FDA approves daratumumab plus carfilzomib and dexamethasone for the treatment of RRMM

On August 20, 2020, the U.S. Food and Drug Administration (FDA) approved daratumumab in combination with carfilzomib and dexamethasone (DKd) for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received 1–3 prior therapies. The DKd combination has been approved in two carfilzomib dosing regimens: 70 mg/m² once weekly and 56 mg/m² twice weekly, making it the first-ever approval of an anti-CD38 antibody with carfilzomib. This approval was based on positive results from the phase III CANDOR (NCT03158688) and phase 1b EQUULEUS (MMY1001) trials.¹

CANDOR

CANDOR randomized 466 patients in a 2:1 ratio to receive either the DKd combination (n = 312) or Kd alone (n = 154) in patients with RRMM.

• Carfilzomib was administered at 20 mg/m², and then increased to 56 mg/m² twice weekly
• Dexamethasone was given at a dose of 40 mg. During the cycles when patients received carfilzomib and/or daratumumab, a split dose of dexamethasone 20 mg was given.^1,2

The 18-month progression-free survival (PFS) rates were 62% and 43% with DKd and Kd, respectively. The median PFS was not reached in the DKd cohort and was 15.8 months in the Kd cohort (HR, 0.63; 95% CI, 0.46–0.85; p = 0.0027), after a median follow-up of 16.9 months and 16.3 months, respectively. These results show the risk of disease progression or death for patients receiving the DKd regimen was reduced by 37% compared with that of patients receiving Kd alone, thus the study met its primary endpoint of improving PFS. The efficacy of the triplet combination was consistent across subgroups, even in patients previously exposed or refractory to immunomodulatory agents.

In CANDOR, the safety profile of the DKd combination regimen was consistent with the known safety profiles of daratumumab and Kd. Frequent Grade ≥ 3 adverse events (AEs) in either group were thrombocytopenia, hypertension, anemia, pneumonia, neutropenia, fatigue, and lymphopenia. The occurrences of AEs were similar in the two treatment arms. Grade ≥ 3 AEs occurred at a rate of 82% in DKd and 74% in Kd; serious AEs occurred at rates of 56% and 46% in the DKd and Kd arms, respectively. Fatal AEs were observed in 10% of the DKd cohort and 5% of the Kd cohort, and the most common fatal AE was infection (5% in DKd; 3% in Kd).

EQUULEUS

EQUULEUS is a multi-cohort trial that evaluated the safety and tolerability of daratumumab in different dosing regimens, when administered in combination with various backbone therapies. A subgroup of this trial included 85 patients with RRMM who were treated with DKd; these patients received 1-3 previous lines of therapy. Daratumumab was given either as a single dose of 16 mg/kg or at a split first dose of 8 mg/kg on Days 1 and 2.

• Carfilzomib was administered as a once-weekly dosing regimen, starting at 20 mg/m², which was increased to 70 mg/m²

Data showed the safety and pharmacokinetic profiles of daratumumab in the split and single dose arms were comparable.^3,4

Infusion-related reactions were experienced by 50% of patients who received the single daratumumab infusion versus 36% of patients who were given the first split dose and 4% who received the second split dose. The most frequent treatment-emergent AEs were thrombocytopenia (67%), anemia (51%), nausea (41%), upper respiratory tract infection (41%), asthenia (40%), and vomiting (40%). The most frequent Grade 3 or 4 treatment-emergent AEs were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%).