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Final Results From The Phase 1b/2 Study (PX-171-006) Of Carfilzomib (CFZ) In Combination With Lenalidomide And Low-Dose Dexamethasone (CRd) For Patients With Relapsed Or Progressive Multiple Myeloma

EHA 2013 Congress Abstract S577 (Oral Presentation)

Authors: Ruben Niesvizky1,*, Thomas Martin2, William Bensinger3, Melissa Alsina4, David Siegel5, Michael Wang7, Edward Kavalerchik6

Affiliations: 1Myeloma Center, Weill Cornell Medical College, New York, 2UCSF Medical Center, San Francisco,3University of Washington, Seattle, 4Moffitt Cancer Center, Tampa, 5John Theurer Cancer Center, Hackensack, 6Clinical Science, South San Francisco, 7Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, United States

Background: Carfilzomib (CFZ) is a selective inhibitor of the chymotrypsin-like activity of both the constitutive proteasome and the immunoproteasome, and was approved in the United States in 2012 as a single-agent treatment for patients with multiple myeloma (MM) who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. We previously reported interim data from PX-171-006 (NCT00603447), a phase 1b/2 study of CRd in patients with relapsed or progressive MM (Wang M et al., ASCO 2011; Niesvizky R et al., Clin Cancer Res. 2013).

Aims: Herein we report final results from the PX-171-006 study.

Methods: Patients (1–3 prior treatments) received CRd in 28-day (D) cycles—CFZ IV on D1, 2, 8, 9, 15, and 16; lenalidomide PO D1–21; and dexamethasone weekly. During the phase 1 portion of the study, CFZ (15–27 mg/m2) and lenalidomide (10–25 mg) doses were escalated to determine the maximum tolerated dose (MTD). The maximum planned dose (MPD) of CFZ was 20 mg/m2 on D1 and 2 of Cycle 1 and 27 mg/m2 there­after, which was used in combination with lenalidomide (25 mg/d) and dexamethasone (40 mg/wk). During the phase 2 dose expansion portion of the study, CFZ was used at the MTD/MPD. Endpoints included overall response rate (ORR) (assessed by IMWG criteria), duration of response (DOR), progression-free survival (PFS), and safety.

Results: A total of 84 patients were enrolled since June 2008. Overall, prior treatments included bortezomib (77%; 18% refractory) and lenalidomide (70%; 35% refractory); 20% had high-risk cytogenetics/FISH. The MTD was not reached in phase 1, supporting expansion at the MPD (n=52; 23% bortezomib refractory and 42% lenalidomide refractory). As of November 2012 (median follow-up 24.4 mo), ORR was 69% overall and 76.9% at MPD. In addition, very good partial response was reported in 36.9% (overall) and 38.5% (MPD) of patients. Stringent complete response was reported in 3.6% (overall) and 3.8% (MPD) of patients. Re­sponses were durable with a median DOR of 18.8 mo (95% CI 9.7–41.5) overall and 22.1 mo (95% CI 9.5–NE) at the MPD. Median PFS was 11.8 mo (95% CI 7.6–20.7) overall and 15.4 mo (95% CI 7.9–NE) at the MPD. In the 35% of patients refractory overall to lenalidomide, ORR was 58.6%, median DOR 13.8 mo (95% CI 6.47–NE), and median PFS 9.9 mo (95% CI 5.55-NE). In total, 10 and 12 patients at the MPD pur­sued other therapies and were censored for DOR and PFS, respectively. Seven patients at the MPD were censored for DOR and PFS after undergoing stem cell transplant/maintenance. Overall, a median of 8.5 (range 1−46) cycles of CFZ were started. Fifteen percent of patients discontinued CFZ due to adverse events (AEs); dose reductions were required by 4% of patients. The most common grade 3/4 hematologic AEs included neutropenia (35.7%), lymphopenia (29.8%), and thrombocytopenia (25.0%). The most common grade 3/4 nonhematologic AEs included hypophosphatemia (20.2%) and hyperglycemia (13.1%).Grade 3/4 peripheral neuropathy was infrequent (1%).

Summary / Conclusion: CRd was well tolerated and highly active and provided robust and durable re­sponses in patients with relapsed or progressive MM where 35% were lenalidomide refractory. In patients who received the MPD, ORR was 76.9% with a DOR of 22.1 mo. Grade 3/4 hematologic AEs were generally consistent with earlier studies in advanced MM that used similar doses of single-agent CFZ. CRd is being further evaluated in several ongoing phase 2/3 trials.

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