Several anti-cancer agents are derivative from natural products and microorganisms. The dolastatins are natural peptides derived from the marine mollusc Dolabella auricularia, which have recently been reported as an anti-cancer agent. Dolastatin 10 and 15 are small peptides; most preclinical studies have used dolastatin 10. It has been reported that dolastatins have cytotoxic activity by inhibiting microtubule assembly, and several clinical studies have already begun for solid tumors. However, the effects of dolastatin 15 against hematological malignancies such as myeloma cells have never been reported. We demonstrate here for the first time that dolastatin 15 induces cell cycle arrest at the G2/M phase followed by apoptosis in various human myeloma cell lines (RPMI8226, U266, and IM9), suggesting that it has effects on mitotic spindles. In addition, we showed that dolastatin 15 induces apoptosis of myeloma cells via activation of both mitochondrial- and Fas (CD95)/Fas-L (CD95-L)-mediated pathways. Our investigations have identified a novel inhibitor of microtubule assembly that induces mitotic arrest and apoptosis of myeloma cells. Therefore, it is possible that dolastatin 15 might be a novel and safe therapeutic agent for patients with multiple myeloma.