Irreversible proteasome inhibitor carfilzomib appears to cause reticulocytosis in multiple myeloma by inhibiting terminal erythroid maturation, reported a study published in Leukemia.
To establish that carfilzomib does in fact induce reticulocytosis, the study researchers first retrospectively analyzed 40 patients with relapsed multiple myeloma. Compared with baseline, significantly elevated levels of reticulocytes were seen after the second treatment cycle (P <.001).
The study researchers then investigated possible avenues through which carfilzomib may cause reticulocytosis.
First, they showed that exposure of differentiating erythroid cells to carfilzomib did not affect impact differentiation efficiency, indicating that carfilzomib does not induce reticulocytosis by stimulating erythropoiesis. Next, they measured erythropoietin levels in patients who were treated with carfilzomib and found that the levels did not change significantly during the first treatment cycles, suggesting that carfilzomib does not increase erythropoietin production.
Reticulocytes were then exposed to proteasome inhibitors carfilzomib, bortezomib, ixazomib, and MG-132, and terminal erythroid maturation was significantly inhibited when reticulocytes were exposed to carfilzomib (P <.001). The other proteasome inhibitors inhibited terminal erythroid maturation but to a lesser extent.
An additional experiment was performed to more accurately recapitulate the short half-life of carfilzomib. Reticulocytes were exposed to the 4 different proteasome inhibitors at 1-hour pulses and then the medium was changed. Exposure to carfilzomib showed significant inhibition of terminal erythroid maturation (P <.01), whereas the other proteasome inhibitors did not, further showing that inhibition of terminal erythroid maturation may be the underlying mechanism for carfilzomib-induced reticulocytosis.
“Our data thus support the hypothesis that clinical reticulocytosis in patients treated with carfilzomib is caused by a block in reticulocyte maturation, but not by increased erythroid expansion or differentiation,” the study authors wrote.
- Kint NG, Heylen E, Pepe D, De Keersmaecker K, Verfaillie CM, and Delforge M. Carfilzomib-induced reticulocytosis in patients with multiple myeloma is caused by impaired terminal erythroid maturation [August 29, 2019]. Leukemia. doi: 10.1038/s41375-019-0565-y