Proteasome inhibitors are one of the most important classes of agents to have emerged for the treatment of
multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration-the first-in-class compound
bortezomib, the second-generation agent
carfilzomib, and the first oral
proteasome inhibitor,
ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the
26S proteasome, which plays a critical role in the pathogenesis and proliferation of the disease.
Proteasome inhibition results in multiple downstream effects, including the inhibition of NF-κB signaling, the accumulation of misfolded and unfolded
proteins, resulting in endoplasmic reticulum stress and leading to the unfolded protein response, the downregulation of
growth factor receptors, suppression of adhesion molecule expression, and inhibition of angiogenesis; resistance to
proteasome inhibition may arise through cellular responses mediating these downstream effects. These multiple
biologic consequences of
proteasome inhibition result in synergistic or additive activity with other chemotherapeutic and targeted agents for myeloma, and
proteasome inhibitor-based combination regimens have become established as a cornerstone of
therapy throughout the myeloma treatment algorithm, incorporating agents from the other key classes of antimyeloma agents, including the
immunomodulatory drugs,
monoclonal antibodies, and
histone deacetylase inhibitors. This review gives an overview of the critical role of the
proteasome in myeloma and the characteristics of the different
proteasome inhibitors and provides a comprehensive summary of key clinical efficacy and safety data with the currently approved
proteasome inhibitors.