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

Abstract

Purpose: Carfilzomib is 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 carfilzomib's 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. Carfilzomib was given intravenously at 36, 45, 56, and 70 mg/m2/day on days 1, 8, 15, and 22 with melphalan and prednisone, for nine 35-day induction cycles, followed by carfilzomib maintenance 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 carfilzomib was 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 carfilzomib weekly is 70 mg/m2 in eNDMM, and 56 mg/m2 for patients older than 75 years. Carfilzomib used weekly in combination has a good efficacy and safety profile in eNDMM.

Efficacy and Toxicity Profile of Carfilzomib-Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review

“…Carfilzomib, Melphalan, and Prednisone (CMP) IFM 2012-03, a phase I trial by Leleu et al, 2019 27 studied the role of weekly CMP in 30 transplant-ineligible elderly NDMM patients (median age=73 years; high-risk cytogenetics, n=3) and determined the MTD of CFZ. Patients underwent nine 35-day cycles of CMP induction with CFZ given in four intravenous dosing cohorts [36 mg/m 2 (n=6), 45 mg/m 2 (n=6), 56 mg/m 2 (n=6), and 70 mg/m 2 (n=12)] followed by CFZ maintenance for 1 year (36 mg/m 2 every 2 weeks).…”

Current approaches to management of newly diagnosed multiple myeloma

“…KMP has proven to be safe and effective in NDMM 110,111 . The CLARION trial compared transplant ineligible patients receiving KMP versus VMP and found that KMP did not improve PFS as compared to VMP (22.3 months vs. 22.1 months, HR = 0.906, 95% CI: 0.74–1.1); suggesting that carfilzomib in combination with melphalan might not be a good option for NDMM 112 …”

Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies—Current Research and Clinical Approaches

“…In a preclinical model, carfilzomib showed a stronger anti-myeloma effect than bortezomib. In addition, this new generation proteasome inhibitor has a different safety profile than bortezomib, showing a very low incidence of neuropathy [ 84 ]. The side effects of drugs were described in the phase III ENDEAVOR clinical trial.…”