PRODUCT LABELING

Please note the following as stated in the DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS, sections of the DARZALEX Prescribing Information:

2.2 Recommended Dosage

Infusion Rates

• Administer DARZALEX infusion intravenously (IV) at the appropriate infusion rate. Consider incremental escalation of the infusion rate only in the absence of infusionrelated reactions (IRRs).¹
• The recommended dose of 16 mg/kg to be administered on Day 1 when DARZALEX is administered as monotherapy or in combination may be split over two consecutive days, such that an 8 mg/kg dose is administered on Day 1 and Day 2, respectively, as defined in table: Infusion Rates for DARZALEX (16 mg/kg) Administration.¹

2.3 Recommended Concomitant Medications

Pre-infusion Medication

• Administer the following pre-infusion medications 1-3 hours before every DARZALEX infusion¹:
  • Corticosteroid (long- or intermediate-acting):
    • Monotherapy: Administer methylprednisolone 100 mg (or equivalent) IV. Following the second infusion, consider reducing the dose to 60 mg (or equivalent) administered either orally (PO) or IV.
    • In Combination: Administer dexamethasone 20 mg (or equivalent) PO or IV. When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX infusion days. Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX infusion days when patients have received dexamethasone (or equivalent) as a pre-medication.
  • Acetaminophen 650 to 1,000 mg PO
  • Diphenhydramine 25 to 50 mg (or equivalent) PO/IV

Post-infusion Medication

• Administer post-infusion medications¹:
  • Monotherapy: Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid PO for 2 days starting the day after the administration of DARZALEX.
  • In Combination: Consider administering PO methylprednisolone at a dose ≤20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after the administration of a DARZALEX infusion. If a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZLEX infusion, additional corticosteroids may not be needed.
• For patients with a history of chronic obstructive pulmonary disease, consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 DARZALEX infusions, consider discontinuing these additional post-infusion medications, if the patient does not experience a major IRR.¹

2.4 Dosage Modifications for Adverse Reactions

IRRs

• 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 as outlined below¹:
  • Grade 1-2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour. See table: Infusion Rates for DARZALEX (16mg/kg) Administration.
  • Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in table: Infusion Rates for DARZALEX (16mg/kg) Administration. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater IRR.
  • Grade 4 (life threatening): Permanently discontinue DARZALEX.

4 CONTRAINDICATIONS

• 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

5.1 IRRs

• DARZALEX can cause severe and/or serious IRRs including anaphylactic reactions. 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 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.¹
• 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.¹

CLINICAL DATA

Phase 2 DARZALEX Monotherapy Study

SIRIUS (MMY2002; clinicaltrials.gov identifier: NCT01985126) was an open-label, multicenter, international, phase 2 study evaluating the efficacy and safety of DARZALEX monotherapy in patients with multiple myeloma (MM) who have received ≥3 prior lines of therapy including a PI and an immunomodulatory agent or have disease refractory to both a PI and an immunomodulatory agent. Lonial et al (2016)² evaluated the efficacy and safety of DARZALEX monotherapy in patients with MM (N=106) who were refractory to both a PI and an immunomodulatory agent. Vorhees et al (2015)¹⁰ further described the management of IRRs in this study.

Study Design/Methods

• Patients were initially randomized 1:1 to receive DARZALEX 8 mg/kg every 4 weeks (n=18); or DARZALEX 16 mg/kg every week for 8 weeks, DARZALEX 16 mg/kg every 2 weeks for 16 weeks, then DARZALEX 16 mg/kg every 4 weeks thereafter (n=16).
• Response was evaluated and the DARZALEX 16 mg/kg dose was established as the recommended dose for further evaluation. An additional 90 patients were enrolled in the DARZALEX 16 mg/kg group.
• The DARZALEX infusion was initiated in 1000 mL at 50 mL/hr.¹⁰
  • In the absence of IRRs, the rate increased to 200 mL/hr at 50 mL/hr intervals.
  • Second and subsequent infusions (in 500 mL) began at 50 mL/hr and 100 mL/hr, respectively, and increased to 200 mL/hr.
• Premedication for the management of IRRs, administered 1 hour (±15 minutes) prior to the DARZALEX infusion, included:¹⁰
  • Methylprednisolone 100 mg (or equivalent) IV for the first 2 infusions, and 60 mg with subsequent infusions
  • Acetaminophen 650-1000 mg
  • Diphenhydramine 25-50 mg (or equivalent)
• A corticosteroid (methylprednisolone 20 mg or equivalent) was given on the 2 consecutive days following DARZALEX infusions.¹⁰
• Specific recommendations were provided to investigators for the management of grade 1/2 and grade ≥3 IRRs. See table: Recommendations for the Management of Grade 1/2 IRRs and Table: Recommendations for the Management of Grade ≥3 IRRs.¹⁰
  • IV saline, antihistamine, oxygen, corticosteroids, and/or bronchodilators could be used per investigator discretion.

