Phase I/II Study of Lenalidomide and High Dose Melphalan As Preparative Regimen in Autologous Transplant in Myeloma: Report of Phase II Efficacy and Safety Data

Background: High-dose melphalan and autologous hematopoietic stem cell transplantat (auto-HCT) is a standard consolidation therapy for eligible multiple myeloma (MM) patients due to superior survival outcome as compared to chemotherapy alone. However, patients remain at continuous risk of disease relapse following auto-HCT. Lenalidomide is active in newly diagnosed and relapsed MM and has synergistic activity with melphalan, but has not previously been incorporated into preparative regimen for auto-HCT. While high dose lenalidomide induces myelosuppression, the anti-tumor activity of lenalidomide is dose-dependent.

Methods:We conducted a single center, phase I/II study of lenalidomide and melphalan in patients with MM undergoing auto-HCT. The phase I portion included MM patients at all disease stages, including patients undergoing auto-SCT as salvage therapy. The phase II portion enrolled patients undergoing a first auto-SCT after achieving at least stable disease following their induction regimen. Phase I objectives included determination of side effect profile and recommended phase II dose (RP2D). Phase II objectives were disease response at day +100 and toxicity.

Treatment: All patients received a standard melphalan dose of 200 mg/m² (100 mg/m² IV days -1 and -2). Phase I lenalidomide dose was escalated from 50 mg, 75mg, 100 mg, and 150 mg and administered orally daily from days -7 to +2. Phase I data were previously reported (Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 3146). Thirteen patients were treated and no MTD was reached. The RP2D lenalidomide dose (150 mg orally daily days -7 to +2) was further explored in the phase II portion of this study. Post-transplant lenalidomide maintenance therapy was started between days +100 and +120 in all responders. We now report the planned interim analysis of the efficacy and safety profile of the phase II study.

Results:

From 5/1/12 to 7/9/15, forty seven subjects were enrolled to the phase II portion of the study. Study accrual is complete. We report below on the 37 patients with at least 100 days follow-up (median duration of follow-up of 12 months). 36 patients were assessable for response.  Responses are as followed: stringent CR 8 (22%), CR 3 (8%), VGPR 20 (54%), PR 3 (8%), progressive disease 2 (5%).

Among responders, 34 were able to start maintenance lenalidomide on days +100 to +110 (two withdrew from the study to pursue tandem stem cell transplant).  To date, 21 patients remain on the treatment. Of 13 who discontinued the therapy; 4 was due to progression, 4 due to physician/patient preference, 2 due to toxicities and 3 from other reasons. Median progression free survival has not been reached.

Toxicities were considered treatment related if they occur after the initiation of study drugs. DLTs are defined as any AEs occurring from days -7 to -2 that cause delay or prevent subjects from proceeding to auto-SCTs, grade 3 or more non-hematologic toxicities that do not resolve to a grade 2 or less by day 30 after auto-SCT, or engraftment failure. No DLTs were observed. The median time for ANC and platelet engraftment was 12 and 15 days and no delayed engraftment was observed. Toxicities and posttransplant hematopoietic recovery rates were similar to historical data observed with single agent high dose melphalan. Lenalidomide related toxicities occurred more commonly during the maintenance phase. Common toxicities occurring in more than 10% of patients were diarrhea (24%), peripheral neuropathy (21%) and fatigue (10%). Grade 3-4 toxicities occurred in 16% percent of patients: fatigue (5%), neutropenia (5%) neuropathy (3%), and thrombocytopenia (3%).

Conclusion

The use of high dose lenalidomide in combination with high-dose melphalan as a preparative regiment for auto-SCT is well tolerated. High VGPR or better disease response rates, compared to historical control, suggest that the preparative combination regimen may improve the depth of response. Stem cell rescue likely overcome lenalidomide induced myelosuppression. The study is now closed to accrual. Updated data on primary endpoints from all subjects will be reported at the meeting.