The overall survival of patients with multiple myeloma has significantly improved over the last decade, mainly due to the use of novel agents such as thalidomide, lenalidomide and bortezomib; however, multiple myeloma remains incurable due to its eventual relapse, necessitating urgent development of newer agents. YM155 is a novel small molecule that suppresses transactivation of survivin and induces apoptosis in various cancer cell types. However, the effects of YM155 on multiple myeloma cells have not been fully elucidated. We herein found that YM155 inhibited proliferation of and induced caspase-dependent apoptosis in myeloma cells, partially via the suppression of survivin, myeloid cell leukemia sequence-1, and X-linked inhibitor of apoptosis protein. Interestingly, YM155 suppressed c-Myc protein expression via the proteasomal degradation. Moreover, YM155 increased F-box and WD-40 domain protein 7α expression that is a component of the Skp, Cullin, F-box-like ubiquitin ligase complex, suggesting that YM155-induced c-Myc down-regulation may be due to the proteasomal degradation through ubiquitination by F-box and WD-40 domain protein 7α. These results warrant further clinical evaluation of YM155 in MM patients.