Inhibition of proteasome, a proteolytic complex responsible for the degradation 
of ubiquitinated proteins, has emerged as a powerful strategy for treatment of 
multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, 
bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in 
pre-clinical and in clinical studies. However, despite its high efficiency, a 
large proportion of patients do not achieve sufficient clinical response. 
Therefore, the development of a second-generation of proteasome inhibitors (PIs) 
with improved pharmacological properties was needed. Recently, several of these 
new agents have been introduced into clinics including carfilzomib, marizomib 
and ixazomib. Further, new orally administered second-generation PI oprozomib is 
being investigated. This review provides an overview of main mechanisms of 
action of PIs in MM, focusing on the ongoing development and progress of novel 
anti-proteasome therapeutics.