Adding daratumumab to carfilzomib-dexamethasone significantly reduces the risk of disease progression in patients with relapsed/refractory MM
Results of the phase III CANDOR trial, presented as a late breaking abstract during ASH 2019, demonstrate that the addition of daratumumab (D) to carfilzomib-dexamethasone (Kd) leads to a statistically significant 37% reduction in the risk of disease progression or death in patients with relapsed/refractory multiple myeloma. Furthermore, patients treated with KdD also obtained deeper responses than patients who only received Kd, with a nearly 10-times higher rate of patients with MRD-negative complete responses at 12 months. Importantly, the PFS superiority of KdD over Kd was maintained across all investigated subgroups, including lenalidomide-exposed and lenalidomide-refractory patients. The addition of D to Kd did not lead to unacceptable toxicity with comparable treatment discontinuation rates in both treatment arms.
Background
The introduction of new therapeutic options for patients with newly diagnosed multiple myeloma (MM) along with continuous or maintenance therapy paradigm have significantly improved the survival prospects for MM patients. However, many patients will eventually progress or have to discontinue first-line therapy for reasons of toxicity. Despite the recent introduction of multiple triplet regimens in the treatment of patients with relapsed/refractory MM (RRMM), there is still a need for novel, efficacious, and tolerable regimens and this is especially the case for patients who are exposed or refractory to lenalidomide and/or bortezomib. The proteasome inhibitor carfilzomib and the anti-CD38 monoclonal antibody daratumumab have both been approved as components of combination regimens for the treatment of RRMM. During ASH 2019, results were presented of a phase III trial evaluating the combination of carfilzomib, dexamethasone, and daratumumab (KdD) in patients with RRMM.
In the randomized, phase III CANDOR trial, 466 RRMM patients with measurable disease who had received 1–3 prior lines of therapy and obtained a partial response or better to at least 1 prior line of therapy, were randomized (2:1) to KdD or Kd. All patients received carfilzomib as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). 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 (cycles 3 to 6), and every 4 weeks thereafter. Finally, all patients received 40 mg dexamethasone oral or IV weekly (20 mg for patients >75 years). The primary endpoint of the trial was progression-free survival (PFS), with overall response rate (ORR), minimal residual disease (MRD) negative-complete response at 12 months (threshold, 10-5 cells), overall survival (OS), time to response, and safety as secondary study objectives.
Results
The median age of the 466 patients enrolled in the trial was 64 years. Of the randomized patients, 42.3% and 90.3% received previous lenalidomide- and bortezomib-containing regimens, respectively. Overall, 33% of patients were lenalidomide-refractory at study entry. While the median PFS of patients treated with KdD was not yet reached, patients in the Kd arm had a median PFS of 15.8 months. This translates into a statistically significant 37% reduction in the risk of disease progression or death for patients treated with KdD compared to those who received Kd alone (HR 0.63 [95% CI: 0.46-0.85]; p=0.0014). Importantly, KdD improved the PFS compared to Kd regardless of prior lenalidomide use (median PFS: not reached versus 12.2 months; HR 0.52 [95% CI: 0.34-0.80]) and was also maintained in patients with lenalidomide-refractory disease (median PFS: not reached versus 11.1 months; HR 0.45 [95% CI: 0.28-0.74]). At a median follow-up of 17 months, the median OS was not reached in either of the two study arms (HR 0.75 [95% CI: 0.49-1.13]; p=0.08).
In addition to the improvements in PFS, KdD also resulted in a significantly higher ORR compared to Kd (84.3% versus 74.7%, p=0.0040) and the responses obtained with KdD also proved to be deeper than the responses to Kd. The latter is clearly illustrated by a higher rate of patients with a CR or better (28.5 versus 10.4%) and a tenfold increase in the rate of patients with an MRD-negative CR at 12 months (12.5% versus 1.3%). The time to response was similar in both arms at a median of 1 month.
The median treatment duration of 70.1 weeks in the KdD arm was longer than the 40.3-week median treatment duration with Kd. The clinical benefit of adding D to Kd did come at the cost of some added toxicity. In total, 82.1% of patients in the KdD arm experienced a grade ≥3 adverse event as compared to 73.9% with Kd alone. Serious adverse events occurred in 56.2% of KdD patients and in 45.8% of patients treated with Kd alone. However, these higher toxicity rates did not lead to more treatment discontinuations due to adverse events with KdD (22.4% versus 24.8% with Kd). The frequency of grade ≥3 cardiac failure was 3.9% with KdD and 8.5% with Kd alone. The rate of cardiac failure events leading to carfilzomib discontinuation was similar in both arms (3.9% and 4.6%). In total, 5 deaths were reported as treatment-related, all in the KdD arm (pneumonia, sepsis, septic shock, acinetobacter infection, and cardio-respiratory arrest).
Conclusions
In conclusion, adding daratumumab to Kd resulted in a significant improvement in PFS, which was maintained in both lenalidomide-exposed and lenalidomide-refractory patients. Furthermore, patients treated with KdD achieved deeper responses than patients treated with Kd, with a nearly 10-times higher MRD negative-CR rate at 12 months versus Kd-treated patients. Although KdD patients had higher rates of grade ≥3 adverse events, treatment discontinuations due to adverse events were similar in both arms and the safety profile was tolerable. As such, the investigators concluded that KdD should be considered as a novel, efficacious and tolerable immunomodulatory-free treatment option for patients with RRMM.
Reference
Usmani S, 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 ASH 2019, Abstract LBA-6.
