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 infections with DARZALEX/DARZALEX FASPRO treatment. Clinical judgment should be exercised when managing infections during DARZALEX/DARZALEX FASPRO-containing treatment regimens.

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
  • Part 1: Moreau et al (2019)¹ reported results from Part 1 of the CASSIOPEIA study. Infections of any grade were an adverse event (AE) of interest. In the D-VTd arm vs bortezomib, thalidomide, and dexamethasone (VTd) arm, any grade infections were reported in 65% vs 57% of patients, and grade 3/4 infections were reported in 22% vs 20% of patients.
  • Part 2: Moreau et al (2021)^2,3 reported results from Part 2 of the CASSIOPEIA study. Infections occurred in 77.5% of patients in the DARZALEX monotherapy arm vs 64% in the observation arm.
• GRIFFIN: phase 2, 2-part study evaluating the safety and efficacy of DARZALEX when administered in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in patients with newly diagnosed multiple myeloma (NDMM) eligible for high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT).^4-6
  • Part 1: Voorhees et al (2021)⁷ reported the final analysis of the safety run-in cohort (N=16) of the GRIFFIN study with a median follow-up of 40.8 months. Fourteen (87.5%) patients experienced any grade infections, and 5 (31.3%) patients experienced grade 3/4 infections.
  • Part 2: Voorhees et al (2020)^5,6 presented the primary analysis of the randomized portion of this study (n=207). Similar rates of any grade and grade 3/4 infections occurred for D-VRd vs bortezomib, lenalidomide, and dexamethasone (VRd). Voorhees et al (2023)⁸ reported the final analysis results of the GRIFFIN study (median follow-up, 49.6 months) after all patients completed ≥1 year of long-term follow-up after the end-of-study treatment, death, or withdrawal. The median duration of follow-up was 49.6 months. In the D-VRd vs VRd arm, any grade infections were reported in 93% vs 66% of patients, respectively, and grade 3/4 infections were reported in 29% vs 26% of patients, respectively.
  • DARZALEX/DARZALEX FASPRO is not approved by the regulatory agencies for use in combination with VRd 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.
• 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.^9,10
  • Yimer et al (2022)¹¹ reported the end-of-study analysis of LYRA. In patients with NDMM, the most common grade 3/4 infection-related treatment-emergent adverse event (TEAE) was pneumonia (3.5%).
  • 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.
• 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.^12-16
  • Chari et al (2020)¹² presented updated safety and efficacy results of the D-VRd arm for patients with transplant-eligible NDMM in the PLEIADES study (n=67). Pneumonia was reported in 3% of patients in this arm.
• PERSEUS (MMY3014) is an ongoing, open-label, multicenter, randomized, phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO when administered in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) vs VRd induction and consolidation followed by maintenance with DARZALEX FASPRO and lenalidomide (D-R) in D-VRd group or lenalidomide (R) in VRd group in patients with NDMM eligible for ASCT.¹⁷
  • Sonneveld et al (2023)¹⁷ reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT. At a median follow-up duration of 47.5 months (range, 0-54.4), the most common infection-related grade 3/4 AE recorded in the D-VRd vs VRd group was pneumonia (10.5% vs 6.1%).
• MASTER was a phase 2, single-arm, open-label, multicenter study evaluating the efficacy and safety of DARZALEX in combination with carfilzomib, lenalidomide, and dexamethasone (D-KRd) in patients with NDMM.¹⁸ The most common serious TEAE was pneumonia (n=8).
• Rodriguez-Otero et al (2024)¹⁹ 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. A higher incidence of grade 3/4 infections was observed in the D-VRd vs VRd group, with slightly higher rates in patients aged ≥65 years (36.3% vs 24.8%) than in all patients (29.5% vs 22.5%).

