Carfilzomib is an irreversible proteasome inhibitor indicated for the treatment of patients with relapsed/ refractory multiple myeloma (RRMM) as a single agent and in combination with lenalidomide/dexamethasone for the treatment of patients with relapsed MM, on a twice-weekly schedule (20/27 mg/m2).1 At the ASH meeting, Berenson and colleagues reported the updated results of the phase 1/2 CHAMPION-1 study, which evaluated the safety and efficacy of carfilzomib with dexamethasone in patients with RRMM, on an alternate once-weekly schedule.2 Following a standard 3+3 dose-escalation scheme, patients on the phase 1 portion of the study received a starting dose of 20 mg/m2 of carfilzomib, and received successive 45-, 56-, 70-, or 88-mg/m2 increments until the maximum tolerated dose (MTD) was reached. In the phase 2 portion, patients received the starting dose of carfilzomib (20 mg/m2), escalating to the MTD thereafter. Twenty-seven patients were enrolled in phase 1, and the MTD of carfilzomib was determined to be 70 mg/m2. A total of 104 patients were treated at the carfilzomib MTD in both the phase 1b (n = 15) and phase 2 (n = 89) portions of the study. The majority of the patients had received prior bortezomib (84%) and lenalidomide (54%); 52% were bortezomib-refractory, and 34% were lenalidomide-refractory. In this RRMM patient population, carfilzomib treatment resulted in an overall response rate (ORR) of 77%, a clinical benefit rate (?minimal response) of 84%, and progression-free survival of 13.2 months; the duration of response was 16.3 months, and the time to response was 1.6 months. Patients who were bortezomib-refractory also achieved an ORR of 63%, as did those who were lenalidomide-refractory (69%) and double-refractory (55%). Grade 3/4 adverse events occurring in ?5% of patients treated at the carfilzomib MTD included fatigue (11%), anemia (6%), hypertension (7%), pneumonia (6%), dyspnea (5%), asthenia (5%), back pain (5%), and chronic obstructive pulmonary disease (5%). Five patients died on study, each due to disease progression, acute respiratory distress syndrome, acute respiratory failure, acute kidney injury, and cardiopulmonary arrest. Based on the promising efficacy and safety results of the CHAMPION-1 trial, an ongoing phase 3 superiority study (ARROW) is comparing the once-weekly carfilzomib (70 mg/m2) dosing schedule with dexamethasone with the approved twice-weekly carfilzomib dose and schedule (NCT02412878).
