Summary

• DARZALEX is contraindicated in patients with a history of severe hypersensitivity (e.g. anaphylactic reactions) to daratumumab or any of the components of the formulation.¹
• DARZALEX can cause severe and/or serious infusion-related reactions (IRR) including anaphylactic reactions. These reactions can be life-threatening and fatal outcomes have been reported. Interrupt DARZALEX infusion for IRRs of any severity. Permanently discontinue the infusion in case of anaphylactic reactions or life-threatening (Grade 4) infusion related reactions and institute appropriate emergency care.¹
• Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision.¹
• Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.¹
• In clinical trials (monotherapy and combination: N=2,066), IRRs occurred in 37% of patients with the week 1 (16 mg/kg) infusion, 2% with the week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a grade 3/4 IRR at week 2 or subsequent infusions.¹
  • The median time to onset of a reaction was 1.5 hours (range: 0 to 73 hours). The incidence of infusion modification due to reactions was 36%. Median durations of
    16 mg/kg infusions for the week 1, week 2, and subsequent infusions were approximately 7, 4, and 3 hours, respectively.
  • Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, IRRs occurred up to 48 hours after infusion.
  • When DARZALEX dosing was interrupted in the setting of autologous stem cell transplant (ASCT; CASSIOPEIA) for a median of 3.75 months (range:
    2.4 to 6.9 months), upon re-initiation of DARZALEX the incidence of IRRs was 11% for the first infusion following ASCT. Infusion rate/dilution volume used upon reinitiation was that used for the last DARZALEX infusion prior to interruption for ASCT. IRRs occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (grade 3 or 4:<1%) with those reported in previous studies at week 2 or subsequent infusions.
  • In EQUULEUS, patients receiving daratumumab combination treatment (n=97) were administered the first 16 mg/kg daratumumab dose at week 1 split over two days (ie, 8 mg/kg on day 1 and day 2, respectively). The incidence of any grade IRRs was 42%, with 36% of patients experiencing IRRs on day 1 of week 1, 4% on day 2 of week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 hours for week 1-day 1, 4.2 hours for week 1-day 2, and 3.4 hours for the subsequent infusions.
• For IRRs of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms. Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX.¹
• IRRs from the following studies are presented below:
  • CASSIOPEIA, MAIA, and ALCYONE for newly diagnosed multiple myeloma (NDMM) patients.^2-5
  • POLLUX, CASTOR, CANDOR, and EQUULEUS for relapsed and refractory multiple myeloma (RRMM) patients receiving combination treatment with DARZALEX.^6-10
  • SIRIUS and GEN501 for RRMM patients receiving DARZALEX as monotherapy.^11,12

CLINICAL DATA in newly diagnosed multiple myeloma

Combination Treatment with Bortezomib, Thalidomide, and Dexamethasone

CASSIOPEIA (MMY3006; clinicaltrials.gov identifier: NCT02541383) is an ongoing, open-label, 2-arm, multicenter, randomized, phase 3 study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) in patients with previously untreated multiple myeloma (MM) who are eligible for high-dose chemotherapy and ASCT.^2,4 Moreau et al (2019)² reported the results from Part 1 of this study. Moreau et al (2021)⁴ reported the results from Part 2 of the CASSIOPEIA study (maintenance treatment). Safety results related to IRRs in Part 1 and Part 2 have been summarized below.

Study Design/Methods

• Part 1: Patients randomized to 1 of 2 treatment groups (each cycle is 4 weeks):
  • Arm A: Up to 4 cycles of VTd induction therapy followed by ASCT, followed by 2 cycles 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 groups:
  • 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 100 days after ASCT (or immediately after consolidation if
  >100 days); Part 2: progression-free survival (PFS) after second randomization.
• Secondary endpoints: Part 1: PFS, time to progression (TTP), proportion of post ASCT/consolidation minimal residual disease (MRD), proportion of post-induction sCR, PFS after next line of therapy (PFS2), and overall survival (OS); Part 2: TTP from second randomization, 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.