Results-Safety

• Treatment-emergent adverse events (TEAEs) with ≥20% frequency included fatigue (40%), anemia (33%), nausea (29%), thrombocytopenia (25%), neutropenia (23%), back pain (22%), and cough (21%).²
• Serious TEAEs occurred in 32 (30%) patients. A total of 24 (23%) patients had grade 3/4 serious TEAEs.²
• IRRs occurred in 38% of patients in the DARZALEX 16 mg/kg group and 44% of patients in the DARZALEX 8 mg/kg group and were mostly grade 1/2.¹⁰
  • Grade 3 IRRs consisted of: bronchospasm (DARZALEX 16 mg/kg, n=2); dyspnea (DARZALEX 16 mg/kg, n=1); chills and cytokine release syndrome (DARZALEX 8 mg/kg, n=1 each); and hypertension (DARZALEX 8 mg/kg, n=1).
  • There were no grade 4 IRRs reported.
  • 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 DARZALEX 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 DARZALEX 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. See 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.

Retrospective and Subgroup Analysis of CASTOR and POLLUX Studies

Moreau et al (2017)⁵ evaluated the management of IRRs associated with DARZALEX in combination with bortezomib, and dexamethasone (DVd) and in combination with lenalidomide, and dexamethasone (DRd) combination arms of the phase 3 CASTOR³ and POLLUX⁴ studies. Mateos et al (2020)⁶ further conducted a subgroup analysis of safety and efficacy data of patients aged 65-74 and ≥75 treated in the CASTOR (N=498) (median follow-up, 19.4 months) and POLLUX (N=569) (median follow-up, 25.4 months) studies.

Study Design/Methods

• Patients with MM previously treated with ≥1 line of therapy.
• CASTOR dosing:
  • Vd: bortezomib 1.3 mg/m² subcutaneously (SC) on days 1, 4, 8, and 11 of each 21-day cycle for 8 cycles; dexamethasone 20 mg PO/IV on days 1-2, 4-5, 8-9, and 11-12 of the 8 cycles.
  • DVd: bortezomib and dexamethasone as above, plus DARZALEX 16 mg/kg IV weekly for the first 3 cycles, once every 3 weeks of cycles 4-8, then every 4 weeks thereafter.
• POLLUX dosing:
  • Rd: lenalidomide 25 mg PO on days 1-21 of each 28-day cycle; dexamethasone 40 mg weekly.
  • DRd: lenalidomide and dexamethasone as above, plus DARZALEX 16 mg/kg IV weekly for 8 weeks in cycles 1 and 2, every 2 weeks for 16 weeks in cycles 3-6, and then every 4 weeks thereafter.
• Pre-infusion medication consisted of 20 mg dexamethasone (or equivalent) PO/IV, 650-1000 mg paracetamol, and 25-50 mg diphenhydramine (or equivalent).
• Patients with high-risk respiratory complications received diphenhydramine on Days 1 and 2, a short-acting β2 adrenergic receptor agonist, and control medications for lung disease post-DARZALEX infusion.

