DARZALEX - Split First Dose Infusion

CLINICAL STUDIES

Phase 3 Study of DARZALEX in Combination with Kd

CANDOR (NCT03158688) is a phase 3, randomized, open-label, multicenter study which evaluated the efficacy and safety of DARZALEX in combination with carfilzomib and dexamethasone (D-Kd) vs carfilzomib and dexamethasone alone (Kd) in patients with relapsed/refractory multiple myeloma (RRMM).^2,3

Study Design/Methods

• Patients were randomized 2:1 to receive either of the following as 28-day cycles until disease progression:
  • D-Kd:
    • DARZALEX 16 mg/kg intravenous (IV; first dose split over 2 days [8 mg/kg each] of cycle 1) weekly cycles 1-2; every 2 weeks cycles 3-6, every 4 weeks thereafter
    • Carfilzomib 20 mg/m² IV on days 1, 2 of cycle 1; and 56 mg/m² thereafter
    • Dexamethasone 40 mg orally (PO) or IV weekly (or 20 mg if ≥75 years starting on the second week)
  • Kd: Carfilzomib and dexamethasone as above.

DARZALEX in Combination with CyBorD in RMM

LYRA (MMY2012; NCT02951819) is a phase 2, single-arm study evaluated the safety and efficacy of DARZALEX (the first DARZALEX administration being given as a divided dose over 2 days) when administered in combination with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) for the treatment of multiple myeloma (MM) in patients who have not received previous treatment or have relapsed after receiving 1 line of treatment.^4,5

Study Design/Methods

• Patients received 4-8 cycles (28 days per cycle) of the following induction treatment:
  • DARZALEX: 16 mg/kg IV
    • Cycle 1: 8 mg/kg IV on days 1 and 2, followed by 16 mg/kg weekly
    • Cycle 2: weekly
    • Cycles 3-6: every 2 weeks
    • Cycles 7-8: every 4 weeks
  • Bortezomib: 1.5 mg/m² subcutaneous (SC) weekly on days 1, 8, and 15 in all cycles
  • Cyclophosphamide: 300 mg/m² PO weekly on days 1, 8, 15, and 22 in all cycles
  • Dexamethasone: 40 mg
    • Cycle 1: 20 mg IV on days 1 and 2, followed by 40 mg weekly
    • Cycles 2-8: 40 mg IV/PO weekly
• After the induction phase, all patients received up to 12 cycles (28 days per cycle) of the following maintenance treatment:
  • DARZALEX: 16 mg/kg IV every 4 weeks
  • Dexamethasone: 12 mg IV/PO on DARZALEX dosing days
• When DARZALEX was administered as a split first dose, dexamethasone 20 mg IV was administered as a premedication on cycle 1 day 1 (C1D1) and cycle 2 day 2 (C2D2) and 4 mg was administered as a post-infusion medication PO on cycle 1 day 3 (C1D3).¹³

Phase 1b Stuy of DARZALEX in Combination with Kd or KRd

EQUULEUS (MMY1001;NCT01998971) is a phase 1b, open-label, multicenter study that evaluated the safety and efficacy of DARZALEX when administered in combination with various treatment regimens, including Kd and KRd, for the treatment of MM.^6,7

Study Design/Methods

D-Kd Arm

• Patients in the D-Kd arm received 28-day cycles of the following study treatment until disease progression:
  • DARZALEX: 16 mg/kg IV weekly on cycles 1-2, every 2 weeks on cycles 3-6, and every 4 weeks thereafter
    • Ten patients received a single first DARZALEX dose (16 mg/kg) on C1D1, while the remaining patients received the first dose split over 2 days (8 mg/kg) on C1D1 and cycle 1 day 2 (C1D2).
  • Carfilzomib: 20 mg/m² on C1D1, escalated to 70 mg/m² on cycle 1 day 8 (C1D8) onward, if tolerated. Carfilzomib was administered weekly on days 1, 8, and 15 of each cycle.
  • Dexamethasone: 40 mg/week (20 mg/week in patients aged >75 years)
• Pre-infusion medications included diphenhydramine, acetaminophen, and dexamethasone; montelukast was required before the first dose and was optional for subsequent doses.

D-KRd Arm

• Patients in the D-KRd arm received 28-day cycles of:
  • DARZALEX:16 mg/kg IV every week on cycles 1-2, every 2 weeks on cycles 3-6, and every 4 weeks thereafter
    • All patients received the first dose of DARZALEX split over 2 days (8 mg/kg days 1-2 of cycle 1).
  • Carfilzomib: 20 mg/m² on C1D1 escalated to 70 mg/m² on C1D8.
    • Carfilzomib was administered weekly on days 1, 8, and 15 of each cycle.
  • Lenalidomide: 25 mg: days 1-21 of each cycle
  • Dexamethasone: 40 mg/week
• Pre-infusion medications included dexamethasone 20 mg, diphenhydramine 25-50 mg, acetaminophen 650-1000 mg, and montelukast 10 mg (required before the first dose and was optional for subsequent doses).
• For DARZALEX as a split dose, dexamethasone 20 mg IV was administered as a premedication on C1D1 and C1D2; on cycle 1 day 3, administration of low-dose methylprednisolone (≤20 mg PO) was optional.
• Post-infusion medications included dexamethasone 20 mg or methylprednisolone 20 mg.

