Phase Ii Study Of Carfilzomib In Patients With Relapsed/Refractory Multiple Myeloma And Renal Insufficiency

8128 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 (t¾ = 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. Evaluable pts Cohort CrCL, mL/min Enrolled Efficacy Safety PK Normal 80 10 10 2 4 Mild RI 50-79 9 8 8 6 Moderate RI 30-49 9 7 6 6 Severe RI <30 9 8 4 6 On hemodialysis 2 2 2 2 Total 39 22 35 24 AE All G (n) G 3/4 (n) Fatigue 14 3 Anemia 10 9 Diarrhea 9 Nausea 8 Constipation 7 Thrombocytopenia 7 6 Hypokalemia 7 Creatinine increase 4 Mental status change 3 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Celgene, Millennium, Onyx Onyx Celgene, Millennium Celgene, Cepahlon, Millennium, Onyx, Seattle Genetics