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.

Abstract

LBA3 Background: Bortezomib (btz) combined with lenalidomide (len) and dexamethasone (dex) (VRd) is a standard initial therapy for NDMM. Carfilzomib (cfz), a next-generation proteasome inhibitor, in combination with len-dex (KRd) has shown higher efficacy in phase II trials. This randomized phase III trial was designed to examine if KRd improves progression free survival (PFS) compared to VRd in NDMM (current results), and whether indefinite maintenance with len improves OS compared with two-year maintenance (to be analyzed once data matures). Methods: Patients (Pts) with NDMM, were randomized to receive VRd or KRd in a 1:1 fashion for 36 weeks followed by a second randomization (1:1) to indefinite versus two years of len maintenance. Pts without del17p, t (14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled. VRd arm included btz 1.3 mg/m2 on days(d) 1, 4, 8, and 11 (d 1, 8 for cycles 9-12), len 25 mg d 1-14, and dex 40 mg d 1, 2, 4, 5, 8, 9, 11, 12 of a 3-week (wk) cycle for 12 cycles, while pts in the KRd arm received cfz 36 mg/m2 d 1, 2, 8, 9, 15, 16 with len 25 mg daily on d 1-21 and dex 40 mg wkly, in 4 wk cycles for 9 cycles. Maintenance included len 15mg d 1-21 every 4 wks. The study was designed to detect a hazard ratio (HR)=0.75 with 80% power at 1-sided 2.5% alpha and 399 PFS events (progression or death regardless of intervening therapy). Results: The study accrued 1087 pts (VRd=542, KRd=545). The median age was 65y. Treatment, efficacy, and toxicity data are in the table. At the second of 3 planned interim analyses, with PFS HR=1.04 (95% CI, 0.8 to 1.3, p=0.74), futility was met. Median PFS was VRd=34.4m and KRd=34.6m; no differences were seen based on age (<65 or ≥65), presence or absence of t(4;14) or ISS stage. The three-year OS (95% CI) was similar: VRd 84% (80 to 88) and KRd 86% (82 to 89). Conclusions: In this randomized phase 3 trial, KRd did not improve PFS compared with VRd in NDMM. A significantly higher rate of cardio-pulmonary and renal toxicity was observed with KRd, while neuropathy rates were higher with VRd. VRd remains the standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4 drug combinations. Clinical trial information: NCT01863550 . [Table: see text]

Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†

“…The ENDURANCE trial, which compared KRd versus VRd in NDMM patients without an immediate intent for ASCT, failed to show superiority of KRd regarding PFS in the study population (n ¼ 1087), which included a low number of patients with high-risk cytogenetics. 42 The addition of Dara to VMP and Rd has created two new standards of care. DaraVMP and DaraRd were approved by the EMA in October 2019, based on the results of two large phase III studies.…”

Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma

“…Recently, the phase 3 ENDURANCE study, which compared KRd with RVd in patients with NDMM not undergoing ASCT, reported a higher rate of cardio-pulmonaryrenal events with KRd but a higher rate of peripheral neuropathy with RVd. 11 The ongoing phase 3 ATLAS trial (NCT02659293) will compare the efficacy and safety of maintenance therapy with KRd vs lenalidomide after transplantation.…”

“…The phase 3 ENDURANCE study compared KRd and RVd regimens in patients with NDMM, with no intention for immediate ASCT and without high-risk disease. 11 Patients were randomly assigned to induction with KRd (9 cycles, 4 weeks per cycle) or RVd (12 cycles, 3 weeks per cycle), with a second random assignment to indefinite or 2 years of lenalidomide maintenance. Initial outcomes were recently presented, with no significant difference in the co-primary end point of PFS (median, 34.6 months for KRd vs 34.4 months for RVd), although KRd was associated with a higher rate of VGPR or better after induction (73.8% vs 64.7%).…”

“…7,9 However, a preferred PI-IMiD-based regimen has not been clearly established in the first-line setting. 10,11 Ongoing efforts to further improve treatment outcome in patients with NDMM include incorporation of monoclonal antibodies [12][13][14] and/or autologous stem cell transplantation (ASCT) into treatment with novel regimens. [14][15][16][17][18] Results from randomized trials have shown that incorporation of ASCT into RVd treatment improved clinical outcomes compared with RVd without ASCT, which supports the use of ASCT with novel regimens as a standard of care.…”

Multiple Myeloma: An Overview of the Current and Novel Therapeutic Approaches in 2020

“…Furthermore, we moved from fixed-duration therapy (MPV) to a prolonged treatment approach with Rd-based associations for NTE patients upfront in order to improve the outcome, achieve deep responses, and delay relapse [ 10 , 21 , 23 ]. The addition of carfilzomib to Rd was also tested for NTE patients in the phase 3 ENDURANCE trial (KRd vs. VRd), but it did not improve the progression-free survival and added more toxicity (median PFS 34.6 months for KRd vs. 34.4 months for the VRd group, p = 0.74) [ 24 ]. Nevertheless, it confirmed that VRd is suitable and efficient for older patients.…”