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Multiple myeloma gammopathies

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

Leukemia volume 34, pages 651–655 (2020)Cite this article

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Proteasome inhibition constitutes one of the principal therapeutic strategies for treating multiple myeloma (MM). Three proteasome inhibitors (PIs) are approved for clinical use; bortezomib, ixazomib, and carfilzomib. Among these three, only carfilzomib causes irreversible proteasome activity inhibition [1].

While treating relapsed myeloma patients with carfilzomib, we repeatedly observed a marked reticulocytosis in the absence of signs of hemolysis or acute blood loss. The ubiquitin–proteasome system plays a major role in erythropoiesis, including erythroid differentiation and terminal maturation. The latter is defined as the transition from enucleated reticulocytes to mature erythrocytes, which involves membrane remodeling, hemoglobin synthesis, and clearance of residual RNA and organelles [2,3,4]. This led to the hypothesis that proteasome inhibition may affect erythroid differentiation and/or maturation.

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Acknowledgements

This study was supported in part by the UZ Leuven Janssen Hematology Fund and “the Luc Fraiture” Fund. We would like to acknowledge Dr Christa Maes for providing the osteoblastic cell lines and Mrs Annouschka Laenen (L-Biostat and Leuven Cancer Institute, KU Leuven, Belgium) for statistical support, Dr Francis Impens (Proteomics Expertise Center, Flemish Institute of Biotechnology, Ghent, Belgium) for processing and analyzing the LC-MS/MS data and Somersault 18:24 (Diest, Belgium) for their assistance in constructing Fig. 2c.

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Authors and Affiliations

  1. Department of Internal Medicine—Hematology, University Hospitals Leuven, Leuven, Belgium

    Nicolas G. Kint, Elien Heylen & Michel Delforge

  2. Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium

    Nicolas G. Kint, Elien Heylen, Catherine M. Verfaillie & Michel Delforge

  3. Laboratory for Disease Mechanisms in Cancer, KU Leuven, Leuven, Belgium

    Elien Heylen, Daniele Pepe & Kim De Keersmaecker

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  1. Nicolas G. Kint
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  5. Catherine M. Verfaillie
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  6. Michel Delforge
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Contributions

NK, KDK, CV and MD designed the research. NK and EH performed the research. NK obtained patient samples. DP performed bioinformatics analyses. NK wrote the manuscript. KDK, CV and MD critically reviewed the manuscript.

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Correspondence to Nicolas G. Kint.

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Conflict of interest

NK: travel support from Celgene, Amgen and Takeda, MD: speaker’s honoraria from Amgen, Celgene, Janssen, Takeda. Other authors declare that they have no conflict of interest.

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Kint, N.G., Heylen, E., Pepe, D. et al. Carfilzomib-induced reticulocytosis in patients with multiple myeloma is caused by impaired terminal erythroid maturation. Leukemia 34, 651–655 (2020). https://doi.org/10.1038/s41375-019-0565-y

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