Transplant-INEligible

• MAIA was phase 3 study evaluating the safety and efficacy of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) compared with lenalidomide and dexamethasone (Rd) in transplant-ineligible patients with NDMM.²⁰ At a median follow-up duration of 89.3 months (range, 0-102.2), in the D-Rd arm vs Rd arm, deaths due to infections/infestations were reported in 2.5% vs 8.2% of patients.²¹
• 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.²² In the D-VMP vs VMP arm, grade 3/4 infections were reported in 30.3% vs 15% of patients.²³
• OCTANS: phase 3 study evaluating the efficacy and safety of D-VMP vs VMP in Asian patients with NDMM who were not eligible for ASCT.²⁴
  • In the final analysis at a median follow-up of >3 years, grade 3/4 infection TEAEs were reported in 67 (46.5%) vs 22 (31%) patients in the D-VMP vs VMP arm, respectively.
  • Pneumonia was the most common infection-related serious TEAE (D-VMP, 21.5%; VMP, 5.6%).
• PLEIADES: phase 2 study evaluating the clinical benefit of DARZALEX FASPRO for SC use administered in combination with 4 standard-of-care treatment regimens.^12-16 Specifically, with:
  • Moreau et al (2020)¹⁶ presented updated safety and efficacy results of the D-VMP arms in the PLEIADES study (n=67). Pneumonia was reported in 7% of patients in the D-VMP arm.
• AURIGA (MMY3021) is an ongoing, open-label, active-controlled, multicenter, randomized phase 3 study evaluating the conversion rate to minimal residual disease (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. A total of 200 patients were randomized (D-R, n=99; R, n=101).^25-27
  • Badros et al (2024)^25,26,28 reported primary results from the phase 3 AURIGA study. Slightly higher occurrence rates of grade 3/4 infections (18.8% vs 13.3%) were observed with D-R vs R.
  • Foster et al (2024)²⁹ 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 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. D-R maintenance did not increase grade 3/4 infection rates in patients ≥65 years of age.
• CEPHEUS (MMY3019) is a 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). The trial has enrolled 395 patients in 13 countries.^30-32
  • Usmani et al (2025)³² 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, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%). Any grade infections occurred in 91.9% vs 85.6% of patients from the D-VRd vs VRd arm, respectively. Grade 3/4 TEAE infections occurred in 40.1% and 31.8% of patients from the D-VRd vs VRd arm, respectively.
• Tai et al (2020)³³ reported on the proportion of United States (US) patients who received prophylaxis for infection when initiating DARZALEX-containing regimens for NDMM or relapsed/refractory multiple myeloma (RRMM). Prophylaxis for bacterial infection was <20% in both patients with NDMM and RRMM. Prophylaxis for herpesvirus occurred in 57.6% of patients with NDMM.
• van de Donk et al (2020)³⁴ conducted an analysis from pooled data from the ALCYONE and MAIA studies to identify predictive markers of grade ≥3 serious infections that occurred during the first 6 months of treatment. The final predictive model included albumin, age, elevated baseline alanine aminotransferase (ALT) levels and lactic acid dehydrogenase (LDH). In the ALYCONE study, the most common (>10 patients) grade 3/4 infection was pneumonia (D-VMP, 13%; VMP, 4%). In the MAIA study, the most common (>10 patients) grade 3/4 infections were pneumonia (D-Rd, 15%; Rd, 9%), influenza (D-Rd, 3%; Rd, 2%), bronchitis (D-Rd, 3%; Rd, 1%), and sepsis, urinary tract infections, and lower respiratory tract infections (3% each in both arms).

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 in Previously Untreated MM

CASSIOPEIA (MMY3006; clinicaltrials.gov identifier 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 HDT and ASCT.¹ Moreau et al (2019)¹ reported the results from Part 1 of this study. Moreau et al (2021)^2,3 reported results from Part 2 of the CASSIOPEIA study. Safety results related to infections have been summarized below.

Study Design/Methods

• Part 1: patients were randomized to 1 of 2 treatment arms (each cycle is 4 weeks):
  • Arm A: Up to 4 cycles of VTd induction therapy followed by ASCT, followed by 2 weeks of VTd consolidation.
  • Arm B: Up to 4 cycles of D-VTd induction therapy, followed by ASCT, followed by 2 cycles of D-VTd consolidation.
• Part 2: Responders rerandomized to 1 of 2 treatment arms:
  • Arm A: Observation
  • Arm B: DARZALEX 16 mg/kg maintenance therapy every 8 weeks for 2 years
• Primary endpoint: Part 1: stringent complete response (sCR) after consolidation therapy assessed at 100 days after ASCT (or immediately after consolidation if >100 days); Part 2: progression-free survival (PFS) after maintenance therapy.
• Secondary endpoints: Part 1: PFS, time to progression (TTP), proportion of post ASCT/consolidation MRD, proportion of post-induction sCR, PFS after next line of therapy (PFS2), and overall survival (OS); Part 2: TTP from second randomization, rate of complete response or better (≥CR), MRD-negativity rates (in patients with ≥CR at a threshold of 10^-5 by next-generation sequencing [NGS]), PFS2, overall response rate (ORR), and OS from second randomization.

Results - Safety - Infection-Related Events in Part 1

• Infections of any grade were an AE of interest. In the D-VTd arm, 65% (n=351) of patients and 57% (n=306) in the VTd arm reported infections of any grade.
• Grade 3/4 infections were reported in 22% (n=118) of patients in the D-VTd arm and 20% (n=105) in the VTd arm. See Table: Most Common Infection-Related Adverse Events During Treatment in Safety Population (CASSIOPEIA Part 1).
• Six patients discontinued DARZALEX treatment due to TEAEs of infections.
• Among the most common serious adverse events (SAEs; ≥3% of patients in either arm), pneumonia was reported in 4% (n=19) in the D-VTd arm and 2% (n=9) in the VTd arm.
• A total of 14 deaths were reported in the D-VTd arm and 32 in the VTd arm. Septic shock was reported as a cause of death (n=1) in the VTd arm.³⁵

Results - Safety - Infection-Related Events in Part 2

• Infections occurred in 77.5% (n=341) of patients in the DARZALEX monotherapy arm vs 64% (n=284) in the observation arm.³
  • DARZALEX monotherapy arm vs observation arm had a greater incidence of pneumonia (n=29 [6.6%] vs n=19 [4.3%]) and lung infections (n=21 [4.8%] vs n=15 [3.4%]).³
• Majority of infections were grade 1/2 (DARZALEX monotherapy arm, 303 of 331 [88.9%]; observation arm, 254 of 284 [89.4%]).³
• See Table: Most Common Infection-Related AEs during Treatment/Observation in Maintenance-Specific Safety Population (CASSIOPEIA Part 2).
• SAEs that occurred in >1% of patients in the DARZALEX monotherapy vs observation arms were pneumonia (n=11 [3%] vs n=7 [2%]) and lung infection (n=6 [1%] vs n=7 [2%]), respectively.
• Two AEs led to death in the DARZALEX monotherapy arm (septic shock and natural killer-cell lymphoblastic lymphoma, n=1 each); both were treatment-related.

DARZALEX in Combination with Bortezomib, Lenalidomide and Dexamethasone

GRIFFIN (MMY2004; clinicaltrials.gov identifier: NCT02874742) is a 2-part, phase 2, randomized, active-controlled US study evaluating the safety and efficacy of DARZALEX in combination with VRd in patients with NDMM eligible for HDT and ASCT.^4-6 Voorhees et al (2021)⁷ reported the final analysis of the safety run-in cohort (Part 1) of the GRIFFIN study. Voorhees et al (2020)⁶ presented the primary analysis and updated analysis of the randomized portion (Part 2) of this study (n=207). Voorhees et al (2023)⁸ reported the final efficacy and safety results at a median follow-up of 49.6 months after all patients completed ≥1 year of follow-up after the end-of-study treatment, died, or withdrew from study participation. Safety results related to infections have been summarized below.

Study Design/Methods

• Part 1: The safety run-in phase consisted of an induction phase (cycles 1-4; 21-day cycles), followed by ASCT, followed by a consolidation phase (cycles 5-6; 21-day cycles), that was initiated 60-100 days after ASCT, followed by a maintenance phase (cycles 7-32; 28-day cycles).
• Part 2: Following successful completion of the safety run-in phase, in part 2 of the study patients were randomized 1:1 to an induction phase (D-VRd or VRd [cycles 1-4; 21-day cycles]), followed by ASCT, followed by a consolidation phase (D-VRd or VRd [cycles 5-6; 21-day cycles]), followed by a maintenance phase (D-Rd or Rd [cycles 7-32; 28-day cycles]), following the dosing illustrated above, +/- DARZALEX.
• A data review committee was established to review safety data after 8, 12, and 16 patients in the safety run-in phase completed cycle 1, and to determine if the study should proceed to the randomized phase 2 portion or stop.
• Primary endpoint: sCR (by end of post-ASCT consolidation)
• Secondary endpoints: MRD 10^-5 via NGS, CR, ORR, very good partial response or better (≥VGPR)

Results - Safety - Infection-Related Events in Part 1

• During cycle 1, 3 of 16 patients developed 4 dose-limiting toxicities (DLTs) fatigue, gastroenteritis, hypotension, and pneumonitis.
  • All DLTs were grade 3 and none resulted in treatment discontinuation during induction or consolidation therapy.
• Fourteen (87.5%) patients experienced any grade infections, and 5 (31.3%) patients experienced grade 3/4 infections.
  • During the maintenance phase 31.3% (n=5) of patients experienced any grade infections. The most common being upper respiratory tract infections. One (6.3%) patient experienced 2 grade 3/4 infections (pneumonia and bronchitis).
• Pneumonia was the most common grade 3/4 infection-related TEAE reported in 5 (31.3%) patients.

Results - Safety - Infection-Related Events in Part 2

• Any grade infections were more common in the D-VRd vs VRd arm (93% [n=92] vs 66% [n=67]). Similar incidence rates were reported across treatment arms for grade 3/4 infections (D-VRd, 29%; VRd, 26%) and infections leading to treatment discontinuation (D-VRd, 2%; VRd, 3%).
  • During maintenance therapy (cycle 7 and onwards) in the D-VRd vs VRd arm, any grade infections occurred in 35% (n/N=31/89) vs 32% (n/N=23/71) of patients, respectively, and grade 3/4 infections occurred in 18% (n=16) vs 21% (n=15) of patients, respectively.
  • In the D-VRd vs VRd arm, Coronavirus Disease 2019 (COVID-19) infections were reported in 5% (n=5) vs 2% (n=2) of patients, respectively. Of these, 1 patient in each arm had a grade 3 COVID-19-related event (including 1 serious event in the D-VRd arm).
• Pneumonia was the most common infection-related serious TEAE (D-VRd vs VRd, 15% vs 14%, respectively).
• For the incidence of most common infection-related TEAEs by grade in the safety population, see Table: Most Common Infection-Related TEAEs in the Safety Population (GRIFFIN).

DARZALEX in Combination with Cyclophosphamide, Bortezomib, and Dexamethasone

LYRA (clinicaltrials.gov identifier: 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.^9,10 Yimer et al (2022)¹¹ reported the end-of-study analysis results of the LYRA study. Safety results related to infections reported in patients with NDMM are summarized below.

Study Design/Methods

• Patients received 4-8 cycles (28 days per cycle) of the following induction treatment⁹:
  • DARZALEX: 16 mg/kg IV
    • Cycle 1: 8 mg/kg IV on days 1 and 2, followed by 16 mg/kg weekly
    • Cycle 2: weekly
    • Cycles 3-6: every 2 weeks
    • Cycles 7-8: every 4 weeks
  • Bortezomib: 1.5 mg/m² SC weekly on days 1, 8, and 15 in all cycles
  • Cyclophosphamide: 300 mg/m² orally (PO) weekly on days 1, 8, 15, and 22 in all cycles
  • Dexamethasone: 40 mg
    • Cycle 1: 20 mg IV on days 1 and 2, followed by 40 mg weekly
    • Cycles 2-8: 40 mg IV/orally (PO) weekly
• After the induction phase, all patients received up to 12 cycles (28 days per cycle) of the following maintenance treatment⁹:
  • DARZALEX: 16 mg/kg IV every 4 weeks
  • Dexamethasone: 12 mg IV/Oral (PO) on DARZALEX dosing days
• Patients underwent HDT and ASCT at the discretion of the investigator after the induction phase.¹¹
• Primary endpoint: ≥VGPR after 4 induction cycles¹¹
• Key secondary endpoints: ORR, time to ≥VGPR, time to partial response or better (≥PR), PFS, OS, safety, and tolerability¹¹

Results - Safety - Infection-Related Events in Patients with NDMM

• For the incidence of most common any grade and grade 3/4 infection-related TEAEs during induction phase, see Table: Most Common Infection-Related TEAEs in the Safety Analysis Set (Induction phase; LYRA).
• For the incidence of most common any grade and grade 3/4 infection-related TEAEs during maintenance phase, see Table: Most Common Infection-Related TEAEs in the Safety Analysis Set (Maintenance phase; LYRA).
• The most common serious TEAE was pneumonia (2.3%).

DARZALEX FASPRO in Combination with Bortezomib, Lenalidomide and Dexamethasone

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 4 standard-of-care treatment regimens in patients with MM.^12-16 Specifically with:

• D-VRd for patients with transplant-eligible NDMM (n=67).
• D-VMP for patients with transplant-ineligible NDMM (n=67).
• D-Rd for patients with RRMM with ≥1 prior line of therapy (PL) (n=65).
• DARZALEX FASPRO in combination with carfilzomib and dexamethasone (D-Kd) in patients with RRMM with 1PL (n=60).

Chari et al (2020)¹² presented updated safety and efficacy results of the D-VRd arm in the PLEIADES study. Safety results related to infections specific to the D-VRd arm have been summarized below.

Study Design/Methods

• Primary endpoint: ≥VGPR after the 4 induction cycles for the D-VRd arm
• Key secondary endpoints: maximum observed serum concentrations (C_max) and minimum observed serum concentrations (C_min) of daratumumab, immunogenicity, percentage of participants with infusion-related reactions (IRR), ≥CR, duration of responses (DOR), MRD-negativity rate and ≥VGPR for the D-VMP arm, ORR for the D-VRd arm.

Results - Safety - Infection-Related Events in the D-VRd arm

DARZALEX FASPRO in Combination With Bortezomib, Lenalidomide, and Dexamethasone

PERSEUS (MMY3014; clinicaltrials.gov identifier: 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 D-VRd group or lenalidomide in VRd group in patients with NDMM eligible for ASCT. Sonneveld et al (2023)¹⁷ reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT.

Study Design/Methods

• A total of 709 patients were randomized 1:1 to into D-VRd (n=355) vs VRd (n=354) arm.
  • Stratification was done based on the ISS disease stage (I, II, or III) and standard or high cytogenetic risk (defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16]).
• Dosing:
  • Induction and consolidation: Total duration of induction and consolidation treatment was 6 cycles. Each cycle was 28 days.
    • D-VRd:
      • DARZALEX FASPRO- 1800 mg once a week (QW) at cycles 1-2 and every 2 weeks (Q2W) at cycles 3-4
      • SC bortezomib- 1.3 mg/m² on days 1, 4, 8, and 11 of each cycle
      • PO lenalidomide- 25 mg on days 1-21 of each cycle
      • PO/IV dexamethasone- 40 mg on days 1-4 and days 9-12 of each cycle
    • VRd:
      • SC bortezomib- 1.3 mg/m² on days 1, 4, 8, and 11 of each cycle
      • PO lenalidomide- 25 mg daily on days 1-21 of each cycle
      • PO/IV dexamethasone-40 mg on days 1-4 and days 9-12 of each cycle
  • Maintenance: Total duration of maintenance (≥24 months) was cycle 7 until progressive disease. Each cycle was 28 days.
    • D-VRd:
      • DARZALEX FASPRO- 1800 mg SC every 4 weeks (Q4W)
      • PO lenalidomide- 10 mg until PD or unacceptable toxicity
      • Patients who achieved sustained MRD for 12 months after ≥24 months of maintenance discontinued DARZALEX FASPRO, but continued PO lenalidomide until PD or unacceptable toxicity. Once they experienced loss of MRD-negativity or CR, they restarted on DARZALEX FASPRO.
      • Patients who did not achieved sustained MRD for 12 months after ≥24 months of maintenance continued DARZALEX FASPRO and PO lenalidomide
    • VRd:
      • PO lenalidomide-10 mg daily until PD or unacceptable toxicity
• Primary endpoint: PFS.
• Key secondary endpoints: Overall ≥CR, overall MRD-negativity, and OS.
• Other secondary endpoints: ORR, ≥VGPR, sCR, duration of MRD-negativity.