Safety Results - IRRs

Part 1 Results

• Any grade IRRs related to DARZALEX were reported in 190 of 536 (35%) patients in the safety population.²
• Grade 3/4 IRRs were reported in 19 of 536 (4%) patients in the safety population.²

Part 2 Results

• IRRs occurred in 54.5% (n=115) of patients in the DARZALEX monotherapy group. IRRs were grade 1/2 (90% [n=103]).^4,13
• DARZALEX infusions were interrupted in 21% (n=93) of patients due to IRRs (except for 1 patient).⁴

Combination Treatment with Lenalidomide and Dexamethasone

MAIA (MMY3008; clinicaltrials.gov identifier: NCT02252172) is an international, randomized, open-label, active-controlled, multicenter, phase 3 study evaluating the safety and efficacy of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) compared to lenalidomide and dexamethasone (Rd) in patients with NDMM not eligible for high-dose chemotherapy and ASCT (N=737).³ Facon et al (2019)³ reported the prespecified interim results of this ongoing study (median follow-up, 28.0 months). Kumar et al (2022)¹⁴ presented the results of the updated efficacy and safety analysis (median follow-up, 64.5 months), including updated OS results (median follow-up, 73.6 months). Safety results related to IRR events have been summarized below.

Study Design/Methods

• Primary endpoint: PFS
• Secondary endpoints: ≥CR, duration of response (DOR), MRD-negativity rate, ORR, OS, PFS2, safety, sCR, time to next (second-line) treatment, time to response (TTR), TTP, and very good partial response or better (≥VGPR)

Safety Results - IRRs

• Any grade IRRs were reported in 40.9% of patients and grade 3/4 IRRs were reported in 2.7% of patients in the D-Rd arm. See table: IRRs in ≥2 Patients in the DARZALEX Group.³
  • With the first dose of DARZALEX, 98% of patients reported IRRs and 1 patient (grade 4 hypertension) discontinued DARZALEX treatment after an IRR.

Updated Analysis of MAIA Study (Median Follow-up of 64.5 Months)

Kumar et al (2022)¹⁴ presented the results of the updated efficacy and safety analysis (median follow-up, 64.5 months), including updated OS results (median follow-up, 73.6 months).

Safety Results - IRRs

• There were no reports of IRRs with the longer follow-up based on the summary of any grade (≥30%) and grade 3/4 (≥20%) TEAEs in the safety population.¹⁴

Combination Treatment with Bortezomib, Melphalan, and Prednisone

ALCYONE (MMY3007; clinicaltrials.gov identifier: NCT02195479) is an ongoing, open-label, active controlled, multicenter, randomized, phase 3 study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, melphalan, and prednisone (VMP) vs VMP in patients with NDMM who were ineligible for high-dose chemotherapy with ASCT. Mateos et al (2018)⁵ reported results of a planned interim analysis of data from the ALCYONE study (median follow-up, 16.5 months). Mateos et al (2022)¹⁵ presented an updated efficacy and safety analysis of the ALCYONE study at a median follow-up of almost 7 years. Safety results related to IRR events have been summarized below.

Study Design/Methods

• Primary endpoint: PFS
• Secondary endpoints: ≥CR rate, ≥VGPR rate, MRD negativity (10^-5), ORR, and median OS

Safety Results - IRRs

• At a median follow-up of 16.5 months, IRRs related to DARZALEX occurred in 27.7% of patients (mostly during the first infusion) and were mainly grade 1/2. Grade 3/4 IRRs occurred in 4.3% and 0.6% of patients, respectively. See Table: IRRs in ≥2 Patients in the DARZALEX Group.⁵

Updated Analysis of ALCYONE Study (Median Follow-up 78.8 Months)

Mateos et al (2022)¹⁵ presented an updated analysis of ALCYONE at a median follow-up of almost 7 years (78.8 months).

Safety Results - IRRs

• There were no reports of IRRs with the longer follow-up based on the summary of any grade (≥15%) and grade 3/4 (≥5%) TEAEs in the safety population.¹⁵

clinical data in Relapsed/Refractory Multiple Myeloma

Combination Treatment with Lenalidomide and Dexamethasone

POLLUX (MMY3003; clinicaltrials.gov identifier: NCT02076009) is a randomized, open-label, active-controlled, multicenter, phase 3 study that evaluated the safety and efficacy of lenalidomide and dexamethasone (Rd) and DARZALEX + Rd in patients with RRMM (N=569). Dimopoulos et al (2016)⁶ reported prespecified interim results from this study, at a median follow-up of 13.5 months. Dimopoulos et al (2023)¹⁶ reported updated results of the POLLUX study, including OS, at a median follow-up of 79.7 months. Safety results related to IRR events are summarized below.

