Overcoming Bortezomib Resistance: A Review of the Second-Generation Proteasome Inhibitor Carfilzomib in the Treatment of Multiple Myeloma

Abstract

Proteasome inhibitors now form the backbone of many myeloma therapeutic regimens in either the upfront or relapsed settings, but both innate and acquired drug resistance have emerged as significant clinical challenges. The second-generation proteasome inhibitor carfilzomib recently received regulatory approval after showing promising activity in bortezomib-resistant preclinical models and human studies. Although similar to its predecessor in targeting the chymotrypsin-like activity of both the constitutive proteasome and the immunoproteasome, carfilzomib has distinct mechanistic and structural properties. These allow it to bind irreversibly and provide a more sustained target inhibition than bortezomib, which is characterized by slowly reversible binding kinetics, and may in part contribute to its ability to overcome proteasome inhibitor resistance. Numerous clinical studies with carfilzomib are now underway investigating its use in various clinical settings and in combination with other novel agents that will provide valuable insight on its optimal use. However, despite the important advance in myeloma therapeutics that carfilzomib represents, cross-resistance between proteasome inhibitors remains a significant problem. This highlights the need for a better understanding of proteasome inhibitor resistance biology to inform the design of next-generation proteasome inhibitors and the development of rational drug combinations to overcome such resistance.