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The proteasome and proteasome inhibitors in multiple myeloma

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Abstract

Proteasome inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration—the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S proteasome, which plays a critical role in the pathogenesis and proliferation of the disease. Proteasome inhibition results in multiple downstream effects, including the inhibition of NF-κB signaling, the accumulation of misfolded and unfolded proteins, resulting in endoplasmic reticulum stress and leading to the unfolded protein response, the downregulation of growth factor receptors, suppression of adhesion molecule expression, and inhibition of angiogenesis; resistance to proteasome inhibition may arise through cellular responses mediating these downstream effects. These multiple biologic consequences of proteasome inhibition result in synergistic or additive activity with other chemotherapeutic and targeted agents for myeloma, and proteasome inhibitor-based combination regimens have become established as a cornerstone of therapy throughout the myeloma treatment algorithm, incorporating agents from the other key classes of antimyeloma agents, including the immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. This review gives an overview of the critical role of the proteasome in myeloma and the characteristics of the different proteasome inhibitors and provides a comprehensive summary of key clinical efficacy and safety data with the currently approved proteasome inhibitors.

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Funding source statement

Development of this review was funded by Dana-Farber Cancer Institute.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, 44 Binney Street, Dana 1B02, Boston, MA, 02115, USA

    Sara Gandolfi, Jacob P. Laubach, Teru Hideshima, Dharminder Chauhan, Kenneth C. Anderson & Paul G. Richardson

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  1. Sara Gandolfi
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  2. Jacob P. Laubach
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  3. Teru Hideshima
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  4. Dharminder Chauhan
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  5. Kenneth C. Anderson
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  6. Paul G. Richardson
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Contributions

PGR led the development of this review. All other authors contributed equally to this review.

Corresponding author

Correspondence to Paul G. Richardson.

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Conflict of interest

Sara Gandolfi, Teru Hideshima, and Dharminder Chauhan have no conflict of interest to disclose.

Jacob P. Laubach has research funding from Celgene and consulting fees from Takeda.

Kenneth C. Anderson is an advisor for Celgene, Millennium Pharmaceuticals, and Gilead Sciences, and is a Scientific Founder of OncoPep, Acetylon, and C4 Therapeutics.

Paul G. Richardson is an advisor for Millennium Takeda, Celgene, and Janssen, and received research funding from Millennium Takeda, Celgene, and Bristol Myers-Squibb.

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Gandolfi, S., Laubach, J.P., Hideshima, T. et al. The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev 36, 561–584 (2017). https://doi.org/10.1007/s10555-017-9707-8

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