Dose Finding Study of Lenalidomide as Maintenance Therapy In Multiple Myeloma After Allogeneic Stem Cell Transplantation

Abstract 2376

Allogeneic stem cell transplantation (HSCT) for multiple myeloma is a potential curative treatment approach. A high number of relapses after allogeneic stem cell transplantation after reduced intensity conditionings underlying the need of post transplant strategies to improve remission rates and disease free survival.

Lenalidomide is an effective drug in treatment of multiple myeloma patients. The efficacy and the immunmodulatory properties on T- and NK- cells may augment the Graft versus Myeloma effect after HSCT, but myelosuppression as well as induction of GvHD is a concern of using the drug early after allogeneic stem cell transplantation.

Study objective was to determine the maximal tolerable dose (evaluating three dose levels) of lenalidomid after HSCT in patients with multiple myeloma. A total of 18 patients with multiple myeloma were enrolled so far.

Lenalidomide as single agent maintenance treatment was started between 100 and 180 days after HSCT. In the first subgroup three patients started with dose of 5 mg daily from day 1 till 21 for duration of four cycles. In this group dose limited toxicities not appear. The next higher dose level was 10 mg/d lenalidomide for a total of 6 patients. In this cohort of patients, 3 patients showed dose limiting toxicities, which were caused by an acute pancreatitis in one case, elevated liver enzymes (CTC grade III), attribute to liver GvHD in one case and renal insufficiency in one patient. Because 3 patients in 10 mg cohort developed DLT, the maximum tolerate dose has been declared as 5 mg.

So far 6 additional patients were treated with this dose level (5 mg/d, day 1–21). In these cohort four patients experienced CTC grad III toxicity was observed: two cases with acute GvHD, one case with elevated liver enzymes and one case with intolerance and dizziness.

Beside lenalidomide’s effect on myeloma cells, the drug is a known immune modulator. We therefore, analysed T- and NK cell subsets of patient peripheral blood by flow cytometry after lenalidomide treatment. An increase of 6% in activated CD3 cells was observed, as indicated by expression of HLA-DR molecules. Furthermore, except for the increase of whole CD8 cell number, we also observed increased proinflammatory CD8/INFg+ T cell numbers (1,5% to 4,5% p=ns). Along with the T cell date, NK cells expressed more activating receptors, like NKp44 and less inhibitory receptors, like NKG2A, support the immunmodulatory efficacy of lenalidomide.

We concluded 5 mg lenalidomide as a single agent is the maximum tolerate dose if used early after allogeneic stem cell transplantation (day 100 – 180). Lenalidomide has high immune modulatory properties that might increase the risk of GvHD by activating CD8 cell. Combining lenalidomide with immunosuppressive drugs such as dexamethasone or bortezomib may reduce the risk of GvHD.