@article{b0e8b97527984503b9155bfe39b9f98b,
title = "Combined autophagy and proteasome inhibition a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma",
abstract = "The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.",
keywords = "Autophagy, Myeloma, Proteasome",
author = "Vogl, {Dan T.} and Stadtmauer, {Edward A.} and Tan, {Kay See} and Heitjan, {Daniel F.} and Davis, {Lisa E.} and Laura Pontiggia and Reshma Rangwala and Shengfu Piao and Chang, {Yunyoung C.} and Scott, {Emma C.} and Paul, {Thomas M.} and Nichols, {Charles W.} and Porter, {David L.} and Janeen Kaplan and Gayle Mallon and Bradner, {James E.} and Amaravadi, {Ravi K.}",
note = "Funding Information: The authors thank Cezary R Swider, Joy Cannon, and Martin Carroll at the University of Pennsylvania Stem Cell and Xenograft Core, for processing samples. One of the authors (RR) is now an employee of Merck. This research was supported by a Special Fellow in Clinical Research award from the Leukemia & Lymphoma Society (DTV), a research grant from Millennium Pharmaceuticals, a pilot project grant from the University of Pennsylvania Abramson Cancer Center, National Cancer Institute grants K23CA120862 (RKA), K23CA130074 (DTV), and P30CA016520 (DFH, KST), and National Center for Research Resources grant UL1-RR-024134. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, the National Center for Research Resources, or the National Institutes of Health. Funding Information: The research described in this manuscript was supported in part by a research grant from Millennium Pharmaceuticals, which manufactures and distributes bortezomib (Velcade). DTV currently holds a separate research grant from Millennium Pharmaceuticals. DTV has in the past worked as a consultant for Millennium Pharmaceuticals. DTV currently holds a research grant from Acetylon Pharmaceuticals, which manufactures the HDAC6 inhibitor referred to in the Discussion section. DTV is currently participating as an investigator in the clinical trial referred to in the Discussion.",
year = "2014",
month = aug,
doi = "10.4161/auto.29264",
language = "English (US)",
volume = "10",
pages = "1380--1390",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",
number = "8",
}