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

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Resistance to Proteasome Inhibitors in Cancer

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

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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.

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Abbreviations

AE:

Adverse event

ChT-L:

Chymotrypsin-like activity

C-L:

Caspase-like

DLTs:

Dose-limiting toxicities

FDA:

Food and Drug Administration

IMiD:

Immunomodulatory drug

JNK:

c-Jun NH2-terminal kinase

MM:

Multiple myeloma

MRs:

Minor responses

MTD:

Maximum tolerated dose

nCR:

Near-complete responses

NDA:

New Drug Application

NF-κB:

Nuclear factor kappa B

NHL:

Non-Hodgkin lymphoma

ODAC:

Oncologic Drugs Advisory Committee

ORR:

Overall response rate

PFS:

Progression-free survival

PR:

Partial response

PSMB:

Proteasome subunit β type

SD:

Stable disease

T-L:

Trypsin-like

TTP:

Time to progression

uCR:

Unconfirmed complete response

VGPRs:

Very good partial responses

WM:

Waldenström’s macroglobulinemia

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Acknowledgments

R.Z.O. would like to acknowledge support from the National Cancer Institute in the form of The MD Anderson Cancer Center SPORE in Multiple Myeloma (P50 CA142509) and the Southwest Oncology Group (U10 CA032102). H.C.L. would like to acknowledge support from the Conquer Cancer Foundation (American Society of Clinical Oncology Young Investigator Award).

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Authors and Affiliations

  1. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Hans C. Lee M.D.

  2. Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Robert Z. Orlowski M.D., Ph.D.

  3. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 429, Houston, TX, 77030, USA

    Robert Z. Orlowski M.D., Ph.D.

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  1. Hans C. Lee M.D.
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  2. Robert Z. Orlowski M.D., Ph.D.
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Correspondence to Robert Z. Orlowski M.D., Ph.D. .

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  1. Wayne State University, Detroit, Michigan, USA

    Q. Ping Dou

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Lee, H.C., Orlowski, R.Z. (2014). Overcoming Bortezomib Resistance: A Review of the Second-Generation Proteasome Inhibitor Carfilzomib in the Treatment of 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_3

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