PRODUCT LABELING

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

CLINICAL STUDIES

DARZALEX in Combination with Carfilzomib and Dexamethasone

CANDOR (clinicaltrials.gov identifier: NCT03158688) is a randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of DKd vs Kd in patients with RRMM.^{2, 3}

Study Design/Methods

• Patients were randomized 2:1 to receive either of the following as 28-day cycles until disease progression:
  • DKd:
    • 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 IV; 20 mg/m² 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.
• Key eligibility criteria: RRMM; 1-3 prior therapies with ≥ partial response (PR) to ≥ 1 prior therapy; Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; creatinine clearance ≥20 mL/min; left ventricular ejection fraction (LVEF) ≥40%.
• Minimal residual disease (MRD) samples were collected at baseline and analyzed at
  12 months for MRD negativity (10^-5) complete response (CR) rate.
• Primary endpoint: progression-free survival (PFS)
• Key secondary endpoints: overall response rate (ORR), MRD (10^-5), and overall survival (OS).

DARZALEX in Combination with CyBorD in RMM

LYRA (clinicaltrials.gov identifier: NCT02951819) is a phase 2, single-arm study evaluating the safety and efficacy of DARZALEX (the first DARZALEX administration being given as a divided dose over 2 days) when administered in combination with CyBorD for the treatment of MM in patients who have not received previous treatment or have relapsed after receiving 1 line of treatment.^{4, 5}

Study Design/Methods

• Key eligibility criteria: Patients of ≥18 years of age documented MM as per the International Myeloma Working Group (IMWG) criteria, ECOG performance status score of 0-2, and previously untreated NDMM or RMM with 1 prior line of therapy were eligible. Patients with RMM were included only if they achieved partial response or better (≥PR) with prior therapy before disease progression.⁵
• Patients refractory to a proteasome inhibitor (PI) or a combination of PI and immunomodulatory imide drug (IMiD) were excluded.⁵
• Patients received 4-8 cycles (28 days per cycle) of the following induction treatment⁵:
  • 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 treatment⁵:
  • 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).¹²
• Patients underwent high-dose therapy (HDT) and autologous stem cell transplant (ASCT) at the discretion of the investigator after the induction phase.¹³
• Primary endpoint: Very good partial response or better (≥VGPR) after 4 induction cycles¹³
• Key secondary endpoints: ORR, time to ≥VGPR, time to ≥PR, PFS, OS, safety, and tolerability¹³

DARZALEX in Combination with Kd or KRd

EQUULEUS (MMY1001; clinicaltrials.gov identifier: NCT01998971)^{6, 7} is an ongoing study evaluating the safety and efficacy of DARZALEX when administered in combination with various treatment regimens, including Kd and KRd, for the treatment of MM. Moreau et al (2023)^{6, 14} presented the final results from the DKd arm in which 10 patients received a standard first DARZALEX dose and the remaining patients received the first dose split over 2 days, and Chari et al (2017)⁷ presented the results from the DKRd arm in which all patients received the first DARZALEX dose as a split dose.

Study Design/Methods

• Phase 1b, open-label, multicenter study that evaluated DKd in patients with RRMM who received 1-3 prior lines of therapy (N=85).

DKd Arm

• Patients in the DKd 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.
• Patients in the DKd arm were followed until patient withdrawal, death, or end of study.
• Key eligibility criteria for the DKd arm: RRMM (1-3 prior lines of therapy, including bortezomib and an immunomodulatory drug); ≥PR to 1 prior line of therapy and disease progression after the last line of therapy; DARZALEX and carfilzomib-naïve; ECOG performance status ≤2; and LVEF ≥40%. Lenalidomide-refractory patients with disease progression after their last therapy were allowed.
• Primary endpoints: safety and tolerability
• Secondary endpoints: ORR and OS
• Exploratory endpoints: PFS and pharmacokinetics (PK)

DKRd Arm

• Patients in the DKRd 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.
• All patients received aspirin prophylaxis.
• Growth factors were permitted for patients experiencing neutropenia.
• Patients in the DKRd arm participated in the study for either a maximum 1-year treatment duration or until disease progression.
• Eligibility criteria for the DKRd arm: NDMM; transplant eligible and non-eligible; treatment duration: ≤13 cycles or until elective discontinuation for ASCT; no clinically significant cardiac disease
• Primary endpoints: safety and tolerability
• Secondary endpoints: ORR, duration of response, time to response, and IRRs
• Exploratory endpoint: PFS

Results - DKd Arm

Baseline Characteristics

• Baseline patient and treatment characteristics are presented in Table: Baseline Characteristics and Prior Multiple Myeloma Therapies Received for the DKd Regimen.
• At a median follow-up of 23.7 months, 50 (58.8%) patients discontinued treatment (progressive disease, 36 [42.4%]; patient withdrawal, 6 [7.1%]; adverse events [AEs], 5 [5.9%]; physician decision, 2 [2.4%]; and death, 1 [1.2%]).
• Median number of treatment cycles were 21 (range, 1-37), and median duration of treatment was 19.8 (range, 0.3-34.5) months.
• Median relative dose intensity was 99.8% (range, 49%-108%) for DARZALEX, 95% (range, 22%-105%) for carfilzomib, and 97.9% (range, 50%-101%) for dexamethasone.
• 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

