Author(s): A. Z. Badros, R. Vij, T. Martin, J. A. Zonder, A. F. Wong, T. Woo, K. Boussina, Z. Wang, R. Niesvizky

ABSTRACT:

Background: Renal impairment (RI) affects >50% of patients (pts) with multiple myeloma (MM). It confers shorter survival and prevents adequate dosing by exacerbating drug side effects. Carfilzomib (CFZ) is a selective proteasome inhibitor with established single-agent activity in pts with relapsed and/or refractory (R/R) MM (even in the bortezomib-refractory setting), including those with moderate RI.

Methods: This open-label, multicenter phase II trial enrolled pts with MM and varying degrees of RI (Table). Pts received CFZ 15 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 every 28 d for cycle (C) 1, escalating to 20 mg/m2 in C2 and 27 mg/m2 in C3. After response assessment, pts failing to achieve > PR by C2 or CR by C4 could receive dexamethasone 40 mg/week. Study objectives included PK, safety, pharmacodynamics (proteasome inhibition in blood and PBMC [PDn]), and efficacy (overall response rate [ > PR; ORR], clinical benefit response [ > MR; CBR] stable disease (SD) > 6 wk, duration of response, and time to progression).

Results: To date 39 pts have been enrolled. Pts received a median of 5 prior therapies (range 2-10). 97% had received bortezomib; all had received > 1 immunomodulatory agent; 67% had prior stem cell transplant. Thus far, 22 pts received a median of 3 C (range 1-10+); 9 have completed > 6 C. Side effects (AEs), including grade (G) 3/4 AEs (apparently independent of renal status), are presented in the Table. No QT/QTc prolongations were seen. PK/PDn were similar across all groups; CFZ was undetectable in plasma within 3 h (t3/4= 30-60 min) and did not accumulate after 2 C. Proteasome inhibition 1 h post-dose ranged from 75-89% at doses of 15-20 mg/m2. The CBR was 37% (8 PR and 5 MR) with an additional 37% SD (n=13).

Conclusions: Pts with MM and substantial RI can receive CFZ without dose adjustment. Responses are encouraging and toxicity is mild and manageable.