SUMMARY

• DARZALEX is not approved by the regulatory agencies to be administered as a 90minute infusion. DARZALEX intravenous (IV) is not approved by the regulatory agencies for the treatment of patients with immunoglobulin (Ig) light chain (AL) amyloidosis. Janssen does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
• Stakiw et al (2019)⁴ presented safety results of a phase 2, multi-center, open-label study of 25 patients that evaluated an accelerated DARZALEX infusion regimen beginning after administration of an initial half-dose of DARZALEX (8 mg/kg) on day 1 of cycle 1 (C1D1) over 4 hours, with all subsequent doses (16 mg/kg) administered over 90 minutes in patients with relapsed/refractory multiple myeloma (RRMM). No grade ≥3 infusion-related reactions (IRRs) were reported. IRRs occurred in 32% of patients; all occurred on C1D1 and were grade 1 or 2. There were no grade ≥3 IRRs.
• Stakiw et al (2023)¹⁰ conducted an investigator-initiated, nonrandomized, prospective, multicenter, single-arm, phase 2 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) on C1D1 over 4 hours, with all subsequent doses (starting from second dose, 16 mg/kg) administered over 90 minutes, in patients with multiple myeloma (MM). Grade 1 and 2 IRRs were observed in 2.5% of total DARZALEX infusions. No grade ≥3 IRRs were reported.
• Maouche et al (2020)⁷ conducted a prospective, multi-center, observational study to assess the safety of rapid rate 90-minute DARZALEX infusion beginning with the 3^rd   dose in patients with MM. During rapid rate DARZALEX infusions, 4 patients experienced a grade 1/2 IRR.
• Gozzetti et al (2020)⁶ presented an observational, prospective, single-arm, singlecenter study of 39 patients to assess the safety and efficacy of a 90-minute DARZALEX infusion beginning with the 3^rd 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 1^st DARZALEX split infusion on C1D1 and were grade 1 or 2.  
• Barr et al (2018)⁵ conducted a prospective, open-label study of 28 patients receiving a 90-minute DARZALEX infusion beginning with the 3^rd dose to evaluate the safety and tolerability of incidence of IRRs. No grade ≥3 IRRs were reported.
• Attardi et al (2021)⁸ conducted a single-center observational study to evaluate the safety of 90-minute rapid infusions of DARZALEX in patients with RRMM who received 90-minute rapid infusions of DARZALEX after 4 prior doses of standard DARZALEX infusion. No adverse events (AEs) or IRRs were reported during or within 30 minutes of rapid infusion.
• Bonello et al (2022)⁹ performed a retrospective, multicenter, chart-review to evaluate the safety of 90-minute rapid infusion of DARZALEX in patients with RRMM. IRRs were reported in 7 (5%) patients (grade 1, n=2; grade 2, n=4; grade 3, n=1) during 7 of 754 rapid infusions.
• Patel et al (2021)¹ conducted a retrospective analysis of 75 patients with MM to evaluate the safety of accelerated 90-minute DARZALEX infusions beginning with the 3^rd dose and the incidence of grade ≥1 IRRs. Twelve patients (7.9%) that received the rapid 90-minute infusion experienced an IRR.
• Hamadeh et al (2018)² conducted a retrospective analysis of 100 patients with RRMM or amyloidosis to evaluate the safety and tolerability of the 90-minute DARZALEX infusion. The rate of IRRs was not statistically significant for patients who received 90minute rapid infusion compared to patients who received standard infusion: 1.9% vs 4.3% (p=0.59).
• Gordon et al (2021)³ conducted a real-world, retrospective, observational study of 147 patients with MM to evaluate the utilization, effectiveness, and safety of 90-minute DARZALEX rapid infusion beginning with the 3^rd  dose and any associated IRRs among adult patients. Fifty-four patients (36.7%) experienced ≥1 IRR during DARZALEX infusion. No IRRs occurred in patients after receiving DARZALEX rapid infusion.
• GRIFFIN is an ongoing, open-label, multi-center, 2-part, phase 2, randomized, activecontrolled study evaluating the safety and efficacy of DARZALEX (D) when administered in combination with bortezomib, lenalidomide, and dexamethasone (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).^11-13 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. Results for patients who received ≥1 rapid infusion have not yet been presented.
  • DARZALEX 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 in a manner that is inconsistent with the approved labeling.

PRODUCT LABELING

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

BACKGROUND

• 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.¹⁴
• 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 1^st, 2^nd, and subsequent infusions were 7, 4, and 3 hours respectively.¹⁴
• Severe IRRs included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other IRRs included nasal congestion, cough, chills, throat irritation, vomiting and nausea.¹⁴

CLINICAL DATA

Phase 2 Study Assessing the Safety of a 90-Minute Infusion: MCRN 009

Stakiw et al (2019)⁴ (MCRN 009) presented safety results of an accelerated DARZALEX infusion regimen in patients with RRMM beginning after administration of an initial half-dose of DARZALEX (8 mg/kg) on C1D1 over 4 hours, with all subsequent doses (16 mg/kg) administered over 90 minutes.

Study Design/Methods

• A phase 2, multi-center, open-label study to assess the safety of a 90-minute DARZALEX infusion.
• 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.
• 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.
• All patients received the following fixed pre- and post-medication regimen:
  • 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.
  • Dexamethasone 20 mg on the day of and day after DARZALEX infusion.
  • Acetaminophen 975-1000 mg PO 1 hour prior to DARZALEX infusion.
  • Diphenhydramine 50 mg IV 1 hour prior to DARZALEX infusion.

Results

Patient Characteristics

• The median age of patients was 70 years.
• A total of 222 accelerated DARZALEX infusions were administered to 25 patients.

Safety

• Eight patients (32%) experienced IRRs that all occurred on C1D1 and were grade 1 (n=1) or grade 2 (n=7).
• There were no grade ≥3 IRRs.
• Thirteen patients discontinued study participation due to disease progression or death.

Investigator-Initiated, Nonrandomized, Prospective, Multicenter, Single-Arm, Phase 2 Study: CMRG-009

Stakiw et al (2023)¹⁰ (CMRG-009; clinicaltrials.gov identifier: NCT03697629) evaluated the safety of accelerated DARZALEX infusions in patients with MM, 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

• An investigator-initiated, nonrandomized, prospective, multicenter, single-arm, phase 2 study by CMRG.
• Primary objective: Incidence of IRRs in the first 6 months of daratumumab administration.
• Dosing: On C1D1, the first dose of DARZALEX (8 mg/kg in 500 mL dilution) was administered over 4 hours, followed by subsequent infusions (16 mg/kg in 500 mL dilution) at a duration of 90 minute on days 8, 15, and 22 of cycle 1, and days 1, 8, 15, and 22 of cycle 2, and days 1 and 15 of cycles 3-6.
  • All patients received the following fixed pre- and postmedication regimens to prevent IRRs:
    • Montelukast 10 mg 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.
  • The planned treatment duration was 6 treatment cycles, until disease progression, or intolerance, or with an option to continue DARZALEX treatment off-trial beyond 6 cycles.

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.
• The baseline patient demographics and characteristics are presented in Table: Patient Demographics and Baseline Characteristics.
  • 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.

Safety

• Most common (≥10%) all-grade IRRs have been presented in Table: Summary of Most Common (≥10%) All-Grade IRRs.
• A total of 91.7% IRRs were observed in the first DARZALEX infusion. See Table: Summary of IRRs by Infusion.
  • Grade 1 and 2 IRRs were observed in 2.5% of total DARZALEX infusions.
    • Grade 1 and 2 IRRs were observed in 27.5% of the first DARZALEX infusions.
  • Grade ≥3 IRRs were not observed during any cycle of DARZALEX infusion.
    • Summary of grade ≥3 IRRs reported at different infusion rates have been presented in Table: Rates of Grade ≥3 IRRs.
• There were 3 fatal AEs reported (n=2, cardiac arrest; n=1, pneumonia), and none of them were related to DARZALEX treatment.
• Three other deaths were reported during the study period due to myeloma progression.

Efficacy

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

Prospective, Multi-Center, Observation Study

Maouche et al (2020)⁷ evaluated the safety of the administration of a rapid rate 90minute DARZALEX infusion beginning with the 3^rd dose in patients with MM.

Study Design/Methods

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

Results

Patient Characteristics

• A total of 383 rapid rate DARZALEX infusions were administered to 69 patients.
• Median age: 69 years (range: 43-91 years).
• Gender: 42 male patients, and 27 female patients.
• Comorbidities: pre-existing cardiac, 43.5%; pre-existing respiratory, 13%.
• Montelukast 10 mg was used as a premedication in 53 (76.8%) patients.
• Thirty-five patients who received DARZALEX monotherapy as a rapid rate infusion received the following pre- and post-medication:
  • 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-medications:
  • Prednisolone 75 mg on day 1 of DARZALEX infusion
  • Prednisolone 25 mg for 2 days after DARZALEX infusion
• Patients who received a combination of DARZALEX + bortezomib + dexamethasone (DVd) and DARZALEX + lenalidomide + dexamethasone (DRd) received steroid as a pre and post-medication.

Patient Disposition

• Out of 69 patients, 40 patients received DARZALEX monotherapy as a rapid infusion, 27 patients received DVd, and 2 patients received DRd.
• Median number of prior standard rate DARZALEX infusions was 4 (range: 2-51).
• Median number of rapid rate 90-minute DARZALEX infusions was 6 (range: 1-15).

Safety

• Of the 69 patients, 4 patients (5.7%) experienced a grade 1/2 IRR during rapid rate DARZALEX infusions.
  • IRRs included decrease in oxygen saturation (n=1), pyrexia during 3^rd dose (n=1), mild rash during 1^st dose (n=1), and dyspnea, vomiting, and headache during 2^nd dose (n=1). No patients had an IRR following the 4^th or later administrations.
• Twenty-three patients (33.3%) experienced an IRR during 1^st dose of standard rate DARZALEX infusions and all were grade 1/2.

Prospective, Single-arm, Open-Label Study Assessing 90-minute Infusion

Gozzetti et al (2020)⁶ assessed the safety and efficacy of a 90-minute DARZALEX infusion beginning with the 3^rd dose in patients with RRMM and in patient receiving DARZALEX as a consolidation therapy after induction treatment.

Study Design/Methods

• An observational, prospective, single-arm, single-center study to assess the safety and efficacy of a 90-minute DARZALEX infusion beginning with the 3^rd dose (if no IRRs were reported during the previous infusion).
• 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.
• 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.
• 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.
• 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 remainder (80%) of the dose for the remaining 60 minutes.
• 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.
  • 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/wk.

Results

Patient Characteristics

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

Patient Disposition

• Nineteen patients with RRMM received DARZALEX alone or in combination with other agents.
  • Ten patients received the combination of DRd, 4 patients received DVd, 1 patient received DARZALEX+ pomalidomide + dexamethasone (DPd), and 4 patients received DARZALEX monotherapy.
• Twenty patients received DARZALEX as consolidation therapy after induction treatment.
• Median number of rapid infusions per patient was 14 (range: 1-10).
• Median number of prior DARZALEX standard infusions was 12 (range: 5-16).

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.
  • All were grade 1-2 (allergic rhinitis [7], dyspnea [3], chills [3]) and occurred on day 1. 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.
• Seventy-nine percent (33 of 39) of patients were administered DARZALEX as a rapid infusion.
  • 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%).
  • Pneumonia/infection was reported in 2 patients who received DARZALEX and lenalidomide and discontinued treatment. Septic shock was reported in 1 patient and bacterial pneumonia in 1 patient.

Efficacy

• Response improvement was observed in 72% (23 of 32) evaluable patients during DARZALEX therapy.
• 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 negative by next-generation flow).
• Partial response (PR) was observed in 14 of 16 evaluable patients with RRMM.
• 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.
• At the last follow-up, 32 patients were reported to be alive.

Open-label Prospective Trial Assessing an Accelerated DARZALEX Infusion

Barr et al (2018)⁵ assessed the safety and tolerability of an accelerated DARZALEX infusion beginning with the 3^rd dose in patients with MM.

Study Design/Methods

• A single-center, open-label, prospective trial to assess the safety and tolerability of a 90minute DARZALEX infusion regarding the incidence of IRRs beginning with the 3^rd dose in patients with MM receiving standard-of-care DARZALEX therapy.
• Inclusion criteria: any patient who received ≥2 prior infusions of DARZALEX therapy administered according to the standard prescribing information rates.
• Previous IRRs were not an exclusion criteria.
• 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.
• 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 remainder (80%) of the dose.

Results

Patient Characteristics

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

Patient Disposition

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

Safety

• There were no grade ≥3 IRRs.
• 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.
• The variation of the premedication regimen among the patients did not affect the tolerability of the accelerated infusion.
• The accelerated rate was maintained in all patients who stayed on DARZALEX.