• The most common any grade (≥25%) and grade 3/4 (≥5%) treatment-emergent adverse events (TEAEs) are presented in Table: Most Common Any Grade (≥25%) or Grade 3/4 (≥5%) TEAEs.
  • Grade 3/4 infections occurred in 18 (21.2%) patients, with the most common being pneumonia (4.7%).
• Serious TEAEs occurred in 41 (48.2%) patients, with the most common being basal cell carcinoma, pneumonia, and upper respiratory tract infection (URTI; 4.7% each).
• Five (5.9%) patients discontinued treatment due to TEAEs, and 3 patients reported grade 5 TEAEs (general physical health deterioration, n=2; multiple organ dysfunction syndrome, n=1).
• Grade 3/4 cardiac TEAEs occurred in 9 (10.6%) patients and included sinus tachycardia, cardiac failure, and systolic dysfunction (n=2 each) and atrial fibrillation, congestive cardiomyopathy, left ventricular failure, myocardial ischemia, and myocarditis (n=1 each).
• Median LVEF did not change notably over time; see Table: Echocardiogram Assessment.
• IRRs with DARZALEX were reported in 6 (60.0%) patients who received a single first dose and 31 (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 (50.0%) patients experienced IRRs during C1D1 with a single first DARZALEX dose and 27 (36.0%) experienced IRRs during C1D1 with a split first DARZALEX dose.

Efficacy

• Efficacy outcomes are described in Table: Efficacy Outcomes.

PK 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.

Results - DKRd Arm

Baseline Characteristics

• Among patients who received the DKRd regimen (N=22):
  • Baseline patient demographics and disease characteristics are presented in Table: Baseline Characteristics for the DKRd Regimen.
  • Median follow-up: 16.1 (range, 5.7-18.3) months
  • Median number of treatment cycles: 13 (range, 1.0-13.0)
  • All patients, except 3, were escalated to carfilzomib 70 mg/m² by C2D1.
    • 1 discontinued treatment at C2D1; 1 dose reduction to 56 mg/m² at C2D1; 1 escalated to 70 mg/m² at cycle 3 day 8 (C3D8)
  • A total of 8 patients discontinued treatment (n=1, AE; n=1, progressive disease; n=6, ASCT).⁷

Safety

• Among patients who received the DKRd regimen (N=22):
  • The most common hematologic TEAEs are presented in Table: Hematologic TEAEs Occurring in ≥30% of Patients Who Received the DKRd Regimen.
  • The most common nonhematologic TEAEs are presented in Table: Nonhematologic TEAEs Occurring in ≥30% of Patients Who Received the DKRd Regimen.
  • Serious adverse events (SAEs) occurred in 10 (46%) of patients, with pulmonary embolism (PE, 3 [14%] patients) being the most common SAE.
  • One treatment discontinuation was due to PE unrelated to DARZALEX or carfilzomib.
  • No change in baseline median LVEF occurred over time
  • One patient had a transient grade 3 cardiac failure.
  • IRRs occurred in 6 (27%) patients; no grade 3/4 IRRs occurred.
  • Occurrence of IRRs:
    • First infusion: 5 (23%) patients; second infusion: 1 (5%) patient; subsequent infusions: 1 (5%) patient
  • 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)⁷

Efficacy

• Among patients who received the DKRd regimen (N=22):
  • The median number of treatment cycles was 13 (range, 1.0-13.0).
  • After 4 cycles (n=21), response rates were: sCR: 14%, ≥CR: 14%, ≥VGPR: 71%, and ≥PR: 100%
  • After 8 cycles (n=15), response rates were: sCR: 27%, ≥CR: 27%, ≥VGPR: 87%, and ≥PR: 100%. Five patients who proceeded to ASCT before cycle 8 and 1 patient who discontinued due to progressed disease at cycle 7 were excluded.
  • Best responses (n=21): sCR: 43%, ≥CR: 57%, ≥VGPR: 91%, and ≥PR: 100%.
  • MRD-negative rates: 10^-4 sensitivity threshold: 23%, 10^-5 sensitivity threshold: 14%, and 10^-6 sensitivity threshold: 0%.
  • One patient had progressed at the clinical cutoff date.
    • The 12-month PFS rate was 95% based on Kaplan-Meier estimate; all patients remain alive.
  • Median number of cluster of differentiation 34⁺(CD34⁺) cells collected from patients: 10.6 x 10⁶ cells/kg (n=20).
  • Patients received a median of 5 (range, 4-9) treatment cycles prior to stem cell harvest.
  • Among eligible patients (n=20), 15 (75%) had a best response of ≥VGPR prior to stem cell harvest.
    • Among 6 patients who underwent ASCT, 3 (50.0%) had a best response of sCR, and 3 (50.0%) had a best response of VGPR.
    • Two patients upgraded their previous confirmed responses from VGPRs to sCRs.

rETROSPECTIVE STUDIES

Retrospective, Multicenter Study

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 (DVd) or in combination with lenalidomide and dexamethasone (DRd).
• 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 (range, 32-89) years.
• A total of 53 patients were identified in this review; 34 (64%) patients received DRd and 19 (36%) received DVd.

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, Observational Study

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, Observational, Chart Review

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 26 June 2023.