Carfilzomib Weekly plus Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (IFM 2012-03): A Phase I Trial

Purpose: Carfilzomibis a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice-weekly KMP ( carfilzomib, melphalan, prednisone) might challenge the MPV ( melphalan, prednisone, bortezomib) standard. We sought to study KMP weekly, allowing to increase carfilzomib9s dose with maintained efficacy and improved safety profile. Patients and Methods: IFM2012-03, a phase I multicenter study of KMP weekly in elderly patients with newly diagnosed multiple myeloma (eNDMM), aimed to determine the MTD of carfilzomib. Carfilzomibwas given intravenously at 36, 45, 56, and 70 mg/m2/day on days 1, 8, 15, and 22 with melphalanand prednisone, for nine 35-day induction cycles, followed by carfilzomibmaintenance for 1 year. Three dose-limiting toxicities (DLT) determined MTD at the lower dose. Results: Thirty eNDMMs were treated, 6 per cohort at 36, 45, and 56 mg/m2 and 12 at 70 mg/m². There was one DLT at 36 mg/m2 (lymphopenia), one at 45 mg/m2 (lysis syndrome), two at 56 mg/m2 (cardiac insufficiency and febrile neutropenia), and two at 70 mg/m2 (vomiting and elevated liver enzymes). The safety profile was acceptable; however, specific attention must be paid to the risk of cardiovascular events, especially for elderly patients. The overall response rate was 93.3%, with 46.6% complete response. Conclusions: The MTD dose of carfilzomibwas 70 mg/m2 in this KMP weekly study in eNDMM. Response rates, and especially CR rate, were remarkable in this population, and would benefit from being assessed in a larger-scale study. The IFM2012-03 study demonstrated that the MTD of carfilzomibweekly is 70 mg/m2 in eNDMM, and 56 mg/m2 for patients older than 75 years. Carfilzomibused weekly in combination has a good efficacy and safety profile in eNDMM.