In patients with newly diagnosed multiple myeloma, carfilzomib with lenalidomide and dexamethasone (KRd) did not improve progression-free survival (PFS), when compared with the current standard of care of bortezomib with lenalidomide and dexamethasone (VRd), according to results of the ENDURANCE (E1A11) trial presented by Prof. Shaji Kumar .
Phase-2 studies of carfilzomib have suggested good efficacy and excellent tolerability. The rationale of the phase-3 ENDURANCE trial was to determine if carfilzomib could replace bortezomib as the standard of care triplet induction therapy for newly diagnosed multiple myeloma. With a median age of 65, 1,087 patients with newly diagnosed multiple myeloma were randomized to receive either VRd or KRd for 36 weeks. At that point, patients were randomized again 1:1 to either receive lenalidomide maintenance therapy indefinitely or to lenalidomide maintenance therapy for a defined period of 2 years.
The VRd arm (n=542) received bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 (days 1 and 8 for cycles 9-12), 25 mg lenalidomide on days 1-14, and dexamethasone at 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 3-week cycle for 12 cycles. The KRd arm (n=545) received 36 mg/m2 carfilzomib on days 1, 2, 8, 9, 15, and 16 with lenalidomide at 25 mg daily on days 1-21 and dexamethasone at 40 mg weekly, in 4-week cycles for 9 cycles. All patients received 15 mg of lenalidomide in the maintenance phase on days 1-21 of every 4-week cycle.
At 3 years of follow-up, no difference was observed in PFS (34.4 months for the VRd cohort vs 34.6 months for KRd; HR 1.04; 95% CI 0.8-1.3; P=0.74). Likewise, subgroup analyses did not see any PFS differences based on age, the presence or absence of t(4;14), or disease stage. Overall survival at 3 years was also similar in both arms, at 84% in the VRd arm and 86% in the KRd arm.
The data are still too immature to determine whether indefinite lenalidomide maintenance improves overall survival as opposed to 2-year maintenance.
With regard to safety, grade 3-4 adverse events were reported in 42% of patients in the VRd arm versus 48% of patients in the KRd arm. Although neuropathy rates were higher with VRd compared with KRd (8% vs 1%, respectively), rates of cardio-pulmonary and renal toxicities were higher with KRd (5% vs 16%). In conclusion, VRd remains the best triplet induction option for newly diagnosed multiple myeloma patients.
1. Kumar S, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): Results of ENDURANCE (E1A11) phase III trial. ASCO Virtual Meeting, 29-31 May 2020, Abstract LBA3.