SUMMAry

• Janssen does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
• 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.¹
• The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 2,459 patients with multiple myeloma (MM) including 2,303 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy.¹
• The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion-related reactions (IRRs), thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.¹
• The most common (any grade) adverse events (AEs) are presented from the following studies:
  • CASSIOPEIA for newly diagnosed multiple myeloma (NDMM) patients eligible for autologous stem cell transplant (ASCT).^2-5
  • GRIFFIN for NDMM patients eligible for high-dose therapy (HDT) and ASCT.^6-10
  • MAIA and ALCYONE for NDMM patients ineligible for ASCT.^11-13
  • POLLUX, CASTOR, CANDOR, GEN503, and EQUULEUS for relapsed/refractory multiple myeloma (RRMM) patients receiving DARZALEX in combination with background regimens.^14-19
  • GEN501 and SIRIUS for patients with RRMM receiving DARZALEX as monotherapy.^20,21
• Please refer to the following sections of the full Prescribing Information that are relevant to your inquiry: DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS.

CLINICAL DATA - Newly diagnosed multiple myeloma - TRANSPLANT ELIGIBLE

Combination Treatment with Bortezomib, Thalidomide, and Dexamethasone

CASSIOPEIA (MMY3006; NCT02541383) is an ongoing, open-label, 2-arm, multicenter, phase 3 study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) in patients with NDMM who are eligible for HDT/ASCT.^2,3 Moreau et al (2019)² reported the results from Part 1 of this study. Moreau et al (2021)³ reported results from Part 2 of the CASSIOPEIA study (maintenance treatment). Moreau et al (2024)⁴ reported long-term outcomes of the CASSIOPEIA study after a median follow-up of 80.1 months from the first randomization and at a median follow-up of 70.6 months from the second randomization.

Safety Results - Part 1  

• AEs are presented in Table: Most Common AEs During Treatment in the Safety Population (CASSIOPEIA Part 1).
• The most common any-grade AEs occurring in ≥20% of patients in either arm (D-VTd [n=536] vs VTd [n=538]) were peripheral sensory neuropathy (59% vs 63%), constipation (51% vs 49%), asthenia (32% vs 29%), peripheral edema (30% vs 28%), nausea (30% vs 24%), neutropenia (29% vs 17%), pyrexia (26% vs 21%), paresthesia (22% vs 20%), and thrombocytopenia (20% vs 14%).
• The most common grade 3/4 AEs occurring in ≥10% of patients (D-VTd vs VTd) were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), stomatitis (13% vs 16%), and thrombocytopenia (11% vs 7%).
• Serious adverse events (SAEs) occurred in 251 (47%) patients in the D-VTd arm and 255 (47%) patients in the VTd arm. The most common SAEs (occurring in ≥3% of patients in either arm) were neutropenia (D-VTd, 4%; VTd, 1%), pneumonia (D-VTd, 4%; VTd, 2%), pyrexia (D-VTd, 3%; VTd, 4%), and pulmonary embolism (D-VTd, 1%; VTd, 4%).

Safety Results - Part 2  

• Any treatment-emergent adverse events (TEAEs) occurred in 95% (n=420) of patients in the DARZALEX monotherapy arm vs 89% (n=394) in the observation arm.
• SAEs occurred in 23% (n=100) patients in the DARZALEX monotherapy arm vs 19% (n=84) in the observation arm.
• 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.
• Grade ≥3 TEAEs occurred in 28% (n=122) of patients in the DARZALEX monotherapy arm (who received at least 1 dose) vs 24% (n=108) in the observation arm.
• IRRs occurred in 54.5% (n=115) of patients in the DARZALEX monotherapy arm.
• 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.²²
• Safety data of patients in the DARZALEX monotherapy arm vs observation arm is presented in Table: Most Common AEs (≥10%) in CASSIOPEIA Part 2 Study.

Long-term Follow-up in CASSIOPEIA

Moreau et al (2024)⁴ reported the long-term outcomes of the CASSIOPEIA study after a median follow-up duration of 80.1 months from the first randomization and at a median follow-up duration of 70.6 months from the second randomization.

Safety Results

• A total of 83 vs 139 deaths occurred in the D-VTd vs VTd group, respectively. The causes of death during and after the maintenance phase by induction/consolidation treatment in the maintenance-specific safety population are presented in Table: Causes of Death During and After the Maintenance Phase by Induction/Consolidation Treatment in the Maintenance-Specific Safety Population.
• Second primary malignancies by induction/consolidation treatment in the maintenance-specific safety population are presented in Table: SPMs by Induction/Consolidation Treatment in the Maintenance-Specific Safety Population.

