ABSTRACT
Introduction: Proteasome inhibitors (PIs) are therapeutic backbones of multiple myeloma treatment, with PI-based therapies being standards of care throughout the treatment algorithm. Proteasome inhibition affects multiple critical signaling pathways in myeloma cells and interacts synergistically with mechanisms of action of other conventional and novel agents, resulting in substantial anti-myeloma activity and at least additive effects.
Areas covered: This review summarizes the biologic effects of proteasome inhibition in myeloma and provides an overview of the importance of proteasome inhibition to the current treatment algorithm. It reviews key clinical data on three PIs, specifically bortezomib, carfilzomib, and ixazomib; assesses ongoing phase 3 trials with these agents; and looks ahead to the increasingly broad role of both approved PIs and PIs under investigation in the frontline and relapsed settings.
Expert commentary: Progress to date with PIs in multiple myeloma has been impressive, but there remain unmet needs and challenges, as well as increasing opportunities to optimize the use of these agents. Understanding discrepancies between PIs in terms of efficacy and safety profile is a key goal of ongoing research, along with proteomics-based efforts to identify potential biomarkers of sensitivity and resistance, thereby enabling increasingly personalized treatment approaches in the future.
Acknowledgments
The authors gratefully acknowledge writing assistance from Steve Hill of FireKite, an Ashfield company, part of UDG Healthcare plc, during the development of this manuscript and editorial assistance from Jack Sparacino.
Declaration of interest
K. Anderson is an advisor for Celgene, Takeda, Bristol Myers Squibb, and Gilead; Founder: C4 Therapeutics and OncoPep. P. Richardson has received research support from Takeda and Celgene, and is a member of advisory committees for Takeda, Celgene, Janssen, and Amgen.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose