Vorinostat Overcomes Lenalidomide-Dexamethasone and Lenalidomide-Bortezomib-Dexamethasone Resistance In Relapsed/Refractory Multiple Myeloma

Significant improvements have been made in the treatment of relapsed/refractory (RR) multiple myeloma (MM), although the disease remains incurable. Recently, a number of clinical trials have evaluated the efficacy of vorinostat (Zolinza^®), an oral inhibitor of Class I and II histone deacetylases. Vorinostat has been evaluated as a single agent, showing minimal activity. In vitro studies demonstrated synergy between vorinostat and other pro-apoptotic agents. This led to Phase I and II trials of vorinostat in combination with both proteasome inhibitors and IMiDs. Based upon the positive phase I data, large, multinational phase II and III trials combining vorinostat (Z) and bortezomib (V) are ongoing. Previously presented Phase I data on the combination of lenalidomide (R), dexamethasone and vorinostat has been encouraging. To date, no large experience with this combination in patients previously found to be refractory to lenalidomide and dexamethasone (RD) has been reported. Here we report our single institution experience of 28 consecutive patients with RD refractory myeloma or VRD refractory myeloma treated with the RDZ or VRDZ respectively.

This is a retrospective chart review of patients who received commercially available oral vorinostat 300 mg or 400 mg once daily (days 1–7 and days 15–21) and lenalidomide 10–25mg (days 1–21) in a 28-day cycle. Ten patients also received bortezomib 1.3 mg/m² as an intravenous bolus on days 1, 4, 8, and 11.

All patients were refractory to prior RD. Most of the patients were relapsed and refractory not only to RD, but also to VRD. (Please refer to the table below.) All of the patients treated with VRDZ were R/R to prior VRD. 23/28 of these patients had previous autologous peripheral blood stem cell transplants (ASCT). 11 had two transplants, 1 had three and 5 had previous allogeneic transplants. The median prior lines of therapy were 4 (2-10) and median prior regimens was 5 (2-11).

An overall response rate (ORR) of 43% was noted. This included 8 partial responses (PRs) and 4 very good partial responses (VGPRs) or better. An additional 5 showed minimal responses (MRs) and 8 showed stable disease (SD). The overall clinical benefit rate (including MRs and SD) was 89%. The duration of response ranged from two months to 23+ months. The most common toxicities were GI, mostly diarrhea and cramping. Cytopenias were also experienced, but were not different from those expected for this population treated with lenalidomide-based therapy alone. We will report on additional patients, more complete toxicity data, event-free (EFS) and overall survival (OS), as well as a limited subgroup analysis.

These results suggest that this convenient oral regimen of vorinostat combined with lenalidomide and dexamethasone is well tolerated in patients with heavily pretreated, RD relapsed/refractory MM. These results further demonstrate the ability of vorinostat to overcome resistance to RD and VRD.

Siegel:Celgene: Advisory board, Speakers Bureau; Merck: Advisory board; Millennium: Advisory Board, Speakers Bureau. Off Label Use: vorinostat for multiple myeloma. Bilotti:Celgene: Advisory Board, Speakers Bureau; Merck: Honoraria; Millennium: Advisory Board, Speakers Bureau. McNeill:Celgene: Advisory Board, Speakers Bureau; Millennium: Advisory Board, Speakers Bureau. Graef:Merck Research Laboratories: Employment. Vesole:Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Speakers Bureau.