Update On the Phase IIb, Open-Label Study of Vorinostat in Combination with Bortezomib in Patients with Relapsed and Refractory Multiple Myeloma.

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow. MM accounts for approximately 1% of all new cancer diagnoses and is the second most common hematologic malignancy in adults. Despite recent advances in therapy, MM remains largely incurable and there is a need to develop new treatments or treatment regimens to combat MM. Vorinostat is an oral histone deacetylase (HDAC) inhibitor approved for the treatment of cutaneous manifestations of T-cell lymphoma in patients with progressive, persistent, or recurrent disease on or following two systemic therapies. As HDACs are over-expressed and involved in the regulation of transcription with recruitment by oncogenic transcription factors in a variety of tumor types, the efficacy of vorinostat is currently under investigation in a number of hematologic and solid malignancies, including MM. Bortezomib is a proteasome inhibitor that has provided significant survival advantages for patients with MM. Preclinical studies have shown that the combination of vorinostat and bortezomib synergistically induces MM cell apoptosis. Results from two Phase I studies showed that the combination of vorinostat and bortezomib (+/- dexamethasone) is well tolerated and achieves ∼ 40% objective response rate in a relapsed/refractory MM population, even in those patients who were refractory to prior bortezomib treatment (Weber et al. Clinical Lymphoma and Myeloma 2009;9:S44, abstract A248) (Weber et al. Clinical Lymphoma and Myeloma 2009; 9:S42, abstract A242). Encouraging results observed in these trials led to the design of a Phase IIb, international, multicenter, open-label study that will assess the efficacy and tolerability of vorinostat in combination with bortezomib in advanced MM patients.

Patients (aged ≥18 years) with relapsed and refractory MM after two prior treatment regimens, including at least one bortezomib-containing regimen, and who are relapsed, refractory, intolerant, or ineligible for other therapies, including immunomodulatory agents, were included in this trial. Patients received intravenous bortezomib 1.3 mg/m² on Days 1, 4, 8, and 11 and oral vorinostat 400 mg once daily on Days 1-14 of each 21-day cycle. The addition of oral dexamethasone (20 mg on the day of and day after each bortezomib dose) was permitted for patients who experienced disease progression after two treatment cycles or no change (stable disease) after four cycles, until further disease progression. The primary endpoint is objective response rate and secondary endpoints include assessment of: safety, time to disease progression, progression-free survival, and overall survival. Patient-reported outcomes were collected in this study as an exploratory objective.

At the time of submission, 38 patients (out of 142) have been enrolled in the trial. A first interim futility analysis is planned after the 43^rd patient has been enrolled. At the time of the meeting, safety data, along with enrollment status and timelines for future data read-outs, will be reported.

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. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Dimopoulos:MSD: Honoraria; Celgene: Honoraria. Graef:Merck: Employment, Equity Ownership. Pietrangelo:Merck: Employment, Equity Ownership. Lupinacci:Merck: Employment, Equity Ownership. Reiser:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment. Anderson:Millennium: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding.