Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study

The combination of lenalidomidedexamethasone is active in multiple myeloma (MM). Preclinical data showed that the Akt inhibitor, perifosine, sensitized MM cells to lenalidomide and dexamethasone, providing the rationale for this Phase I, multicentre, single-arm study to assess the safety and determine the maximum-tolerated dose (MTD) of perifosinelenalidomidedexamethasone in relapsed and relapsed/refractory MM. Patients received escalating doses of perifosine 50100mg daily and lenalidomide 1525mg once daily on days 121 of each 28-d cycle, plus dexamethasone 2040mg weekly thereafter, as indicated. Thirty-two patients were enrolled across four dose cohorts. MTD was not reached, with 31 patients evaluable for safety/tolerability. The most common all-causality grade 1-2 adverse events were fatigue (48%) and diarrhoea (45%), and grade 34 neutropenia (26%), hypophosphataemia (23%), thrombocytopenia (16%), and leucopenia (13%). Among 30 evaluable patients, 73% (95% confidence interval, 57.589.2%) achieved a minimal response or better, including 50% with a partial response or better. Median progression-free survival was 10.8months and median overall survival 30.6months. Response was associated with phospho-Akt in pharmacodynamic studies. Perifosinelenalidomidedexamethasone was well tolerated and demonstrated encouraging clinical activity in relapsed and relapsed/refractory MM.