The Combination of Vorinostat and Bortezomib Provides Long-Term Responses in Patients with Relapsed or Refractory Multiple Myeloma.

A better understanding of multiple myeloma (MM) disease biology has led to the development of targeted agents such as the proteasome inhibitor bortezomib. While bortezomib has provided significant survival advantages for both previously untreated and treated patients with MM, nearly all patients eventually relapse or become refractory to bortezomib therapy. Therefore, there remains a need to develop specific new approaches that are active against MM or enhance the efficacy of existing treatments. Vorinostat (Zolinza^®), a potent oral inhibitor of Class I and Class II histone deacetylase (HDAC) enzymes, has demonstrated antiproliferative and proapoptotic activity in preclinical models of MM as a single agent and in combination with bortezomib. Preliminary results from an ongoing open-label, escalating dose, multicenter Phase I trial of vorinostat in combination with bortezomib have shown that the combination is generally well tolerated and effective in heavily pretreated patients with advanced MM (Weber et al. Clinical Lymphoma and Myeloma 2009; 9: S44, abstract A248), including patients refractory to prior bortezomib treatment (Weber et al. Clinical Lymphoma and Myeloma 2009; 9: S42, abstract A242). Here we report the safety and efficacy results for a cohort of patients with relapsed/refractory MM who have received ≥12 cycles of treatment with vorinostat in combination with bortezomib.

Patients (aged ≥18 years) with relapsed or refractory MM (ECOG performance status 0-2) were sequentially enrolled on escalating doses of vorinostat combination therapy using a standard 3+3 design for ≤8 cycles. Cycles were repeated every 21 days and consisted of vorinostat 200 mg bid or 400 mg once daily (Days 1-14) in combination with bortezomib 0.7 or 0.9 mg/m² i.v. on Days 4, 8, 11, and 15; or escalated to 0.9, 1.1, or 1.3 mg/m² i.v. on Days 1, 4, 8, and 11. The addition of oral dexamethasone 20 mg on Days 1-4 and 9-12 of each cycle was permitted for disease progression (PD). Patients without disease progression at Cycle 8 were allowed to continue on study treatment.

Of the 34 patients who have entered the study, 9 have received combined vorinostat and bortezomib treatment for ≥12 cycles and are the focus of this report. In this population, drug-related adverse events (AEs) occurred in 9/9 patients; 99% of these AEs were mild to moderate in severity (NCI Grade 1-3) and 6 patients had serious AEs (9 events). One patient experienced Grade 4 neutropenia, and 5 patients experienced Grade 3 drug-related AEs. The most common drug-related toxicities of any grade were diarrhea, nausea, and fatigue. The best responses observed in 9 evaluable patients were 5 partial response (duration 147 to 609 days), 2 minimal response (duration 42 to 161 days), and 2 stable disease (duration 371 to 742 days). Seven of 9 patients have now discontinued treatment; all due to progressive disease (median [range] time to progression was 294 days [42 to 742 days]).

These preliminary data indicate that extended treatment with vorinostat in combination with bortezomib (+/- dexamethasone) administered in a 21-day cycle shows significant long-term clinical activity with acceptable tolerability in patients with relapsed/refractory MM.

Jagannath:Celgene: Honoraria; Millennium: Ad Board, Honoraria; Merck: Honoraria. 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:Millenium: Research Funding, Speakers Bureau; Celgene : Research Funding, Speakers Bureau; Merck : Research Funding, unpaid advisory board. Schiller:Denzyme: Research Funding; Cellegne: Research Funding; Eli Lilly: Research Funding; Centocor: Research Funding; Millennium: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Vion: Research Funding. Lupinacci:Merck: Employment, Equity Ownership. Reiser:Merck: Employment, Equity Ownership. Allen:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership.