DARZALEX + DARZALEX FASPRO - Infections in Patients with Relapsed/Refractory Multiple Myeloma

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 is no systematically 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 is a phase 3 study evaluating the safety and efficacy of DARZALEX for intravenous (IV) use in combination with bortezomib and dexamethasone (D-Vd) vs bortezomib and dexamethasone alone (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%).²
• CANDOR is a 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 relapsed/refractory multiple myeloma (RRMM).³ The most common infection-related any grade TEAE was URTI (D-Kd, 34.1%; Kd, 24.2%).⁴
• POLLUX is a 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
• APOLLO is a phase 3 study evaluating the safety and efficacy of D-Pd vs pomalidomide and dexamethasone (Pd) alone in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a proteasome inhibitor.^7,8 The most common infection-related TEAE (any grade) was URTI (D-Pd, 24.8%; Pd, 16%).⁸
• PLEIADES is a phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with 4 SOC 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.^9,10
  • Moreau et al (2020)¹⁰ 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.
• COLUMBA is a 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
• EQUULEUS is a phase 1b study evaluating DARZALEX with various standard of care (SOC) regimens in patients with multiple myeloma (MM) and those who received prior treatment.^9,13
  • Chari et al (2017)¹³ 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 is a 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).¹⁴
• Usmani et al (2020)¹⁵ 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.
• PAVO is a 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.¹⁶
  • All-grade infection-related TEAE was URTI in part 1 (1200 mg group, 38%; 1800 mg group, 24%) and part 2 (DARZALEX FASPRO, 8%).¹⁶
  • In the updated results from part 2, the most common all-grade infection-related TEAEs was nasopharyngitis (24%).¹⁷
  • 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%).¹⁸

PRODUCT LABELING

• DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.jnjlabels.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.jnjlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf

CLINICAL DATA

Phase 3 Study of DARZALEX in Combination with Vd

CASTOR (MMY3004; 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

Updated Efficacy and Safety Analysis of the CASTOR Study

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.

Safety Results - Infection-Related

• Infection-related TEAEs are summarized in Table: Any Grade or Grade 3/4 Infection-Related TEAEs (CASTOR).²

• The most common serious TEAE was pneumonia (D-Vd, 10.7%; Vd, 10.1%).²
• 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.²
• Pneumonia was reported as the most frequent TEAE (0.8% in both arms) with an outcome of death in the D-Vd arm.²
• Three deaths occurred due to COVID-19 disease (D-Vd, n=1; Vd, n=2).²

Phase 3 Study of DARZALEX in Combination with Kd  

CANDOR (NCT03158688) is a phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of D-Kd vs Kd in patients with RRMM.^3,4

Final Analysis of the CANDOR Study

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.

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).⁴

• 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.⁴
• Grade ≥3 infections and infestations occurred in 46% (n=142) vs 32% (n=49) of patients in the D-Kd vs Kd arm and led to carfilzomib discontinuation in 22% (n=69) vs 20% (n=30) of patients.⁴
• 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.¹⁹

• Fatal infection rates were 7% (n=21) vs 3% (n=5) in the D-Kd vs Kd arm; correspondingly, when adjusted for exposure, fatal infection rates were 3.5 vs 2.55 per 100 patient-years.⁴
• TEAEs related to COVID-19 occurred in 11% (n=33) vs 4% (n=6) of patients in the D-Kd vs Kd arm, and deaths related to COVID-19 occurred in 2% (n=6) vs 1% (n=1) of patients.⁴

Phase 3 Study of DARZALEX in Combination with Rd

POLLUX (MMY3003; 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

Updated Safety and Efficacy Analysis of the POLLUX Study

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.

Safety Results - Infection-Related

• Infection-related TEAEs are summarized in Table: Any Grade or Grade 3/4 Infection-Related TEAEs (POLLUX).⁶

• 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.⁶
• 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%).⁶

Phase 3 Study of DARZALEX FASPRO in Combination with Pd

APOLLO (MMY3013; NCT03180736) is a 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).⁷

Updated Safety Analysis of the APOLLO Study

Dimopoulos et al (2022)⁸ presented the updated safety analysis at a median follow-up of 39.6 months. Safety results related to infections have been summarized below.

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).⁸

• Treatment discontinuation due to infection was reported in 1 patient (0.7%) in both arms.⁸
• TEAEs resulting in deaths due to COVID-19 were reported in 1.3% (n=2) vs 0.7% (n=1) of patients in the D-Pd vs Pd arm.⁸
• 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%).⁸

Phase 2 Study of DARZALEX FASPRO in Combination with 4 SOC Regimens

PLEIADES (MMY2040; NCT03412565) is a phase 2, non-randomized, open-label, multicenter study evaluating the clinical benefit of DARZALEX FASPRO when administered in combination with 4 SOC treatment regimens in patients with MM.^9,10

Final Analysis of the PLEAIDES Study: D-Kd Arm

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 arm of the PLEIADES study are summarized below.

Safety Results - Infection-Related

• 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 patients (33.3%), 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

Phase 3 Non-Inferiority Study of DARZALEX vs DARZALEX FASPRO

COLUMBA (MMY3012; NCT03277105) is a 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

Final Efficacy and Safety Analysis of the COLUMBA Study

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.

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).¹²

• The most common SAE was pneumonia (DARZALEX FASPRO, 4.6% [n=12]; DARZALEX, 5% [n=13]).¹²
• 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).¹²
  • 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.

Phase 1b Study of DARZALEX in Combination with Pd

EQUULEUS (MMY1001; NCT01998971) is a phase 1b, open label, non-randomized, multicenter study evaluating the safety, tolerability, and dose regimen of DARZALEX in combination with various backbone treatment regimens for the treatment of patients with MM.

Final Analysis of the EQUULEUS Study: D-Kd Arm

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-Kd arm of EQUULEUS have been summarized below.

Safety Results - Infection-Related - D-Kd Arm

• Grade 3/4 infections occurred in 18 (21.2%) patients, the most common being pneumonia (4.7%).⁹
• The most common serious TEAEs were pneumonia and URTI (4.7% each).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

Phase 1/2 Study of DARZALEX in Combination with Rd

GEN503 is a phase 1/2, dose escalation and dose expansion study assessing the safety and efficacy of DARZALEX with Rd.¹⁴

Final Analysis of the GEN503 Study

Plesner et al (2019)¹⁴ reported final results from the GEN503 study assessing the safety and efficacy of D-Rd in patients with RRMM (N=32). Safety results related to infections have been summarized below.

Safety Results - Infection-Related

• In part 2, two deaths were reported due to viral pneumonia and Epstein-Barr virus association (n=1 each).¹⁴
• For information regarding infection-related TEAEs, see Table: Most Common (≥25%) Infection-Related TEAEs in Part 2 of GEN503 Study.¹⁴

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
16 June 2026. In response to your specific request, summarized in this response is the relevant data from company-sponsored studies pertaining to this topic.