A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM)

SUMMARY: Bortezomib (VELCADE®) is a parenteral proteosome inhibitor with remarkable activity in multiple myeloma. This agent however, can be associated with neuropathy in about 30- 40% of the patients, when given intravenously twice a week, and in about 10-15% of patients when given subcutaneously. MLN9708 is an oral, reversible proteasome inhibitor with favorable toxicity profile and lower incidence of peripheral neuropathy (PN). In the phase I component of this trial, 15 patients were enrolled and a maximum tolerated dose of 4 mg of MLN9708, taken orally once a week, was established. For the phase II component of this study, 50 treatment naïve patients with multiple myeloma were enrolled and MLN9708 was given at a dose of 4 mg orally on days 1, 8, and 15, in combination with lenalidomide (REVLIMID®) (25 mg once daily on days 1 to 21) and dexamethasone (40 mg on days 1, 8, 15, and 22) every 28 days for up to 12 cycles. Patients subsequently went on to receive maintenance therapy with MLN9708 once a week until progression. In this regimen, MLN9708 was essentially substituted for VELCADE®. The overall response rate was 96%, with Very Good Partial Response seen in more than 44% of patients and 26% Complete Response rate. More importantly grade 1 neuropathy was only seen in 8% and grade 3 neuropathy developed in 3% of the patients. The authors concluded that the responses with this new combination is similar to the VRD (VELCADE®, REVLIMID®, and Dexamethasone) regimen but with significantly less neuropathy and more importantly, all three drugs can be given orally. Kumar SK, Berdeja JG, Niesvizky R, et al. 54th ASH Annual Meeting and Exposition 2012, Abstract 332