A Prospective, Randomized, Phase III Study of Enoxaparin Versus Aspirin Versus Low-Fixed-Dose of Warfarin in Newly Diagnosed Myeloma Patients Treated with Thalidomide-Containing Regimens.

Abstract

Background: The risk of venous thromboembolism (VTE) is high in newly diagnosed myeloma (MM) patients who receive thalidomide-containing regimens. Anticoagulant prophylaxis is recommended but it's not clear which is more appropriate. In this prospective, multicenter phase III trial we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) or low-fixed dose warfarin (WAR) as anticoagulant prophylaxis.Methods: In a GIMEMA study, newly diagnosed MM patients were randomized to VTD (Velcade 1.3 mg/m² d 1,4,8,11; Thalidomide 200 mg/d; high-dose Dexamethasone 320 mg/21 d) or TD (Thalidomide 200 mg/d; high-dose Dexamethasone 320 mg/21 d) or VMPT (Velcade 1.3 mg/m² d 1,8,15,22; Melphalan 9 mg/m² d 1–4; Prednisone 60 mg/m² d 1–4; Talidomide 50 mg/d) or VMP (Velcade 1.3 mg/m² d 1,8,15,22; Melphalan 9 mg/m² d 1–4; Prednisone 60 mg/m² d 1–4). In a sub-study, patients treated with VTD or TD or VMPT were randomly assigned to receive LMWH (Enoxaparin 40 mg/d) or ASA (Aspirin 100 mg/d) or WAR (Warfarin 1.25 mg/d) for the duration of the induction therapy. Patients treated with VMP did not receive any prophylaxis and were used as controls. End-points were incidence of VTE, acute cardiovascular events, sudden death, bleeding and any other serious adverse events. A total of 950 patients will be included in this study. An interim analysis was performed after the first 200 patients were enrolled.Results: Eighty-two patients received VTD, 84 TD, 34 VMPT and 35 VMP. Two-hundred patients (117 males, median age 58 years) were analyzed: 65 patients were randomized to LMWH, 66 to ASA and 69 to WAR. Patient characteristics were similar in all groups. All patients completed at least the first 3 cycles of therapy. The incidence of VTE was 2/65 (3%) in the LMWH group, 6/66 (9%) in the ASA group and 2/69 (3%) in the WAR group, but differences did not reach statistical significance. VTEs were 2/35 (6%) in the VMP group who did not received any prophylaxis. The cumulative incidence of VTE was 4/116 (3%) in patients treated with Velcade plus Thalidomide, and 6/84 (7%) in those treated with TD (p=0.33). No acute cardiovascular events or sudden deaths were reported. The incidence of bleeding was 0/65 (0%) in the LMWH group, 2/66 (3%) in the ASA group and 2/69 (3%) in the WAR group.Conclusion: The overall incidence of VTE was less than 10% in all groups. ASA patients had higher frequency of VTE; LMWH patients had lower risk of bleeding; patients who received Velcade had lower frequency of VTE. An update of these data and an analysis of risk factors will be presented at the meeting.