DARZALEX FASPRO - Occurrence and Management of Administration-Related Reactions in Patients with Multiple Myeloma

SUMMARY

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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.
• DARZALEX FASPRO is for subcutaneous (SC) use only. Do not administer intravenously.¹ Johnson & Johnson does not recommend the use of DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• There are no systematically collected data to support the administration of a test dose for DARZALEX FASPRO.
• In the below clinical studies of DARZALEX FASPRO for SC administration, systemic administration-related reactions (ARRs) are referred to as infusion-related reactions (“IRRs”). There are no systemically collected data on the management of ARRs, IRRs, and injection-site reactions (ISRs) with DARZALEX FASPRO. Clinical judgement should be exercised when managing ARRs, IRRs, or ISRs during DARZALEX FASPRO-containing treatment regimen.
• COLUMBA was a phase 3 study evaluating the efficacy, pharmacokinetics (PK) and IRRs of DARZALEX for intravenous (IV) use vs DARZALEX FASPRO.^2,3
  • Mateos et al (2020)² reported the primary efficacy and safety results of the study at a median follow-up of 7.5 months. IRRs occurred in 13% vs 34% of patients in the DARZALEX FASPRO vs DARZALEX arms, respectively. ISRs occurred in 7% of patients in the DARZALEX FASPRO arm.  
  • Usmani et al (2022)³ reported the final efficacy and safety results of the study at a median follow-up of 29.3 months. IRRs occurred in 12.7% vs 34.5% of patients in the DARZALEX FASPRO vs DARZALEX arms, respectively. One ISR occurred in the DARZALEX FASPRO arm.
• CEPHEUS was a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) or bortezomib, lenalidomide, and dexamethasone (VRd) alone in patients with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred).⁴
  • Usmani et al (2025)⁴ reported the primary analysis of the study at a median follow-up of 58.7 months. Any injection-related reaction occurred in 7 patients (3.6%) in the D-VRd group, including 1 patient (0.5%) with a grade 3 reaction.  
• PERSEUS was a phase 3 study evaluating the efficacy and safety of D-VRd vs VRd induction and consolidation followed by maintenance with DARZALEX FASPRO in combination with lenalidomide (D-R) in D-VRd group or lenalidomide (R) alone in VRd group in patients with NDMM eligible for autologous stem cell transplant (ASCT).⁵
  • Sonneveld et al (2024)⁵ reported efficacy and safety results from the study at a median follow-up of 47.5 months. Among patients receiving D-VRd, any grade IRRs were reported in 21 patients (6%) while grade 3/4 IRRs were reported in 3 patients (0.9%).
• APOLLO was a phase 3 study evaluating the safety and efficacy of daratumumab in combination with pomalidomide and dexamethasone (D-Pd) in patients with relapsed or refractory multiple myeloma (RRMM) who received ≥1 prior treatment with both lenalidomide and a proteasome inhibitor.
  • Dimopoulos et al (2021)⁶ reported the primary results of this study at a median follow-up of 16.9 months. IRRs were reported in 8 of 149 patients (5%) in the D-Pd arm; all were grade 1/2. Local ISRs were reported in 3 of 142 patients (2%) who received DARZALEX FASPRO; all were grade 1.
• PLEIADES was a phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with 4 standard-of-care (SOC) treatment regimens in patients with multiple myeloma (MM).
  • Chari et al (2021)⁷ presented updated safety and efficacy results of the PLEIADES study with a median follow-up of 3.9 months for D-VRd, 6.9 months for DARZALEX FASPRO in combination with bortezomib, melphalan, and prednisone (D-VMP), and 7.1 months for DARZALEX FASPRO in combination with lenalidomide and dexamethasone (D-Rd). Any grade IRRs were reported in 9%, 9%, and 4.6% of patients in the D-VRd, D-VMP, and D-Rd arms, respectively. Across all three cohorts, local ISRs occurred in 7.5% of patients (all grade 1/2).
  • Moreau et al (2020)⁸ presented updated safety and efficacy results of the PLEIADES study with a median follow-up of 9.2 months for DARZALEX FASPRO in combination with carfilzomib and dexamethasone (D-Kd), 25.7 months for D-Rd, and 25.2 months for D-VMP. Any grade IRRs were reported in 5%, 5%, and 9% of patients in the D-Kd, D-Rd, and D-VMP arms, respectively. Across all three cohorts, local ISRs occurred in 6% of patients (all grade 1/2).
• PAVO was a phase 1b study evaluating the safety, PK, and efficacy of DARZALEX FASPRO in patients with RRMM who have received ≥2 prior therapies.⁹
  • San-Miguel et al (2021)¹⁰ published results from part 2 of the study. IRRs occurred in 16% patients, and grade 1 injection-site TEAEs occurred in 12% patients.
  • Nahi et al (2023)¹¹ published the updated safety and efficacy results from part 3 of the PAVO study, which was conducted to evaluate the safety of tapering off pre- and post-dose corticosteroids during DARZALEX FASPRO administration. IRRs occurred in 11.9% patients (2-week corticosteroid-taper group, 20.0%; 1-week corticosteroid-taper group, 16.7%).