Study Design/Methods

• Primary endpoint: PFS
• Secondary endpoints: TTP, ORR, ≥VGPR, ≥CR, OS, DOR, MRD, and safety assessments

Safety Results - IRRs

• At a median follow-up of 13.5 months, any grade IRRs were reported in 49% of patients who received DARZALEX. IRRs were mostly grade 1/2 (grade 3 were observed in 5% of patients) and most (92%) occurred during the first infusion. No grade 4 IRRs were reported.⁶

Updated Analysis of POLLUX Study (Median Follow-up 79.7 Months)

Dimopoulos et al (2023)¹⁶ reported updated results of the POLLUX study, including OS, at a median follow-up of 79.7 months.

Safety Results - IRRs

• There were no reports of IRRs with the longer follow-up based on the summary of most common (>15%) and grade 3/4 (>5%) of TEAEs in the safety population.¹⁶

Dose Escalation, Dose Expansion Study in Combination with Lenalidomide and Dexamethasone

GEN503 is an open-label, multicenter, dose escalation (Part 1) and dose expansion (Part 2) phase 1/2 study. Plesner et al (2016)⁹ reported results from this study assessing the safety and efficacy of D-Rd in patients with RRMM (N=32). Safety results related to IRR events are summarized below.

Study Design/Methods

• Primary endpoint: ORR
• Secondary endpoints: TTP, DOR, PFS, and OS

Safety Results - IRRs

• IRRs in ≥2 patients are noted in Table: IRRs in ≥2 Patients.⁹
• All patients with IRRs experienced them during the first infusion, with none in the second infusion, and 3 (9.7%) during subsequent infusions.⁹
• Two patients had grade 3 IRRs (laryngeal edema and hypertension) and no grade 4 IRRs were reported.⁹

Combination Treatment with Bortezomib and Dexamethasone

CASTOR (MMY3004; clinicaltrials.gov identifier: NCT02136134) is an open-label, randomized, multicenter, active-controlled, phase 3 study that evaluated the safety and efficacy of DARZALEX in combination with bortezomib and dexamethasone (D-Vd) and Vd alone in patients with RRMM (N=498).⁷ Palumbo et al (2016)⁷ reported prespecified interim results, at a median follow-up of 7.4 months. Sonneveld et al (2023)¹⁷ reported updated results of the CASTOR study, including OS, at a median follow-up of 72.6 months. Safety results related to IRR events are summarized below.

Study Design/Methods

• Primary endpoint: PFS
• Secondary endpoints: TTP, overall response, DOR, TTR, ≥VGPR, OS, and MRD

Safety Results - IRRs

• At a median follow-up of 7.4 month, IRRs occurred in 45% of patients in the D-Vd arm⁷:
  • IRRs were mostly grade 1/2. No grade 4 reactions were reported.
  • 98% of patients with IRRs experienced the events with the first infusion.
  • Two patients discontinued treatment due to IRRs (bronchospasm in 1 patient; bronchospasm, laryngeal edema, and skin rash in the other patient).

Updated Analysis of CASTOR Study (Median Follow-up 72.6 Months)

Sonneveld et al (2023)¹⁷ presented updated results of the CASTOR study, including OS, at a median follow-up of 72.6 months. Safety results related to IRR events are summarized below.

Safety Results - IRRs

• There were no reports of IRRs with the longer follow-up based on the summary of most common (>15%) and grade 3/4 (>5%) TEAEs in the safety population.¹⁷

Combination Treatment 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 DARZALEX in combination with carfilzomib and dexamethasone (D-Kd) vs carfilzomib and dexamethasone (Kd) in patients with RRMM.⁸ Usmani et al (2023)¹⁸ reported final analysis of the CANDOR study after a median follow-up of 50 months. Safety results related to IRR events are summarized below.

Study Design/Methods

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

Safety Results - IRRs

Combination Treatment with Pomalidomide and Dexamethasone

EQUULEUS (MMY1001; clinicaltrials.gov identifier: NCT01998971) is an ongoing, open-label, multicenter, phase 1b study evaluating the safety, tolerability, and efficacy of DARZALEX when administered in combination with various treatment regimens for the treatment of MM.^10,19 Chari et al (2017)¹⁰ reported safety and tolerability results of DARZALEX in combination with pomalidomide and dexamethasone (D-Pd), with a median follow-up of 13.1 months in patients with RRMM. Moreau et al (2023)¹⁹ 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 IRR events in the D-Pd and D-Kd (EQUULEUS study only) arms have been summarized below.

