The future of treatment for patients with relapsed/refractory multiple myeloma The Future of Proteasome Inhibitors in Relapsed/Refractory Multiple Myeloma

• Published in: Oncology (Williston Park, N.Y.) Vol. 25; no. 12 0 2
• Main Author: Orlowski, Robert Z.
• Format: Journal Article
• Language: English
• Published: 15.11.2011
• ISSN: 0890-9091

The ubiquitin-proteasome pathway was first validated as a target for cancer therapy with the demonstration of the activity of the boronic acid proteasome inhibitor bortezomib against relapsed and relapsed/refractory multiple myeloma. Another generation of proteasome inhibitors is now entering the clinical arena, including intravenous agents such as carfilzomib, CEP-18770, and marizomib, and oral drugs such as MLN9708 and ONX 0912. These novel agents will likely first be used for patients with disease that has either relapsed or been refractory to their prior therapy, including bortezomib-based regimens, through their ability to overcome drug resistance, or in patients who are intolerant of, or are not candidates for bortezomib. Preclinical studies also suggest that there is potential for proteasome inhibitors to act synergistically with other conventional and novel agents, and even with one another in rationally designed combination regimens. In addition, other inhibitors that selectively target only the immunoproteasome and not the constitutive proteasome, as well as drugs that bind to non-catalytic proteasome subunits, are emerging as potential drug candidates. Taken together, it seems likely that we have only begun to appreciate the full potential of inhibition of the proteasome, and this review will attempt to extrapolate our current knowledge in this area into a future algorithm for use of these inhibitors against multiple myeloma.