Combined Autophagy and Proteasome Inhibition: A Phase 1 Trial of Hydroxychloroquine and Bortezomib in Patients With relapsed/refractory Myeloma

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

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Autophagy* / drug effects
  • Boronic Acids / pharmacokinetics
  • Boronic Acids / pharmacology
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Hydroxychloroquine / pharmacokinetics
  • Hydroxychloroquine / pharmacology
  • Hydroxychloroquine / therapeutic use*
  • Male
  • Middle Aged
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / pathology*
  • Proteasome Inhibitors / pharmacology
  • Proteasome Inhibitors / therapeutic use*
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology
  • Pyrazines / therapeutic use*
  • Recurrence

Substances

  • Boronic Acids
  • Proteasome Inhibitors
  • Pyrazines
  • Hydroxychloroquine
  • Bortezomib