to COVID-19 occurred in 11% (n=33) vs 4% (n=6) patients in the D-Kd vs Kd arm, and deaths related to COVID-19 occurred in 2% (n=6) vs 1% (n=1) patient.

DARZALEX in Combination with Lenalidomide and Dexamethasone

POLLUX (MMY3003; clinicaltrials.gov identifier: NCT02076009) is a randomized, open-label, active-controlled (Rd arm), multicenter, phase 3 study that evaluated the safety and efficacy of Rd and D-Rd in patients with RRMM (N=569).^5,6 Dimopoulos et al (2023)⁶ reported the updated safety and efficacy results of the POLLUX study at a median follow-up of 79.7 months. Safety results related to infections have been summarized below.

Study Design/Methods

• Primary endpoint: PFS
• Key secondary endpoints: ORR, ≥VGPR, rate of complete response or better (≥CR), MRD-negativity, time to response, and OS

Safety Results - Infection-Related

• Infection-related TEAEs are summarized in Table: Any Grade or Grade 3/4 Infection-Related TEAEs (POLLUX).
• In the D-Rd vs Rd arm, grade 3/4 infections were reported in 126 (44.5%) vs 79 (28.1%) patients and treatment discontinuation due to infections was reported in 13 (4.6%) vs 11 (3.9%) patients.
• In the D-Rd vs Rd arm, the most common TEAEs resulting in death included septic shock (1.4% vs 0.4%) and pneumonia (0.7% vs 1.1%).

DARZALEX FASPRO in Combination with Pomalidomide and Dexamethasone

APOLLO (MMY3013; clinicaltrials.gov identifier: NCT03180736) is an ongoing, phase 3 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 proteasome inhibitor (N=304).¹³ Dimopoulos et al (2022)¹⁴ presented the updated safety analysis at a median follow-up of 39.6 months. Safety results related to infections 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, and health-related quality of life

Safety Results - Infection-Related

• For information regarding infection-related TEAEs, see Table: Most Common Any Grade (≥15%) and Grade 3/4 (≥5%) Infection-Related TEAEs in the Safety Population (APOLLO).
• Treatment discontinuation due to infections was reported in 1 (0.7%) patient in both arms.
• TEAEs resulting in deaths due to COVID-19 were reported in 1.3% (n=2) vs 0.7% (n=1) patients in the D-Pd vs Pd arm.
• The most common serious TEAEs (>10%) were pneumonia (D-Pd, 15.4%; Pd, 8.7%) and lower respiratory tract infection (D-Pd, 12.1%; Pd, 9.3%).

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 when administered in combination with 4 standard-of-care treatment regimens in patients with MM.^9,15 Moreau et al (2020)¹⁵ presented the updated safety and efficacy results of the D-Kd arm with a median follow-up of 9.2 months and the updated safety and efficacy results of the and D-Rd arm with a median follow-up of 25.7 months in the PLEIADES study. Moreau et al (2023)⁹ reported the final results from the D-Kd arm of the PLEIADES and EQUULEUS studies. Safety results related to infections in the D-Kd and D-Rd arms have been summarized below.

Study Design/Methods

• Patients were placed into the treatment arms below until progressive disease (PD), unacceptable toxicity, or end of study.
  • RRMM with ≥1PL: D-Rd (n=65; 28-day cycles until PD)
  • RRMM with 1PL: D-Kd (n=60; 28-day cycles)
• 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 - Infection-Related - D-Kd and D-Rd Arms

• TEAEs related to infection leading to treatment discontinuation were observed in the D-Rd arm: pneumonia (n=2), diverticulitis (n=1), and Enterobacter infection (n=1).¹⁵ See Table: Most Common Infection-Related Grade 3/4 (≥5%) TEAEs in D-Kd and D-Rd arms (PLEIADES).

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

• Grade 3/4 infections were reported in 9 (13.6%) patients, the most common being pneumonia (4.5%).⁹
• For information regarding infection-related TEAEs, see Table: Most Common Infection-Related Any Grade (≥25%) and Grade 3/4 (≥5%) TEAEs in the D-Kd arm (PLEIADES).⁹
• Serious TEAEs were reported in 22 (33.3%) patients, the most common being pneumonia (4.5%).⁹
• Grade 5 TEAEs were reported in 3 patients (COVID-19 pneumonia, sepsis, and respiratory failure; 1 patient each).⁹

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.^16,28 Yimer et al (2022)¹⁶ 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 infections 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 - Infection-Related - End-of-Study Analysis

• In the RMM arm, the most common any grade infection-related TEAE was URTI (50.0%) and the most common serious TEAE was pneumonia (14.3%).¹⁷
• Infection-related TEAEs are summarized in Tables: Most Common Any Grade (≥25%) and Grade 3/4 (≥10%) Infection-Related TEAEs in the Safety Analysis Set (LYRA) and Most Common Any Grade (≥20%) and Grade 3/4 (≥5%) Infection-Related TEAEs Occurring During the Maintenance Phase 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.^11,12 Usmani et al (2022)¹² 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 infections have been summarized below.

