Erythropoietin has an anti‐myeloma effect – a hypothesis based on a clinical observation supported by animal studies

Abstract

Recombinant human erythropoietin (rHuEpo) was introduced into clinical practice more than a decade ago, and has been found to be effective in the treatment of several types of anemia, including anemia of end-stage renal failure and cancer-related anemia. No study has suggested that Epo might have an effect on the biology of the disease, nor any survival advantage to cancer patients treated with Epo for anemia has been reported. Here we report six patients with advanced multiple myeloma (MM) with very poor prognostic features, whose expected survival was <6 months. All six patients were treated with rHuEpo for their anemia, either without any chemotherapy or very mild chemotherapy for a short time. Yet, surprisingly they lived for 45-133 months totally from MM diagnosis and 38-94 months with rHuEpo (with a good quality of life). In fact, one patient, is still alive and well, more than 8 yr after chemotherapy was discontinued because of a resistant aggressive disease. The course in these six MM patients led us to hypothesize that Epo might have an antineoplastic or antimyeloma effect. We proceeded and tested that hypothesis in mouse models of myeloma (Mittelman M et al., Proc Natl Acad Sci USA 98:5181,2001). In these models we confirmed that rHuEpo induced tumor regression in about 50% of the BALB/c mice inoculated with MOPC-315 myeloma cells. We then presented evidence that the mechanism is a new immune-mediated phenomenon, via activation of CD8+ T cells. Furthermore, evidence from the literature supports the antineoplastic effect of Epo. Epo might be used as an adjunct immune treatment in various malignant diseases, in addition to the current regimens and chemotherapeutic protocols. Future trials should determine the role of Epo in myeloma and cancer treatment, besides clarifying concerns about the presence of Epo receptors on some tumor cells.

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

“…Our previous studies have demonstrated EPO-associated anti-neoplastic activities, which were related to EPO's action on the immune system (Mittelman et al, 2004;PrutchiSagiv et al, 2006). These studies were led by the observation that multiple myeloma (MM) patients treated with rHuEPO for their anemia, exhibited prolonged survival and improved quality of life (Baz et al, 2007;Mittelman et al, 1997;Mittelman et al, 2004).…”

“…These studies were led by the observation that multiple myeloma (MM) patients treated with rHuEPO for their anemia, exhibited prolonged survival and improved quality of life (Baz et al, 2007;Mittelman et al, 1997;Mittelman et al, 2004).…”

Activities of erythropoietin on tumors: An immunological perspective

“…Previous studies from these authors indicated that EPO may prolong survival in MM patients [8], and these results have been supported by other scientists [9]. The effect of EPO on MM was also reproduced in murine models, where EPO promotes the development of an effective and long-lasting anti-tumor specific immune response mediated via activated CD8 + T cells [10].…”

New Insights Into Erythropoietin and Epoetin Alfa: Mechanisms of Action, Target Tissues, and Clinical Applications

“…In addition, epoetin alfa treatment, either in the absence of chemotherapy or concomitant with mild chemotherapy for a short duration, produced an antimyeloma effect and prolonged survival in a small study of patients with MM (n = 5) who had advanced disease and an expected survival of less than 6 months [111]. Despite a poor prognosis, patients survived an additional 42-82 months after initiation of epoetin alfa therapy [111]. These findings are consistent with data from a murine model of MM, where tumor regression believed to be mediated via activated CD8 + T cells occurred in 50% of mice inoculated with MM cells [112].…”

“…Epoetin alfa alone had no effect on growth of a lung carcinoma xenograft; however, in synergy with cisplatin, it induced a fivefold reduction in tumor mass [110]. In addition, epoetin alfa treatment, either in the absence of chemotherapy or concomitant with mild chemotherapy for a short duration, produced an antimyeloma effect and prolonged survival in a small study of patients with MM (n = 5) who had advanced disease and an expected survival of less than 6 months [111]. Despite a poor prognosis, patients survived an additional 42-82 months after initiation of epoetin alfa therapy [111].…”