Evolution of carfilzomib dose and schedule in patients with multiple myeloma: a historical overview

Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to its target. In July 2012, carfilzomib received accelerated approval in the United States for the treatment of relapsed and refractory multiple myeloma. Based on emerging preclinical data and clinical results, the total dose, infusion time, and administration schedule of carfilzomib have evolved during phase I and phase II clinical studies, with the aim of optimizing the risk-benefit profile of the agent. Based on in vitro and in vivo findings and encouraging phase I tolerability data, a consecutive-day, twice-weekly dosing schedule was implemented early in the development program. Other phase II studies have led to further refinements in the dosing schedule of carfilzomib, resulting in the current approved schedule for carfilzomib to be administered intravenously over 2-10 min on 2 consecutive days each week for 3 weeks of a 28-day cycle. Prolonged infusion over 30 min has also been assessed in clinical studies to enable the use of higher carfilzomib doses with the aim of improving drug tolerability and efficacy. These data collectively informed the dosing and scheduling schemas for carfilzomib in ongoing trials, including phase I and II studies of combination regimens, and the randomized phase III trials ASPIRE, FOCUS, ENDEAVOR, and CLARION. Additional studies are underway to examine alternative dosing schedules (e.g., once-weekly dosing [CHAMPION-1]).