The efficacy of carfilzomib and daratumumab with dexamethasone was assessed in two clinical trials, CANDOR and EQUULEUS. The phase III CANDOR trial was a randomized, open-label, multicenter trial assessing the combination of carfilzomib (20/56 mg/m2 twice-weekly regimen) with IV daratumumab and dexamethasone (DKd) versus carfilzomib (20/56 mg/m2 twice-weekly regimen) and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy.
In the study, a total of 466 patients were randomized: 312 to the DKd arm and 154 to the Kd arm. Efficacy was analyzed by an independent review committee (IRC) evaluating progression-free survival (PFS) using response criteria from the International Myeloma Working Group (IMWG). Median PFS was not attained for the DKd arm and was 15.8 months (95% CI: 12.1, NE) for the Kd arm (HR 0.63; 95% CI: 0.46, 0.85; 1-sided P = 0.0014).
In addition, the EQUULEUS trial was an open-label, multicohort trial assessing the combination of carfilzomib (20/70 mg/m2 once-weekly regimen) with IV daratumumab and dexamethasone (DKd). Efficacy was based on overall response rate (ORR) as evaluated by the IRC using IMWG response criteria. Of the 85 patients with relapsed or refractory MM who had received one to three prior lines of therapy enrolled in the DKd cohort, the ORR was 81% (95% CI: 71, 89) with a duration of response of 27.5 months (20.5, not estimable).
The recommended dosage regimens of carfilzomib, when administered in combination with IV daratumumab and dexamethasone are as follows: Once-weekly 20/70 mg/m2 regimen: administer carfilzomib IV as a 30-minute infusion on Days 1, 8, and 15 of each 28-day cycle at a dose of 20 mg/m2 on Cycle 1 Day 1 and, if tolerated, increased to 70 mg/m2 on Cycle 1 Day 8 and thereafter. The second recommended dosage regimen is a twice-weekly 20/56 mg/m2 regimen as follows: administer carfilzomib IV as a 30-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle at a dose of 20 mg/m2 on Days 1 and 2 of Cycle 1 and, if tolerated, increased to 56 mg/m2 on Cycle 1 Day 8 and thereafter.
The recommended dosage regimen of IV daratumumab, when administered in combination with carfilzomib and dexamethasone, is 16 mg/kg actual body weight given as split dosing of 8 mg/kg on Days 1 and 2 of Cycle 1, followed by standard dosing of 16 mg/kg for subsequent doses administered weekly from Weeks 2 to 8, every 2 weeks from Weeks 9 to 24, and every 4 weeks from Week 25 and thereafter.
In the clinical trials, the most common adverse reactions reported in an estimated 20% of patients treated with carfilzomib and daratumumab in the combination therapy trials included infusion-related reactions, anemia, diarrhea, fatigue, hypertension, pyrexia, respiratory tract infection, thrombocytopenia, neutropenia, lymphopenia, cough, dyspnea, insomnia, headache, and back pain.
In a press release, Craig Tender, MD, vice president, late development and global medical affairs, Janssen Research & Development, LLC, said, “With this most recent approval of the DKd regimen, patients with multiple myeloma now have the option to receive treatment with DARZALEX and carfilzomib as early as their first relapse, which is a critical time in their treatment journey. With our deep disease focus and commitment to develop regimens which can help improve patient outcomes for patients with relapsed multiple myeloma, the CANDOR study further establishes another DARZALEX-containing regimen (DKd) which may provide benefit for this patient population.”
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