A combination therapy of carfilzomib, dexamethasone, and daratumumab (KdD) has resulted in a significant progression-free survival (PFS) benefit compared with carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma (RRMM), according to late-breaking data presented at the American Society of Hematology Annual Meeting and Exposition.

“This study is really important in the context of the current available regimens we have, in the United States especially,” study author Saad Z Usmani, MD, MBBS, of Atrium Health, said in a briefing about the results. 

According to Dr Usmani, the majority of patients have disease progression while on lenalidomide, and of the 6 treatment combinations that are currently approved in this setting, 4 have lenalidomide as part of their regimen.

“So there is a need for novel therapeutic options for patients with multiple myeloma who have relapsed or are refractory to lenalidomide-based treatments,” he said.

This phase 3 CANDOR study compared KdD versus Kd in 466 patients with RRMM. Patients included in the study had previously received 1 to 3 prior therapies.

All patients received carfilzomib (K) as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab 8 mg/kg was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles. All patients received 40 mg of dexamethasone oral or IV weekly.

The primary endpoint was PFS. Secondary endpoints were overall response rate, minimal residual disease (MRD) negative-complete response at 12 months, overall survival (OS), time to response and safety.

Of the patients in the study, 42.3% and 90.3% received previous LEN- and BTZ-containing regimens, respectively, and 33% of patients were LEN-refractory.

Overall, the study found that KdD treatment resulted in a 37% reduction in the risk of progression or death versus Kd in patients with RRMM. At a median follow-up of 17 months, median OS was not reached in either arm.

Importantly, KdD improved PFS regardless of prior lenalidomide or lenalidomide-refractory disease, Usmani explained. Median PFS was 12.1 and 11.1 for patients with prior lenalidomide exposure and lenalidomide-refractory disease, respectively.  

Median time to first response was 1 month in the KdD and Kd arms. ORR was 84.3% in the KdD arm compared with 74.7% in the Kd arm. Patients treated with KdD achieved deeper responses, with a nearly 10-times higher MRD negative-complete response rate versus patients treated with Kd.

Looking at safety, adverse effects (AEs) were generally manageable and the incidence of AEs leading to treatment discontinuation was similar in both arms. The incidence of grade 3 or 4 adverse events was 82.1% in patients with KdD and 73.9% in patients with Kd. Serious AEs occurred in 56.2% of the KdD arm and 45.8% of the Kd arm.

“Interestingly, we saw lower degree of grade 3 or higher cardiac failure in the KdD arm than in the Kd arm,” Usmani noted. The frequency of grade ≥3 cardiac failure was 3.9% in the KdD arm compared with 8.5% in the Kd arm. However, Usmani indicated that they are unsure as to why.

Although patients treated with KdD had higher rates of grade ≥3 AEs overall, treatment discontinuation due to AEs were similar in both arms of the study.

Overall, the combination therapy KdD was associated with a favorable benefit-risk profile and represents an efficacious new regimen for RRMM, including for patients who are LEN-exposed and/or LEN-refractory. The findings suggest that KdD should be considered as a novel, efficacious, and tolerable immunomodulatory-drug-free treatment option for RRMM, Usmani concluded.

Reference
  1. Usmani S, Quach H, Mateos MV, et al. LBA-6 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: ASH Annual Meeting and Exposition. December 10, 2019. Orlando, Florida.