PRODUCT LABELING

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

CLINICAL DATA

DARZALEX Phase 3 Study

CANDOR (clinicaltrials.gov identifier: NCT03158688) is a randomized, openlabel, multicenter, phase 3 study evaluating the efficacy and safety of DARZALEX with carfilzomib and dexamethasone (DKd) vs carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma (RRMM).^1,2 Dimopoulos et al (2020)² reported the results of this study at a median duration of follow-up of approximately
17 months. Usmani et al (2023)³ reported the final efficacy and safety results of this study after a median duration of follow-up of approximately 50 months.

Study Design/Methods

• Patients were randomized 2:1 to receive either of the following as 28-day cycles until disease progression^1,2:
  • DKd:
    • DARZALEX 16 mg/kg intravenously (IV; first dose split over 2 days [8 mg/kg each] of cycle 1) weekly for cycles 1-2; every 2 weeks for cycles 3-6, every
      4 weeks thereafter.
    • Carfilzomib 56 mg/m² IV; 20 mg/m² on days 1, 2 of cycle 1; and 56 mg/m² thereafter.
    • Dexamethasone 40 mg orally 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 performance status (ECOG PS) of 02; creatinine clearance ≥20 mL/min; left ventricular ejection fraction (LVEF) ≥40%.¹
• Minimal residual disease (MRD) samples were collected at baseline and analyzed at 12 months for MRD-negativity (10^-5) complete response (CR) rate.^1,2
• Primary endpoint: Progression-free survival (PFS).²
• Key secondary endpoints: Overall response rate (ORR), MRD (10^-5), and overall survival (OS).^1,2

Results

Patient Characteristics

• A total of 466 patients received either DKd (n=312) or Kd (n=154).² Baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.

Efficacy

• Median PFS follow-up for the DKd vs Kd arms: 16.9 months vs 16.3 months.²
• Treatment with DKd resulted in a 37% reduction in the risk of progression or death (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.460.85; two-sided P=0.0027).²
• Median PFS for the DKd vs Kd arms: Not estimable (NE) vs 15.8 months.²
• Number of events that resulted in progression/death for the DKd vs Kd arms: 110 (35%) vs 68 (44%).²
• The HR for PFS favored the DKd arm across other prespecified subgroups including age, International Staging System (ISS) stage, cytogenetic risk status, number of prior lines of therapy, lenalidomide-exposed patients, and lenalidomide-refractory patients.² See Table: Progression-Free Survival in Prespecified Subgroups.

• The response rates and MRD-negativity rates (10^-5) are summarized in Table: Response Rates and MRD-Negative Rates.
• At a median duration of follow-up of 17.2 and 17.1 months in the DKd and Kd arms, respectively, the median OS was not reached in both arms (HR for death, 0.75; 95% CI, 0.49-1.13; P=0.17).²

Safety

• Treatment exposure is summarized in Table: Treatment Exposure.

• Adverse events (AEs) are summarized in Tables: Treatment-Emergent Adverse Events, Adverse Events of Interest, Adverse Events Leading to Treatment Discontinuation, and Fatal Events.

• The most common AE leading to DARZALEX treatment discontinuation was pneumonia (n=4 in the DKd arm; n=0 in the Kd arm) and cardiac failure for carfilzomib treatment discontinuation (n=6 in the DKd arm; n=3 in the Kd arm).²

Final Efficacy and Safety Results of CANDOR

Usmani et al (2023)³ reported the final efficacy and safety results of the CANDOR study after a median duration of follow-up of approximately 50 months.

Results

Efficacy

• In the DKd vs Kd arm, the median duration of follow-up was 50.6 (range, 0-57) months vs 50.1 (range, 0-58) months.³
• Survival and MRD-negativity rates are summarized in Table: OS and MRD-Negativity (10^-5) Rates.
• Prespecified subgroup analyses showed an OS improvement in the DKd vs Kd arm in most subgroups.³
  • The greatest OS benefit of DKd was observed in patients with high-risk cytogenetics (HR, 0.52; 95% CI, 0.29-0.94) and ISS stage III at screening (HR, 0.58; 95% CI, 0.35-0.99).
• In the DKd vs Kd arm, 49% (n=153) vs 68% (n=105) of patients received subsequent antimyeloma therapy, respectively.³