Study Design/Methods

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

Safety Results - Infection-Related

• TEAEs-related to infection are summarized in Table: Most Common Any Grade (≥10%) and Grade 3/4 (≥5%) Infection-Related TEAEs in the Safety-Evaluable Population (COLUMBA).
• The most common serious adverse event (SAE) was pneumonia (DARZALEX FASPRO, 4.6% [n=12]; DARZALEX, 5% [n=13]).
• 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%) Infection-Related TEAEs Across Body Weight Subgroups (COLUMBA).
  • In the ≤65 kg subgroup, there was no increase in the incidence of infections for any grade TEAEs (DARZALEX FASPRO, 57.0%; DARZALEX, 57.6%), and grade 3/4 TEAEs (DARZALEX FASPRO, 10.8%; DARZALEX, 17.4%).
  • In the ≤65 kg subgroup, incidence of serious infections was 10.8% vs 18.5% in the DARZALEX FASPRO vs DARZALEX arms, respectively.

DARZALEX Monotherapy in Patients with Heavily Pretreated RRMM

Usmani et al (2020)⁷ 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). Safety results related to infections have been summarized below.

• 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 ≥2 lines of prior treatment, including a proteasome inhibitor 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 ≥3 lines of prior treatment, including a proteasome inhibitor or an immunomodulatory drug.

Safety Results - Infection-Related

• Three deaths occurred during the studies due to TEAEs: aspiration pneumonia (n=1), pneumonia (n=1), viral H1N1 infection (n=1).
• Infections of any grade were amongst the most common TEAEs (>10% of patients). Grade 3 AEs for URTIs were reported in 1% of patients, and any grade in 22%. Most URTIs were reported as grade 1/2 (22%, n=32). One patient (1%) reported a grade 3 URTI.

DARZALEX in Combination with Pomalidomide and Dexamethasone

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)⁸ 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)⁹ 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 infections in the 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 - Infection-Related - D-Pd arm

• URTI was the most common any grade (n/N=29/103 [28%]) and grade 3/4 (n/N=3/103 [3%]) TEAE reported in >25% of patients.⁸
• The most common (>5%) grade 3/4 TEAEs were pneumonia (10%) and febrile neutropenia (8%).⁸
• Pneumonia (9%) and sepsis and febrile neutropenia (5% each) were among the most common (>2%) serious TEAEs.⁸
• No patient discontinuations due to febrile neutropenia was reported.⁸
• Of the 9 deaths reported during treatment or within 30 days of receiving their last dose, sepsis was reported as 1 patient’s cause of death. Sepsis was also reported as a cause of death in a patient death occurring with the first cycle of treatment; it was not considered to be related to DARZALEX.⁸

Safety Results - Infection-Related - D-Kd arm (Final Results)

• Grade 3/4 infections occurred in 18 (21.2%) patients, the most common being pneumonia (4.7%).⁹
• For information regarding infection-related TEAEs, see Table: Most Common Infection-Related Any Grade (≥25%) and Grade 3/4 (≥5%) TEAEs in the D-Kd arm (EQUULEUS).⁹
• The most common serious TEAEs were pneumonia and URTI (4.7% each)⁹

DARZALEX Dose Escalation, Dose Expansion Study in Combination with Rd

Plesner et al (2019)¹⁰ reported final results from GEN503, a dose escalation and dose expansion study assessing the safety and efficacy of D-Rd in patients with RRMM (N=32). Safety results related to infections 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 - Infection-Related

• In part 2, two deaths were reported due to viral pneumonia and Epstein-Barr virus association (n=1 each).
• For information regarding infection-related TEAEs, see Table: Most Common (≥25%) Infection-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.¹⁸ Chari et al (2017)¹⁸ presented results from the part 1 and Part 2 of the PAVO study. San-Miguel et al (2021)¹⁹ published updated results from the part 2 of the PAVO study. Safety results related to infections 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 2.¹⁸
• Primary endpoints: C_trough of daratumumab at cycle 3 day 1; safety
• Key secondary endpoints: CR, ORR, DOR, and TTR

Safety Results - Infection-Related - 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 infection-related TEAEs, see Table: All-Grade and Grade 3/4 Infection-Related TEAEs - Part 1 and Part 2 (PAVO).

Updated Analysis of the Part 2 of the PAVO Study

San-Miguel et al (2021)¹⁹ 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 infection-related TEAEs, see Table: All-Grade and Grade 3/4 Infection-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)²⁰ 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 infections have been summarized below.

