Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (E1A11): a multicenter, open label, phase 3, randomized, controlled trial

SUMMARY: BACKGROUND: Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma (NDMM). Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide, and dexamethasone (KRd) has shown excellent efficacy in phase II trials and may improve outcomes compared with VRd. METHODS: In this randomized, open label, phase 3 trial, we recruited patients with NDMM, aged 18 years and older, who were not planned for immediate autologous stem-cell transplant (ASCT). Key inclusion was absence of the following high-risk features (del17p, t(14;16), t(14;20), plasma cell leukemia) and Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Patients were randomized (1:1) to receive VRd or KRd for 36 weeks followed by a 2(nd) randomization (1:1) to indefinite versus 2 years of lenalidomide maintenance. Allocation was stratified by intent to ASCT at disease progression and was not masked to investigators and patients. VRd regimen included bortezomib 1·3 mg/m(2) on days 1, 4, 8, and 11 (d 1, 8 for cycles 9–12), lenalidomide 25 mg daily on days 1–14, and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 for twelve 3-week cycles. KRd regimen included carfilzomib 36 mg/m(2) on days 1, 2, 8, 9, 15, 16, lenalidomide 25 mg daily on days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22 for nine 4-week cycles. The primary endpoint was progression-free survival, defined as the time from first randomization to disease progression or death, analyzed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete, all patients have completed induction therapy, and patients continue on maintenance as per second randomization and follow up is ongoing. The trial is registered at ClinicalTrials.gov:NCT01863550. FINDINGS: Between December 6, 2013 and February 6, 2019, we randomly assigned 1087 patients at 272 participating institutions (542 to VRd, 545 to KRd). At an estimated median (IQR) follow-up of 9 (5–23) months from randomization, median PFS was 34·4 (95% CI 30·1-NE) months for VRd compared with 34·6 (95% CI 28·8–37·8) months for KRd; the PFS treatment hazard ratio (HR=KRd/VRd) was 1·04 (95% CI 0·83–1·31); P=0·74. The most common grade 3–4 non-hematologic adverse events included fatigue (34 [6%] vs. 29 [6%]), hyperglycemia (23 [4%] vs. 34[7%]), peripheral neuropathy (44 [8%]vs. 4 [