COMPANY CORE DATA

• DARZALEX FASPRO should never be injected into areas where the skin is red, bruised, tender, or hard, or areas where there are scars. Injection sites should be rotated for successive injections.¹
• Pause or slow down delivery rate of DARZALEX FASPRO if the patient experiences pain. In the event pain is not alleviated by slowing down the injection, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.¹
• DARZALEX FASPRO can cause severe and/or serious IRRs, including anaphylactic reactions. In clinical trials, approximately 8% (134/1639) of patients experienced an IRR. Most IRRs occurred following the first injection and were grade 1/2. IRRs occurring with subsequent injections were seen in 1% of patients. The median time to onset of IRRs was 3.3 hours (range, 0.08-83). The majority occurred on the day of treatment. Delayed IRRs occurred in 1% of patients.¹
  • Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritis, chills, vomiting, nausea, hypotension, and blurred vision. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, and ocular adverse events (including choroidal effusion, acute myopia and acute angle closure glaucoma).
  • Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Patients should be monitored and counselled regarding IRRs, especially during and following the first and second injections. If an anaphylactic reaction or life-threatening (grade 4) reactions occur, institute appropriate emergency care and permanently discontinue DARZALEX FASPRO.
  • To reduce the risk of delayed IRRs, administer oral corticosteroids to all patients following DARZALEX FASPRO injections. Patients with a history of chronic obstructive pulmonary disease (COPD) may require additional post-injection medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with COPD. If ocular symptoms occur, interrupt DARZALEX FASPRO infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO.
• In clinical trials (N=1639) with DARZALEX FASPRO, the incidence of any grade IRRs was 7.2% with the first injection of DARZALEX FASPRO (1800 mg, week 1), 0.5% with the week 2 injection, and 1.3% with subsequent injections. Grade 3 and 4 IRRs were seen in 0.7% and 0.1% of patients, respectively.¹
  • Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritis, chills, vomiting, nausea, and hypotension. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, and tachycardia.  
• In clinical trials (N=1639) with DARZALEX FASPRO, the incidence of any grade ISR was 9.8%. There were no grade 3 or 4 ISRs. The most common (>1%) ISRs were erythema and rash.¹

CLINICAL DATA

Phase 3 Study of DARZALEX vs DARZALEX FASPRO in Patients with RRMM

COLUMBA (MMY3012; NCT03277105) was a phase 3, randomized, open-label, multicenter, non-inferiority study evaluating the efficacy, PK, and IRRs of DARZALEX vs DARZALEX FASPRO in patients with RRMM.

Primary Analysis of the COLUMBA Study

Mateos et al (2020)² published the efficacy and safety results of the primary analysis at a median follow-up of 7.5 months.