Single-Center Observational Study

Attardi et al (2021)⁸ conducted a single-center observational study to evaluate the safety of 90-minute rapid infusions of DARZALEX in patients with RRMM.

Study Design/Methods

• A single-center observational study of patients with RRMM who received 90-minute rapid infusions of DARZALEX after 4 prior doses of standard DARZALEX infusion between February 2019 and December 2020.
• DARZALEX was administered at 200 mL/h for the first 30 minutes and progressively increased to 400 mL/h for the next 60 minutes.
• Premedication with standard of care regimen (chlorphenamine 10 mg, acetaminophen 1000 mg, and dexamethasone 20 mg or 40 mg IV, according to the DVd or DRd regimens, respectively) was administered 60 minutes prior to DARZALEX infusion.

Results

Patient Characteristics

• Overall, 72 patients with RRMM were included.
• At baseline, patients had received a median of 2 (range, 2-5) prior lines of therapy and 8 (range, 4-30) infusions of DARZALEX.
• Ten (14%) patients received DARZALEX monotherapy, 15 (21%) received DVd, and 47 (65%) received DRd.
• The baseline patient and treatment characteristics are presented in Table: Baseline Patient and Treatment Characteristics.

Safety

• The median number of rapid infusions per patient was 12, and the total number of rapid infusions analyzed was 900.
• No AEs or IRRs were reported during or within 30 minutes of rapid infusion in all patients, including ‘at-risk’ patients with the following comorbidities:
  • Cardiovascular disease (CVD; arterial hypertension, arrhythmia, or valvulopathy)
  • Pulmonary comorbidities (COPD, asthma, allergic rhinitis, and susceptibility to aeroallergens)
  • Cardiac or renal amyloidotic involvement
  • Grade I and II anemia
• Rapid infusion was not required to be discontinued in any patient during subsequent administrations.

Retrospective, Multi-Center, Chart-Review

Bonello et al (2022)⁹ evaluated the safety of rapid 90-minute DARZALEX infusions in patients with RRMM.

Study Design/Methods

• Retrospective, multicenter, observational study of patients with RRMM who received rapid 90-minute DARZALEX infusions.
• Key inclusion criteria: patients who had received ≥1 rapid infusion of DARZALEX as a monotherapy or in combination with Vd or Rd and had tolerated the first two doses of DARZALEX at the standard 200 mL/hour rate before switching to rapid infusion.
• During the rapid infusion, 20% of the total dose of DARZALEX was delivered in the first 30 minutes (200 mL/hour) and the remaining 80% in the following 60 minutes (450 mL/hour). Premedication with acetaminophen, antihistamine, and dexamethasone was administered as per the institutional policy.
• Primary endpoint: safety analysis (incidence, type, and severity of IRRs and other related AEs occurring during the first 3 months from the first rapid infusion)
• Key secondary endpoint: rates of IRRs as per age group and comorbidities

Results

Patient Characteristics

• Overall, 134 patients who received a total of 754 rapid infusions were included.
  • The median age was 69 years (range, 42-83), 32 (24%) patients were of age ≥75 years, 65 (49%) patients had cardiovascular comorbidities (hypertension, 40%), and 8 (6%) patients suffered from COPD.
• A total of 120 (89.5%) patients initiated the rapid infusion protocol after a median of 4 prior cycles of DARZALEX (range, 0-33), and 58 (43%) patients had experienced a prior IRR during the first administration of DARZALEX without recurrence in subsequent infusions.
  • The IRRs reported during the first DARZALEX infusion were of grade 1 (41.5%) or grade 2 (58.5%) and were respiratory (48%), gastrointestinal (27.5%), or cutaneous (26%) in nature.
• The treatment characteristics are summarized in Table: DARZALEX Rapid Infusion Characteristics.

