SUMMARY

• DARZALEX for intravenous (IV) infusion is not approved by the regulatory agencies to be administered as a 90minute infusion. Johnson & Johnson does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
• Stakiw et al (2023)^2,3 conducted a phase 2, investigator-initiated, prospective, nonrandomized, multicenter study by Canadian Myeloma Research Group (CMRG-009) to evaluate the safety of accelerated DARZALEX infusions beginning after administration of an initial half-dose of DARZALEX (8 mg/kg) over 4 hours on cycle 1 day 1 (C1D1), with all subsequent doses (starting from second dose, 16 mg/kg) administered over 90 minutes, in patients with relapsed/refractory multiple myeloma (RRMM). Grade 1 and 2 infusion-related reactions (IRRs) were observed in 30% of patients. No grade ≥3 IRRs were reported.
• Barr et al (2018)⁴ conducted a prospective, open-label, single-center study of 28 patients receiving a 90-minute DARZALEX infusion beginning with the third dose to evaluate the safety, tolerability, and incidence of IRRs. No grade ≥3 IRRs were reported.
• Gozzetti et al (2020)⁵ presented a prospective, observational, singlecenter study of 39 patients to assess the safety and efficacy of a 90-minute DARZALEX infusion beginning with the third dose in patients with RRMM and in patients receiving DARZALEX as consolidation therapy after induction treatment over a 22 month period. During rapid infusions, no serious adverse events (SAEs) were reported. IRRs occurred in 33% of patients after the first DARZALEX split infusion on C1D1 and were grade 1 or 2.
• Maouche et al (2020)⁶ conducted a prospective, observational, multicenter study to assess the safety of rapid rate 90-minute DARZALEX infusion beginning with the third  dose in patients with multiple myeloma (MM). During rapid rate DARZALEX infusions, 4 patients experienced a grade 1/2 IRR.  
• GRIFFIN was a phase 2, active-controlled, randomized, open-label, multicenter, 2-part, study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) induction/consolidation therapy and lenalidomide maintenance therapy in patients with newly diagnosed multiple myeloma (NDMM) eligible for high-dose therapy (HDT) and autologous stem cell transplant (ASCT).⁷ The study was amended to allow patients in the D-VRd group to receive remaining doses of DARZALEX in the maintenance phase of therapy as a rapid infusion.⁸

COMPANY CORE DATA

• In clinical trials (monotherapy and combination treatments; N=2066) the incidence of any grade IRRs was 37% with the first infusion of DARZALEX, 2% with the second infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 IRR with second or subsequent infusions.¹
• The median time to onset of a reaction was 1.5 hours (range: 0 to 72.8 hours). The incidence of infusion modifications due to reactions was 36%. Median durations of infusions for the first, second, and subsequent infusions were 7, 4, and 3 hours respectively.¹
• Severe IRRs included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other IRRs included nasal congestion, cough, chills, throat irritation, vomiting and nausea.¹

CLINICAL DATA

Phase 2 Prospective Study of Accelerated DARZALEX Infusions

Stakiw et al (2023)² (CMRG-009; NCT03697629) evaluated the safety of accelerated DARZALEX infusions in patients with RRMM, with administration of an initial half-dose of DARZALEX (8 mg/kg) on C1D1 over 4 hours, and all subsequent doses (starting from second dose, 16 mg/kg) administered over 90 minutes.