Final Analysis of the D-Kd Arm of EQUULEUS

Moreau et al (2023)^6,14 presented the final results from the D-Kd arm in which 10 patients received a standard first DARZALEX dose and the remaining patients received the first dose split over 2 days.

Results - D-Kd Arm

Baseline Characteristics

• The median infusion time was as follows:
  • Single dose first infusion of DARZALEX (n=9):
    • C1D1: 7.1 (range, 6.5-8.9) hours
  • Split dose first infusion of DARZALEX (n=75):
    • C1D1: 4.3 (range, 3.9-10.6) hours; C1D2: 4.2 (range, 3.9-8.6) hours
• Median infusion time was similar for all subsequent infusions in patients who received single (3.4 [range, 2.5-5.6] hours) and split (3.4 [range, 2.3-5.9] hours) first DARZALEX doses.

Safety

• IRRs with DARZALEX were reported in 6 patients (60.0%) who received a single first dose and 31 patients (41.3%) who received a split first dose.
• Most IRRs were mild (grade 3/4 IRRs, n=2) and occurred during the first infusion. Five patients (50.0%) experienced IRRs during C1D1 with a single first DARZALEX dose and 27 patients (36.0%) experienced IRRs during C1D1 with a split first DARZALEX dose.

Pharmacokinetic Analyses

• The maximum concentration of DARZALEX was observed at the end of infusion on C1D1 after the first dose or cycle 3 day 1 (C3D1) after the ninth dose.
• Serum trough concentration (C_trough) increased to maximum on C3D1 pre-dose and then decreased with less frequent dosing.
• PK profiles of single (n=10) and split first (n=75) DARZALEX doses were similar from cycle 2 day 1 (C2D1) pre-infusion onward (see Table: DARZALEX Serum Concentration with Single vs Split First Dose).
• No patient in the immunogenicity-evaluable population of this study tested positive for anti-daratumumab antibodies.

Analysis of the D-KRd Arm of the EQUULEUS Study

Chari et al (2017)⁷ presented the results from the D-KRd arm in which all patients received the first DARZALEX dose as a split dose.

Results - D-KRd Arm

Patient Characteristics

• Median infusion time, hours:
  • First infusion: C1D1; 4.15 (range, 4.0-6.0), C1D2; 4.15 (range, 3.9-6.0), second infusion: 4.18 (range, 3.6-7.1), subsequent infusions: 3.38 (range, 1.4-6.1).

Safety

• IRRs occurred in 6 patients (27%); no grade 3/4 IRRs occurred.
• Occurrence of IRRs:
  • First infusion: 5 patients (23%); second infusion: 1 patient (5%); subsequent infusions: 1 patient (5%).

rETROSPECTIVE STUDIES

Retrospective Study of IRRs in Patients who Received Split Dose of DARZALEX

Geirnaert et al (2021)⁸ reported a retrospective medical record review of incidence of IRRs in patients with relapsed MM who received ≥1 DARZALEX infusion in a split dose initiation regimen.

Study Design/Methods

• 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 a regimen in combination with bortezomib and dexamethasone (D-Vd) or in combination with lenalidomide and dexamethasone (D-Rd).
• Main objectives: The rates of DARZALEX-related IRRs when using a split dose infusion, safety of DARZALEX rapid infusions, and overall incidence of IRRs with DARZALEX infusions in real world setting.

Results

Patient Characteristics

• Median age was 68 years (range, 32-89).
• A total of 53 patients were identified in this review; 34 (64%) patients received D-Rd and 19 (36%) received D-Vd.

Safety

• 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 1, 2, 8, 15, and 22. One (2%) patient reported a grade 1/2 IRR (cycle 1 day 22).
• No IRRs were reported in patients who received DARZALEX as a slow or rapid infusion (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 Study of Split vs Standard Doses of DARZALEX

Rifkin et al (2018, 2019)^9,10 reported results from a retrospective, observational cohort study of MM patients who were administered DARZALEX in select community clinical practices within the USON (N=622) to compare split first dose vs standard dose schedules in relation to IRRs and infusion times.

