Phase I Trial of Lenalidomide + Vorinostat After Autologous Transplant in Multiple Myeloma.

Post autologous transplant maintenance therapy for patients with multiple myeloma (MM) is standard of care (McCarthy et al, NEJM, 2012). Vorinostat (SAHA, Zolinza) is a HDAC inhibitor for which preclinical evidence suggests that its combination with bortezomib is synergistic via HDAC-6. Preclinical data suggests that HDAC-I's increase MHC class I and class II expression, rendering tumor cells more susceptible to host innate immune killing. Lenalidomide activates NK cells via PP2A inhibition and induces CD56 expression in CD16+CD56- cells thereby enhancing NK cell-mediated ADCC. Initiating lenalidomide to enhance NK cell activity against tumor cells in the early post transplant period, especially if administered after increased MHC class I expression induced by HDAC-I pretreatment. We hypothesized that the combination of Vorinostat and lenalidomize would be both tolerable and effective post-transplant.

This was a phase I trial for myeloma patients after hematopoietic stem cell transplant (HSCT) following the 3×3 phase I design. Patients were required to have an ANC³ 1000/μL, platelet count³ 75,000/μL, and a serum creatinine² 1.5x institutional upper limit of normal. Vorinostat was administered starting day +90 after HSCT for days 1–7 and 15–21 starting at 200 mg and escalating to a max of 400 mg combined with lenalidomide 10 mg days 1–21 of a 28-day cycle until progression or clinically significant toxicity. Lenalidomide could be escalated after cycle 1 in 5 mg increments to a maximum of 25 mg. The primary endpoint was maximum tolerated dose (MTD) and dose limiting toxicities were assessed during the first cycle. Correlative endpoints included quality of life assessments with the Brief Pain Inventory (Short Form), The Center for Epidemiologic Studies Depression Scale (CES-D-10), Brief Fatigue Inventory (BFI), Brief Pain Inventory (BPI), and the FACT-G. Peripheral blood flow cytometry for NK cells and Tregs were obtained day 1 of the first cycle of combined therapy (C1D1/3 mos. post transplant), C2D1 (4 mos.), C3D1 (5 mos.), C4D1 (6 mos.), and off study.

Sixteen patients were enrolled after HSCT with a median age 58 y.o. (range 41–67) with a median number of prior therapies at enrollment of 2 (range 1–8) and mean ISS stage 1.5 (range 1–3). Twelve patients had only trisomies on CD138-selected FISH, one patient had normal cytogenetics, and three patients had high risk features [complicated karyotype, t(4;14), or abnormal chromosome 1]. Median follow-up has not been reached.

Fifteen patients received more than one cycle of therapy. 11/15 (73%) were able to escalate the lenalidomide dose with 4/11 (36%) reaching the maximum lenalidomide dose, and all but 1 of the 11 required lenalidomide dose reduction due to subsequent neutropenia. Of the adverse events possibly, probably, or definitely related to therapy (table 1), the most common toxicities were neutropenia (11.8% of all AEs), fatigue (11.1%), thrombocytopenia (9.7%), diarrhea (7.6%), anemia (6.9%), hypokalemia (6.3%), and rash (4.9%). Infection with a normal ANC occurred only twice and no patient suffered a DVT. One patient had therapy stopped due to toxicities, one due to progressive disease, and one due to megacolon that was present prior to transplant.

Four patients improved their transplant response after starting lenalidomide/vorinostat. Preliminary analysis of quality of life from the start of therapy through the first three cycles found no significant change in the BFI, FACT-G, CES-D, or BPI.

Lenalidomide/vorinostat post HSCT was well tolerated and 14/16 (87%) of patients remain on protocol therapy. There were no DLTs and patients the final cohort starting at 400 mg vorinostat and 10 mg lenalidomide completed accrual. The median dose of lenalidomide for those patients receiving maintenance therapy 1 year post-transplant is 5 mg daily. Analysis of peripheral blood flow NK cells and Tregs, cumulative dose intensity, and median progression free survival will be presented at the meeting.

No relevant conflicts of interest to declare.