Study Title:

Carfilzomib and Lenalidomide With Dexamethasone (CRD) Combination in Newly Diagnosed, Previously Untreated Multiple Myeloma

Coordinator:

Principal Investigator: Andrzej Jakubowiak, University of Michigan Cancer Center, Ann Arbor, MI

ClinicalTrials.gov Identifier:

Sponsors and Collaborators:

University of Michigan Cancer Center, Onyx Therapeutics, Inc., and Celgene Corporation

Participating Centers:

This study will be conducted at five medical centers in the following U.S. cities: Ann Arbor, MI; St. Louis, MO; Hackensack, NJ; Boston, MA and New York, NY.

Accrual Goal:

36 patients

Study Design:

Multicenter, open-label, single-arm, phase Ib/II study of the safety and efficacy of CRD for patients with newly diagnosed, previously untreated multiple myeloma requiring systemic chemotherapy.

Primary Outcome Measures:

Phase Ib - Safety and maximum tolerated dose of CRD; Phase II - Week 16 (end of cycle 4) complete and near complete response rates.

Secondary Outcome Measures:

Determining the overall response rate, time on study, duration of response, progression-free survival, time to progression, and overall survival.

Rationale:

A phase I/II study of the use of carfilzomib, a new proteasome inhibitor, in combination with lenalidomide and dexamethasone for treatment of multiple myeloma was reported at the ASH annual meeting in 2010. The safety profile was encouraging with the maximum tolerated dose not reached. The main adverse effect was myelosuppression, but with grade 3/4 toxicity observed in fewer than 15 percent of cases. Importantly, no peripheral neuropathy was observed, and 86 percent of patients continued treatment without dose modification. Remarkably, the response rate (partial and better) was 100 percent after the first four months of treatment. Follow-up was too short to demonstrate an impact on progression-free survival and overall survival, but the observations made in this phase I study supported an expanded study with a phase II component.

Comment:

The addition of novel agents to front-line treatment of newly diagnosed patients with multiple myeloma, whether or not eligible for autologous transplantation, has significantly improved response rates and survival. The most striking progress has been observed in patients eligible for therapeutic intensification who are treated with a three-drug regimen consisting of bortezomib, dexamethasone, and an immunomodulatory drug (either lenalidomide or thalidomide). These regimens have improved response rates such that more than 90 percent of patients achieve a partial or better response, and approximately 50 percent experience a complete response. Adverse events (myelosuppression, neuropathy, gastrointestinal problems, and thrombophilia) associated with these regimes cause significant morbidity, however, making imperative the development of novel agents such as carfilzomib with similar or better efficacy and an improved toxicity profile.