A Multicenter, Open-Label, Phase 1b Study of Carfilzomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients (CHAMPION-2)

Introduction: Carfilzomib is an irreversible second-generation proteasome inhibitor that is currently approved for the treatment of relapsed or refractory multiple myeloma (MM). The primary objective of the CHAMPION-2 study was to determine the maximum tolerated dose (MTD) of carfilzomib when used with cyclophosphamide and dexamethasone (KCyd) for newly diagnosed MM, and secondary objectives were to evaluate the overall response rate (ORR), time to response (TTR), and safety of KCyd. Methods: This was a multicenter, open-label, single-arm, phase 1b study that enrolled patients 18 years or older with newly diagnosed symptomatic MM. Patients deferring transplant and transplant-ineligible patients were allowed. Treatment was given in 28-day cycles and continued for 8 cycles, or until unacceptable toxicity, withdrawal of consent, or progressive disease. A traditional 3+3 dose escalation scheme was used to determine the MTD of carfilzomib, with the following dose levels evaluated: 36, 45, and 56 mg/m². Carfilzomib (30-minute infusion) was administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle, beginning with 20 mg/m² on days 1 and 2 of cycle 1, then stepping up to the assigned dose level. In each cycle, cyclophosphamide (oral, 300 mg/m²) was administered on days 1, 8, and 15, and dexamethasone (oral or intravenous, 40 mg) was administered on days 1, 8, 15, and 22. An expansion cohort was enrolled at the established MTD or the maximum planned dose (MPD). Results: There were no dose-limiting toxicities observed at any of the dose levels evaluated, and thus the MPD of 56 mg/m² was brought forward into dose expansion. A combined total of 16 patients (dose escalation + dose expansion) received carfilzomib at 56 mg/m². The median age of patients who received KCyd at 56 mg/m² was 65 years (range, 49-81), 56.3% were male, and 93.8% had an ECOG performance status of 0 or 1. At 56 mg/m²,the ORR was 87.5% (95% CI, 61.7%-98.4%), and best overall responses were complete response (n = 1); very good partial response (n = 7); partial response (n = 6); and stable disease (n = 2). The median TTR for patients who received the 56 mg/m² dose and achieved partial response or better was 1 month. At 56 mg/m²,the most common adverse events of any grade were nausea (68.8%), cough (62.5%), diarrhea (56.3%), anemia (50.0%), fatigue (50.0%), and headache (43.8%), and the most common grade ≥ 3 adverse events were anemia (25.0%), hypokalemia (18.8%), neutropenia (18.8%), acute kidney injury (12.5%), and decreased white blood cell count (12.5%). Any-grade peripheral neuropathy was reported for 1 patient treated with the 56 mg/m² dose. The mean number of treatment cycles started among patients who received the 56 mg/m² dose was 7 (range, 3-8). In total, 6 of the 16 patients who received carfilzomib at 56 mg/m² did not complete the 8 cycles of study treatment: 1 patient discontinued due to progressive disease (which manifested during a break in treatment for renal insufficiency), 1 patient withdrew from the study, and 4 patients discontinued treatment because of adverse events. Adverse events that led to treatment discontinuation were acute renal failure (n = 1), creatinine increase and dehydration (n = 1), intermittent nausea (n = 1), and urinary tract infection (n = 1). One patient in the 45 mg/m² cohort experienced death due to sudden cardiac arrest; no deaths in the 36 or 56 mg/m² cohorts occurred during the study. Conclusions: Carfilzomib administered at 56 mg/m² twice weekly in combination with cyclophosphamide and dexamethasone was effective and showed acceptable toxicity for treating patients with newly diagnosed MM. The CHAMPION-2 study suggests that KCyd may be considered for first-line treatment of MM, including for patients not eligible for transplant.

Acknowledgments: This study was supported by Onyx Pharmaceuticals, Inc. an Amgen, Inc. subsidiary. The authors would like to thank Jesse Potash of Amgen, Inc. for medical writing assistance.