Phase I/II Trial of Lenalidomide and High-Dose Melphalan As Preparative Regimen for Relapsed Myeloma

Background:Lenalidomide (LEN) in combination with standard-dose melphalan has shown significant anti-multiple myeloma (MM) activity. In this phase I/II trial we evaluated the safety and efficacy of combining escalating doses of LEN and high-dose melphalan (HDM) for patients undergoing autologous hematopoietic stem cell transplantation (auto-HCT) for relapsed MM.

Methods: Doses were chosen adaptively for successive cohorts of size 3 using an extension of the safety-efficacy trade-off design.Each cohort received melphalan 200 mg/m²plus LEN at one of the four dose levels orally, for 7 days. Primary endpoints were dose-limiting toxicity (DLT), defined as regimen-related death, graft failure, grade 3 or 4 atrial fibrillation, grade 4 deep venous thrombosis, or pulmonary embolism occurring within 30 days post auto-HCT, and efficacy, defined as complete response (CR) at day +90.

Results: 57 patients were enrolled between March 2010 and April 2013. After safely escalating to 100 mg of LEN, patients were adaptively randomized among the 4 LEN dose levels. Three, 5, 24 and 25 patients were treated at 25, 50, 75 or 100 mg respectively. Median age at auto-HCT was 60 (34-72) years, and median time from diagnosis to auto-HCT was 33 (5-214) months, with no significant differences between the 4 dose levels. Sixteen (28%) patients had high-risk abnormalities on conventional cytogenetic or fluorescent in-situ hybridization (FISH) studies. Median prior lines of treatment were 3 (1-11). Eighteen patients (32%) had a prior auto-HCT. Twenty-four (42%) patients received post auto-HCT maintenance.  DLT was not seen at any of the 4 dose levels prior to adaptive randomization.  Grade 3-4 non-hematologic toxicity was seen in 40 (70%) patients, with no significant differences between the 4 dose levels. Two patients died of nonrelapse causes (viral infection 1, cardiac failure 1) with a TRM of 3%. Median time to both neutrophil and platelet engraftment  was  11 days. At day 90, 7 (12%) patients achieved a CR, 30  (53%) achieved CR or very good partial response (VGPR),, and 51 (89.5%) achieved CR, VGPR or partial response (PR), with no significant differences in response rates among the 4 LEN dose levels.  With a median follow up of 10.5 months (range 0.5-33.4), median progression-free (PFS) and overall survival (OS) have not yet been reached. One and 2-year PFS were 63% and 59%, respectively. One and 2-year OS were 82% and 72%, respectively. These compare favorably with our previous experience of 2-year PFS and OS of 24% and 59%, respectively, after salvage auto-HCT with melphalan alone. No second primary malignancy (SPM) has been seen so far.

Conclusion: LEN up to 100 mg daily x 7 days can be safely combined with high-dose melphalan for relapsed myeloma. The regimen is associated with a high overall response rate and 2 year PFS and OS of 59% and 72% in relapsed and heavily pretreated patients, with no SPM so far.