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New Proteasome Inhibitors in Myeloma

  • Multiple Myeloma (V Rajkumar, Section Editor)
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Abstract

Proteasome inhibition has a validated role in cancer therapy since the successful introduction of bortezomib for the treatment of multiple myeloma (MM) and mantle cell lymphoma, leading to the development of second-generation proteasome inhibitors (PI) for MM patients in whom currently approved therapies have failed. Five PIs have reached clinical evaluation, with the goals of improving efficacy and limiting toxicity, including peripheral neuropathy (PN). Carfilzomib, an epoxyketone with specific chymothrypsin-like activity, acts as an irreversible inhibitor and was recently FDA approved for the response benefit seen in relapsed and refractory MM patients previously treated with bortezomib, thalidomide and lenalidomide. ONX-0912 is now under evaluation as an oral form with similar activity. The boronate peptides MLN9708 and CEP-18770 are orally bioactive bortezomib analogs with prolonged activity and greater tissue penetration. NPI-0052 (marizomib) is a unique, beta-lactone non-selective PI that has been shown to potently overcome bortezomib resistance in vitro. All of these second-generation PIs demonstrate encouraging anti-MM activity and appear to reduce the incidence of PN, with clinical trials ongoing.

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Disclosures

P. Lawasut, D.Chauhan, J. Laubach, C. Hayes, C. Fabre, and M. Maglio declare no potential conflicts of interest relevant to this article.

T. Hideshima is a consultant for Acetylon Pharmaceuticals.

C. Mitsiades has been a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Merck &Co., Centocor, and Arno Therapeutics, and has received research funding from Amgen, AVEO Pharma, OSI, EMD Serono, Sunesis, Genzyme, and Johnson & Johnson.

K. Anderson is a member of advisory committees for Millennium, Nereus, Onyx, Johnson & Johnson, and Celgene Corporation, and is a founder of Acetylon Pharmaceuticals.

P. Richardson is a member of advisory committees for Millennium, Nereus, Onyx, Johnson & Johnson and Celgene Corporation.

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Authors and Affiliations

  1. Division of Hematologic Oncology, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Mayer 228, Boston, MA, 02215, USA

    Panisinee Lawasut, Dharminder Chauhan, Jacob Laubach, Catriona Hayes, Claire Fabre, Michelle Maglio, Constantine Mitsiades, Teru Hideshima, Kenneth C. Anderson & Paul G. Richardson

  2. Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand

    Panisinee Lawasut

  3. Department of Medical Oncology, Curie Institute, 26 rue d’Ulm, Paris, France

    Claire Fabre

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  1. Panisinee Lawasut
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Lawasut, P., Chauhan, D., Laubach, J. et al. New Proteasome Inhibitors in Myeloma. Curr Hematol Malig Rep 7, 258–266 (2012). https://doi.org/10.1007/s11899-012-0141-2

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