FDA Approves Daratumumab Plus Kd Regimen in Relapsed/Refractory Multiple Myeloma

The FDA has granted approval to the combination of daratumumab (Darzalex) plus carfilzomib (Kyprolis) and dexamethasone (DKd) as treatment of adult patients with relapsed or refractory multiple myeloma who have received up to 3 prior lines of therapy, Genmab A/S announced in a press release.¹

The approval includes 2 doses of carfilzomib, 70 mg/m² administered once weekly and 56 mg/m² administered twice weekly. The approval was granted based on positive data from the phase 3 CANDOR clinical trial (NCT01998971) and the phase 1b EQUULEUS clinical trial (NCT01998971).

“We are extremely pleased that multiple myeloma patients in the U.S. will now have yet another treatment option as this is the eighth overall U.S. FDA approval for Darzalex and the fifth in the relapsed/refractory setting. In addition, Darzalex is now the first CD38 antibody approved for use in combination with carfilzomib,” said Jan van de Winkel, PhD, chief executive officer of Genmab, in a statement.

CANDOR was a randomized, open-label study that included 466 patients with multiple myeloma who had relapsed after 1 to 3 prior line of treatment. This was a 2-arm study in which patients either received DKd or Kd alone. Daratumumab was administered at 16 mg/kg on days 1, 8, 15, and 22, of cycles 1 and 2, every 2 weeks during cycles 3 to 6, and every 4 weeks during cycle 7 and on. The anticancer agent carfilzomib was given to patients at a dose level of 20 mg/m² loading dose on days 1 and 2 of cycle 1 only, then at 56 mg/m² for all subsequent doses on days 1, 2, 8, 9, 15, and 16. Finally, patients received dexamethasone 40 mg on days 1, 8, 15, and 22 of each cycle.^1,2

As a primary end point, CANDOR evaluated the progression-free survival (PFS) and the key secondary end points were minimal residual disease (MRD)-negative status, complete response (CR) rate at 12 months, OS, duration of response, and safety.

According to the most recent data from the trial, the addition of daratumumab to Kd reduced the risk of disease progression or death by 37% compared with Kd alone. The median PFS was not reached in the DKd arm compared with 15.8 months in the Kd arm (HR, 0.63; 95% CI, 0.46-0.85;P = .0014). At a median follow-up of 17 months, the median OS in the study was not yet reached in either arm (HR, 0.75; 95% CI, 0.49-1.13; P = .08).

In the safety analysis, 461 of the 466 were evaluated. Overall, the safety profile observed with the combination was similar to was previously reported with daratumumab monotherapy. A total of 308 patients (56.2%) experienced ≥3-grade adverse events (AEs) versus 45.8% of the Kd arm. Serious AEs were observed in 56.2% versus 45.8%, respectively. Patients who received the combination discontinued treatment at a rate of 22.4% compared with 24.8% of those treated with dexamethasone alone. A notable ≥3-grade event was a cardiac failure, which occurred in 3.9% of patients who received daratumumab compared with 8.5% of those who received Kd.

EQUULEUS was an open-label, multi-cohort trial that assessed the safety, tolerability, and dosing of daratumumab in combination with a number of regimens indicated for the treatment of patients with multiple myeloma. Dkd versus Kd alone was one of the regimens evaluated in the trial in a cohort of 85 patients with relapsed/refractory disease who were previously treated with up to 3 prior lines of therapy. The study also explored daratumumab (Darzalex) plus pomalidomide (Pomalyst) and dexamethasone.¹

Patients in the study were given DKd at a starting dose of 20 mg/m², which was later increased to 70 mg/m² on Cycle 1, Day 8, and beyond. Thus far, no data from the trial have been publicly reported.

_References:

_{1. Genmab announces janssen granted U.S. FDA approval for darzalex® (daratumumab) in combination with carfilzomib and dexamethasone in relapsed or refractory multiple myeloma. News release. Genmab A/S. August 20, 2020. Accessed August 20, 2020.}

_{2. Janssen announces submission to U.S.FDA for new Darzalex (daratumumab)-based combination regimen for patients with relapsed/refractory multiple myeloma [new release]. Raritan, New Jersey: The Janssen Pharmaceutical Companies of Johnson & Johnson; February 10, 2020.https://bit.ly/31Qsj9F. Accessed February 11, 2020.}

_{3. Usmani SZ, Quach H, Mateos M-V, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (RRMM): primary analysis results from the randomized, open-label, phase 3 study CANDOR (NCT03158688). Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract LBA6.}