Results - Safety - Infection-Related Events

• The most common infection-related grade 3/4 AE recorded in the D-VRd vs VRd group was pneumonia (10.5% vs 6.1%)
• The number of deaths recorded due to COVID-19 in the D-VRd vs VRd group was 4 (1.1%) vs 1 (0.3%) patients, respectively.
• For the incidence of most common infection-related AEs by grade, see Table: Most Common Infection-Related AEs (PERSEUS).
• For the incidence of infection-related SAEs occurring in ≥2% of patients in either treatment group, see Table: Infection-Related SAEs Occurring in ≥2% of patients (PERSEUS).

DARZALEX in Combination With Carfilzomib, Lenalidomide, and Dexamethasone

MASTER (clinicaltrials.gov identifier: NCT03224507) was a phase 2, single-arm, open-label, multicenter study evaluating the efficacy and safety of D-KRd in patients with NDMM.¹⁸ Costa et al (2023)¹⁸ reported the final analysis results of the MASTER study. Safety results related to infections have been summarized below.

Study Design/Methods

• Patients received 4 cycles (28 days per cycle) of the following induction treatment:
  • DARZALEX: 16 mg/kg IV
    • Cycles 1 and 2: days 1, 8, 15, and 22
    • Cycles 3 and 4: every 2 weeks
  • Carfilzomib: 56 mg/m² IV on days 1, 8, and 15 in all cycles
  • Lenalidomide: 25 mg PO on days 1-21 in all cycles
  • Dexamethasone: 40 mg PO or IV on days 1, 8, 15, and 22 in all cycles
• After the induction phase, all patients received high-dose IV melphalan (140-200 mg/m²) followed by autologous hematopoietic stem cell transplantation (HSCT).
• After subsequent response assessment (60-80 days after transplantation), patients requiring additional therapy based on MRD status received up to 2 phases of consolidation with D-KRd, each comprising 4 cycles:
  • DARZALEX: 16 mg/kg IV
    • Cycles 5 and 6: every 2 weeks
    • Cycles 7-12: every 4 weeks
    • Patients received the same dose of carfilzomib, lenalidomide, and dexamethasone as in the induction phase
• Primary endpoint: MRD-negativity (<10^-⁵) at any point during treatment
• Key secondary endpoints: Safety, rate and kinetics of MRD resurgence upon treatment discontinuation, PFS, and OS

Results - Safety - Infection-Related Events

• The most common serious TEAE was pneumonia (n=8).
• One patient died during protocol-directed therapy from metapneumovirus pneumonia, which was considered as not related to study treatment.
• One patient died after therapy and while on MRD surveillance without disease progression from COVID-19 pneumonia.
• For the incidence of most common infection-related TEAEs by grade, see Table: Most Common Infection-Related TEAEs (MASTER).

Post hoc Analysis of Patients Aged ≥65 Years From the PERSEUS and GRIFFIN Studies

Rodriguez-Otero et al (2024)¹⁹ presented (at the 21^st 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 237 patients aged ≥65 years.

Results - Safety - Infection-Related Events

• A higher incidence of grade 3/4 infections was observed in the D-VRd vs VRd group, with slightly higher rates in patients ≥65 years (36.3% vs 24.8%) than in all patients (29.5% vs 22.5%).
• The summary of infection-related TEAEs is presented in Table: Summary of Infection-related TEAEs in Patients Aged ≥65 Years and All Patients Irrespective of Age in the Pooled PERSEUS/GRIFFIN Safety Population.

CLINICAL DATA - NEWLY DIAGNOSED MULTIPLE MYELOMA TRANSPLANT - INELIGIBLE

DARZALEX in Combination with Lenalidomide and Dexamethasone

MAIA (MMY3008; clinicaltrials.gov identifier: NCT02252172) is an international, phase 3, randomized, open-label, active-controlled, multicenter study in patients with NDMM not eligible for HDT and ASCT (N=737).²⁰ Kumar et al (2022)³⁷ presented the updated safety and efficacy results of the MAIA study at a median follow-up of 64.5 months. Facon et al (2024)²¹ presented the updated safety results for the D-Rd vs Rd arm of the MAIA study at a long-term median follow-up of around 89.3 months (range, 0-102.2). Safety results related to infections have been summarized below.

Study Design/Methods

• Patients were randomized 1:1 to D-Rd (n=368) or Rd (n=369) and received 28-day cycles of the following treatment until PD or unacceptable safety event:
  • Rd arm:
    • Lenalidomide 25 mg PO daily on days 1-21 until PD (10 mg daily if creatinine clearance [CrCl] is between 30 and 50 mL/min).
    • Dexamethasone: 40 mg PO or IV weekly on days 1, 8, 15, and 22, until PD (20 mg weekly in patients >75 years of age or with a body mass index [BMI] <18.5 kg/m²).
  • D-Rd arm:
    • DARZALEX 16 mg/kg IV weekly during cycles 1-2, every 2 weeks during cycles 3-6, then every 4 weeks during cycle 7+. Following a protocol amendment (2020), patients in the D-Rd arm were given the option to switch from DARZALEX IV to DARZALEX FASPRO for SC use. DARZALEX FASPRO was to be administered at a fixed dose of 1800 mg SC over 3-5 minutes in the abdominal SC tissue once every 4 weeks.
    • Same dosage and schedule of lenalidomide and dexamethasone as the Rd arm.
• Primary endpoint: PFS
• Secondary endpoints: ≥CR rate, DOR, ≥VGPR rate, MRD-negativity rate, ORR, OS, PFS2 (time from randomization to disease progression on the next line of therapy or death), sCR, time to next (2nd-line) treatment, time to response, TTP, and safety.

Results - Safety - Infection-Related Events

• At a median follow-up duration of 89.3 months (range, 0-102.2), in the D-Rd arm vs Rd arm, deaths due to infections/infestations were reported in 2.5% (n=9) vs 8.2% (n=30) of patients.²¹

DARZALEX in Combination with Bortezomib, Melphalan, and Prednisone

ALCYONE (MMY3007; clinicaltrials.gov identifier: 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 HDT with ASCT.²² Mateos et al (2022)²³ presented an updated efficacy and safety analysis of the ALCYONE study at a median follow-up of almost 7 years (78.8 months). Safety results related to infections have been summarized below.

Study Design/Methods

• Patients were randomly assigned 1:1 to receive either VMP alone or D-VMP as follows (randomization was stratified according to disease stage [I, II, or III], geographic region [Europe vs other], and age [<75 vs ≥75 years]):
  • VMP: up to 9 cycles (42 days/cycle) of:
    • Bortezomib 1.3 mg/m² SC twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9
    • Melphalan 9 mg/m² PO once daily on days 1-4 of each cycle
    • Prednisone 60 mg/m² PO once daily on days 1-4 of each cycle
  • D-VMP: Up to 9 cycles (42 days/cycle) of VMP as described above plus:
    • DARZALEX 16 mg/kg IV once weekly in cycle 1, once every 3 weeks in cycles 2-9, and once every 4 weeks thereafter until there was disease progression or unacceptable toxicity
    • Patients in this arm also received dexamethasone 20 mg PO or IV and other pre-infusion medications (approximately 1 hour before DARZALEX infusion) for management of infusion reactions. On day 1 of each cycle, the dexamethasone 20 mg dose was substituted for the prednisone dose in the VMP regimen.
• Primary Endpoint: PFS
• Secondary Endpoints: ≥CR rate, ≥VGPR rate, MRD-negativity (10^-5), OR, and median OS.

Results - Safety - Infection-Related Events

• In the D-VMP vs VMP arm, grade 3/4 infections were reported in 30.3% vs 15% of patients. See Table: Most Common Infection-Related TEAEs (ALCYONE).
• The most common serious TEAE in both treatment arms was pneumonia (D-VMP, 14.7%; VMP, 3.7%).

DARZALEX in Combination with Bortezomib, Melphalan, and Prednisone in Asian Patients

OCTANS (MMY3011; clinicaltrials.gov identifier: NCT03217812) is a multicenter, randomized, open-label, active-controlled, phase 3 study evaluating the efficacy and safety of D-VMP vs VMP in Asian patients with NDMM who were not eligible for ASCT.²⁴ Fu et al (2023)³⁸ reported the prespecified primary results of the OCTANS study (median follow-up, 12.3 months [range, 0-29.3]). Fu et al (2023)²⁴ reported the final analysis results of the OCTANS study (median follow-up, >3 years). Safety results related to infections from the final analysis have been summarized below.

Study Design/Methods

• Patients were randomized 1:2 to receive D-VMP or VMP (42 days/cycle).
  • Patients in the D-VMP arm received:
    • DARZALEX 16 mg/kg IV once weekly during cycle 1, once every 3 weeks during cycles 2 through 9, and once every 4 weeks thereafter until PD or unacceptable toxicity
    • Bortezomib 1.3 mg/m² SC twice weekly during weeks 1, 2, 4, and 5 of cycle 1 and once weekly during weeks 1, 2, 4, and 5 of cycles 2 to 9
    • Melphalan 9 mg/m² PO once daily on days 1 to 4 of each cycle
    • Prednisone 60 mg/m² PO once daily on days 1 to 4 of each cycle
  • Patients in the VMP arm received the same dose of bortezomib, melphalan, and prednisone as the D-VMP arm.
• Primary endpoint: rate of ≥VGPR
• Key secondary endpoints: PFS, time to next treatment (TTNT), ORR, sCR rate, CR rate, time to response, DOR, and OS

Results - Safety - Infection-Related Events

• At a median follow-up of >3 years, grade 3/4 infection TEAEs were reported in 67 (46.5%) vs 22 (31%) patients in the D-VMP vs VMP arm, respectively.
• Infection-related events are summarized in Table: Most Common Infection-Related TEAEs in the Safety Population (OCTANS).
• Pneumonia was the most common (≥5% of patients in either arm) infection-related serious TEAE (D-VMP, 21.5%; VMP, 5.6%).

DARZALEX FASPRO in Combination with Bortezomib, Melphalan and Dexamethasone

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 4 standard-of-care treatment regimens in patients with MM.^12-16 Moreau et al (2020)¹⁶ presented updated safety and efficacy results of the D-VMP arms in the PLEIADES study. Safety results related to infections specific to the D-VMP arm have been summarized below.

Study Design/Methods

• Primary endpoint: ORR for the D-VMP arm
• Key secondary endpoints: C_max and C_min of daratumumab, immunogenicity, percentage of participants with IRR, ≥CR rate, DOR, MRD-negativity rate and ≥VGPR for the D-VMP arm.

Results - Safety - Infection-Related Events in the D-VMP arm

• In the D-VMP arm, infection-related TEAEs leading to treatment discontinuation were: neutropenic sepsis, pneumonitis (n=1 each).

DARZALEX FASPRO in Combination with Lenalidomide

AURIGA (MMY3021; clinicaltrials.gov identifier: 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 R alone in patients with NDMM who are anti-CD 38 naïve, have ≥VGPR, and are MRD-positive after ASCT.^25-27 Badros et al (2024)^25,26 reported primary results from the phase 3 AURIGA study.

Study Design/Methods

• The trial enrolled 200 patients from the United States and Canada.²⁵
• Patients underwent 1:1 randomization to receive D-R maintenance (n=99) or R alone maintenance (n=101) across 28-day cycles.^25,27
  • D-R: DARZALEX FASPRO 1800 mg SC QW in cycles 1-2, Q2W in cycles 3-6, Q4W in cycles 7+.
  • R: Lenalidomide 10 mg PO once a dayon days 1-28.
• The treatment regimen continued until unacceptable toxicity, disease progression, consent withdrawal, or for a maximum of 36 cycles.²⁵
• Primary endpoint: MRD-negativity conversion rate from baseline to 12 months.²⁵
  • MRD was assessed at 12, 18, 24, and 36 months.
  • If lenalidomide is well tolerated, the dose may be increased to 15 mg daily after cycle 3, at the investigator’s discretion.
• Secondary endpoints: Safety, PFS, overall MRD-negativity conversion rate, sustained MRD-negativity rate (≥6 months), response rates including CR/sCR as assessed by International Myeloma Working Group 2016 criteria, duration of ≥CR, OS, HRQoL changes based on patient reported outcomes.²⁵

Results - Safety - Infections

• The most common nonhematological infection-related AEs in the safety population are summarized in Table: Most Common Nonhematological Infection-Related AEs in the Safety Population.
  • Slightly higher occurrence rates of grade 3/4 infections (18.8% vs 13.3%) were observed with D-R vs R.

Clinically Relevant Subgroup Analysis - Phase 3 AURIGA Study

Foster et al (2024)²⁹ presented (at the 66^th ASH Annual Meeting) a post hoc analysis of the phase 3 AURIGA study that evaluated clinically relevant subgroups at a median follow-up of 32.3 months. The clinically relevant subgroups included elderly and black patients, patients with high-risk disease per ISS disease staging, and patients with a high cytogenetic risk per standard, revised, and IMS 2024 high-risk criteria.

Results - Safety - Infection-Related Events

• No unexpected safety concerns were observed in patients aged ≥65 years or in Black patients.²⁹
  • The median duration of therapy was 25 months (D-R, 30.5 months; R, 23.5 months) for patients aged <65 years and 24.4 months (D-R, 32.7 months; R, 19.2 months) for patients aged ≥65 years. Infection-related safety results based on age for patients with ≥1 TEAE are summarized in Table: Infection-Related Safety Results Based on Age for Patients With ≥1 TEAE.
  • The median duration of therapy was 23.7 months (D-R, 29.3 months; R, 18.9 months) for White patients and 25.4 months (D-R, 28.3 months; R, 25.4 months) for Black patients. Infection-related safety results based on race for patients with ≥1 TEAE are summarized in Table: Infection-Related Safety Results Based on Race for Patients With ≥1 TEAE.
• D-R maintenance did not increase grade 3/4 infection rates in patients ≥65 years of age.²⁹

CEPHEUS (MMY3019; clinicaltrials.gov identifier: 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 transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred).^30-32 Usmani et al (2025)³² reported results from the phase 3 CEPHEUS study.

