FDA Approves Daratumumab, Carfilzomib, Dexamethasone Triplet to Treat Multiple Myeloma

August 21, 2020

The FDA approved daratumumab in combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 previous lines of therapy.

The FDA has approved daratumumab (Darzalex) for use in combination with carfilzomib (Kyprolis) and dexamethasone (DKd) to treat adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 previous lines of therapy, according to the Janssen Pharmaceutical Companies of Johnson & Johnson, the developer of the agent.

Specifically, daratumumab was approved in combination with 2 carfilzomib dosing regimens, including 70 mg/m2 once weekly and 56 mg/m2 twice weekly, based on positive results from the phase 3 CANDOR and phase 1b EQUULEUS studies. This approval represents the first-ever approval of a CD38 antibody with carfilzomib.

“The significant increase in progression-free survival (PFS) 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,” Saad Z. Usmani, MD, division chief of Plasma Cell Disorders at Atrium Health’s Levine Cancer Institute and principal investigator of the CANDOR study, said in a press release. "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 open-label, phase 3 CANDOR study randomized 466 patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy to receive either the DKd triplet or carfilzomib and dexamethasone (Kd). Of note, the twice weekly dose of carfilzomib was administered in this study.

The primary end point was PFS, and the key secondary end points were overall response rate, minimal residual disease, and overall survival.

The primary end point was met after a median follow-up of 16.9 months and 16.3 months for the DKd and Kd arms, respectively. The median PFS had not been reached in the DKd arm and was 15.8 months in the Kd arm (HR, 0.63; 95% CI, 0.46-0.85; P = 0.0014), which represents a 37% reduction in the risk of disease progression or death for patients treated with DKd compared with those treated with Kd.

Moreover, the safety profile of DKd was generally consistent with the known safety profiles of daratumumab and Kd and reflected a median treatment duration of 16.1 months for the DKd arm and 9.3 months for the Kd arm.

Serious adverse events (AEs) occurred in 56% and 46% of patients who received DKd and Kd, respectively. The most frequent serious AE in the DKd arm, compared with the Kd arm, was pneumonia (14% vs 9%, respectively). Further, fatal AEs occurred in 10% of patients administered DKd and 5% of patients administered Kd, with the most frequent fatal AE being infection (5% vs 3%, respectively).

“With this most recent approval of the DKd regimen, patients with multiple myeloma now have the option to receive treatment with [daratumumab] and carfilzomib as early as their first relapse, which is a critical time in their treatment journey,” Craig Tendler, MD, vice president of Late Development and Global Medical Affairs at Janssen Research & Development, LLC, said in the release. “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 [daratumumab]-containing regimen which may provide benefit for this patient population.”

The inclusion of once-weekly dosing of carfilzomib as an approved DKd regimen was supported by positive results from the open-label, multi-cohort, phase 1b EQUULEUS trial. The study evaluated the safety, tolerability, and dosing regimen of daratumumab when administered in combination with various treatment regimens for the treatment of multiple myeloma.

Of the regimens evaluated, the DKd combination was studied in 85 patients with relapsed or refractory multiple myeloma who had received at least 1 to 3 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.

Thus far, daratumumab has been used to treat more than 143,000 patients worldwide and more than 68,000 patients in the US alone since it was approved by the FDA in 2015. The agent is the first CD38-directed antibody globally approved to treat multiple myeloma.

Reference:

U.S. FDA Approves New DARZALEX® (daratumumab)-Based Combination Regimen for Patients with Relapsed/Refractory Multiple Myeloma [news release]. Horsham, Pennsylvania. Published August 20, 2020. Accessed August 21, 2020. https://www.janssen.com/us/sites/www_janssen_com_usa/files/us_fda_approves_new_darzalex_daratumumab_based_combination_regimen_for_patients_with_relapsed_refractory_multiple_myeloma.pdf.