Study Design/Methods

• DARZALEX preparation and administration protocol utilized by USON:
  • Split first dose protocol: On each of 2 consecutive days, DARZALEX was diluted to a total volume of 500 mL with normal saline and administered at 50 mL/hour for 1 hour. If no IRRs were noted, the infusion rate could be increased by 50 mL/hour every hour to a maximum of 200 mL/hour.
  • Standard dose protocol: On a single day, DARZALEX was diluted to a total volume of 1000 mL with normal saline and administered at 50 mL/hour for 1 hour. If no IRRs were noted, the infusion rate could be increased by 50 mL/hour every hour to a maximum of 200 mL/hour.
• Two study cohorts were identified from the USON between November 1, 2015 and June 30, 2017 based on DARZALEX dosing administered on the first day of the dosing schedule:
  • Split first dose (8 mg/kg; n=364; 58.5%)
  • Standard dose (16 mg/kg; n=258; 41.5%)
• Study cohorts were followed until the administration of their next scheduled dose.
• Structured queries and chart abstraction were used to collect data from the USON’s iKnowMed (iKM) electronic health record system.
• Inclusion criteria: adult patients diagnosed with MM that initiated DARZALEX therapy of either a split first dose or standard dose schedule administered during the identified study period, ≥2 visits at a USON site utilizing iKM capabilities
• Exclusion criteria: enrollment in clinical trials during the study period
• Endpoints: safety (IRRs) and infusion times

Results

Patient Characteristics

• Patients (54.2% male) ranged in age from 31.8-90+ years (median 63.6 years)
• Karnofsky performance status (KPS) scores tended to be higher among patients treated with split first dose vs standard dose (P=0.0213 for trend).
• Other baseline characteristics were balanced between the cohort groups.

Safety

• Random chart review data (n=302) reported that IRRs with the first administration of DARZALEX were reported in 48.0% (n=145) of all patients:
  • Split first dose patients: 47.8% (n=88/184)
  • Standard dose patients: 48.3% (n=57/118)
• Most commonly reported IRRs included lower-respiratory (26.1%, n=79), upper-respiratory (17.2%, n=52), and gastrointestinal reactions (12.5%, n=38), chills (8.9%, n=27) and flushing (6.6%, n=20). No statistically significant differences were noted for any IRRs between the study groups.
• Of the patients who received split first dose of DARZALEX, 3.8% experienced an IRR during day 2 which included lower respiratory related events (1.1%, n=4), gastrointestinal events (0.8%, n=3) and musculoskeletal pain (0.5%, n=2)

Infusion Time

• Split first dose schedule utilization increased significantly over time within the USON with more patients in 2017 second quarter having received split first dose versus standard dose (P<0.0001).
• The median infusion duration of the day 1 split first dose was 4.5 hours (range, 0.1-8.1) compared to the standard dose infusion time of 6.5 hours (range 0.7-9.9) (P<0.0001). Total duration for both infusions of the split first dose regimen was 8.7 hours.
• Utilizing multivariate linear regression analysis, the only factor associated with total administration time was dosing schedule. The administration time for split first dose patients was over 2.5 hours longer than standard dosing (split first dose or standard dose administration; β, 2.65; standard error, 0.2471; P<0.0001).

Retrospective Chart Review of Patients who Received Split Dose of DARZALEX

Arnall et al (2019)¹¹ reported results from a retrospective, observational chart review of RRMM patients who were administered DARZALEX in the outpatient setting (n=13) to evaluate split first dose in relation to IRRs and infusion times.

Study Design/Methods

• DARZALEX preparation and administration:
  • Standard 16 mg/kg dose infused 50% on day 1 and the remaining half on day 2 of the first cycle
  • If no IRR was experienced on days 1 and 2 of treatment, the day 8 dose would be administered at the standard infusion rate per labeling.
  • If an IRR was experienced on days 1 or 2 of treatment, split dosing was continued on days 8 and 9 at the same initial infusion titration rate.
  • Incidence of IRRs were collected.

Results

Patient Characteristics

• Patients (38.4% male) ranged in age from 56-85 years.
• Companion therapies included bortezomib (n=5), pomalidomide (n=5). Three patients had no companion therapy.
• Pre-medications were reported as similar for all patients and included acetaminophen, corticosteroids, diphenhydramine and montelukast.

Safety

• Two patients (15%) experienced an IRR:
  • One patient experienced a grade 3 IRR on day 1. The IRR did not reoccur on day 2. DARZALEX was discontinued prior to day 8 due to rapid disease progression.
  • One patient experienced a grade 1 IRR on day 1. The infusion was temporarily stopped and restarted upon IRR resolution with no further incident.
  • No patient experienced an IRR with day 15 or subsequent doses of DARZALEX.

Infusion Time

• The mean infusion duration on days 1 and 2 was 4.72 hours (range, 4.40-6.48) and 4.19 hours (range, 3.25-4.47), respectively.

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 01 July 2026.