MCRN¯003/MYX·1: A Single Arm Phase II Study of High-Dose Weekly Carfilzomib Plus Cyclophosphamide and Dexamethasone in the Treatment of Relapsed Multiple Myeloma after 1-3 Prior Therapies

Background: Carfilzomib, a second generation proteosome inhibitor, is effective in the treatment of relapsed and refractory multiple myeloma (RRMM). Recent phase II and phase III trials have demonstrated the efficacy of weekly dosing strategies. The aim of this study was to examine high dose once weekly carfilzomib in combination with weekly dexamethasone and low dose weekly cyclophosphamide (wCCD) in RRMM. It was hypothesized that this may offer a potent yet convenient and more financially viable triplet-based treatment option than existing combinations. Methods: The MCRN-003/MYX.1 multi-centre single arm phase II clinical trial is run through the Myeloma Canada Research Network (MCRN) with support from the Canadian Cancer Trials Group (CCTG). Patients who had at least one but not more than three prior lines of therapy and who did not have proteosome inhibitor (PI) refractory disease were eligible. Treatment consists of carfilzomib (20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28-day cycle, plus weekly oral dexamethasone 40 mg and cyclophosphamide 300 mg/m2 capped at 500 mg on days 1, 8, 15 and 22. Treatment continues until progression or intolerance, except for cyclophosphamide which is discontinued after 12 cycles. The total sample size of 76 patients includes a 6 patient lead-in phase where safety at 70 mg/m2 was evaluated. The primary objective was to observe an overall response rate (ORR) ≥ 80% after 4 cycles of protocol therapy. Secondary endpoints include safety, toxicity, kinetics of and maximal response depth and overall survival. This analysis is based on the locked data base of 2018 July 13. Results: Of the 76 patients accrued 1 was subsequently determined to be ineligible on the basis of bortezomib refractory disease, and 1 did not receive any protocol therapy due to a cardiac event occurring post-study registration but prior to treatment commencement. All patients who received therapy were included in the analysis as per protocol inclusive of the bortezomib exposed patient. Among these 75 patients, median age was 66 years with 33% being > 70 years of age. Thirty-seven percent were female. Thirty-nine percent received 1 prior line, 44% received 2 prior lines and 17% received 3 prior lines of therapy. High risk cytogenetics [(t4;14), t(14;16) and del P53] were identified in 32%. Twenty percent had ISS stage III disease and 11% had R-ISS stage III disease. Prior PI and immunom