In a late-breaking abstract at ASH, the addition of daratumumab to carfilzomib and dexamethasone (KdD) led to a statistically significant improvement in progression-free survival over Kd alone in the phase 3 CANDOR trial.
Although survival in multiple myeloma has greatly improved with the introduction of novel therapies, it remains an incurable disease, and the majority of patients will eventually relapse.
“KdD represents an efficacious new regimen for relapsed/refractory multiple myeloma, including in lenalidomide-exposed and lenalidomide-refractory patients,” said Saad Z. Usmani, MD. The treatment resulted in a 37% reduction in the risk of progression or death versus Kd in a total of 466 patients who were relapsed/refractory after 1 to 3 prior lines of therapy.
In patients with relapsed or refractory multiple myeloma, the proteasome inhibitor carfilzomib and the anti-CD38 monoclonal antibody daratumumab are approved as single agents or as components of combination regimens. A phase 1 study found the triplet safe and effective, leading to this international randomized phase 3 trial in relapsed/refractory patients.
In the primary analysis of CANDOR, after a median follow-up of approximately 17 months, the primary end point was met, with median progression-free survival not reached in the KdD arm of 312 patients, versus 15.8 months for the Kd arm containing 154 patients (hazard ratio, 0.63; P = .0014). The progression-free survival benefit of KdD was maintained across prespecified clinically important subgroups, including lenalidomide-exposed and lenalidomide-refractory patients. Median overall survival was not reached in either arm.
Patients treated with KdD achieved deeper responses than patients treated with Kd alone. The rate of minimal residual disease–negativity was nearly 10 times greater with daratumumab in the regimen (12.5% vs 1.3%; P <.0001). Also higher were the rates of objective response (84.3% vs 74.7%; P = .0040) and complete response (28.5% vs 10.4%). Median time to first response was 1 month in both arms.
All patients received carfilzomib as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1, at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles (cycles 3-6) and every 4 weeks thereafter. All patients received 40 mg of dexamethasone (20 mg if >75).
Although KdD patients had higher rates of grade ≥3 adverse events, the rate of treatment discontinuations was similar in both arms (approximately 24%) and the safety profile was tolerable. The incidence of grade ≥3 adverse events was 82.1% and 73.9% in the KdD and Kd arms, respectively, with serious adverse events seen in 56.2% and 45.8%, respectively.
Interestingly, the frequency of grade ≥3 cardiac failure was lower with KdD: 3.9% versus 8.5% with Kd; this led to discontinuation of carfilzomib in 3.9% and 4.6%, respectively. “We’re not exactly sure why this happened,” he said, noting that he and his co-investigators are conducting further research into patient features and comorbidities at baseline.
Five deaths were reported as treatment-related, all in the KdD arm (pneumonia, sepsis, septic shock, acinetobacter infection, and cardiorespiratory arrest [n = 1 each]).
“KdD should be considered as a novel, efficacious, and tolerable IMiD-free treatment option for relapsed/refractory multiple myeloma,” said Dr Usmani.
Usmani SZ, et al. ASH Abstract LBA-6.