Results

• Pre-infusion medications were administered to all patients treated with DARZALEX.
• Post-infusion medications were administered to 31 (13%) CASTOR patients and 21 (7%) POLLUX patients.
• In both CASTOR and POLLUX studies, median DARZALEX infusion duration was ~7.0, 4.3, and ~3.4 hours for the first, second, and subsequent infusions, respectively.
• IRRs were experienced by 45% and 48% of patients with 98% and 96% occurring during the first infusion in the CASTOR and POLLUX studies, respectively.
• IRRs were mostly grade 1/2; no ≥grade 4 IRRs were reported.
• Median time to onset of IRRs following the initial DARZALEX infusion was 84 minutes in the CASTOR study and 90 minutes in the POLLUX study.
• A total of 2 CASTOR study patients discontinued treatment due to IRRs. In the POLLUX study, 1 patient discontinued DARZALEX but continued Rd following a grade 3 IRR.
• In a CASTOR subgroup analysis among elderly patients, any-grade IRRs occurred in 65% of patients aged ≥75 years (10% had grade 3/4 IRRs) and 45.7% of patients aged 65-74 years (8.5% had grade 3/4 IRRs); all IRRs were manageable and no elderly patients discontinued treatment due to an IRR.⁶
• In a POLLUX subgroup analysis among elderly patients, any-grade IRRs occurred in 41.4% of patients aged ≥75 years (13.8% had grade 3/4 IRRs) and 46.3% of patients aged 65-74 years (4.9% had grade 3/4 IRRs); all IRRs were manageable and no patients discontinued treatment due to an IRR.⁶

Multicenter, Retrospective Review

Geirnaert et al (2021)⁸ conducted a retrospective analysis for the incidence of IRRs in patients with relapsed MM who received ≥1 DARZALEX infusion in a split-dose initiation regimen.

Study Design/Methods

• Multicenter, retrospective review of medical records.
• Patients received a split dose of DARZALEX (8 mg/kg IV on days 1 and 2) for the first week of administration as a part of DVd or DRd treatment regimen.
• Main objectives: The rates of DARZALEX related IRRs when using a split dose infusion (DARZALEX 8 mg/kg IV on days 1, and 2 of cycle 1), safety of DARZALEX rapid infusions, and overall incidence of IRRs with DARZALEX infusions in real world setting.

Results

• Median age (range) was 68 (32-89) years.
• A total of 53 patients were identified in this review; 34 (64%) patients received DRd and 19 (36%) received DVd.
• Many of the IRRs occurred on the first DARZALEX infusion as summarized in the Table: IRRs on Cycle 1, Days 1, and 2.
• There were no grade 3/4 IRRs reported on cycle 1, days 8, 15, and 22. One (22%) patient reported a grade 1/2 IRR (cycle 1 day 22).
• No IRRs were reported in patients who received DARZALEX infusions (cycle ≥2).

• The IRRs were managed with medications and/or by interrupting the infusion and resuming at a lower rate once symptoms resolved.
• Antiemetics for nausea, additional antihistamine or corticosteroids were the most common medications used for post-infusion management of IRRs with DARZALEX.

Retrospective, Observational Study

Redondo Galan et al (2021)¹¹ evaluated the impact of reduced DARZALEX infusion time on IRRs.

Study Design/Methods

• Retrospective, observational study
• Patients were treated with DARZALEX at an infusion rate of 200 ml/hour (over 30 mins) and, if there are no IRRs during first 3 doses, increase up to 400 ml/hour (total infusion time, 90 min).

Results

• Mean age: 68.9 years
• Gender: 4 male patients and 7 female patients
• A total of 11 patients received DARZALEX infusion treatment.
• Of the 11 patients, 4 patients were treated with DARZALEX at an infusion rate of 50 ml/hour to a maximum of 200 ml/hour.
  • Intense cough and dyspnea requiring hospitalization occurred in 2 patients with the first infusion of DARZALEX.
• Of the 11 patients, 7 patients were treated with DARZALEX at an infusion rate of 400 ml/hour.
  • There were no IRRs reported.

Single-Center, Observational, Retrospective Chart Review

Coffman et al (2023)⁷ evaluated the impact of administering montelukast as a
pre-medication on the incidence of IRRs with DARZALEX infusions.

Study Design/Methods

• Single-center, observational, retrospective chart review
• Inclusion criteria: ≥18 years with documented MM and received DARZALEX in the outpatient setting
• Exclusion criteria: received DARZALEX in the inpatient setting, received DARZALEX FASPRO, or had a history of prior DARZALEX infusions
• Patients were divided into two groups: Patients who received montelukast 10 mg PO (n=27) once 30-60 minutes prior to the DARZALEX infusions vs patients who did not receive montelukast (n=46) prior to the DARZALEX infusions.
• Pre-infusion medications included acetaminophen, diphenhydramine, cetirizine, and methylprednisolone.
• Primary endpoint: incidence of IRRs between the montelukast and no montelukast groups
• Secondary endpoints: IRR symptoms, rescue medication utilization, grade/severity of IRRs, and safety of 90-minute rapid rate DARZALEX infusions

