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Published on: May 15, 2019
The future of proteasome inhibitors in relapsed/refractory multiple myeloma
Abstract:
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 (PI) bortezomib (Velcade) against relapsed and relapsed/refractory multiple myeloma. Another generation of PIs is now entering the clinical arena; this includes 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 prior therapy (including bortezomib-based regimens) because of their ability to overcome drug resistance, or will be used in patients who are intolerant of, or are not candidates for bortezomib. Preclinical studies also suggest that PIs may act synergistically with other conventional and novel agents, or 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 agents that bind to noncatalytic 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. This article extrapolates our current knowledge into an algorithm for the future use of these inhibitors against multiple myeloma.
Insights
Novel proteasome inhibitors (PIs) offer new hope for multiple myeloma patients, especially those resistant to existing treatments. These agents show promise in combination therapies and targeting specific proteasome types.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The ubiquitin-proteasome pathway is a validated target in cancer therapy.
- Bortezomib, a proteasome inhibitor (PI), is effective against relapsed/refractory multiple myeloma.
- A new generation of PIs is emerging for clinical use.
Purpose of the Study:
- To review the current landscape of proteasome inhibitors (PIs) in multiple myeloma treatment.
- To explore the potential of novel PIs, including their use in combination regimens.
- To propose an algorithm for the future clinical application of PIs in multiple myeloma.
Main Methods:
- Review of existing literature on proteasome inhibitors and their clinical applications.
- Analysis of preclinical data suggesting synergistic effects of PIs.
- Extrapolation of current knowledge to formulate future treatment strategies.
Main Results:
- Multiple novel PIs (e.g., carfilzomib, marizomib, MLN9708) are entering clinical trials.
- These agents demonstrate potential in overcoming drug resistance and managing bortezomib-intolerant patients.
- Preclinical data support synergistic activity of PIs with other agents and among themselves.
- Emerging inhibitors target specific proteasome subtypes, including the immunoproteasome.
Conclusions:
- Proteasome inhibition represents a rapidly evolving therapeutic strategy for multiple myeloma.
- Novel PIs offer expanded treatment options, particularly for resistant or intolerant patient populations.
- Combination regimens and targeted inhibitors are key areas for future development in multiple myeloma therapy.
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