Study Design/Methods

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

Safety Results - Infection-Related - 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.
• Grade ≥3 infections were reported in 3 (20.0%), 2 (13.3%), and 1 (8.3%) patients in the 3-week, 2-week, and 1-week corticosteroid taper group, respectively.
• TEAEs led to death in 3 patients in the 1-week corticosteroid taper group, of which 1 was due to staphylococcal pneumonia (grade 5).
• For information regarding infection-related TEAEs, see Table: Most Common Infection-Related TEAEs - Updated Results from 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 ≥3 prior lines of therapy.²¹ Rodriguez-Otero et al (2022)²² presented the updated results from the TECVAYLI SC + DARZALEX FASPRO cohort of the TRIMM-2 study at a median follow-up of 8.6 months. Safety results related to infections 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 for each treatment combination.
  • Part 2: safety and tolerability at the selected RP2D of each treatment combination.
  • Antitumor activity, PK, and pharmacodynamics.
• 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.²¹

Safety Results - Infection-Related

• Infections were reported in 44 (67.7%) patients, of which 27.7% were grade 3/4.
• Four deaths were reported due to adverse events (AEs). None were related to TECVAYLI or DARZALEX FASPRO (bacterial pneumonia, sepsis, hepatic failure, COVID-19).

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

Dholaria et al (2023)²³ 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 infections 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 (QW; n=14) or
  0.8 mg/kg SC Q2W (n=44).
• 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 - Infection-Related

• Infections were generally low grade, except for pneumonia, most cases of which were of grade 3/4. The incidence and types of infections are presented in Table: Any Grade or Grade 3/4 Infection-Related AEs (TRIMM-2; TALVEY + DARZALEX FASPRO).
• Among patients with grade ≥3 infections, 75.0% had onset within the first 6 months.
• Overall, 95.4% of patients received antibacterial, antifungal, or antiviral prophylaxis.
• Overall, 10.8% of patients had opportunistic infections, and 3.1% had cytomegalovirus reactivation.
• Pneumonia (treatment-related) caused the death of 1 patient who received TALVEY 0.8 mg/kg SC Q2W + DARZALEX FASPRO.
• In both the cohorts combined, no reduction in the total CD19 B cells was observed, which may explain the relatively low grade 3/4 infection rate.
• Immunoglobulin G (IgG) <500 mg/dL was reported in 35.4% of patients at baseline, which increased to 86.2% post-baseline; 33.8% of these patients received intravenous immunoglobulin.

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.^24,25 Searle et al (2022)²⁴ 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. Safety results related to infections have been summarized below.

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 - Infection-Related

• The incidence of ≥1 infections (any grade) was reported in 90.6% of patients (n=29). The incidence of ≥1 grade 3/4 infections was reported in 37.5% of patients (n=12).
• The most common infections (any grade; ≥25%) were: COVID-19 (37.5%), upper respiratory infections (31.3%), and pneumonia (25.0%).
  • Among the 12 patients that reported COVID-19 during treatment; 4 patients (33.3%) were not vaccinated.
• The incidence and types of infections are presented in Table: MajesTEC-2 (Cohort E): Infections (Any Grade; ≥25% and/or Grade 3/4; ≥3.1%).
  • Additionally, grade 3/4 AEs for anorectal infection (n=1), gastroenteritis (n=1), haemophilius infection (n=1), urinary tract infection (n=1) have been reported.

Cilta-cel vs Standard Care (Physician's Choice of PVd or D-Pd) - 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 vs standard care (physician's choice of PVd or D-Pd) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.²⁶ San-Miguel et al 2023²⁶ reported efficacy and safety results from the interim analysis of this study. Safety results related to infections have been summarized below.

Study Design/Methods

• Patients were randomized 1:1 into one of two arms to receive cilta-cel or standard care (PVd or D-Pd).
• After undergoing apheresis, patients received ≥1 cycle of bridging therapy (physicians’ choice) with PVd or D-Pd (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 - Infection-Related

• Infections occurred in 62.0% of cilta-cel patients (n=129) and in 71.2% of standard care arm patients (n=148).
  • COVID-19 (includes preferred terms COVID-19, COVID-19 pneumonia, and asymptomatic COVID-19) infection was reported in 13.9% of cilta-cel patients (n=29) and in 26.4% of standard care patients (n=55). Grade 3/4 COVID-19 occurred in 2.9% of cilta-cel patients (n=6) and in 5.8% of standard care patients (n=12).
• The incidence and types of infections are presented in Table: All Grade and Grade 3/4 Infection-Related AEs (CARTITUDE-4).

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
17 June 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.