Relapsed and refractory lymphoid neoplasms and multiple myeloma with a focus on carfilzomib

• Type of Material: Article
• Authors: Ajay Nooka, Emory University; Charise Gleason, Emory University; Daniela Casbourne, Emory University; Sagar Lonial, Emory University
• Language: English
• Date: 2013-01-30
• Publisher: Dovepress
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Nooka et al, publisher and licensee Dove Medical Press Ltd.
• Final Published Version (URL): http://dx.doi.org/10.2147/BTT.S24580
• Title of Journal or Parent Work: Biologics: Targets and Therapy
• Volume: 7
• Issue: 1
• Start Page: 13
• End Page: 32
• Grant/Funding Information: Dr Lonial is supported by the Richard and Annelly Deets Foundation for Multiple Myeloma.
• Keywords: carfilzomib; second generation; epoxyketone; proteasome inhibitor; myeloma
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Proteasomal inhibition revolutionized myeloma therapies in this decade of novel agents. The only US Food and Drug Administration approved proteasome inhibitor so far, bortezomib effectively targets the constitutive proteasome subunit β5 of the 26S proteasome. Bortezomib induces high and quality response rates that are durable. However, myeloma cells acquire resistance to bortezomib through various mechanisms. Further, grade 3/4 peripheral neuropathy is seen in up to a quarter of patients treated with bortezomib. While the recent change in the mode of administration via the subcutaneous route is associated with a lower incidence of grade 3/4 peripheral neuropathy, it remains a major concern. The second generation proteasome inhibitors are promising, with increased preclinical efficacy and a better administration schedule. The current review spotlights the second generation proteasome inhibitors with special focus on the safety and efficacy of carfilzomib, an epoxyketone with lesser peripheral neuropathy, which exhibits irreversible proteasome inhibition. In this article, we review the pharmacology and preclinical and clinical efficacy and safety of carfilzomib alone and in combination with other chemotherapeutic agents in the various lymphoid neoplasms and multiple myeloma as well as ongoing clinical trials.