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Autophagy. 2014 Aug;10(8):1380-90. doi: 10.4161/auto.29264. Epub 2014 May 20.

Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma.

Author information

1
Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
2
Department of Biostatistics and Epidemiology; University of Pennsylvania; Philadelphia, PA USA.
3
Department of Pharmacy Practice and Pharmacy Administration; University of the Sciences in Philadelphia; Philadelphia, PA USA.
4
Department of Mathematics, Physics and Statistics; University of the Sciences in Philadelphia; Philadelphia, PA USA.
5
Division of Hematologic Neoplasia; Dana-Farber Cancer Institute; Boston, MA USA.

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

PMID:
24991834
PMCID:
PMC4203515
DOI:
10.4161/auto.29264
[Indexed for MEDLINE]
Free PMC Article
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