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

Dan T. Vogl, Edward A. Stadtmauer, Kay See Tan, Daniel F. Heitjan, Lisa E. Davis, Laura Pontiggia, Reshma Rangwala, Shengfu Piao, Yunyoung C. Chang, Emma C. Scott, Thomas M. Paul, Charles W. Nichols, David L. Porter, Janeen Kaplan, Gayle Mallon, James E. Bradner, Ravi K. Amaravadi

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170 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1380-1390
Number of pages11
JournalAutophagy
Volume10
Issue number8
DOIs
StatePublished - Aug 2014

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Keywords

  • Autophagy
  • Myeloma
  • Proteasome

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Vogl, D. T., Stadtmauer, E. A., Tan, K. S., Heitjan, D. F., Davis, L. E., Pontiggia, L., Rangwala, R., Piao, S., Chang, Y. C., Scott, E. C., Paul, T. M., Nichols, C. W., Porter, D. L., Kaplan, J., Mallon, G., Bradner, J. E., & Amaravadi, R. K. (2014). Combined autophagy and proteasome inhibition a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy, 10(8), 1380-1390. https://doi.org/10.4161/auto.29264