Results

• A total of 73 patients were included in this study; 27 patients were in the montelukast group and 46 in the no montelukast group.
• Baseline characteristics were similar between both groups. See Table: Demographics and Baseline Characteristics.
• There were 22 (81.4%) and 29 (63%) patients in the montelukast and no montelukast groups, respectively, who received DARZALEX monotherapy.
• A total of 27 patients received 90-minute rapid rate DARZALEX infusions.

• In total, 57.5% (n=42) of patients experienced IRRs.
• The incidence of IRRs was higher in the no montelukast (65.2%; n=30) vs montelukast (44.4%; n=12) group; P=0.044.
  • The majority of IRRs were grade 2, with 80% (n=24) and 75% (n=9) of patients in the no montelukast and montelukast groups, respectively.
• The most common pulmonary symptom was throat irritation (no montelukast group, 36.7% [n=11]; montelukast group, 16.7% [n=2]). See Table: Most Common IRRs in the Montelukast vs No Montelukast Group.
• Gastrointestinal symptoms were similar across both groups.
• No grade ≥3 IRRs were reported.
• Diphenhydramine was the most common medication used for the post-infusion management of IRRs with DARZALEX. See Table: Rescue Medications for IRR management.
• No IRRs were reported for the 27 patients who received 90-minute rapid rate DARZALEX infusion.

Single-Center, Retrospective Chart Review

Moore et al (2020)⁹ assessed the impact of administering montelukast as a premedication on the incidence of IRRs with the first infusion of DARZALEX.

Study Design/Methods

• Single-center, retrospective chart review
• Inclusion criteria: ≥18 years with documented MM, amyloidosis or plasma cell leukemia; received ≥ 1 dose of DARZALEX.
• Patients were divided in two groups: Patients who received montelukast 10 mg PO once 30 to 60 minutes prior to the first infusion of DARZALEX (n=94) vs patients who did not receive montelukast (n=47) prior to the first infusion of DARZALEX.
  • Some patients may have received montelukast 10 mg PO at home 12 to 24 hours prior to the first infusion.
• Pre-infusion medications included acetaminophen, diphenhydramine, and a corticosteroid.
• Patients were treated with DARZALEX 16 mg/kg IV on day 1 or split-dose DARZALEX 8 mg/kg IV on day 1 and 2.
  • Montelukast 10 mg PO was administered prior to split-dose DARZALEX infusion.
• Post-infusion medications included: diphenhydramine, famotidine, corticosteroids, meperidine, albuterol, and oxygen.

Results

• A total of 141 patients received DARZALEX infusion treatment.
• In total, 33% (n=46) of patients experienced an IRR with the first infusion of DARZALEX. See table: Incidence of IRRs with First DARZALEX Administration.
• Incidence of IRRs in patients who received montelukast as a premedication was 27% (n=25) and in patients who did not receive montelukast was 45% (n=21); P=0.0371.
• Diphenhydramine was the most common medication used for post-infusion management of IRRs with DARZALEX (n=40; 87%).
• Patients who did not receive montelukast as a pre-medication and experienced IRRs were more likely to receive corticosteroids (95% vs 52%; P=0.0022) and albuterol (57% vs 4%; P=0.0001) for the management of IRRs, as compared to patients who received montelukast as a post-medication.

Open-label Early Access Treatment Protocol

Chari et al (2018)¹² evaluated safety and patient-reported outcomes (PRO) of DARZALEX in an early access treatment protocol (EAP), which included a subpopulation that received montelukast as premedication.

