Erythropoiesis stimulating agents are associated with reduced survival in patients with multiple myeloma

Abstract

The impact of erythropoiesis-stimulating agent (ESA) on cancer patients' survival has recently become a matter of extensive discussion. Studies in solid tumors demonstrated that ESA adversely affects survival. This issue has not been sufficiently studied in patients with multiple myeloma. In this study, which included 323 multiple myeloma patients followed in our Institution between 1988 and 2007, we demonstrated by using a proportional hazards model including multiple covariates (age, LDH, Hb, platelets, serum creatinine, ISS score, b2 microglobulin, and ESA administration) that ESA administration is associated with reduced survival (hazards ratio: 1.88, 95% CI: 1.28-2.77). Anemia, which is considered a predictor for survival, platelets, serum creatinine, ISS score, and LDH, were not significant, whereas, age and b2 microglobulin confirmed their predicting value in the multivariate analysis. With a median follow-up of 31 months (range 1-238), the median survival of patients in the ESA group was 31 months (95% CI: 25-37), whereas in the group without ESA administration it was 67 months (95% CI: 55-79) (P < 0.001). The median progressionfree survival for patients in the ESA group was 14 months (95% CI: 12-16), and for the group without ESA it was 30 months (95% CI: 24-36) (P < 0.001). These results indicate that ESA may have a detrimental impact on MM patients' outcomes and, thus, in this context, they should be used with rigorous criteria. Am. J. Hematol. 83:697-701, 2008. V

In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2

“…6,10,11 The hepcidin levels correlated negatively with hemoglobin, indicating that hepcidin could be causal in the anemia of MM. In addition, our cellular reporter system also displayed higher hepcidin promoter activity after treatment with serum of MM patients, compared with serum from healthy individuals.…”

“…10 In a study evaluating 34 MM patients at diagnosis or recurrence, Katodritou et al similarly demonstrated that patients' serum hepcidin levels were elevated and inversely correlated with hemoglobin concentrations. 11 Using Hep3B cells in vitro, we showed that treatment with MM patients' sera induced hepcidin mRNA expression more than healthy sera, and that with some samples, hepcidin induction was abrogated by neutralizing anti-IL-6 antibodies. 6 However, for other sera, the antibodies had no effect, suggesting that additional serum factors can induce hepcidin expression.…”

“…The hematologic parameters were previously measured. 6,10,11 These patients all had a normocytic/normochromic anemia. For the US patients (n ϭ 13), mean hemoglobin level was 10.0 g/dL (range 7.5-12).…”

“…Sera samples used in this study were from Durie-Salmon stage III 19 myeloma patients from Veterans Administration (VA) hospitals in Los Angeles, Pittsburgh, San Antonio, and Chicago, 6 (n ϭ 13) as well as from stage I, II, or III myeloma patients from Theagenion Cancer Center, Thessaloniki, Greece (n ϭ 12). 11 All MM samples were from patients who were newly diagnosed and had not received any cytotoxic chemotherapy. Control sera (n ϭ 15) were obtained from L.T.-H. and University of California Los Angeles.…”

Biological functions and therapeutic use of erythropoiesis‐stimulating agents: perplexities and perspectives

“…A retrospective study of 257 patients with multiple myeloma has recently demonstrated that ESAs are associated with improved overall survival in anaemic patients at Southwestern Oncology Group stages II, III and IV [hazard ratio (HR) 0AE6; 95% confidence interval (CI) = 0AE38-0AE94] (Baz et al, 2007). In contrast, another retrospective assessment of 323 myeloma patients treated with ESAs and followed up between 1988 and 2007 has shown their shorter survival (31 vs. 67 months; P < 0AE001) and median progression-free survival (14 vs. 30 months; P < 0AE001) compared to untreated patients (Katodritou et al, 2008). However, this study has important limitations in its design, especially because of baseline differences between the two groups in the most important prognostic factors for multiple myeloma (higher age, higher International Staging System stage, lower platelet count, haemoglobin levels, serum albumin, higher serum creatinine, lactate dehydrogenase and b2-microglobulin in the ESAs group), as well as in disease stage and lines of treatment .…”