Anemia is a common finding in patients with multiple myeloma (MM): it is present in two-thirds of patients (pts) at diagnosis and reflects the course of the disease, since it worsens during resistant or progressive disease and ameliorates when the disease is controlled by treatment [1, 2]. Generally, anemia during myeloma is normochromic and normocytic, characterized by shortened erythrocyte survival with failure of bone marrow to compensate red cell production. The multifactor basis of bone marrow impairment includes: (a) impaired availability of storage iron, (b) inadequate erythropoietin response to the level of anemia, and (c) overproduction of cytokines capable of direct erythropoiesis inhibition. These cytokines (including tumor necrosis factor, interleukin-1 and interleukin-6) may also decrease reutilization of iron stores from reticuloendothelial cells and may interfere with kidney erythropoietin production [3]. Recombinant human erythropoietin (rHuEPO) has been extensively used throughout the course of the disease to increase hemoglobin (Hb) concentration, reduce transfusion requirement and improve the quality of life. Treatment of anemia in lymphoproliferative disorders with erythropoiesis-stimulating agents (ESA) has been shown to be safe, efficacious and effective. Response rate (RR) varied from 31 to 78%, according to the criteria utilized for response [4]. In MM, RR was influenced by the disease duration, ratio between observed and predicted serum erythropoietin concentration and Epo dose. RR at 4 weeks (wk) represents the most powerful predictor of a durable response [5]. Recently, ASCO/ASH guidelines for the use of epoetin and darbepoetin have been revised: FDA-approved starting dose of epoetin is 150 IU/kg 3 times/week or 40,000 IU/week subcutaneously; FDA-approved starting dose of darbepoetin is 2.25 μg/kg/week or 500 μg every 3 week subcutaneously. Alternative starting doses or dosing schedules have shown no consistent differences in transfusion and Hb response, although they may be considered to improve cost/effectiveness. Dose escalation should follow those approved by FDA; no convincing evidences indicate that other schedules may be associated with better results. The threshold for initiating ESA therapy should be a concentration of Hb ≤ 10 g/dL [6]. The aim of this study is to evaluate the safety and efficacy of a regimen based on rHuEPO alfa 40000 IU twice/week as starting dose with weekly IV iron supplementation in MM pts with severe anemia.

Between January 2003 and March 2004, 20 pts (10 M/10 F) with MM were enrolled in this open-label trial. The starting dose consisted of 40000 IU subcutaneously twice/week for 5 doses (up to 8 doses if no major response was obtained at week 3), maintained by rHuEPO at the conventional schedule in the responder patients. All pts received iron supplementation (oral or IV). The main pre-treatment characteristics were the following: median age 67.5 years (58–81); 9 pts were in first line treatment, 6 pts in second line and 5 received more than 3 lines of chemotherapy (CHT); mean baseline Hb was 8.44 g/dL (6.9–8.9), while the baseline median level of endogenous erythropoietin was 17.55 IU/mL (10.6–335); finally, 3 pts were transfusion-dependent (Table 1). The response was defined as an increase in Hb level of at least 1 g/dl at week 4 and of 2 g/dL, or the achievement of Hb level ≥12 g/dL at any subsequent time point during the study. Overall response rate at week 4 was 67.7%; in the responding pts, and increase of Hb level was 2.07 g/dL (range 10.47–8.40 g/dl). Three pts showed no response, 2 of whom were heavily pre-treated and had progressive disease, not responding to CHT (Fig. 1). All transfusion-dependent pts became independent. Response could be maintained with conventional dose of rHuEPO, until disease progression. No serious adverse events were observed during the dose intensity treatment and only 1 pt had a hypertensive peak, responding to standard therapy.

Table 1 Patients’ baseline characteristics (n = 20)
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Fig. 1
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Mean weekly Hb levels

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The occurrence of anemia is frequently observed in cancer patients and may significantly alter the quality of life. Furthermore, anemia may also have detrimental effects on disease progression. EPO may improve Hb levels and ameliorate the quality of life. ESA increases Hb levels in approximately two-thirds of treated patients with chemotherapy-induced anemia. Up to 46% of patients who respond to epoetin alfa have an increase in Hb level of ≥1 g/dl within the first 4 weeks of therapy, and 67% of patients experience an increase in Hb level ≥2 g/dl (or an increase in Hb level to 12 g/dl) at 8 weeks [7–10]. Data from this small study suggest that high-dose rHuEPO regimen in MM pts with severe anemia is safe and allows a prompt and sustained hematologic response in a high proportion of pts, including those heavily pre-treated and with very low baseline Hb level, significantly reducing transfusion requirement.

Limited iron stores and functional iron deficiency are common causes of response failure during ESA treatment in cancer patients and should be diagnosed. There is substantial scientific support for the use of IV iron supplementation to improve response and this has been acknowledged in international and national guidelines; however, prospective long-term data on the safety and efficacy of IV iron in this setting are yet awaited [11, 12].

In summary, high-dose epoetin remains an alternative and effective treatment strategy for MM pts with severe anemia. The identification of clinical or biological characteristics of “no responders” to epoetin alfa would be certainly of benefit to MM patients and could prompt physicians to employ alternative treatments, thereby avoiding delays in Hb and QOL improvements.