Combined Vorinostat, Lenalidomide and Dexamethasone Therapy in Patients with Relapsed or Refractory Multiple Myeloma: A Phase I Study.

Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable despite recent therapeutic advances. Treatment of patients with relapsed and refractory MM is extremely challenging and represents a specific unmet medical need. However, novel treatment combinations have the potential to improve patient outcomes. Vorinostat, an oral inhibitor of Class I and II histone deacetylase enzymes, enhances the anti-MM activity of other pro-apoptotic agents, providing potential synergy in combination with lenalidomide and dexamethasone. This Phase I, multicenter, open-label, non-randomized, dose-escalation study evaluated vorinostat plus lenalidomide and dexamethasone in patients with relapsed or refractory MM.

The primary objective was to determine the maximum tolerated dose (MTD); secondary objectives included overall safety and tolerability, and evaluation of clinical activity.

Patients aged ≥18 years with relapsed or refractory MM were enrolled sequentially into 1 of 5 escalating dosing levels (Table) using a standard 3+3 design for ≤8 cycles. Patients who were tolerating, and receiving clinical benefit from, the regimen were allowed to continue into the extension phase of the study. In the absence of dose-limiting toxicities (DLTs) in the first cycle, dose escalation continued until the MTD was established. In the event that the MTD was not established, dose level 5 would become the maximum administered dose (MAD) and an additional 8 patients would be enrolled in an expansion cohort to confirm safety. Response to treatment was assessed using modified European Group for Blood and Marrow Transplantation (EBMT) criteria with the overall response rate (ORR) defined as minimal or greater, and all adverse events (AEs) recorded.

Of 28 patients assessed for safety to date, all have experienced ≥1 AE, with 24 (87.5%) patients experiencing a total of 65 drug-related AEs overall, the majority of which were mild or moderate in severity. The most common drug-related AEs were diarrhea (n=12, 42.9%), fatigue (n=10, 37.5%), neutropenia (n=10, 37.5%), and thrombocytopenia (n=10, 37.5%). A total of 21 serious AEs, 8 of which were identified by the investigator as being related to study treatment, were reported in 13 (46.4%) patients. Three patients discontinued due to AEs. DLT evaluation is complete and there were no DLTs that prohibited dose escalation. One DLT, Grade 3 diarrhea lasting <48 hours, was observed at dose level 5. As per the protocol, this dose level was expanded to 6 patients in total and no further DLTs were observed. Therefore, the MTD has not yet been reached and dose level 5 is the MAD. Of 25 patients evaluable for efficacy, 21 (84%) experienced clinical benefit while on treatment. Best responses to vorinostat combined with lenalidomide and dexamethasone, defined by modified EBMT criteria, include: 1 complete response (CR), 1 near CR, 2 very good partial responses (VGPR), 8 partial responses (PR), 4 minimal responses (MR), 5 stable disease (SD), and 4 progressive disease (PD), for an ORR of 64%. Twelve of the 13 patients who have received prior lenalidomide therapy were evaluable for response; best responses in these patients included VGPR (n=1), PR (n=3), MR (n=1), SD (n=3); while 4 of these patients progressed. Of the 13 patients who remain on the study, 9 out of 11 (82%) evaluable patients have responded. To date, 10 out of 28 patients have discontinued due to PD.

These preliminary data suggest that vorinostat combined with lenalidomide and dexamethasone may represent a convenient oral combination therapy that is active and generally well tolerated in the treatment of relapsed/refractory MM. In addition, these results indicate that this combination may exhibit activity in patients who have received prior lenalidomide therapy. The study continues to further characterize the tolerability profile and efficacy of this combination.

Siegel:Celegne: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Vorinostat is a histone deacetylase (HDAC) inhibitor that was approved in the FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Weber:Milleninum: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Merck: Research Funding, unpaid advisory board. Mitsiades:Millennium: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis Pharmaceuticals: Research Funding; Pharma Mar: licensing royalties. Dimopoulos:MSD: Honoraria; Celgene: Honoraria. Harousseau:Janssen Cilag: Ad Board, Honoraria; Celgene: Ad Board, Honoraria; Novartis: Honoraria. Rizvi:Merck: Employment, Equity Ownership. Howe:Merck: Employment, Equity Ownership. Reiser:Merck: Employment, Equity Ownership. Byrne:Celgene Corporation: Employment, Equity Ownership. Anderson:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Speakers Bureau. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees; Gentium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees.