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Resistance to Proteasome Inhibitors in Multiple Myeloma

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Resistance to Proteasome Inhibitors in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

Abstract

Multiple myeloma (MM) is a clonal proliferation of malignant plasma cells in the bone marrow associated with a spectrum of clinical symptoms including bone destruction, anemia, hypercalcemia, and renal failure. Although MM remains incurable, a dramatic paradigm shift in the treatment of MM has occurred over the past decade through the introduction of novel agents, including the development of small molecule inhibitors targeting the proteasome. Among the proteasome inhibitors (PIs), bortezomib (BTZ) and carfilzomib (CFZ) have been approved by the FDA for treatment of relapsed/refractory MM in 2003 and 2012, respectively. Recently, other PIs, such as ixazomib (MLN-9708), oprozomib (ONX0912), and marizomib (NPI-0052), have been under evaluation in preclinical and clinical studies. Indeed, it is now well known that malignant plasma cells are exquisitely sensitive to proteasome inhibitors due to protein overload and ER stress. Unfortunately, relapse of myeloma develops due to acquisition of resistance to proteasome inhibitors. Specifically, mutations in overexpression of proteins belonging to the proteasome complex, upregulation of transporter channels or cytochrome components, induction of alternative compensative mechanisms such as the aggresome pathway, and modulation of downstream pathways have been all reported as possible mechanisms of proteasome inhibitor resistance. In this chapter, we will first briefly describe the structure and function of the proteasome in normal and malignant plasma cells, and then define the major mechanisms of resistance to proteasome inhibition, and clinical approaches to overcoming these pathways in the context of both clinical application of PIs and rational combinations of them with other agents in the treatment of MM.

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Abbreviations

BTZ:

Bortezomib

CFZ:

Carfilzomib

C-L:

Caspase-like

CT-L:

Chymotrypsin-like

CR:

Complete response

HDAC:

Histone deacetylase

HDACIs:

HDAC inhibitors

Ig:

Immunoglobulin

MM:

Multiple myeloma

MTD:

Maximum-tolerated dose

OS:

Overall survival

PI:

Proteasome inhibitor

T-L:

Trypsin-like

TTP:

Time to progression

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    Authors and Affiliations

    1. Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA

      Francesca Cottini M.D., Claudia Paba Prada M.D., Teru Hideshima M.D. Ph.D., Michelle Maglio, Cindy Varga M.D., Dharminder Chauhan J.D. Ph.D., Jacob Laubach M.D., Kenneth C. Anderson M.D. & Paul G. Richardson M.D.

    2. Università degli Studi di Milano, Milan, Italy

      Anna Guidetti M.D.

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      Q. Ping Dou

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    Cottini, F. et al. (2014). Resistance to Proteasome Inhibitors in Multiple Myeloma. In: Dou, Q. (eds) Resistance to Proteasome Inhibitors in Cancer. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-06752-0_2

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