Study Design/Methods

• Multicenter, open-label EAP providing early access to DARZALEX treatment designed to collect safety data including IRRs.
• Inclusion criteria: documented MM; age ≥18 years; Eastern Cooperative Oncology Group (ECOG) score 0-2; disease progression within the last 60 days of prior treatment; double refractory to a PI and immunomodulatory drug or received ≥3 prior therapies that included a PI and immunomodulatory drug.
• Exclusion criteria: COPD with a Forced Expiratory Volume in 1 second (FEV1) <50%; uncontrolled asthma or moderate/severe asthma within the past 2 years; cardiac disease, arrhythmia, or clinically significant abnormal electrocardiogram (ECG); hypersensitivity to monoclonal antibodies; prior exposure to any anti-CD38 monoclonal antibody; absolute neutrophil count (ANC) ≤0.5 × 10⁹/L; hemoglobin (Hbg) ≤7 g/dL (≤4 mmol/L); platelets <50 x 10⁹/L; alanine aminotransferase (ALT) ≥2.5 times the upper limit of normal (ULN); total bilirubin level ≥2 × ULN; creatinine clearance (CrCl) ≤20 mL/min/1.73 m²; potassium level <3.0 mEq/L; corrected serum calcium >14.0 mg/dL.
• Patients were on a 28-day cycle and treated weekly for 8 weeks with DARZALEX 16 mg/kg IV, then every other week for 16 weeks, then monthly until progression of their disease, diminished clinical benefit, unacceptable toxicity, or end of study.
• Pre-infusion medications included: acetaminophen (650-1000 mg), diphenhydramine (25-50 mg), and methylprednisolone (100 mg for infusion 1 and 2, then 60 mg for remaining infusions). Montelukast (10 mg) was allowed per investigator discretion. Pre-infusion administered approximately 1 hour before dosing.
• Post-infusion medications for 2 days following infusion included: methylprednisolone (20 mg) for all patients and diphenhydramine (25-50 mg), inhaled corticosteroids and bronchodilators for patients with COPD and asthma.
• The National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) was used to assess safety for patients who received ≥1 DARZALEX dose and treatment-emergent grade ≥3 AEs, serious adverse events (SAEs), and AEs of special interest (bronchospasm, IRR, laboratory abnormalities) were collected.
• Investigator assessment of the patients’ response to DARZALEX was used to guide end-of-treatment decisions and progressive disease. This assessment was based on local standard of care. No efficacy endpoints were included in the study.
• European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) C30, the EORTC Multiple Myeloma Module (QLQ-MY20), and the European Quality of Life Five Dimensions Questionnaire (EQ-5D-5L) were recorded electronically at baseline; on the first day of cycles 2, 3, 6 and every other subsequent cycle; and at the end-of-study visit.

Results

Baseline Characteristics

• A total of 348 patients received ≥1 DARZALEX dose and were included in the analysis. Most patients were white (72%) and male (56%) with a baseline ECOG score of 0-1 (84%). The median (range) duration of treatment was 1.9 (0.03-6.01) months and the median number (range) of DARZALEX infusions received was 8 (1-17).
• The median duration (range) of the first, second, and all subsequent infusions was 7.4 (1.0-24.0), 4.4 (2.9-16.3), and 3.5 (0.8-26.1) hours, respectively.

Safety

• The most frequent grade 3/4 AEs reported in the study were thrombocytopenia (15%), anemia (14%), neutropenia (8%), lymphopenia (6%), and hypercalcemia (5%). Thrombocytopenia (6%) and anemia (5%) were the most frequently reported DARZALEX-related grade 3/4 AEs.
• SAEs occurred in 35% of patients (12% considered DARZALEX-related), which included 29% grade 3/4 SAEs. Fifty-six percent of patients experienced an IRR.
• Overall, 60 patients received montelukast pre-treatment and 288 patients did not. IRRs occurred in greater frequency in patients who did not receive montelukast pre-treatment. Likewise, 2% of the montelukast pre-treated cohort experienced grade 3-4 IRRs compared to 9% of the cohort that did not receive this pre-treatment; 4% and 11% of patients experienced gastrointestinal symptoms, respectively. Fourteen percent of patients in both groups experienced chills. Respiratory or thoracic symptoms were the most common IRRs. See Table: Proportion of Patients with IRRs.
• Fifty patients received montelukast before the first DARZALEX infusion. During the first infusion, IRRs occurred less frequently in patients pre-treated with montelukast (38%) compared to those who did not receive this pre-treatment (59%). Respiratory symptoms were observed during the first infusion in 20% and 33% of montelukast pre-treated and untreated patients, respectively. The median duration of the first DARZALEX infusion was 6.7 (range, 1.0-10.7) hours in patients receiving montelukast pre-treatment vs 7.6 (range, 1.4-24.0) hours in those who did not.

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 15 January 2025.