Vorinostat Enhances the Antimyeloma Effects of Melphalan and Bortezomib

Objectives: Examine the antitumor activity of the histone deacetylase inhibitor vorinostat's antitumor activity against multiple myeloma (MM) using cell lines and a murine xenograft model.

Methods: RPMI8226, U266, and MM1S cells were cultured for 48 h in the presence of media, vorinostat, melphalan, or bortezomib alone, or combinations of vorinostat with melphalan or bortezomib. Cell proliferation was measured using the MTS [3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfphophenyl)-2H-tetrazolium, inner salt] assay. Severe combined immunodeficient mice bearing LAGkappa-1B tumors were treated with vorinostat [30, 60, or 100 mg/kg daily for five consecutive days per week (qdx5d), 100 or 300 mg/kg daily for 2 d/wk (qdx2d)], melphalan (1, 3, or 10 mg/kg qdx1d), bortezomib (0.25 or 0.5 mg/kg qdx2d), or combinations thereof for 35 d. Tumor growth was determined via measurement of human immunoglobulin G (hIgG) levels and tumor volume.

Results And Conclusions: Vorinostat enhanced the anti-MM effects of melphalan and bortezomib in vitro. Synergism was observed with vorinostat and melphalan in RPMI8226 and U266 cell lines. Vorinostat 100 mg/kg in combination with melphalan 3 mg/kg resulted in significant inhibition of tumor growth in vivo, compared with control (tumor volume P = 0.0001; hIgG P = 0.0001), single-agent vorinostat (tumor volume P = 0.0025; hIgG P = 0.0137), and single-agent melphalan (tumor volume P = 0.0043; hIgG P = 0.0426). Vorinostat also enhanced the antimyeloma effects of bortezomib in vivo. Vorinostat enhances the anti-MM activity of melphalan and bortezomib in vitro and in vivo. This study provides rationale for further evaluation of vorinostat in combination with chemotherapeutic agents and bortezomib for the treatment of MM.