Carfilzomib-induced reticulocytosis in patients with multiple myeloma is caused by impaired terminal erythroid maturation

ABSTRACT: Proteasome inhibition constitutes a cornerstone of multiple myeloma (MM) treatment, with bortezomib, carfilzomib and ixazomib approved for clinical use. We observed a consistent and highly significant increase in the reticulocyte count during treatment with carfilzomib-based regimens in patients with relapsed MM, an observation not made in a matched cohort of bortezomib-treated patients. As this increased reticulocytosis was neither associated with elevated hemoglobin levels nor with hemolysis, we subsequently performed in vitro experiments to unravel the underlying mechanisms of this clinical observation. While carfilzomib did not affect erythroid differentiation of CD34+ hematopoietic progenitor cells, both continuous and pulse exposure to carfilzomib significantly impaired terminal maturation of purified primary reticulocytes towards erythrocytes. These results indicate that carfilzomib significantly impairs terminal erythroid maturation, independent of erythroid commitment, expansion or differentiation. Our results report the first pharmacologically induced delay in erythroid maturation as a mechanism for carfilzomib-induced reticulocytosis in MM patients. Quantitative proteomics using LC-MS/MS were performed to assess whether carfilzomib treatment alters the protein composition of reticulocytes

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Reticulocyte, Blood

DISEASE(S): Multiple Myeloma

SUBMITTER: Delphi Van Haver  

LAB HEAD: Michel Delforge

PROVIDER: PXD014353 | Pride | 2020-02-20

REPOSITORIES: Pride