DARZALEX + DARZALEX FASPRO - Use in Combination with Carfilzomib and Dexamethasone in Multiple Myeloma

PRODUCT LABELING

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

CLINICAL DATA

Phase 3 Study of DARZALEX in Combination with Kd in RRMM

CANDOR (NCT03158688) is a phase 3, randomized, openlabel, multicenter study evaluating the efficacy and safety of DARZALEX with carfilzomib and dexamethasone (D-Kd) vs carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma (RRMM).^1,2

Study Design/Methods

• Patients were randomized 2:1 to receive either of the following as 28-day cycles until disease progression^1,2:
  • D-Kd:
    • 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 20 mg/m² IV on days 1, 2 of cycle 1 and 56 mg/m² IV 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 or better (≥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

Primary Analysis of the CANDOR Study

Dimopoulos et al (2020)² reported the results of this study at a median follow-up of approximately 17 months.

Results

Patient Characteristics

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

Efficacy

• Median PFS follow-up for the D-Kd vs Kd arms: 16.9 months vs 16.3 months.²
• Treatment with D-Kd 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 D-Kd vs Kd arms: not estimable (NE) vs 15.8 months.²
• Number of events that resulted in progression/death for the D-Kd vs Kd arms: 110 (35%) vs 68 (44%).²
• The HR for PFS favored the D-Kd 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. See Table: Progression-Free Survival in Prespecified Subgroups.^1,2

• The response rates and MRD-negativity rates (10^-5) are summarized in Table: Response Rates and MRD-Negative Rates.²
• At a median duration of follow-up of 17.2 and 17.1 months in the D-Kd 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.¹

• Adverse events (AEs) are summarized in Tables: Treatment-Emergent Adverse Events, Adverse Events of Interest, Adverse Events Leading to Treatment Discontinuation, and Fatal Events.²

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

Final Efficacy and Safety Results of the CANDOR Study

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 D-Kd vs Kd arm, the median duration of follow-up was 50.6 months (range, 0-57) vs 50.1 months (range, 0-58).³
• Survival and MRD-negativity rates are summarized in Table: OS and MRD-Negativity (10^-5) Rates.³

• Prespecified subgroup analyses showed an OS improvement in the D-Kd vs Kd arm in most subgroups.³
  • The greatest OS benefit of D-Kd 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 D-Kd vs Kd arm, 49% (n=153) vs 68% (n=105) of patients received subsequent antimyeloma therapy, respectively.³

Safety

• The safety results were consistent with previous reports, and no new safety signals were identified with the longer follow-up. See Table: Safety Overview.⁶

• Grade ≥3 infections and infestations occurred in 46% (n=142) vs 32% (n=49) of patients in the D-Kd 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 D-Kd 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.⁶

• The most common causes of fatal TEAEs were infections (D-Kd, 7% [n=21]; Kd, 3% [n=5] and cardiac disorders (D-Kd, 2% [n=6]; Kd, 0%).³
  • In the D-Kd vs Kd arm, the exposure-adjusted rates of fatal TEAEs were 6.5 vs 5.6 per 100 patients-years, respectively.
  • In the D-Kd 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.³

Phase 1b Study of DARZALEX in Combination with Various Treatment Regimens

EQUULEUS (MMY1001; NCT01998971) is a phase 1b, open-label, multiarm, multicenter 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).⁴

Study Design/Methods

• Patients in the D-Kd arm received 28-day cycles of the following treatment⁷:
  • 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).
• Pre-infusion medications included diphenhydramine, acetaminophen, and dexamethasone; montelukast was required before the first dose and was optional for subsequent doses.⁷
• Patients in the D-Kd arm were followed until patient withdrawal, death, or end of study.⁷
• Eligibility criteria for the D-Kd 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.⁷
• Primary endpoints: Safety and tolerability.⁴
• Secondary endpoints: ORR and OS.⁷
• Exploratory endpoints: PFS and pharmacokinetics (PK).⁷

Final Analysis of the D-Kd Arm of the EQUULEUS Study

Moreau et al (2023)^5,7 presented the safety and efficacy results from the final analysis of the EQUULEUS study that evaluated D-Kd in patients with RRMM who received 13 prior lines of therapy.

Results: D-Kd Arm

Patient Characteristics

• Baseline demographics and patient characteristics are presented in Table: Baseline Demographics and Patient Characteristics.⁷

• At a median follow-up of 23.7 months, 50 patients (58.8%) discontinued treatment.⁷
  • Thirty-six patients (42.4%) 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 cycles of treatment (range, 1-37). Median treatment duration was 19.8 months (range, 0.3-34.5).⁷
• 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.⁷

Efficacy

• Efficacy outcomes are described in Table: Efficacy Outcomes.⁵

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.⁵
  • Grade 3/4 infections occurred in 18 (21.2%) patients, with the most common being pneumonia (4.7%).

• Serious TEAEs occurred in 41 patients (48.2%), with the most common being basal cell carcinoma, pneumonia, and upper respiratory tract infection (4.7% each).⁵
• Five patients (5.9%) 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 patients (10.6%) 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
• 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
• Median LVEF did not notably change over time; see Table: Echocardiogram Assessment.⁷

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

Phase 2 Study of DARZALEX FASPRO in Combination with Various Treatment Regimens

PLEIADES (MMY2040; NCT03412565) is a 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.^8-11

Study Design/Methods

• Patients received 28-day cycles of the following⁷:
  • DARZALEX FASPRO 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).
• Pre-infusion medications included diphenhydramine, acetaminophen, and dexamethasone.⁷
• Patients in the D-Kd arm were followed for up to 8 weeks after the last dose of treatment.⁷
• Eligibility criteria for the D-Kd 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.⁷
• Primary endpoint: ORR.⁹
• Secondary endpoints: very good partial response or better (≥VGPR), ≥CR rate, duration of response, and IRR rate.⁷

Final Analysis of the D-Kd Arm of the PLEIADES Study

Moreau et al (2023)^5,7 presented the final safety and efficacy results of the PLEIADES study that evaluated D-Kd in patients with RRMM who received 1 prior line of
lenalidomide-based therapy.

Results: D-Kd Arm

Patient Characteristics

• Baseline demographics and patient characteristics are presented in Table: Baseline Demographics and Patient Characteristics.⁷

• At a median follow-up of 12.4 months, 31 patients (47%) discontinued treatment.⁷
  • Twenty-four patients (36.4%) 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 cycles of treatment (range, 1-23). Median treatment duration was 12 months (range, 0-21).⁷
• Median relative dose intensity was 100% (range, 75%-100%) for DARZALEX FASPRO, 94.6% (range, 48%-102%) for carfilzomib, and 86.6% (range, 43%-101%) for dexamethasone.⁷

Efficacy

• PFS and OS were not analyzed.⁵
• Efficacy outcomes are described in Table: Efficacy Outcomes.^5,7

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.⁵
  • 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 FASPRO were reported in 3 patients (4.5%; grade 3, n=2). All patients with IRRs experienced them on the first administration.⁵
• Median time to onset of IRRs was 65 minutes (range, 4-75).⁵
• Local injection-site reactions occurred in 7 patients (10.6%; all grade 1/2).⁵
• Median LVEF did not notably change over time; see Table: Echocardiogram Assessment.⁷

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 FASPRO had numerically higher C_trough (within a similar range) vs DARZALEX IV.⁵
• Three patients (4.7%) 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 21 July 2026. In response to your specific request, summarized in this response is the relevant data from company-sponsored studies pertaining to this topic.