RADAR Update on Thalidomide (Thal)- and Lenalidomide (Len)-Associated Venous Thromboembolism (VTE): Safety Concerns Persist for Multiple Myeloma (MM) Despite FDA Approvals in This Setting

BACKGROUND: At ASH 2004, we reported > 20% VTE rates with thal/dexamethasone (thal/dex) use as an off-label treatment for MM. The abstract prompted Richard Blumenthal, the Connecticut Attorney General, to file a Citizen’s Petition with the FDA in 2005 outlining six recommendations to address this safety concern. In 2006, the FDA indicated that four recommendations were approved. The AG’s request for a randomized clinical trial of aspirin, low molecular weight heparin (LMWH), and warfarin as VTE prophylaxis was denied- with the FDA indicating that preliminary data suggested that these agents are effective for prophylaxis. At ASH 2005, we reported > 20% VTE rates with len/dex treatment for MM. In response, the manufacturer pre-emptively included a “Black Box” warning describing high VTE rates when len was used off-label for MM. In 2006, len and thal received FDA approval for MM. The Research on Adverse Drug Events and Reports (RADAR) project conducted a systematic review of VTE rates when len or thal is prescribed for MM. METHODS: Reports of VTE with thal or len treatment of MM were reviewed. Data sources included: the FDA’s MedWatch program and phase II/III clinical trial reports from 1998 to 7/2006. RESULTS: FDA’s MedWatch program included reports of VTE occurring among 8 len- (3 on aspirin, 2 on warfarin, and 1 on MLWH) and 1076 thal-treated cancer patients. Clinical trials identified VTE rates of 15% among thal/dex treated patients and 14% among len/dex- treated MM patients (Table). Uncontrolled trials found that thal/dex-associated VTE rates were sometimes, but not always, lower with aspirin, LMWH, or warfarin (INR of 2 to 3), while little information on VTE prophylaxis is available for len-dex treated MM patients. CONCLUSIONS: The extant data continue to support our assertion that randomized controlled trials are needed to identify appropriate VTE prophylaxis agents when MM patients receive len or thal with dex. Data on aspirin prophylaxis remain premature. Clinical Trial VTE Results VTE rate among Thal treated MM patients (n = 2690) VTE rates among Len treated MM patients (n = 702) MM-extent of disease Untreated Relapsed/Refractory Untreated Relapsed/Refractory n/a = data not available Thal/Dex None 96/667 (14.4%) 11/256 (4.3%) 38/278 (13.7%) 48/346 (13.9%) Warfarin (1–1.25 mg/d) 16/105 (15.2%) 8/85 (9.4%) n/a n/a Aspirin (81 mg/d) n/a n/a 9/54 (16.7%) n/a LMWH/Warfarin (INR 2–3) 0/63 (0.0%) 2/26 (7.7%) n/a n/a Thal/Dex/Doxorubicin None 148/610 (24.3%) 47/271 (17.3%) n/a n/a Aspirin (81 mg/d) 3/45 (6.7%) n/a n/a n/a LMWH 19/211 (9.0%) n/a n/a n/a Thal/Melphalan/Prednisone None 43/287 (15.0%) n/a n/a n/a Aspirin (81 mg/d) n/a n/a 1/24 (4.2%) n/a LMWH 2/64 (3.1%) n/a n/a n/a