The Speed of Response to Single-Agent Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma: An Exploratory Analysis of Results From 2 Multicenter Phase 2 Clinical Trials,

Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. Phase 1 and 2 studies with carfilzomib have demonstrated durable single-agent antitumor activity with a favorable safety profile in patients with relapsed and/or refractory multiple myeloma (MM). Results from a phase 1 study of carfilzomib in patients with relapsed and/or refractory hematologic malignancies (Alsina et al. Blood. 2007;110: Abstract 411) as well as those from an independent study of carfilzomib in the frontline combination setting (Jakubowiak, et al. Haematologica. 2011;96(2): Abstract P-253) have suggested that initial responses occur rapidly and the depth of response improves with continued treatment. Based on these encouraging findings, we have performed an exploratory analysis to evaluate the time to initial response (or the speed of response) from the following 2 multicenter phase 2 clinical trials with carfilzomib: 1) PX-171-003-A1, an open-label, single-arm phase 2 trial that enrolled patients with relapsed and refractory MM following ≥2 prior regimens and 2) PX-171-004, an open-label phase 2 trial in bortezomib-naïve and bortezomib-treated patients with relapsed or refractory MM following 1–3 prior regimens.

Patients in study PX-171-003-A1 received carfilzomib 20 mg/m² in Cycle 1 on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle and were dose escalated to 27 mg/m² on the same schedule thereafter for up to 12 cycles. Patients enrolled in PX-171-004 either received 20 mg/m² for all treatment cycles or a stepped-up, dose-escalating regimen of 20 mg/m²for Cycle 1 and 27 mg/m²for all treatment cycles thereafter. Responses and progression were determined according to the International Myeloma Working Group criteria modified to include minimal response (MR) per European Blood and Marrow Transplant Group criteria and were assessed and confirmed by an Independent Review Committee. Responses were assessed on Day 15 of Cycle 1 and Day 1 of Cycles 2 through 12 and at the end of study. Time to response, as presented here, is the time from the start of treatment to either 1) the first confirmed response of MR or better or 2) the first confirmed response of PR of better.

A total of 257 response-evaluable patients from PX-171-003-A1 and 162 response-evaluable patients from PX-171-004 were eligible for inclusion in this exploratory analysis. Patients from the 003-A1 study had received a median of 5 prior anti-MM regimens, while bortezomib-naïve patients from the 004 study and bortezomib-treated patients had received a median of 2 and 3 prior regimens, respectively. Of these, 95 patients from 003-A1 and 78 bortezomib-naïve (both dose cohorts combined) and 11 bortezomib-treated patients from 004 had minimal responses (MR) or better and were analyzed for time to response. The specific time to response data are presented in the table below and are separated by study and by prior bortezomib exposure (ie, BTZ-naïve or BTZ-treated) for the 004 study.

Patients from all cohorts in both clinical trials responded relatively rapidly with similar median times to response in patients from the 003-A1 study and from the 004 study (both bortezomib-naïve and treated). At the same time, the depth of responses improved with continued carfilzomib treatment. An analysis of time to best response will be presented.

Based on this exploratory analysis, the speed of response to single-agent carfilzomib was rapid (within a median of 0.5–1.0 months to achieve responses of MR or better) in patients with relapsed and refractory MM in 2 multicenter clinical trials. This preliminary analysis represents the first focused evaluation of the dynamics of response to carfilzomib and the results merit additional evaluation in the setting of ongoing and future clinical trials.

Wang:Onyx Pharmaceuticals: Research Funding. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Dixon:Onyx Pharmaceuticals: Employment. Renau:Onyx Pharmaceuticals: Employment. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau.