A Phase I/II Trial Combining High-Dose Lenalidomide with Melphalan and Autologous Transplant for Multiple Myeloma: A Report of the Phase I Dose-Finding Study.

High dose chemotherapy and stem cell transplantation (HDSCT) has been a standard of care for younger patients with adequate organ function since the early 1980s, due to its superiority over standard chemotherapy in prolonging disease-free and overall survival. Immunomodulatory agents, including thalidomide and lenalidomide, have significant single-agent activity and an additive effect when combined with melphalan. Preclinical data suggest an increased DNA damage and an anti-angiogenic effect with the combination. Additive clinical benefits were also observed when the 2 agents were used in combination in non-transplant settings. The antimyeloma effects of both agents are dose-dependent with myelosuppression being the dose limiting toxicity (DLT). This toxicity can be attenuated with stem cell rescue.

We conducted a phase I/II trial designed to evaluate the safety and efficacy of combining lenalidomide with high-dose melphalan as conditioning for autologous transplant for myeloma. The phase I portion of the study is complete and the results are reported in this abstract.

The enrolled patients included any patients with myeloma, regardless of the status of the disease, undergoing high dose melphalan for autologous stem cell transplantation. The melphalan dose was fixed (200 mg/m2) while the doses of lenalidomode were escalated from 50, 75, 100, and 150 mg/m2 administered orally days -7 to +2 of the transplantation. Dose escalation was based upon a 3+3 phase I design. DLTs were defined as grade ≥4, both hematologic and non-hematologic, occurring between days -7 to -2 which prevents subjects from undergoing stem cell transplantation, or grade 3 or 4 non-hematologic toxicity occurring after day -2 that does not resolve to a grade 2 or less by day +30 after transplantation, or delayed engraftment. The response was assessed at day +100 post transplantation using the International Myeloma Working Group criteria.

13 patients participated in the phase I portion of the study from September 2010 to May 2012. Patients ages ranged from 42– 72 years (median 63 years). Seven patients were undergoing their first autologous transplant with 2 patients having had 2 lines of previous therapy and 5 having one line of therapy. Six patients were undergoing their second transplantationas salvage for control of progressive disease and all had more than 3 lines of prior therapy. At baseline, 5 patients had progressive disease, 1 had SD, 3 had PR, 3 had VGPR and 1 had CR as responses to their most recent lines of therapy. The median time for ANC and platelet engraftment was 10 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. The most common grade ≥ 3 adverse events were myelosuppression, neutropenic fever and electrolyte abnormalities, all of which are commonly observed with single agent high dose melphalan. Adverse events related to the study drugs were electrolyte abnormalities (hypokalemia, hyperkalemia and hypocalcemia), gastrointestinal side effects and rash, all of which were grade 1 to 2 and manageable without a delay or discontinuation of the study drugs. One patient died from disease progression prior to scheduled disease evaluation. One patient has not yet reached day +100 post transplant. Therefore, responses were evaluable for 11 patients. Three patients achieved stringent CR (27%), 3 CR (27%), 2 VGPR (18%), 3 PR (27%) and one had progressive disease (9%). The overall response rate was 91%, with 72% achieving VGPR or better. All patients had adequate count recovery and were able to initiate lenalidomide maintenance treatment by day +100 to +110 post transplantation.

The use of high dose lenalidomide in conjunction with high-dose melphalan is well tolerated, with preliminary data suggesting that the combination is highly efficacious. DLT was not observed; therefore the recommended phase II dose is 150 mg of lenalidomide orally on days -7 to +2 in combination with melphalan 200 mg/m2. The phase II portion of this trial is ongoing in patients undergoing first HDSCT. Complete response at 3 months post transplantation is the primary end point.

Off Label Use: Lenalidomide in myeloma transplant. Abonour:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.