Nonselective proteasome inhibitors in multiple myeloma and future perspectives

ABSTRACT

Introduction

Proteasome inhibition can lead to inhibition of tumor cell proliferation, and therefore it constitutes a potential therapeutic anticancer approach especially in the therapeutic algorithm of patients with multiple myeloma.

Areas covered

Three different proteasome inhibitors are currently approved, bortezomib, carfilzomib, and ixazomib, and they have been investigated in multiple myeloma and other hematological malignancies. However, these agents lack specificity, since they target both the constitutive proteasome and the immunoproteasome. Targeting the constitutive proteasome is the main reason for side toxicity due to the effect on normal tissues. In contrary, immunoproteasome inhibition may reduce the adverse events while maintaining the therapeutic efficacy. In this review, the authors present the role of the available proteasome inhibitors in myeloma therapeutics and future perspectives of both selective and nonselective proteasome inhibitors.

Expert opinion

The available nonselective proteasome inhibitors have changed the therapeutics of multiple myeloma the last 10 years and have significantly improved the clinical outcomes of the patients. Furthermore, selective proteasome inhibitors are now under preclinical investigation and there is hope that their optimization will come with an improved safety profile with at least comparable efficacy.

KEYWORDS:

• Proteasome inhibitors
• multiple myeloma
• immunoproteasome
• bortezomib
• carfilzomib
• ixazomib

Article highlights

• The ubiquitin-proteasome system is the most important proteolytic system not mediated by lysosomes.

• Nonselective proteasome inhibitors have significant anti-myeloma activity by inhibiting the proteasomal degradation of ubiquitinated regulatory proteins.

• Proteasome inhibition can lead to inhibition of tumor cell proliferation, and therefore has emerged as a potential therapeutic anticancer strategy especially in multiple myeloma.

• Bortezomib, carfilzomib, and ixazomib are the three approved non-selective proteasome inhibitors that are broadly used in newly diagnosed and relapsed/refractory multiple myeloma patients achieving deep and durable responses, alone or in combinations.

• Selective proteasome inhibitors are currently under preclinical investigation and their optimization aims to a better safety profile with at least equal efficacy.

Declaration of interest

M Gavriatopoulou declares consultancy fees and honoraria from Amgen, Karyopharm, Genesis Pharma, Janssen Pharmaceuticals and Takeda. MA Dimopoulos declares consultancy fees and honoraria from Janssen Pharmaceuticals, Celgene, Takeda, Amgen and Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.