Study Design/Methods

• Primary endpoint: safety
• Secondary endpoints: ORR and MRD by NGS

Safety Results - IRRs - D-Pd arm

• Any grade IRRs were reported in 50% of patients who received D-Pd. IRRs were mostly grade ≤2 (grade 3 were observed in 4% of patients) and occurred predominantly during the first infusion. No grade 4/5 IRRs occurred.¹⁰

Safety Results - IRRs - D-Kd arm

• IRRs with DARZALEX were reported in 6 of 10 (60%) patients who received the single first dose and in 31 of 75 (41.3%) patients who received the split first dose.¹⁹
  • The majority of IRRs occurred during the first infusion and were mild, with 2 patients experiencing grade 3/4 IRRs.
  • With the single first DARZALEX dose, 5 (50%) patients experienced IRRs during cycle 1 day 1 (C1D1); with the split first DARZALEX dose, 27 (36%) patients experienced IRRs during C1D1.

Monotherapy

SIRIUS (MMY2002; clinicaltrials.gov identifier: NCT01985126) was an open-label, multicenter, international, phase 2 study evaluating the safety and efficacy of DARZALEX monotherapy in patients with MM who had received ≥3 prior lines of therapy, including a protease inhibitor (PI) and an immunomodulatory agent, or had disease refractory to both a PI and an immunomodulatory agent (N=106). Lonial et al (2016)¹¹ evaluated DARZALEX monotherapy in patients with MM. Vorhees et al (2015)²⁰ further described the management of IRRs in this study. Safety results related to IRR events have been summarized below.

Study Design/Methods

• Primary endpoint: ORR
• Secondary endpoints: PFS, OS, DOR, and clinical benefit rate (ORR + minimal response)

Safety Results - IRRs

• IRRs occurred in 38% of patients in the 16 mg/kg group and 44% of patients in the
  8 mg/kg group and were mostly grade 1 or 2.²⁰
  • Grade 3 IRRs consisted of: bronchospasm (n=2 at 16 mg/kg); dyspnea (n=1 at
    16 mg/kg); chills and cytokine release syndrome (both in 1 patient at 8 mg/kg); and hypertension (n=1 at 8 mg/kg).
  • There were no instances of grade 4 IRRs.
  • Most IRRs occurred during the first infusion, and the median duration of infusion decreased with each cycle (see Table: Onset of IRRs and Duration of Infusions for Each Treatment Cycle).
    • Some patients had IRRs during >1 infusion.
  • The most common IRRs in the 8 mg/kg group included: chills (28%), cough (17%), and nasal congestion, dyspnea, pruritus, vomiting, and wheezing (6% each).
  • The most common IRRs in the 16 mg/kg group included: nasal congestion (12%); throat irritation (7%); cough, dyspnea, chills, and vomiting (6% each); nausea (5%); bronchospasm (4%); and pruritus and wheezing (2% each).
  • Treatment modifications, including infusion interruptions and infusion rate decreases, were implemented in most patients who experienced IRRs (Table: Treatment Modifications Due to IRRs Related to DARZALEX).
  • Three patients were unable to finish an infusion due to an IRR but received future DARZALEX infusions.
    • All remaining patients who experienced an IRR continued the infusion and received the full DARZALEX dose with supportive treatment.
  • No patient discontinued treatment due to an IRR.
  • Cytokine changes (interleukin-6, tumor necrosis factor-α, interferon-γ, and interleukin-1β) from baseline to 4 hours after the first DARZALEX infusion did not correlate with IRRs.

Lokhorst et al (2015)¹² reported results from GEN501, a dose escalation and dose expansion, phase 1/2 study assessing the safety of DARZALEX monotherapy patients with MM who had relapsed after or were refractory to ≥2 prior lines of therapy, including PIs, immunomodulatory agents, chemotherapy, and ASCT (N=72). Results related to IRR events from the dose-expansion phase are summarized below.

Study Design/Methods

• Primary endpoint: safety
• Secondary endpoints: pharmacokinetics, objective response according to International Myeloma Working Group uniform response criteria for myeloma, relative reductions in levels of M protein and free light chains, TTP, DOR, PFS, and OS

Safety Results - IRRs

• IRRs were observed in 71% of patients across the DARZALEX8 mg/kg and 16 mg/kg cohorts in part 2 and were mostly grade 1/2 in severity.¹²
  • One patient experienced a grade 3 IRR.
  • No grade 4 IRRs or discontinuations due to IRRs were reported.
  • A total of 67% and 71% of patients in the DARZALEX8 mg/kg and DARZALEX16 mg/kg cohorts, respectively, had an IRR during the first infusion.
  • The incidence of IRRs was lower in patients who received 8 mg/kg in 1000 mL for 6 hours compared to 8 mg/kg in 500 mL for 4-6 hours and 16 mg/kg in 1000 mL for 6 hours.

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 02 August 2024.