The introduction of bortezomib and IMiDs has improved outcomes of patients with multiple myeloma (MM). Moreover, second-generation IMiDs (pomalidomide) have recently been approved in Japan. Due to the incurability of this disease, newer drugs with different mechanisms of action designed to prolong survival and achieve cure are urgently needed. There are novel agents which appear to be promising, such as monoclonal antibodies (elotuzumab, daratumumab), second-generation proteasome inhibitors (carfilzomib), deacethylase inhibitors (panobinostat), and the kinesin protein inhibitor (Arry-520). In the MM-003 trial, there was a significant advantage in the pomalidomide plus dexamethasone arm over high-dose dexamethasone in terms of ORR, PFS, and OS in MM patients who had failed both lenalidomide and bortezomib treatment. In addition, the ASPIRE trial showed carfilzomib in combination with lenalidomide plus dexamethasone to provide a survival advantage over lenalidomide plus dexamethasone for relapsed/refractory MM. These encouraging results indicate that the use of newer agents, alone or in combinations, may overcome double-refractory disease. Other agents such as kinase inhibitors or signaling pathway inhibitors are now under investigation. The use of cocktails of different agents with different mechanisms of action in an earlier stage of the disease may help to obtain durable remissions or even disease cure.