Combination Treatment with Bortezomib, Lenalidomide and Dexamethasone

GRIFFIN (MMY2004; NCT02874742)^6-8 is a 2-part, phase 2, randomized, active-controlled US study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in patients with NDMM eligible for HDT and ASCT. Vorhees et al (2021)²³ reported the final analysis of the safety run-in cohort of this study (Part 1 safety run-in phase final analysis) at a median follow-up of 40.8 months. Voorhees et al (2020)⁸ presented the primary analysis (median follow-up, 13.5 months) and updated analysis of the randomized portion (median follow-up, 22.1 months) of this study. Sborov et al (2022)²⁴ presented the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end of study treatment (median follow-up, 49.6 months). Chari et al (2024)^9,10 reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study at a median follow-up duration of 49.6 months

Part 1: Safety Run-in Phase Final Analysis

Vorhees et al (2021)²³ reported the final analysis of the safety run-in cohort of this study (Part 1 safety run-in phase final analysis) at a median follow-up of 40.8 months.

Safety Results

• Eleven patients (68%) experienced a SAE. For the incidences of grade 3/4 TEAEs. See Table: Most Common Grade 3/4 TEAEs (GRIFFIN; Part 1).
• One patient had a TEAE leading to discontinuation of study treatment.
• 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 a grade 3/4 infection (pneumonia and bronchitis).
• Grade 1/2 IRRs occurred in 31.3% (n=5) of patients. IRRs included pruritus, chills, flushing, maculo-papular rash, and vascular access site swelling; all occurred during cycle 1 except vascular access site swelling.

Part 2: Randomized Phase

Voorhees et al (2020)⁸ presented the primary analysis (median follow-up, 13.5 months) and updated analysis of the randomized portion (median follow-up, 22.1 months) of this study. Sborov et al (2022)²⁴ presented the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end of study treatment (median
follow-up, 49.6 months).

Safety Results

• In the updated safety and efficacy analysis, any grade infections occurred in 91% of patients in the D-VRd arm and 62% of patients in the VRd arm, the most common being grade 1/2 upper respiratory tract infections; grade 3/4 infections were seen in 23% of patients in the D-VRd arm vs 22% of patients in the VRd arm. See Table: Most Common TEAEs (GRIFFIN; Part 2).
• Pneumonia was reported in 13% of patients in the D-VRd arm and 15% of patients in the VRd arm.

Final Safety Analysis of Maintenance Therapy in GRIFFIN

Sborov et al (2022)²⁴ presented the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end of study treatment (median follow-up,
49.6 months).

• TEAEs leading to treatment discontinuation were similar across treatment arms (D-VRd, 33%; VRd, 31%). One patient in each arm died due to TEAEs unrelated to study treatment.
• Rates of infections leading to treatment discontinuation were similar across treatment arms (D-VRd, 2%; VRd, 3%).
  • The most common infection was upper respiratory tract infection in both arms.
  • In the D-VRd vs VRd arms, Coronavirus Disease 2019 (COVID-19) infections were reported in 5 vs 2 patients.
• TEAEs occurring in ≥30% of patients in the safety population are summarized in Table: Most Common TEAEs (Final Analysis of GRIFFIN).
• A total of 14 patients (D-VRd, n=7; VRd, n=7) died, of whom 9 patients (D-VRd, n=5; VRd, n=4) died due to PD.

Final Analysis in Clinically Relevant Subgroups

Chari et al (2024)^9,10 reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study at a median follow-up duration of 49.6 months.

Safety Results

• A summary of the most common (>30%) TEAEs in the safety analysis population separated by age <65 years and ≥65 years is provided in Table: Most Common (>30%) Any Grade TEAEs by Age (<65 Years and ≥65 Years).
• Among patients aged <65 years (84.7% vs 80.0%) and ≥65 years (88.9% vs 77.8%), the rates of grade 3/4 TEAEs were slightly higher for D-VRd vs VRd.
• The incidence of serious TEAEs was lower in D-VRd vs VRd among patients <65 years, 41.7% vs 56.0% respectively.
• The incidence of serious TEAEs was higher in the D-VRd vs VRd among patients ≥65 years, 59.3% vs 40.7% respectively.
• Two deaths due to TEAE occurred and were considered unrelated to study treatment.
  • <65 years (VRd, n=1; cause unknown)
  • ≥65 years (D-VRd, n=1; pneumonia)

clinical data - newly diagnosed multiple myeloma Transplant-INELIGIBLE

Combination Treatment with Lenalidomide and Dexamethasone

MAIA (MMY3008; 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).^11,25,26 Facon et al (2019)¹¹ presented the pre-specified interim results of this ongoing study with a median follow-up of 28.0 months including updated overall survival (OS) results (median follow-up, 73.6 months). Facon et al (2025)²⁶ reported the updated efficacy and safety results at a long-term median follow-up of 64.5 months. Facon et al (2024)¹² presented the results of the updated efficacy and safety analysis at a median follow-up of 89.3 months (range, 0-102.2).

Safety Results

• Summary of AEs and second primary cancers (median follow-up, 28.0 months) are summarized in Table: Most Common AEs and Secondary Primary Cancers in the Safety Population (Prespecified Interim Results; MAIA).¹¹
• SAEs: 62.9% for DARZALEX + lenalidomide + dexamethasone (D-Rd); 62.7% for lenalidomide + dexamethasone (Rd)¹¹
• AEs leading to discontinuation: 7.1% for D-Rd; 15.9% for Rd.¹¹
• TEAEs with outcome of death: 6.9% for D-Rd; 6.3% for Rd. Pneumonia was the most common AE that resulted in death (0.5% for D-Rd; 0.8% for Rd).¹¹

Updated Analysis of the MAIA Study

Facon et al (2025)²⁶ reported the updated efficacy and safety results from the MAIA study at a long-term median follow-up of 64.5 months.

Safety Results

• At clinical cutoff, 52 patients from the D-Rd arm discontinued lenalidomide ± dexamethasone but remained on the rest of the study treatment; 46 (88.5%) of these patients discontinued due to AEs.²⁶
  • The median time to lenalidomide discontinuation was 37.8 months (range, 1-70).
  • The median duration of DARZALEX treatment was 66.2 months (range, 56-77).
  • The estimated 60-month PFS and OS rates were 98.1% and 100.0%, respectively.
  • Of the aforementioned 52 patients, 13 (25.0%) discontinued lenalidomide but continued DARZALEX + dexamethasone and 39 (75.0%) discontinued lenalidomide + dexamethasone and continued DARZALEX monotherapy.
    • In the 39 patients who discontinued lenalidomide + dexamethasone and continued DARZALEX monotherapy, the median time to discontinuation was 39.1 months (range, 3-67) and the median DARZALEX treatment duration was 65.6 months (range, 56-73). The estimated 60-month PFS and OS rates were 97.4% and 100.0%, respectively.
    • One patient in the D-Rd arm stopped DARZALEX after 15 days due to AEs but continued lenalidomide treatment without progression at the clinical cutoff.
• No new safety concerns were observed with a longer follow-up.²⁶
  • Grade 3/4 TEAEs occurred in 95.9% vs 88.8% of patients from the D-Rd vs Rd arm, respectively.
    • Among patients aged ≥75 years, grade 3/4 TEAEs occurred in 95.5% vs 95.0% of patients from the D-Rd vs Rd arm, respectively.
    • Among patients aged ≥80 years, grade 3/4 TEAEs occurred in 92.3% vs 95.7% of patients from the D-Rd vs Rd arm, respectively.
    • The rates of common grade 3/4 TEAEs in patients aged ≥75 years and those aged ≥80 years were similar to those in the overall study population as summarized in Table: Most Common Any-Grade or Grade 3/4 TEAEs in the Safety Population.
    • The most common (≥20%) grade 3/4 TEAEs with D-Rd vs Rd were neutropenia (54.1% vs 37.0%, respectively) and anemia (17.0% vs 21.6%, respectively). A summary of the most common TEAEs is presented in Table: Most Common Any-Grade or Grade 3/4 TEAEs Among Patients Aged ≥75 Years and ≥80 Years in the Safety Population.
  • Grade 3/4 infections occurred in 42.6% vs 29.6% of patients from the D-Rd vs Rd arm, respectively.
  • Serious TEAEs occurred in 78.8% vs 71.0% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (18.7% vs 10.7%, respectively).
    • Among patients aged ≥75 years, serious TEAEs occurred in 80.9% vs 79.2% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (19.7% vs 12.6%, respectively).
    • Among patients aged ≥80 years, serious TEAEs occurred in 81.5% vs 82.9% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (24.6% vs 8.6%, respectively).
  • The overall discontinuation rate due to TEAEs was lower in the D-Rd vs Rd arm (14.6% vs 23.8%).
    • Discontinuation of lenalidomide due to TEAEs was reported in 36.8% vs 24.4% of patients from the D-Rd vs Rd arm, respectively.
    • Discontinuation of dexamethasone due to TEAEs was reported in 39.8% vs 36.2% of patients from the D-Rd vs Rd arm, respectively.
    • Discontinuation of DARZALEX due to TEAEs was reported in 14.6% of patients.
    • Among patients aged ≥75 years, treatment discontinuation due to TEAEs was reported in 15.3% vs 27.7% of patients from the D-Rd vs Rd arm, respectively.
    • Among patients aged ≥80 years, treatment discontinuation due to TEAEs was reported in 6.2% vs 20.0% of patients from the D-Rd vs Rd arm, respectively.
  • TEAEs leading to death were reported in 9.9% vs 9.3% of patients from the D-Rd vs Rd arm, respectively.
    • Among patients aged ≥75 years, TEAEs leading to death were reported in 11.5% vs 13.2% of patients from the D-Rd vs Rd arm, respectively.
    • Among patients aged ≥80 years, TEAEs leading to death were reported in 12.3% vs 11.4% of patients from the D-Rd vs Rd arm, respectively.

Final Survival Analysis of the MAIA Study

Facon et al (2024)¹² presented the results of the updated efficacy and safety analysis of the MAIA study at a median follow-up of 89.3 months (range, 0-102.2).

Safety and Tolerability Results

• Among the safety population, 78.3% (n=285) of patients in the D-Rd arm and 94.5% (n=345) in the Rd arm discontinued study treatment.
  • Progressive disease was the primary reason for discontinuation in both the D-Rd (32.7%) and Rd arms (38.6%).
  • A lower proportion of patients in the D-Rd (16.5%) and Rd arms (25.8%) discontinued study treatment due to AEs.
• In the D-Rd vs Rd arm, 33% reduction in the risk of death was reported.
  • Deaths were reported for 47.5% (n=173) of patients in the D-Rd arm and 59.7% (n=218) of patients in the Rd arm, mostly due to disease progression. See Table: Summary of Death and Causes of Death in the Safety Population.

Combination Treatment with Bortezomib, Melphalan, and Prednisone

ALCYONE (MMY3007; NCT02195479) is a multicenter, randomized, open-label, active-controlled, phase 3 study evaluating the safety and efficacy of DARZALEX when administered in combination with bortezomib, melphalan, and prednisone (D-VMP) compared with administration of VMP alone for the treatment of NDMM in patients (N=706) who were ineligible for high-dose chemotherapy with ASCT.^13,28 Mateos et al (2018)¹³ reported results of a planned interim analysis of this study with a median follow-up of 16.5 months. Mateos et al (2025)²⁹ reported the final efficacy and safety analysis results at a median follow-up of 86.7 months.

Safety Results

• Summary of on-treatment AEs (median follow-up, 16.5 months) are summarized in Table: Most Common Any Grade (≥20%) and Grade 3/4 (≥10%) On-Treatment AEs (Safety Population; Planned Interim Analysis in ALCYONE).
• Grade 3/4 infections were more frequent in the D-VMP arm than in the VMP arm (23.1% vs 14.7%), with pneumonia being the most common grade 3/4 infection (11.3% vs 4.0%). In the D-VMP and VMP arms, respectively:
  • Infections, including pneumonia, resolved in 87.9% and 86.5% of patients.
  • Rates of treatment discontinuation because of infections were 0.9% and 1.4%.
  • Infection-related deaths occurred in 5 (1.4%) patients and 4 (1.1%) patients.
• Rates of SAEs were 41.6% in the D-VMP arm and in 32.5% in the VMP arm, with pneumonia being the most common SAE (10.1% and 3.1%, respectively).
• Tumor lysis syndrome occurred in 2 (0.6%) patients in each treatment arm.
• Second primary malignancy occurred in 8 (2.3%) patients in the D-VMP arm and in 9 (2.5%) in the VMP arm.
• Fatal AEs within a month after the last study treatment occurred in 14 (4.0%) patients in the D-VMP arm and in 16 (4.5%) in the VMP arm.

Final Analysis of the ALCYONE Study

Mateos et al (2025)²⁹ reported the final efficacy and safety analysis results at a median follow-up of 86.7 months.

Safety Results

• No new safety concerns were identified with a longer follow-up.²⁹ 
• TEAEs were experienced by 98% of patients in the D-VMP group and 97% of patients in the VMP group. The most common TEAEs are summarized in Table: Summary of the Most Common TEAEs.²⁹
  • Grade 3 or 4 TEAEs occurred in 83% of patients receiving D-VMP and 77% of patients receiving VMP.²⁹
  • The most common grade 3 or 4 infection in both treatment groups was pneumonia (D-VMP, 16%; VMP, 5%).²⁹
  • Infusion-related reactions (IRRs) of any grade were reported in 29% of patients in the D-VMP group, including a grade 3 reaction in 4% and a grade 4 reaction in 1% of patients.²⁹
    • In the D-VMP group, IRRs of any grade, grade 3 and serious TEAE were reported in <1% of patients.³⁰
    • No IRR of any grade was reported in the VMP group.³⁰
  • The D-VMP group experienced a higher rate of serious TEAEs compared to the VMP group (21% vs 16%). The most common serious TEAE observed in D-VMP vs VMP group was pneumonia (5% vs 2%).²⁹
• The rate of treatment discontinuation due to TEAEs was 9% in both the D-VMP and VMP groups. TEAEs in both groups are detailed in Table: Summary of Treatment Discontinuation Due to TEAEs.^29,30

• The incidence of second primary malignancies in the D-VMP vs VMP group was 8% vs 6%, respectively.²⁹
  • The most frequently reported second primary malignancies in the D-VMP vs VMP group were basal cell carcinoma (1.2% vs 0.6%, respectively) and myelodysplastic syndrome (1.2% vs 0.6%, respectively).^29,30
• Deaths due to an adverse event considered related to at least 1 of 4 study treatment components occurred in 5 (1%) of 346 D-VMP patients (due to pneumonia, acute myocardial infarction, neuroendocrine tumor, tumor lysis syndrome, and acute respiratory failure [1 each]) and in 3 (1%) of 354 VMP patients (due to acute myeloid leukemia, pulmonary embolism, and bacterial pneumonia [1 each]).²⁹

clinical data in Relapsed/Refractory Multiple Myeloma

Combination Treatment with Lenalidomide and Dexamethasone

POLLUX (MMY3003; NCT02076009) is a phase 3, randomized, open-label, active-controlled, multicenter study that evaluated the safety and efficacy of DRd compared with administration of Rd alone in patients with RRMM (N=569).¹⁶ Dimopoulos et al (2016)¹⁶ reported safety and efficacy results of a prespecified interim analysis of this study (median follow-up, 13.5 months). Dimopoulos et al (2023)³¹ reported updated results of the POLLUX study, including OS, at a median follow-up of 79.7 months.

Safety Results

• After a median follow-up of 13.5 months:
  • Any grade infusion reactions were reported in 49% of patients who received DARZALEX. Infusion reactions were mostly grade 1/2 (grade 3 were observed in 5% of patients) and most (92%) occurred during the first infusion. No grade 4 infusion reactions were reported.
  • SAEs were reported in 49% and 42% of patients in the DARZALEX + Rd and Rd arms, respectively.
  • AEs leading to discontinuation were reported in 7% of patients who received D-Rd and 8% in patients who received Rd. The most common of these across both arms were pneumonia, pulmonary embolism, and deterioration of general physical health.
  • AEs leading to death [most commonly (≤1%) acute kidney injury, septic shock, and pneumonia] occurred in 11 (4%) patients in the D-Rd arm and 15 (5%) patients in the Rd arm.

>Six-year Follow-up Update on Safety and Efficacy Outcomes

Dimopoulos et al (2023)³¹ reported results of the POLLUX study, including OS, at a median follow-up of 79.7 months. Safety results from this updated analysis are summarized below.

Safety Results

• Summary of TEAEs (median follow-up, 79.7 months) are presented in Table: Most common (>15% of patients) and Grade 3/4 (>5% of Patients) TEAEs in the Safety Population (Updated Analysis of POLLUX) and Serious TEAEs and TEAEs Leading to Treatment Discontinuation or Deaths (Updated Analysis of POLLUX).
• Grade 3/4 infections were reported in 44.5% vs 28.1% of patients in the D-Rd vs Rd arms, respectively.
• No deaths because of COVID-19 disease occurred during the study.
• With the longer follow-up, second primary malignancies (cutaneous, invasive, and hematologic) were reported in 40 (14.1%) vs 30 (10.7%) patients in the D-Rd vs Rd arm.