On August 20, the U.S. Food and Drug Administration (FDA) approved daratumumab (Darzalex) in combination with carfilzomib (Kyprolis) and dexamethasone (DKd) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three previous lines of therapy. Daratumumab has been approved in combination with two carfilzomib dosing regimens—70 mg/m2 once weekly and 56 mg/m2 twice weekly—based on positive results from the phase III CANDOR and phase Ib EQUULEUS studies, representing the first-ever approval of an anti-CD38 with carfilzomib.
“The significant increase in progression-free survival seen among patients receiving the DKd regimen supports the use of this new combination for patients with relapsed and refractory multiple myeloma. We continue to advance effective regimens for the most critical patients who have already relapsed,” said Saad Z. Usmani, MD, Division Chief of Plasma Cell Disorders at Atrium Health's Levine Cancer Institute, and principal investigator of the CANDOR study. “The DKd regimen fills an important gap in the treatment landscape, as many patients may relapse following an immunomodulatory drug–based therapy, such as lenalidomide-containing regimens, and therefore new therapeutic options are needed.”
The CANDOR study is the first phase III randomized trial to compare DKd to carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma. The study, which administered carfilzomib twice weekly, met its primary endpoint of progression-free survival after a median follow-up of 16.9 months and 16.3 months for the DKd and Kd arms, respectively. The median progression-free survival had not been reached in the DKd arm and was 15.8 months in the Kd arm (hazard ratio = 0.63, 95% confidence interval = 0.46–0.85, P = .0014), representing a 37% reduction in the risk of disease progression or death for patients treated with DKd vs Kd.
In CANDOR, the safety profile of DKd was generally consistent with the known safety profiles of daratumumab and Kd. Serious adverse events occurred in 56% and 46 % of patients who received DKd and Kd, respectively. The most frequent serious adverse event in the DKd arm, compared with the Kd arm, was pneumonia (14% vs 9%). Fatal adverse events occurred in 10% of patients receiving DKd and 5% of patients receiving Kd, and the most frequent fatal adverse event was infection (5% vs 3%).
The inclusion of once-weekly dosing of carfilzomib as an approved DKd regimen was supported by positive results from the open-label, multicohort phase Ib EQUULEUS trial, which evaluated daratumumab in combination with various treatment regimens. Among the regimens evaluated, DKd was studied in 85 patients with relapsed or refractory multiple myeloma who had received at least one to three prior lines of therapy. Carfilzomib was evaluated using a once-weekly dosing regimen, with a starting dose of 20 mg/m2, which was increased to 70 mg/m2 on cycle 1, day 8, and onward.