Recombinant Human Erythropoietin (rHuEpo) as an Anti-Myeloma Immunomodulatory Agent.

Recombinant human erythropoietin (rHuEpo), the main growth regulator of red blood cells, has been used in clinical practice for the treatment of cancer-related anemia. Recent studies suggest that rHuEpo has additional biological effects; including our finding that rHuEpo significantly prolonged the expected survival of six end-stage multiple myeloma (MM) patients whose expected survival was <6 months (Mittelman et al., 2004, EJH 72, 155–65). The course of disease in these six MM patients led us to hypothesize that Epo might have an anti-neoplastic or anti-myeloma effect. This latter observation was further supported by studies, demonstrating a T cell mediated anti-myeloma effect of rHuEpo in mice models (Mittelman et al., 2001, PNAS 98, 5181–6). The mechanisms underlying the effects of Epo on the immune system are not fully clear. Our data show the effects of rHuEpo on the T-cell as well as the B-cell lineage. We found that the ratio of CD4+ to CD8+ T cells, which is decreased in MM patients, increases to the normal range in MM patients who are receiving rHuEpo treatment. rHuEpo-treated MM patients show a significant improvement in the level of mitogen-mediated activation of mononuclear cells, as measured by the early activator marker CD69. Furthermore, mononuclear proliferation in rHuEpo-treated MM patients was increased compared with MM patients who were not on rHuEpo treatment. Elucidating the anti-neoplastic effects of Epo treatment and obtaining a better insight into the immunomodulatory features of these effects will open new avenues in the treatment of hematological malignancies such as MM and related disorders. Moreover, the better understanding of the immunomodulatory properties of Epo may also be applied in other diseases manifesting immune abnormalities and immunocompromised subjects.