Safety

• IRRs were reported in 7 (5%) patients (grade 1, n=2; grade 2, n=4; grade 3 [sudden hypertension with severe oxygen desaturation], n=1) during 7 of 754 rapid infusions. See Table: Safety Outcomes.
  • The patient with the grade 3 IRR required oxygen support, bronchodilators, nitrates, and high doses of hydrocortisone, and DARZALEX was permanently discontinued. The patient had a prior history of COPD (however, pulmonary function tests at baseline were normal). He had not experienced any IRRs during previous DARZALEX infusions administered at a standard rate.
  • The patients with grade 1/2 IRRs safely resumed DARZALEX after receiving treatment with additional steroids and antihistamines.
  • The types of IRRs included respiratory (57%), cardiovascular (14%), gastrointestinal (28.5%), and general (28.5%) symptoms.
  • Five patients reported IRRs during the first rapid DARZALEX infusion when the rate of infusion was increased from 200 mL/hour to 450 mL/hour, 1 patient during the 3rd rapid infusion, and 1 patient during the 6th rapid infusion.
• Treatment was interrupted for ≥2 months in 20 (15%) patients due to ASCT or because of limited access to healthcare facilities due to the Coronavirus Disease 2019 (COVID-19) pandemic. Among these, 18 patients resumed directly with rapid DARZALEX infusion (IRRs reported upon resuming in 4 [22%] patients, including the grade 3 IRR), and 2 patients resumed with DARZALEX standard infusion before subsequently switching to rapid DARZALEX infusion (no IRRs reported).
• Among patients who had (n=58) vs had not (n=76) experienced an IRR during the first standard DARZALEX infusion, IRRs with rapid infusion were reported in 3 (5.2%) vs 4 (5.3%) patients (P=1.00), respectively.
• Among patients aged <75 years vs ≥75 years, IRRs were reported in 6% vs 3% of patients (P=0.68), respectively.
• Among patients who did vs did not experience IRRs during rapid infusion, no difference was observed in the type of premedication administered.
• No other DARZALEX-related AEs apart from IRRs were reported during the observation period for the rapid infusion protocol. No patient reported fluid overload.

Retrospective, Single-Center, Chart-Review

Patel et al (2021)¹ evaluated the safety of accelerated 90-minute DARZALEX infusions with the 3^rd dose and any associated incidence of grade ≥1 for IRRs in patients who received accelerated 90-minute DARZALEX infusions vs standard DARZALEX infusions.

Study Design/Methods

• A single-center, retrospective, chart-review of patients with MM who received accelerated 90-minute DARZALEX infusions after 2 prior doses of the standard DARZALEX infusions between November 1, 2015 to August 31, 2019.
• Pre-medications: All patients received steroid and acetaminophen.
• Primary outcome: incidence of grade ≥1 IRRs in accelerated vs standard DARZALEX infusions.
• Secondary outcomes: amount of supportive medications used pre-, during, and postDARZALEX infusions, and AEs.

Results

Patient Characteristics

• Out of 75 patients who were included in this study, 40 patients received standard DARZALEX infusions and 35 patients received standard DARZALEX infusions that were transitioned to accelerated 90-minute DARZALEX infusions.
• Baseline characteristics are presented in table: Baseline Characteristics.
• Of the 420 DARZALEX infusions that were evaluated, 317 were standard DARZALEX infusions and 103 were accelerated 90-minute DARZALEX infusions.
  • Of the 317 standard DARZALEX infusions administered, 152 were transitioned to accelerated 90-minute DARZALEX infusions from standard DARZALEX infusions.
• The percentage of patients who received premedication with montelukast in accelerated DARZALEX infusions was 93.2% and standard DARZALEX infusions was 77.9%.

Safety

• Twelve patients (7.9%) experienced an IRR in the group that were transitioned from standard DARZALEX infusions to accelerated DARZALEX infusions.
• One patient (0.97%) experienced an IRR in the group that received accelerated DARZALEX infusions. IRRs are presented in the table: Infusion-Related Reactions.
• Grade 1 IRRs occurred in 14 standard DARZALEX infusions and 1 DARZALEX accelerated infusion. Grade ≥1 IRRs in standard vs accelerated DARZALEX infusions are presented in the table: Any Grade and Grade ≥1 IRRs in Standard vs Accelerated DARZALEX Infusions.
  • The most common Grade 1 IRRs: hypotension (n=5), dyspnea (n=3), tachycardia (n=2), and pruritis (n=2).  
• The most common AEs: restlessness, nausea, and vomiting. Patients experienced restlessness and difficulty holding objects during both standard and accelerated DARZALEX infusions.
• There were no treatment discontinuations due to an IRR or AE.

Retrospective Chart Review

Hamadeh et al (2018)² conducted a comparison study evaluating the safety and tolerability of a 90-minute DARZALEX infusion to the standard infusion rate consistent with the current approved labeling in patients with RRMM or amyloidosis.