Results - Safety - IRRs

• IRRs occurred in 33 of 260 patients (13%) in the DARZALEX FASPRO arm vs 89 of 258 patients (34%) in the DARZALEX arm (odds ratio [OR], 0.28; 95% CI, 0.18-0.44; P<0.0001).²
• The most common IRRs in the DARZALEX FASPRO arm vs DARZALEX arm were chills (5% vs 12%), pyrexia (5% vs 3%), and dyspnea (1% vs 7%). Other IRRs reported in ≤1% of the DARZALEX FASPRO arm were nasal congestion, chest pain, influenza-like illness, cough, oropharyngeal discomfort, rhinorrhea, throat irritation, hypertension, hypertensive crisis, oxygen saturation decreased, tachycardia, eyelid edema, lacrimation increased, nausea, vomiting, arthralgia, and tremor.²
• Most IRRs occurred following the first dose and were predominately grade 1/2.²
• Grade 3 IRRs occurred in 4 patients (2%) in the DARZALEX FASPRO arm vs 14 patients (5%) in the DARZALEX arm. No grade 4/5 IRRs were reported.²
• Median time to onset of IRRs after administration of the first dose was longer in the DARZALEX FASPRO arm (3.4 hours; interquartile range [IQR], 1.5-4.4; range, 1-47.8) than the DARZALEX arm (1.5 hours; IQR, 1-1.8; range, 0-24.5).²
• Most IRRs in both arms occurred during or shortly after the first administration of daratumumab; 1 patient in the DARZALEX FASPRO arm and 3 patients in the DARZALEX arm had an IRR on the second or subsequent administrations. No patients had an IRR following the fourth or later administrations.²
• One patient in the DARZALEX FASPRO arm and 2 in the DARZALEX arm had delayed-onset IRRs (defined as occurring on non-treatment days). All delayed onset IRRs were grade 1/2 and non-serious.²
• No IRRs with DARZALEX FASPRO led to treatment discontinuation, dose interruption, or incomplete dose administration.²

Results - Safety - ISRs

• ISRs occurred in 18 patients (7%) in the DARZALEX FASPRO arm; all were of grade 1/2 severity and none led to treatment discontinuation.²
• Injection-site erythema (n=4; 2%) was the only ISR that was reported in >2 patients in the DARZALEX FASPRO arm.²
• Other local ISRs (all grade 1/2) included injection-site bruising, injection-site pruritus, erythema, and contusion, each reported in 2 patients (1%); and injection-site hematoma, injection-site hemorrhage, injection-site pain, injection-site swelling, injection-site urticaria, ecchymosis, SC hemorrhage, and SC hematoma, each reported in 1 patient (<1%).²

Final Analysis of the COLUMBA Study

Usmani et al (2022)³ reported final analysis of efficacy and safety results of the COLUMBA study after a median follow-up of 29.3 months.

Results - Safety - IRRs

• With a longer follow-up of 29.3 months (additional 21.8 months after the primary analysis), no new IRRs occurred³:
  • Rate of IRRs were lower in the DARZALEX FASPRO arm (12.7%; n=33) vs DARZALEX arm (34.5%; n=89); (Odds ratio [OR], 0.28; 95% CI, 0.18-0.44; P<0.0001).
  • Rate of grade 3/4 IRRs were lower in the DARZALEX FASPRO arm (1.5%; n=4) vs DARZALEX arm (15.4%; n=14).
    • There were no grade 4 IRRs reported for either arm.
  • There were no reports of IRRs in patients who switched from DARZALEX to DARZALEX FASPRO (n=13).

Results - Safety - ISRs

• One ISR was reported in the DARZALEX FASPRO arm.³

Phase 2 Study of DARZALEX FASPRO in Combination with SOC Regimens for MM

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

Primary Analysis of the PLEIADES Study

Chari et al (2021)⁷ reported the primary endpoint analysis and updated efficacy and safety data from the PLEIADES study with a median follow-up of 3.9 months for D-VRd, 6.9 months for D-VMP, and 7.1 months for D-Rd.

Results - Safety - IRRs (D-VRd, D-VMP, and D-Rd Cohorts)

• Across all three cohorts, any grade IRRs occurred in 7.5% of patients (D-VRd, 9% [6/67]; D-VMP, 9% [6/67]; D-Rd, 4.6% [3/65]).⁷
  • IRRs were mild (grade 1/2). Only 1 patient had a grade 3 IRR and no patients reported grade 4 IRR.
• The median time to onset of IRRs was 4.4 hours, 6.9 hours, and 5.5 hours in the D-VRd, D-VMP, and D-Rd cohorts, respectively.⁷
• Of patients experiencing ≥1 IRRs after DARZALEX FASPRO administration, 9%, 7.5%, and 4.6% occurred on first administration in the D-VRd, D-VMP, and D-Rd arms.⁷
  • There were no patients who reported IRRs after second DARZALEX FASPRO administration.  
  • After 3+ DARZALEX FASPRO administrations, 1.5%, 3.1%, and 0% IRRs occurred in the D-VRd, D-VMP, and D-Rd cohorts, respectively.
• There were no study drug interruptions due to IRRs.⁷

Results - Safety - ISRs (D-VRd, D-VMP, and D-Rd Cohorts)

• Across all three cohorts, local ISRs occurred in 7.5% of patients; (15/199; all grade 1/2).⁷

Updated Analysis of the PLEAIDES Study

Moreau et al (2020)⁸ presented updated safety and efficacy results of PLEIADES study with a median follow-up of 9.2 months for D-Kd, 25.7 months for D-Rd, and 25.2 months for D-VMP.  