Study Design/Methods

• A phase 2, investigator-initiated, prospective, nonrandomized, multicenter, single-arm, study by CMRG.²
• Primary objective: Incidence of IRRs in the first 6 months of daratumumab administration.²
• On C1D1, the initial half-dose (8 mg/kg) was administered over 4 hours in a diluted volume of 500 mL at an initial rate of 50 mL/h, with rate increments of 50 mL/h and a maximum rate of 200 mL/h.^2,3
• Starting on day 8 of cycle 1, the 90-minute infusion dose (16 mg/kg) was administered in a total volume of 500 mL at an initial rate of 200 mL/h set to deliver 20% of the dose in the first 30 minutes and the remaining 80% over the next 60 minutes. The rate increment was 250 mL/h with a maximum rate of 450 mL/h.^2,3
• All patients received the following fixed pre- and post-medication regimens to prevent IRRs²:
  • Montelukast 10 mg orally (PO) on days -2 and -1, and on day 0 prior to DARZALEX infusion.
  • Cetirizine 10 mg PO on days -2 and -1, and on day 0 prior to DARZALEX infusion.
  • Acetaminophen 1000 mg PO 1 hour prior to DARZALEX infusion.
  • Diphenhydramine 50 mg IV 1 hour prior to DARZALEX infusion.
  • Dexamethasone 20 mg on the day of and day after DARZALEX infusion.
    • Dexamethasone after a day of DARZALEX infusion was stopped from day 15 of cycle 1 in an amendment.
• Prophylactic antivirals including acyclovir, famciclovir, valacyclovir, or an equivalent agent were given to all the patients throughout the study.²
• The planned treatment duration was 6 cycles, until disease progression, or intolerance, or with an option to continue DARZALEX treatment off-trial beyond 6 cycles.²

Results

Patient Disposition and Characteristics

• At a median follow up of 5.1 months, a total of 40 patients received 443 DARZALEX infusions, including the C1D1 standard-rate infusions (>130 minutes) and 373 (84.2%) accelerated infusions (30-130 minutes) during the study.²
• The baseline patient demographics and characteristics are presented in Table: Patient Demographics and Baseline Characteristics.²
  • Of the 43 nonaccelerated infusions recorded, 8 were administered on days other than C1D1.
  • A total of 38 patients (95%) completed cycle 1, and 18 patients (45%) completed all 6 cycles.
• The median duration of DARZALEX treatment was 4.8 months.²

Safety

• All-grade IRRs occurred in 30% (n=12) of patients.²
• IRRs were observed in 12 (2.5%) of the 443 total infusions; all IRRs were grade 1/2.²
  • Of these, 91.7% (n=11) of IRRs were observed during the first DARZALEX infusion.
    • IRRs were observed in 27.5% of first DARZLEX infusions.
  • One (2.6%) grade 1 IRR occurred during cycle 1 day 22.
• Grade ≥3 IRRs were not observed during any cycle of DARZALEX infusion.²
  • Summary of grade ≥3 IRRs reported at different infusion rates have been presented in Table: Rates of Grade ≥3 IRRs.
• There were 3 fatal adverse events (AEs) reported (cardiac arrest, n=2; pneumonia, n=1), and none of them were related to DARZALEX treatment.²
• Three other deaths were reported during the study period due to myeloma progression.²

Efficacy

• The median progression-free survival (PFS) was 3.94 months (95% confidence interval [CI], 1.87-6.04), and the median overall survival (OS) was not reached (NR).²
• Other efficacy parameters have been summarized in Table: Summary of Efficacy Parameters.²

Prospective Study of Accelerated DARZALEX Infusions

Barr et al (2018)⁴ assessed the safety and tolerability of an accelerated DARZALEX infusion beginning with the third dose in patients with MM.

Study Design/Methods

• A prospective, open-label, single-center trial to assess the safety and tolerability of a 90minute DARZALEX infusion regarding the incidence of IRRs beginning with the third dose in patients with MM receiving standard-of-care DARZALEX therapy.⁴
• Inclusion criteria: any patient who received ≥2 prior infusions of DARZALEX therapy administered according to the standard prescribing information rates.⁴
• Previous IRRs were not an exclusion criteria.⁴
• To achieve 80% power an enrollment goal was set at 28 patients. Acceptable safety for the accelerated infusion was defined as ≤1 patient experiencing a grade ≥3 IRR.⁴
• The volume used was 550 mL (includes the institution’s standard estimated overfill) with an initial infusion rate of 200 mL/h to deliver 20% of the dose in the first 30 minutes and 450 mL/h for the remaining 60 minutes to deliver the remaining 80% of the dose.⁴

Results

Patient Characteristics

• Median age: 67 years (range, 44-90).⁴
• Gender: 19 male patients (67.9%), 9 female patients (32.1%).⁴
• Race: 24 patients (85.7%) were Caucasian, 3 patients (10.7%) were African American, and 1 patient (3.6%) was classified as other.⁴
• Premedication was allowed to be altered based on previous tolerability and included the following: dexamethasone in 23 patients (82.1%), acetaminophen in 27 patients (96.4%), diphenhydramine in 27 patients (96.4%), famotidine in 28 patients (100%), montelukast in 8 patients (28.6%), and hydroxyzine in 1 patient (3.6%).⁴
• Delayed dexamethasone was used in 10 patients (35.7%).⁴

Patient Disposition

• Eight patients had 2 prior DARZALEX doses before enrollment.⁴
• Seven patients had 3 to 5 prior DARZALEX doses before enrollment.⁴
• Thirteen patients received ≥10 prior DARZALEX doses before enrollment.⁴

Safety

• There were no grade ≥3 IRRs.⁴
• One patient experienced hypertension (grade 2) during the 450 mL/h rate. This patient had received 10 prior infusions at the standard rate. The infusion was paused, a diuretic was given, and the infusion was resumed at a reduced rate of 200 mL/h. Subsequently, the rate was increased again to the accelerated rate without further hypertension.⁴
• The variation of the premedication regimen among the patients did not affect the tolerability of the accelerated infusion.⁴
• The accelerated rate was maintained in all patients who stayed on DARZALEX.⁴

Prospective Study Assessing DARZALEX Accelerated Infusions

Gozzetti et al (2020)⁵ assessed the safety and efficacy of a 90-minute DARZALEX infusion beginning with the third dose in patients with RRMM and in patient receiving DARZALEX as a consolidation therapy after induction treatment.

Study Design/Methods

• A prospective, observational, single-arm, single-center study to assess the safety and efficacy of a 90-minute DARZALEX infusion beginning with the third dose (if no IRRs were reported during the previous infusion).⁵
• The study evaluated 39 patients, including 19 patients with RRMM and 20 patients who received DARZALEX as consolidation therapy, from December 2018 to October 2020.⁵
• The first DARZALEX dose was split (8 mg/kg on day 1 and day 2), and each dose was infused in 500 mL volume at an initial rate of 50 mL/h, with a maximum infusion rate of 200 mL/h, over a median duration of 4 hours.⁵
• The second DARZALEX dose was infused in 500 mL volume at an initial rate of 50 mL/h, with a maximum infusion rate of 200 mL/h, over a median duration of 4 hours.⁵
• Starting with the third dose, the 90-minute infusion dose was administered in a total volume of 550 mL at a rate of 200 mL/h to deliver 20% of the dose in the first 30 minutes and at 450 mL/h to deliver the remaining 80% of the dose for the remaining 60 minutes.⁵
• Pre-medications: dexamethasone 20 mg IV, acetaminophen 1000 mg PO, chlorphenamine maleate 10 mg IV, salbutamol 2 puffs administered 20 min prior to first infusion.⁵
  • After 10 DARZALEX doses, pre-medications were reduced to loratadine 10 mg PO, dexamethasone 10 mg IV, and acetaminophen 500 mg PO.
  • After 14 DARZALEX doses, dexamethasone was reduced to 4 mg in 6 patients.
• Medications prescribed to all patients: acyclovir 400 mg twice daily and trimethoprim/sulfamethoxazole 160/800 mg twice daily for 2 days per week.⁵

Results

Patient Characteristics

• A total of 484 rapid DARZALEX infusions were administered to 39 patients over a 22month observational period.⁵
• Median Age: 64 years (range, 48-84).⁵
• Gender: 27 male patients, and 12 female patients.⁵
• Chronic obstructive pulmonary disease (COPD) and asthma were absent in previous patient history in 38 out of 39 patients.⁵

Patient Disposition

• Nineteen patients with RRMM received DARZALEX alone or in combination with other agents.⁵
  • Ten patients received the DARZALEX in combination with lenalidomide and dexamethasone (D-Rd), 4 patients received DARZALEX with bortezomib and dexamethasone (D-Vd), 1 patient received DARZALEX with pomalidomide and dexamethasone (D-Pd), and 4 patients received DARZALEX monotherapy.
• Twenty patients received DARZALEX as consolidation therapy after induction treatment.⁵
• The median number of rapid infusions per patient was 14 (range, 1-30).⁵
• The median number of prior DARZALEX standard infusions was 12 (range, 5-16).⁵

Safety

• IRRs with the first split dose of DARZALEX were reported in 13 patients (33%); 5 patients with RRMM and 8 patients receiving DARZALEX as consolidation therapy after induction treatment.⁵
  • All were grade 1-2 (allergic rhinitis [n=7], dyspnea [n=3], chills [n=3]) and occurred on day 1. The median time to recovery after IRRs was 30 minutes.
  • These patients did not have reactions during subsequent infusions.
• No SAEs were reported during rapid infusions.⁵
• Seventy-nine percent (33 of 39) of patients were administered DARZALEX as a rapid infusion.⁵
  • Thirty patients received DARZALEX at the third infusion, cycle 1 day 15.
  • Three patients received DARZALEX as a rapid infusion at the fourth infusion, cycle 1 day 22.
• Treatment-emergent adverse events (TEAEs) not related to infusions were reported: lymphopenia (31%), anemia (23%), thrombocytopenia (23%), neutropenia (23%), arthralgia (20%), and fever of unknown origin (20%).⁵

Efficacy

• Response improvement was observed in 72% (23 of 32) of evaluable patients during DARZALEX therapy.⁵
• Improved response was observed in 9 of 16 patients who received DARZALEX as consolidation therapy. All complete responders received DARZALEX consolidation therapy (minimal residual disease [MRD] negative by next-generation flow).⁵
• Partial response (PR) was observed in 14 of 16 evaluable patients with RRMM.⁵
• Halted progression was observed in 6 of 39 patients; 3 patients were treated at line 6, 2 patients at line 3, and 1 patient at line 2 of DARZALEX therapy.⁵
• At the last follow-up, 32 patients were reported to be alive.⁵

Prospective Study of Accelerated DARZALEX Infusions

Maouche et al (2020)⁶ evaluated the safety of the administration of a rapid rate 90minute DARZALEX infusion beginning with the third dose in patients with MM.

Study Design/Methods

• A prospective, observational, multicenter study of patients with MM who were administered rapid rate 90-minute DARZALEX infusions after 2 prior doses of DARZALEX infusions at the standard rate (if no IRRs grade ≥1 were reported during last standard DARZALEX infusion).⁶

Results

Patient Characteristics

• A total of 383 rapid rate DARZALEX infusions were administered to 69 patients.⁶
• Median age: 69 years (range, 43-91).⁶
• Gender: 42 male patients, and 27 female patients.⁶
• Comorbidities: pre-existing cardiac, 43.5%; pre-existing respiratory, 13%.⁶
• Montelukast 10 mg was used as a premedication in 53 patients (76.8%).⁶
• Thirty-five patients who received DARZALEX monotherapy as a rapid rate infusion received the following pre- and post-medication⁶:
  • Dexamethasone 12-20 mg on day 1 of DARZALEX infusion.
  • Dexamethasone 4 mg on days 2 and 3 after DARZALEX infusion.
• Three patients who received DARZALEX monotherapy as a rapid rate infusion received the following pre- and post-medications⁶:
  • Prednisolone 75 mg on day 1 of DARZALEX infusion.
  • Prednisolone 25 mg for 2 days after DARZALEX infusion.
• Patients who received D-Vd and D-Rd received steroids as a pre and post-medication.⁶

Patient Disposition

• Out of 69 patients, 40 patients received DARZALEX monotherapy as a rapid infusion, 27 patients received D-Vd, and 2 patients received D-Rd.⁶
• The median number of prior standard rate DARZALEX infusions was 4 (range, 2-51).⁶
• The median number of rapid rate 90-minute DARZALEX infusions was 6 (range, 1-15).⁶

Safety

• Of the 69 patients, 4 patients (5.7%) experienced a grade 1/2 IRR during rapid rate DARZALEX infusions.⁶
  • IRRs included decrease in oxygen saturation (n=1), pyrexia during third dose (n=1), mild rash during first dose (n=1), and dyspnea, vomiting, and headache during second dose (n=1). No patients had an IRR following the fourth or later administration.
• Twenty-three patients (33.3%) experienced an IRR during first dose of standard rate DARZALEX infusions and all were grade 1/2.⁶

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 06 February 2026. For streamlining purposes, retrospective analyses, systematic reviews, review articles, and case reports have been excluded.