Combined Proteasome and Autophagy Inhibition in Relapsed/Refractory Multiple Myeloma-A Phase I Trial of Hydroxychloroquine, Carfilzomib, and Dexamethasone.

Multiple myeloma is characterized by malignant cells which produce high amounts of monoclonal immunoglobulin. Myeloma cells are, therefore, dependent on effective protein degradation. Proteasomal protein degradation is targeted by proteasome inhibitors in routine care. Autophagic protein degradation is currently not targeted in myeloma treatment. This Phase I trial showed that the combination of the proteasome inhibitor carfilzomib and the autophagy inhibitor hydroxychloroquine was well tolerated in patients with relapsed/refractory multiple myeloma. Adverse events were mostly Grades 1 and 2. An overall response rate of 44% indicates a meaningful clinical efficacy of this combination. Trial Registration : The study was registered at clinicaltrials.gov # NCT04163107.
Competing Interests: Tobias S. Slørdahl has received honoraria from Takeda, Celgene, Amgen, Janssen, AbbVie, Pfizer; consultancy for Bristol Myers Squibb, GSK, Pfizer, Menarini Group, Sanofi; advisory board consultancy: Bristol Myers Squibb, Sanofi, Amgen, Celgene, GSK, Janssen. Frida Bugge Askeland has received consulting fees from Janssen, Sanofi, and Amgen, honoraria/payment from Janssen and Sanofi, participated in advisory boards for Janssen and Sanofi, and received research support from Sanofi. Fredrik Schjesvold has received grants from Targovax, consulting fees from GSK, BMS, Oncopeptides, XNK Therapeutics, Takeda, Janssen, Sanofi, and Galapagos, honoraria/payment from Amgen, BMS, Takeda, Sanofi, Menarini, AbbVie, Janssen, Oncopeptides, and GSK, and participated in advisory boards for AbbVie, Janssen, Regeneron, and Sanofi. The other authors declare no conflicts of interest.
(© 2025 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)