The combination of lenalidomide–dexamethasone 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 perifosine–lenalidomide–dexamethasone in relapsed and relapsed/refractory MM. Patients received escalating doses of perifosine 50–100 mg daily and lenalidomide 15–25 mg once daily on days 1–21 of each 28-d cycle, plus dexamethasone 20–40 mg 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 3–4 neutropenia (26%), hypophosphataemia (23%), thrombocytopenia (16%), and leucopenia (13%). Among 30 evaluable patients, 73% (95% confidence interval, 57·5–89·2%) achieved a minimal response or better, including 50% with a partial response or better. Median progression-free survival was 10·8 months and median overall survival 30·6 months. Response was associated with phospho-Akt in pharmacodynamic studies. Perifosine–lenalidomide–dexamethasone was well tolerated and demonstrated encouraging clinical activity in relapsed and relapsed/refractory MM.
Overall, 22 (73%) evaluable patients achieved at least a MR; at least partial response (PR) rate [nCR/CR + very good partial response (VGPR) + PR] was 50% (Table I), including seven patients (23%) achieving a VGPR or better. The median time to first response was 1 cycle (range, 1–3 cycles); the median duration of response was 9·2 months (range, 2– 35 months). In the subset of patients with relapsed but not refractory disease (N = 17), at least PR was 71% and at least MR was 82%; and in patients with refractory disease (N = 13) at least PR was 23% and at least MR was 62%. Among the thalidomide-exposed patients (N = 22), PR or better was 45%, 78% in the thalidomide-relapsed patients (7 of 9), and 23% in the thalidomide-refractory patients two of six patients achieved PR or better, and four achieved MR or better.
Table 1 Summary of clinical response, according to the modified European Group for Blood and Bone Marrow Transplant criteria
2. Survival analysis
After a median follow up of 30 months (range, 3·4– 51·3 months), median PFS was 10·8 months in all evaluable patients and 11·7 months in patients who achieved a MR or better (Fig 1A). Median OS was 30·6 months in all evaluable patients and was not reached in patients who achieved at least a MR or better (Fig 1B). As of 10 July 2011, 15 of the 30 evaluable patients were still alive, and seven patients had not progressed. For those patients who achieved a MR or better, nine patients had died and 17 patients had progressed. Patients with relapsed but not refractory disease had longer median PFS and OS than patients with refractory disease (27·7 vs. 3·9 months, P = 0·0002; not reached versus 16·7 months, P = 0·0006; Fig 2).