Patients with relapsed or refractory multiple myeloma (MM) experience prolonged progression-free survival (PFS) with carfilzomib, dexamethasone, and daratumumab, compared with carfilzomib and dexamethasone alone, according to study results published in The Lancet.
Novel agents have increased survival for patients with MM, but these patients inevitably experience relapse, and the disease remains incurable. Lenalidomide and bortezomib are the most common first-line treatments, but patients develop resistance. These therapies also have toxicities that may cause patients to stop receiving treatment; therefore, better treatments for relapsed and refractory disease are needed.
Previous studies have shown the efficacy of combining the selective proteasome inhibitor carfilzomib with the anti-CD38 monoclonal antibody daratumumab. Investigators for the phase 3, multicenter, open-label CANDOR trial (Clinicaltrials.gov Identifier: NCT03158688) compared the safety and efficacy of carfilzomib, dexamethasone, and daratumumab (KdD) with carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory MM.
In the trial, 466 patients were randomly assigned 2:1 to KdD or Kd treatment with a primary endpoint of progression-free survival (PFS). Twice weekly carfilzomib was administered at 56 mg/m2 (20 mg/m2 on days 1 and 2 of cycle 1) to all patients. Dexamethasone was administered weekly (40 mg; 20 mg for patients ≥75 years). Intravenous daratumumab was administered on days 1 and 2 of cycle 1 at 8 mg/kg and increased to 16 mg/kg weekly for the remaining doses for the first 2 cycles, after which treatment was administered every 2 weeks for cycles 3 to 6 and every 4 weeks thereafter. Both groups contained patients who were lenalidomide or bortezomib refractory.
By a median follow-up of 17 months, the KdD group did not meet a median PFS but the Kd group had a median PFS of 15.8 months (hazard ratio, 0.63; 95% CI, 0.46-0.85; P =.0027). The median treatment duration was longer for the KdD cohort (70.1 weeks) compared with the Kd cohort (40.3 weeks). The median time to progression was 17.5 months for the Kd group and was not reached for the KdD group.
Overall response was reported in 84% of patients in the KdD group vs 75% in the Kd group; 69% of patients in the KdD group achieved very good partial response or better and 29% achieved complete response compared with 49% and 10%, respectively, among patients in the Kd group.
Of the entire cohort, 21% of patients discontinued carfilzomib because of adverse events; however, the toxicity profile of KdD was similar to the adverse events noted with carfilzomib or daratumumab alone, therefore, increased toxicity was not demonstrated by combining the two.
The authors concluded that KdD reduced the risk of death by 37% compared with Kd for patients with relapsed or refractory MM. These results are consistent with other studies of these drugs.
One limitation of the study was the short follow-up time of 17 months, which limited conclusions that could be drawn about overall survival.
“With increased use of frontline lenalidomide therapy, there is a rising need for new, tolerable and efficacious lenalidomide-free regimens for patients who have been exposed to, or have relapsed after stopping, lenalidomide treatment,, or have relapsed a
“[T]he immunomodulatory drug-free KdD regimen showed a favourable benefitry drug-free KdD regimen showed efficacious new standard of care for patients with relapsed or refractory multiple myeloma, including patients for whom lenalidomide is no longer a treatment option,” concluded the investigators.
Dimopoulos M, Quach H, Mateos M-V, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197.