Results - Safety - IRRs (D-Kd, D-Rd, and D-VMP Cohorts)

• Across all three cohorts, any grade IRRs occurred in 6% of patients (D-Kd, 5% [3/66]; D-Rd, 5% [3/65]; D-VMP, 9% [6/67]).⁸
• Most patients with IRRs experienced them on the first administration (D-Kd, 100%; D-Rd, 100%; D-VMP, 83%).⁸
• IRRs were mild (grade 1/2); 2 patients in the D-Kd cohort had a grade 3 IRR, and no patients reported grade 4 IRR.⁸
• Median time to onset of IRRs was 65 minutes (range, 4-75), 330 minutes (254-330), and 411 minutes (121-534) in the D-Kd, D-Rd, and D-VMP cohorts, respectively.⁸

Results - Safety - ISRs (D-Kd, D-Rd, and D-VMP Cohorts)

• Across all 3 cohorts, local ISRs occurred in 6% of patients (11/198; all grade 1/2).⁸

Phase 1b Study of DARZALEX FASPRO in RRMM

PAVO (MMY1004; NCT02519452) was a phase 1b open-label, multicenter, dose-finding, proof-of-concept study evaluating the safety, PK, and efficacy of DARZALEX FASPRO in patients with RRMM who have received ≥2 prior therapies.⁹

Primary Analysis of the PAVO Study

San-Miguel et al (2021)¹⁰ published results from part 2 of the PAVO study. Results related to IRRs are summarized below.

Results - Safety - IRRs (Part 2)

• The median time to onset of an IRR was 70 minutes (range, 9-80).¹⁰
• Among patients receiving DARZALEX FASPRO (n=25), 4 patients (16%) experienced the following IRRs¹⁰:
  • Grade 3 hypertension, grade 2 chills, and grade 2 dyspnea in 1 patient (cycle 1 day 1 [C1D1]); grade 1 allergic rhinitis in 1 patient (C1D1); grade 1 sneezing in 1 patient (C1D1); and grade 3 hypertension in 1 patient (cycle 3 day 1)
• Grade 3 hypertension IRRs were reversible and occurred only in patients with a history of hypertension.¹⁰
• No grade 4 IRR occurred, and no patient required treatment discontinuation due to IRRs.¹⁰

Results - Safety - ISRs (Part 2)

• Injection-site TEAEs were reported in 3 patients (12%; grade 1 injection-site induration, n=1; grade 1 injection-site erythema, n=1; grade 1 injection-site hematoma, n=1).¹⁰
  • Measurable erythema (24%) and measurable induration (4%) at the injection site resolved within 1 hour.

Evaluation of Pre- and Post-Dose Corticosteroid Tapering of the PAVO Study

Nahi et al (2023)¹¹ published the updated safety and efficacy results from part 3 of the PAVO study, which was conducted to evaluate the safety of tapering off pre- and post-dose corticosteroids during DARZALEX FASPRO administration.

Results - Safety - IRRs (Part 3)

• IRRs were reported in 5 patients (11.9%) during the first administration only (3-week corticosteroid taper group, n=0; 2-week corticosteroid taper group, n=3 [20.0%]; 1week corticosteroid taper group, n=2 [16.7%]).
• The most common (≥5%) IRRs were chills and pyrexia (n=3 [7.1%] each). Additional IRRs included tachycardia, increased blood pressure, and oropharyngeal pain (n=1 [2.4%] each).
• The median time to onset of IRRs was 79.0 minutes (range, 31-555). All IRRs resolved on the same day.
• All IRRs were generally mild, except for one grade 3 IRR (increased blood pressure) reported in the 2-week corticosteroid taper group.
• No grade 4 IRRs were reported.
• No IRRs met the dose-limiting toxicity definition or required treatment interruptions/discontinuation.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 10 September 2026. For streamlining purposes, retrospective-analyses, systematic reviews, review articles, and case reports have been excluded.

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