The activity observed with proteasome inhibitors and immunomodulatory drugs 
(IMIDs) in multiple myeloma (MM) has prompted the development of second- and 
third-generation agents with similar, but not exactly the same, mechanisms of 
action as their predecessors. This review summarizes the mechanism of action and 
the available data on the clinical activity of novel proteasome inhibitors 
(carfilzomib, oprozomib, ixazomib, and marizomib) and novel IMIDs 
(pomalidomide), stressing the similarities and differences with bortezomib, and 
with thalidomide and lenalidomide, respectively. In summary, these novel agents 
have shown clinical activity as single agents and in combination with 
dexamethasone, with similar or even higher efficacy than their parental drugs; 
moreover, they may even overcome resistance, indicating that there are some 
differences in their mechanisms of action and resistance. These data indicate 
that both the inhibition of the proteasome and the modulation of the immune 
system are good strategies to target MM tumor cells and this, along with the 
absence of complete cross-resistance observed among these drugs, open new 
avenues to optimize their use through the most appropriate sequencing and 
combinations.