Systematic Review and Meta-Analysis of Randomized Controlled Trials of Erythropoietin in Multiple Myeloma.

Background: The current approach for treating anemia in multiple myeloma (MM) patients entails prescribing recombinant erythropoetin (EPO) only if chemotherapy fails initially to raise hemoglobin (Hb) levels. However, this practice is not based on synthesis of the totality of evidence obtained from data of all trials testing EPO exclusively in myeloma patients. Objective: To conduct a systematic review/ meta-analysis (SR/MA) regarding the use of EPO in MM patients. Methods: We conducted a SR of all randomized controlled trials (RCTs) that studied the effect of EPO exclusively in MM patients. We searched all major electronic databases (MEDLINE, LILACS, EMBASE and the Cochrane Controlled Trials Register) as well as performing hand searches of relevant meeting proceedings (ASH, ASCO, EHA), and ongoing NCI trials. We included RCTs that had at least 10 patients in each arm and had compared the use of EPO against a control group. We also identified trials that compared different doses of EPO. We excluded trials that enrolled patients treated with high-dose myeloablative chemotherapy followed by stem cell transplantation or hemodialysis. Results: We identified more than 500 relevant studies; 6 trials met our eligibility criteria and were included in the analysis. Five trials (4 published as full text manuscripts and 1 as the abstract) compared epoetin alpha against a control [placebo (2 trials) or no therapy with or without specification of red cells transfusion trigger level (3 trials)] in anemic MM patients. One trial compared 2 different schedules of epoetin alpha. No trial tested the effect of darbopoeitin. All 5 trials that studied EPO against controls used initial doses of 150 IU 3x/week SC with the possibility of increasing to 300 IU if necessary. In the majority of trials the patients had been receiving chemotherapy at the time EPO was administered. The number of patients included in each trial ranged from 24 to 145. All trials concluded that EPO was superior to a placebo or no treatment in terms of Hb increase. Two trials also concluded that EPO improves quality of life. Our meta-analysis showed that hematological response was favored in the group receiving EPO [relative risk (RR) 7.75; 95% CI 4.19 to 14.35, 4 trials, n = 272]. Mean Hb level improvement with EPO was also significant [weighted mean difference (WMD) 2.29; 95% CI2.00 to -2.58, 3 trials, n = 235]. In terms of adverse events, hypertension was more often found in the EPO arm [RR 5.80; 95% CI 1.30-25.90, 4 trials, n = 290]. Survival and data related to tumor response were not available in all trials. Critical appraisal indicated that available evidence was modest in quantity (5 trials, n= 385 total patients enrolled) and poorly reported in all important methodological domains. Conclusion: Available body of evidence suggests that EPO improves hematological outcomes in patients with myeloma. However, the quality of current evidence is insufficient, data on most important patients’ outcomes are lacking (e.g. survival etc.), thus preventing us from making definitive recommendations regarding the role of EPO in managing anemia in the myeloma setting. A definitive RCT to resolve the role of EPO in myeloma is indicated.