Study Design/Methods

• The trial has enrolled 395 patients from 13 different countries including the United States.³¹
• Primary endpoint: Overall MRD-negativity (≥CR) rate at 10^-5 sensitivity threshold.^30,31
• Key secondary endpoints: PFS, ORR, ≥VGPR, ≥CR, PFS2, OS, and sustained MRD-negativity (10^-5) rate at ≥12 months.^30,31

Results - Safety - Infections

• The safety data were consistent with the established safety profile of each individual drug.³² Infection-related nonhematologic TEAEs in the safety population are summarized in Table: Infection-related Nonhematologic TEAEs in the Safety Population.
  • Overall, deaths were reported in 51 vs 60 patients from the D-VRd vs VRd arm, respectively.
    • The COVID-19 pandemic impacted OS with 24 (21.6%) of all deaths in the study attributed to COVID-19 (D-VRd, n=15 vs VRd, n=9).
    • Overall, 21 COVID-19 deaths occurred during the peak of the pandemic in 2020 and 2021, with 3 additional deaths in 2022 (post-vaccine availability), and none in 2023 or 2024.
• Regional variations were observed in pandemic impact. Brazil reported 54.2% of COVID-19 deaths (17.5% of the study population), while Poland had 16.7% of deaths (18.7% of the study population).
• Two sensitivity analyses of OS adjusting for COVID-19 deaths showed a stronger treatment effect for D-VRd vs VRd (censoring COVID-19 deaths [HR, 0.69; 95% CI, 0.45-1.05] and considering COVID-19 deaths as a competing risk [HR for non-COVID mortality, 0.67; 95% CI, 0.44-1.03]).
  • Grade 5 non-COVID-related TEAEs occurred in 10.7% vs 7.7% of patients from the D-VRd vs VRd arm, respectively.
  • Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%). A summary of the serious TEAEs is presented in Table: Infection-related Serious TEAEs (≥2%) in the Safety Population.

Use of Anti-Infective Prophylaxis in Patients with NDMM and RRMM Initiating Treatment with DARZALEX

Tai et al (2020)³³ presented the results of the use of anti-infective prophylaxis in patients with NDMM or RRMM when initiating treatment with DARZALEX at the 62nd Annual ASH Meeting & Exposition. Safety results related to infections reported in patients with NDMM are summarized below.

Study Methods

• The study reviewed medical, and pharmacy claims from the US patients with NDMM or RRMM who initiated DARZALEX treatment.
• Use of anti-infective prophylaxis assessed in between week before and the week after starting DARZALEX treatments.
• Prophylaxis for infections included anti-viral, systemic anti-bacterial, systemic anti-fungals, Pneumocystis jiroveci pneumonia (PJP) prophylaxis and IV/SC immune globulin (IVIG/SCIG).

Results

• A total of 929 patients were included in this study. Of those, 92 were diagnosed with NDMM and 837 patients were diagnosed with RRMM.
• At the initiation of DARZALEX treatment the following were administered:
  • Prophylaxis for bacterial infections was administered to 12% of patients with NDMM.
  • PJP prophylaxis was administered to 4.4% of patients with NDMM.
  • IVIG/SCID prophylaxis was administered 1.1% in NDMM arm.
• Herpes virus prophylaxis was administered to 57.6% in the NDMM arm. The most commonly used anti-viral for herpes virus prophylaxis was acyclovir (45.7% in NDMM arm).

Predictive Markers of Infections in Patients with NDMM from ALCYONE and MAIA Studies

van de Donk et al (2020)³⁴ presented an analysis with pooled data from ALCYONE and MAIA studies at the 62nd Annual ASH Meeting & Exposition to identify predictive markers of serious or grade ≥3 infections occurring during the initial 6 months of treatment with DARZALEX.

Study Design/Methods

• Training data and validation data was utilized to create a final model based on training data with hazard ratio (HR) and 95% confidence interval (CI).

Results

• A total of 710 patients were pooled from both studies to create the predictive model which included the training data (n=534) and validation data (n=176).
• Follow-up median duration was 40.1 months in ALCYONE and 36.4 months in MAIA.
• The final predictive model included age, albumin, elevated baseline ALT levels, and LDH.
• A summary of the predicative markers of infections with DARZALEX treatment in patient from ALCYONE and MAIA found to be significant in the final model based on training can be found in table: Predictive Markers of Infections in NDMM patients from ALCYONE and MAIA.
• From the ALCYONE pooled data:
  • Most common (>10 patients) grade 3/4 infection was pneumonia: 13% in the D-VMP arm and 4% in the VMP arm.
  • Grade 3/4 infection rate in ALCYONE was: 22% in D-VMP arm vs 15% in VMP arm.
  • The most common (>10 patients) serious infection was pneumonia (12% in D-VMP arm vs 3% in VMP arm).
• From the MAIA pooled data:
  • Grade 3/4 infection rate in MAIA was: 36% in D-Rd arm vs 27% in Rd arm.
  • Most common (>10 patients) grade 3/4 infections were pneumonia (D-Rd, 15%; Rd, 9%), bronchitis (D-Rd, 3%; Rd, 1%), influenza (D-Rd, 3%; Rd, 2%), lower respiratory tract infections (3% in both arms), sepsis (3% in both arms) and urinary tract infections (3% in both arms).
  • The most common (>10 patients) serious infections were: pneumonia (D-Rd, 14%; Rd, 9%), influenza (D-Rd, 4%; Rd, 2%), bronchitis (D-Rd, 4%; Rd, 2%), and upper respiratory infection (3% in both arms).

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 19 February 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.