Current advances in novel proteasome inhibitor-based approaches to the treatment of relapsed/refractory multiple myeloma.

Proteasome inhibitors (PIs) are a proven class of therapeutic agents in the treatment of cancers including multiple myeloma (MM), Waldenstrm macroglobulinemia, and mantle cell lymphoma. Their primary target is the ubiquitin-proteasome system, a universal component of eukaryotic cells involved in regulation of cellular homeostasis, angiogenesis, and cell death. Bortezomib (Velcade) is a potent and reversible PI that has been used successfully in the treatment of patients with MM. While the use of bortezomib has helped to change the natural history of MM, it is not universally effective and is associated with reversible peripheral neuropathy that can limit short-term and long-term use. Newer PIs, some of which are now undergoing clinical investigation, offer several potential advantages over bortezomib, including greater specificity and improved safety and tolerability. Here we provide a summary of the PIs in clinical and preclinical development.