New proteasome inhibitors in the treatment of multiple myeloma

Abstract

The treatment of patients with relapsed and/or refractory multiple myeloma has improved considerably in the last 15 years, after the introduction of proteasome inhibitors and immunomodulatory drugs. The first clinical trials with new proteasome inhibitors have produced exciting results, particularly those comparing triplet regimens with standard doublet regimens, with a gain in progression-free survival accompanied by an acceptable safety profile and either similar or better health-related quality of life. New proteasome inhibitors hold the potential to fill unmet needs in multiple myeloma management regarding improvement of clinical outcomes, including delayed progression of disease in high-risk patients. This review summarizes the main pharmacological properties and clinical outcomes of these agents, and discusses their potential to change the whole multiple myeloma therapeutic landscape.

Keywords: Bortezomib; Carfilzomib; Ixazomib; Multiple myeloma; Proteasome inhibitors.

Figure 1

Ubiquitin–proteasome system. Ubiquitin ligases (E1, E2, E3) attach a chain of ubiquitins to lysine residues on the target protein to be degraded. In the proteasome, the ubiquitin chain is removed, and the target protein is unfolded and translocated to the interior of the proteasome, where it is degraded into peptide fragments by 3 threonine proteases.

Figure 2

Structure of 26S proteasome. 26S proteasome comprises a 20S core flanked by regulatory particles (19S). The 20S core includes four heptameric rings of α or β subunits. The proteolytic sites with caspase-like, trypsin-like and chymotrypsin-like activity are located in the subunits β1, β2 and β5, respectively.