Safety

• The treatment exposure is summarized in Table: Treatment Exposure.
• The safety results were consistent with previous reports, and no new safety signals were identified with the longer follow-up. See Table: Safety Overview.
• Grade ≥3 infections and infestations occurred in 46% (n=142) vs 32% (n=49) of patients in the DKd vs Kd arm and led to carfilzomib discontinuation in 22% (n=69) vs 20% (n=30) of patients, respectively.³
• Treatment-emergent adverse events (TEAEs) related to coronavirus disease 2019 (COVID-19) occurred in 11% (n=33) vs 4% (n=6) of patients in the DKd vs Kd arm, and deaths related to COVID-19 occurred in 2% (n=6) vs 1% (n=1) of patients, respectively.³
• The incidence of carfilzomib and DARZALEX discontinuation due to TEAEs decreased over time, with most discontinuations due to TEAEs occurring in the first 18 months. See Table: TEAEs Leading to Treatment Discontinuation.
• The most common causes of fatal TEAEs were infections (DKd, 7% [n=21]; Kd, 3% [n=5] and cardiac disorders (DKd, 2% [n=6]; Kd, 0%).³
  • In the DKd vs Kd arm, the exposure-adjusted rates of fatal TEAEs were 6.5 vs 5.6 per 100 patients-years, respectively.
  • In the DKd vs Kd arm, the fatal infection rates were 7% (n=21) vs 3% (n=5), and the exposure-adjusted fatal infection rates were 3.5 vs 2.55 per 100 patient-years, respectively.
• TEAEs are summarized in Tables: TEAEs in the Safety Population, TEAEs of Interest, and Fatal TEAEs.

DARZALEX Phase 1b Study

EQUULEUS (MMY1001; clinicaltrials.gov identifier: NCT01998971)⁴ is an ongoing, open-label, multiarm, multicenter, phase 1b study evaluating the safety and efficacy of DARZALEX when administered in combination with various treatment regimens, including Kd, for the treatment of multiple myeloma (MM). Usmani et al (2018)⁷ evaluated the efficacy of DARZALEX in combination with standard of care regimens, including Kd, in patients with RRMM who were previously exposed to or refractory to lenalidomide in the POLLUX, CASTOR, and MMY1001 studies. Moreau et al (2023)^5,8 presented the final safety and efficacy results from the final analysis of the EQUULEUS study that evaluated DKd in patients with RRMM who received 13 prior lines of therapy (n=85).

Study Design/Methods

• Patients in the DKd arm received 28-day cycles of the following treatment⁸:
  • DARZALEX: 16 mg/kg IV every week in cycles 1-2, every 2 weeks in cycles 3-6, and every 4 weeks thereafter.
    • Ten patients received a single first DARZALEX dose (16 mg/kg) on cycle 1
      day 1 (C1D1), while remaining patients received the first dose split over 2 days (8 mg/kg) on C1D1 and C1D2.
  • Carfilzomib: 20 mg/m² on C1D1 escalated to 70 mg/m² on C1D8 onward, if tolerated.
    • Carfilzomib was administered weekly on days 1, 8, and 15 of each 28-day cycle.
  • Dexamethasone: 40 mg/week (20 mg/week in patients aged >75 years).
• Preinfusion medications included diphenhydramine, acetaminophen, and dexamethasone; montelukast was required before the first dose and was optional for subsequent doses.⁸
• Patients in the DKd arm were followed until patient withdrawal, death, or end of study.⁸
• 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 PS ≤2; LVEF ≥40%. Lenalidomide-refractory patients with disease progression after their last therapy were allowed.⁸
• Primary endpoints: Safety and tolerability⁴
• Secondary endpoints: ORR and OS.⁸
• Exploratory endpoints: PFS and pharmacokinetics (PK).⁸

Results: DKd Arm

Patient Characteristics

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

• At a median duration of follow-up of 23.7 months, 50 (58.8%) patients discontinued treatment.⁸
  • Thirty-six (42.4%) patients discontinued treatment due to progressive disease (PD), 6 (7.1%) due to patient withdrawal, 5 (5.9%) due to AEs, 2 (2.4%) due to physician decision, and 1 (1.2%) due to death.
• Patients received a median of 21 (range, 1-37) cycles of treatment. Median treatment duration was 19.8 (range, 0.3-34.5) months.⁸
• 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.⁸

Efficacy

• Efficacy outcomes are described in Table: Efficacy Outcomes.

Safety

• The most common any grade (≥25%) and grade 3/4 (≥5%) 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%).⁵
• Serious TEAEs occurred in 41 (48.2%) patients, with the most common being basal cell carcinoma, pneumonia, and upper respiratory tract infection (4.7% each).⁵
• 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).⁵
• Grade 3/4 cardiac TEAEs occurred in 9 (10.6%) patients and included sinus tachycardia, cardiac failure, systolic dysfunction (n=2 each), atrial fibrillation, congestive cardiomyopathy, left ventricular failure, myocardial ischemia, and myocarditis (n=1 each).⁵
• Median LVEF did not notably change over time; see Table: Echocardiogram Assessment.
• Infusion-related reactions (IRRs) with DARZALEX were reported in 6 (60.0%) patients who received a single first dose and 31 (41.3%) patients 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.⁵

