The effects of the combination of simvastatin and lenalidomide were analyzed in myeloma. Myeloma cell lines and patient myeloma cells were incubated with different concentrations of lenalidomide, simvastatin, or the combination. Co exposure to simvastatin and lenalidomide resulted in a synergistic reduction of cell viability in myeloma cells. This effect was due to induction of apoptosis and inhibition of proliferation. The combination augmented induction of caspase-8 cleavage and enhanced down-regulation of pStat3. Mevalonate and GGOH abrogated the synergy between lenalidomide and simvastatin. These data provide a rationale for the clinical evaluation of lenalidomide and simvastatin in patients with myeloma.