Study Design/Methods

• A retrospective chart review of patients treated with at least one cycle of DARZALEX between April 2016 and November 2018.
• Patients were divided into 2 separate cohorts:
  • Cohort 1: patients were administered a 90-minute rapid infusion protocol treatment, where 20% of the DARZALEX dose was administered over 30 minutes, and the remaining 80% was administered over 60 minutes. These patients were administered the rapid DARZALEX infusion starting on either day 1 of a new cycle if they had prior exposure to DARZALEX, or if DARZALEX naïve, on Day 15 of the first cycle.
  • Cohort 2: patients were administered DARZALEX according to the standard prescribing information rate.
• All patients received the following premedication 30 minutes prior to DARZALEX administration: acetaminophen, diphenhydramine, dexamethasone and montelukast.
• Endpoints were compared using Fisher’s exact test with one degree of freedom and included difference in the rate of IRRs beyond day 1 of cycle 1 among:
  • Patients in cohort 1 vs patients in cohort 2
  • DARZALEX treatment-naïve patients in cohort 1 vs patients in cohort 2
• Data collected: patient demographics, type of plasma cell disorder, comorbidities, premedication, DARZALEX regimens, IRRs and their respective grades.

Results

Patient Characteristics

• A total of 100 patients were included in this study. Baseline characteristics are presented in Table: Baseline Characteristics of Included Patients. The difference in baseline characteristics between cohorts was not statistically significant.
• The percentage of patients who received the combination of DPd, DRd, or DVd was 75%, 17.5%, and 7.5% in the rapid infusion protocol cohort, respectively.  
• The percentage of patients who received DPd, DRd or DVd was 71%, 13%, and 16% in the standard infusion cohort, respectively.

Safety

• During C1D1, 17 patients (32%) in the rapid infusion protocol cohort and 13 patients (30%) in the standard infusion cohort developed IRRs (P=0.83).
• Beyond day 1 of cycle 1, IRR rate was 1.9% in the rapid infusion protocol cohort and 4.3% in the standard infusion cohort (P=0.59).
• Beyond C1D1, IRR rate was 5.5% in the DARZALEX treatment-naïve patients in the rapid infusion protocol cohort vs 4.3% in the standard infusion cohort (P=0.9).

Real-World, Retrospective, Observational Study

Gordon et al (2021)³ evaluated the safety, effectiveness, and utilization, of DARZALEX rapid infusion beginning with the 3^rd dose and any associated IRRs among patients.

Study Design/Methods

• A retrospective observational cohort of patients with MM who completed ≥1 DARZALEX rapid infusion at third or later doses of their first DARZALEX regimen between November 16, 2015 and March 15, 2019.
  • DARZALEX infusions were categorized as rapid if administered ≥90% of the prescribed dose and the duration was ≤110 min (instead of 90 min, to allow for variability in administration duration observed in electronic medical records).
  • IRRs were defined as a directly attributed event that occurred within 24 hours of a DARZALEX infusion and if it was explicitly stated as an IRR in the patient’s charts.
  • Index date was defined as the date of administration of the first DARZALEX infusion.

Results

Patient Characteristics

• Of 534 patients with MM, 147 patients (27.5%) received ≥1 DARZALEX rapid infusion during their first DARZALEX treatment regimen. Baseline characteristics are presented in Table: Baseline Characteristics.
• The percentage of patients who received DARZALEX monotherapy was 34% and those received DARZALEX in combination with pomalidomide, DARZALEX in combination with bortezomib, or other agents were 33.3%, 13.6%, 10.2%, respectively.

Safety

• Of the 147 patients, 54 patients (36.7%) experienced ≥1 IRR during DARZALEX treatment regimen.
  • Fifty-two patients (35.4%) experienced an IRR after receiving their first dose of DARZALEX, 1 patient (0.7%) after their second dose, and 6 patients (4.1%) after their third or later dose.
  • Median number of IRRs per patient was 2 (mean 2.5±1.3; interquartile range [IQR], 1).
• Most common IRRs were chills in 14 patients (19.5), nausea in 17 patients (11.6%), and dyspnea in 11 patients (7.5%).
• No patients experienced IRRs after receiving a DARZALEX rapid infusion.

Efficacy

• Among the 123 patients (83.7%) evaluable, 7 patients (4.8%) had a complete response, 9 patients (6.1%) had a very good partial response, 15 patients (10.2%) had a PR, and 81 patients (55.1%) had a response of unknown depth.
• The overall response rate (ORR) was 91.1%.
• The ORR for DARZALEX rapid infusion was 71.3%.

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 11 February 2025.