PK Analyses

• The maximum concentration was observed on C1D1 (end of infusion) after the first dose or C3D1 (end of infusion) after the ninth dose.⁵
• Serum trough concentration (C_trough) increased to maximum C_trough on C3D1 pre-dose and then decreased with less frequent dosing.⁵
• PK profiles of single first (n=10) and split first (n=75) DARZALEX doses were similar from C2D1 preinfusion onward. No patient in the immunogenicity-evaluable population of this study tested positive for anti-DARZALEX antibodies.⁵

DARZALEX FASPRO Phase 2 Studies

PLEIADES (MMY2040; clinicaltrials.gov identifier: NCT03412565) is an ongoing, phase 2, non-randomized, open-label, multicenter study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various treatment regimens in patients with MM.^9-12 Moreau et al (2023)^5,8 presented the final safety and efficacy results of the PLEIADES study that evaluated DKd in patients with RRMM who received 1 prior line of
lenalidomide-based therapy (n=66).

Study Design/Methods

• Patients received 28-day cycles of the following⁸:
  • DARZALEX subcutaneously (SC): Administered weekly in cycles 1-2, every 2 weeks in cycles 3-6, and every 4 weeks thereafter.
  • Carfilzomib: 20 mg/m² on C1D1 escalated to 70 mg/m² on C1D8 onwards, if tolerated.
    • Carfilzomib was administered weekly on days 1, 8, and 15 of each 28-day cycle.
  • Dexamethasone: 40 mg/week (20 mg/week in patients aged >75 years).
• Preinfusion medications included diphenhydramine, acetaminophen, and dexamethasone.⁸
• Patients in the DKd arm were followed for up to 8 weeks after the last dose of treatment.⁸
• Eligibility criteria for the DKd arm: RRMM (1 prior lines of therapy, including ≥2 lenalidomide cycles); achieved at least PR to the first treatment regimen, and progressed from or were refractory to the first line of treatment; DARZALEX and carfilzomib-naïve; ECOG PS ≤2; LVEF ≥40%. Lenalidomide-refractory patients with disease progression after their last therapy were allowed.⁸
• Primary endpoint: ORR.¹⁰
• Secondary endpoints: At least very good partial response rate, ≥CR rate, duration of response, and IRR rate.⁸

Results: DKd Arm

Patient Characteristics

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

• At a median duration of follow-up of 12.4 months, 31 (47%) patients discontinued treatment.⁸
  • Twenty-four (36.4%) patients discontinued treatment due to PD, 3 (4.5%) due to death, 2 (3%) due to patient withdrawal, 1 (1.5%) due to AEs, and 1 (1.5%) due to other reasons.
• Patients received a median of 13 (range, 1-23) cycles of treatment. Median treatment duration was 12 (range, 0-21) months.⁸
• Median (range) relative dose intensity was 100% (range, 75%-100%) for DARZALEX SC, 94.6% (range, 48%-102%) for carfilzomib, and 86.6% (range, 43%-101%) for dexamethasone.⁸

Efficacy

• PFS and OS were not analyzed.⁵
• Efficacy outcomes are described in Table: Efficacy Outcomes.

Safety

• The most common any grade (≥25%) and grade 3/4 (≥5%) TEAEs are presented in Table: Most Common Any Grade (≥25%) or Grade 3/4 (≥5%) TEAEs.
  • Grade 3/4 infections occurred in 9 (13.6%) patients, with the most common being pneumonia (4.5%).⁵
• Serious TEAEs occurred in 22 (33.3%) patients, with the most common being pneumonia (4.5%).⁵
• One (1.5%) patient discontinued treatment due to TEAEs, and 3 patients reported grade 5 TEAEs (COVID-19 pneumonia, sepsis, and respiratory failure, n=1 each).⁵
• Grade 3/4 cardiac TEAEs occurred in 2 (3%) patients (grade 3 cardiac failure and grade 4 left ventricular dysfunction, n=1 each).⁵
• IRRs with DARZALEX SC were reported in 3 (4.5%) patients (grade 3, n=2). All patients with IRRs experienced them on the first administration.⁵
• Median time to onset of IRRs was 65 (range, 4-75) minutes.⁵
• Local injection-site reactions occurred in 7 (10.6%) patients (all grade 1/2).⁵
• Median LVEF did not notably change over time; see Table: Echocardiogram Assessment.

PK Analysis

• The maximum concentration of DARZALEX SC was observed on C1D4 after the first dose or C3D4 after the ninth dose.⁵
• C_trough increased to maximum C_trough on C3D1 pre-dose and then decreased with less frequent dosing.⁵
• DARZALEX SC had numerically higher C_trough (within a similar range) vs DARZALEX IV.⁵
• Three (4.7%) patients in the recombinant human hyaluronidase PH20 (rHuPH20) immunogenicity-evaluable population (n=64) had treatment-emergent anti-rHuPH20 antibodies after DARZALEX SC administration; none were neutralizing.⁵

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 9 August 2024.