Author(s): A. K. Mahindra, P. G. Richardson, P. Hari, J. Laubach, I. M. Ghobrial, R. L. Schlossman, E. Weller, N. C. Munshi, K. C. Anderson, N. S. Raje

ABSTRACT:

Background: Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (MM) patients following >1 prior therapy. RAD001, an mTOR inhibitor has been studied as a single agent in MM and had no significant single-agent activity, but was well tolerated. Predicated upon our previous preclinical studies demonstrating synergistic anti-MM activity of mTOR inhibitors when combined with Len, we evaluated this combination as a non-steroid containing oral regimen in advanced MM.

Methods: Patients (pts) with relapsed and refractory MM were assigned to Len and RAD001 to be taken for 21 days of a 28 day cycle (NCT00729638). Pts were allowed to continue therapy until disease progression or unacceptable toxicity.

Results: Twenty-eight pts were registered on the trial;2 pts were replaced for rapidly progressive disease or failure to meet eligibility criteria on day 1. Data on 26 pts are currently available. Both cohort 1 and 2 required expansion because of grade 3 neutropenia and grade 4 thrombocytopenia. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 pts in cohort 3 (Len: 20 mg and RAD001: 5 mg x 21 days). The maximum tolerated dose (MTD) was therefore declared at 15 mg of Len and 5 mg of RAD001 for 21 days with a 7 day rest period. Most common (>10%) grade 1/2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which were manageable with supportive care. One pt developed RAD related non-infectious pneumonitis requiring discontinuation of therapy. Grade 3/4 adverse events > 5% included thrombocytopenia (11%) and neutropenia (22%). Nineteen pts completed 2 cycles and are evaluable for response: 12 pts received treatment at MTD. Overall response rate including MR + PR was 63% (90% CI: [30.76%]), with 1 pt achieving SD.

Conclusions: The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. The response rate to date has been encouraging in this heavily pretreated pt population. This combination provides an oral, steroid-sparing treatment strategy which warrants future evaluation in phase II studies.