Synergistic antimyeloma effects of zoledronate and simvastatin.

Despite advances in the treatment of multiple myeloma, it remains an incurable disease because of primary and secondary drug resistance. Mevalonate pathway inhibitors like bisphosphonates and statins have antimyeloma activity in vitro at very high concentrations, which may probably not be reached in vivo. NCI-H929, OPM-2, U266 and RPMI-8226 myeloma cell lines were treated in the presence or absence of bone marrow stromal cells with simvastatin or zoledronate in combination with classical antimyeloma drugs like melphalan or bortezomib. Zoledronate did not show substantial antimyeloma activity at low and intermediate concentrations, whereas simvastatin potently induced apoptosis in myeloma cells without signs of primary, cell-adhesion-mediated drug resistance. Furthermore, sequential blockage of the mevalonate pathway by zoledronate and simvastatin demonstrated synergistic induction of apoptosis and reversal of cell-adhesion-mediated drug resistance. Our data provide a rationale for combining zoledronate and simvastatin with classical antimyeloma drugs.