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.
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Dan T
authors.initials: DT
authors.lastname: Vogl
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stadtmauer
authors.affiliation: Department of Biostatistics and Epidemiology; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Kay-See
authors.initials: KS
authors.lastname: Tan
authors.affiliation: Department of Biostatistics and Epidemiology; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.affiliation: Department of Pharmacy Practice and Pharmacy Administration; University of the Sciences in Philadelphia; Philadelphia, PA USA.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Davis
authors.affiliation: Department of Mathematics, Physics and Statistics; University of the Sciences in Philadelphia; Philadelphia, PA USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Pontiggia
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Reshma
authors.initials: R
authors.lastname: Rangwala
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Shengfu
authors.initials: S
authors.lastname: Piao
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Yunyoung C
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Scott
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Paul
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Nichols
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Janeen
authors.initials: J
authors.lastname: Kaplan
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Gayle
authors.initials: G
authors.lastname: Mallon
authors.affiliation: Division of Hematologic Neoplasia; Dana-Farber Cancer Institute; Boston, MA USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D001897:Boronic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology*; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence
chemical_list: D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D006886:Hydroxychloroquine; D000069286:Bortezomib
keywords: autophagy; myeloma; proteasome