Carfilzomib Triplet Fails to Induce Superior PFS in Newly Diagnosed Multiple Myeloma

Carfilzomib (Kyprolis) combined with lenalidomide (Revlimid) and dexamethasone (Decadron; KRd) failed to improve progression-free survival (PFS), compared with the current standard of care triplet of bortezomib (Velcade), lenalidomide, and dexamethasone (VRd), in patients with newly diagnosed multiple myeloma, according to results of the ENDURANCE (E1A11) trial presented ahead of the 2020 ASCO Virtual Scientific Program.

Given the higher efficacy of carfilzomib seen in recent phase II trials, investigators sought to determine if carfilzomib could replace bortezomib in the current standard of care triplet induction regimen in standard and intermediate risk newly diagnosed multiple myeloma.

To do so, 1087 patients with newly diagnosed multiple myeloma were randomized 1:1 to receive either VRd or KRd for 36 weeks. After this initial period, a second 1:1 randomization was completed, placing patients in 1 of 2 groups: indefinite lenalidomide maintenance therapy or lenalidomide maintenance therapy for only 2 years.

Patients without del17p, t(14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled in the trial. The median age of all patients was 65 years.

The 542 patients in the VRd arm received bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 (days 1 and 8 for cycles 9-12), lenalidomide at 25 mg 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 of 545 patients received carfilzomib at 36 mg/m2 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.

For the maintenance phase, patients received lenalidomide at 15mg on days 1-21 every 4 weeks.

During the second of 3 planned interim analyses, the therapy became ineffective in improving PFS (HR, 1.04; 95% CI, 0.8-1.3; P = 0.74).

In the VRd cohort, median PFS was 34.4 months compared to 34.6 months in the KRd arm. The researchers noted that no differences in PFS were seen based on age, the presence or absence of t(4;14), or disease stage.

The randomized phase III trial also assessed whether indefinite maintenance with lenalidomide improved overall survival (OS) compared to 2-year maintenance; however, data has yet to mature for this endpoint.

Three-year OS (95% CI) was also similar in both arms, with 84% in the VRd arm and 86% in the KRd arm.

Patients in the VRd and KRd cohorts were taken off the trial to pursue alternative therapies (18% vs 14%, respectively), or because of adverse events (AEs; 17% vs 9%), withdrawal (7% vs 4%), or disease progression (6% vs 4%).

The most common grade 3 or higher AEs were non-hematological, appearing in 42% of patients in the VRd arm compared to 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%).

References
Kumar S, Jacobus S, Cohen A, 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. Presented at: 2020 ASCO Virtual Scientific Program; May 28, 2020. LBA3.