Thalidomide (thal), Lenalidomide (len), and Dexamethasone (dex)-Associated Venous Thromboembolism (VTE) and Reported VTE Rates Pre- and Post-FDA Approval: Optimal Prophylaxis Strategies Are Still Unclear

Background: We previously reported that thal and len administration was associated with high VTE rates, particularly for multiple myeloma (JAMA 2006). The Connecticut Attorney General filed a Citizen’s Petition in 2005 with the FDA highlighting this safety concern. In 2006, when the FDA granted approval to thal and len to treat multiple myeloma patients, the FDA upheld much of the Petition and the sponsor included a Black Box warning to package inserts for both drugs when administered to MM patients, and encouraged consideration of VTE prophylaxis (although optimal strategies were not known). Herein, to compare the len/thal/dex-associated VTE rates pre- and post-FDA approval, the Research on Adverse Drug Events and Reports (RADAR) project performed a literary search through Pubmed and Ovid, with the search terms: “VTE,” “thrombosis,” “thromboembolism,” “DVT,” “multiple myeloma,” “thalidomide,” and “lenalidomide.” Methods: Reports of VTE with thal or len treatment of MM were reviewed and ordered by thal and dex dosages (table below). High dose thal was defined as higher than 200mg/d, low dose thal as 200mg/d or lower, and high dose dex as higher than 20mg/d and low dose dex as 20mg/d and lower. Data sources included: Pubmed and Ovid with randomized trials from 2006 to 2008. Results: A total of 56 randomized trials were included, with 35 previously reported trials (JAMA 2006) from 1998 to July 2006 (2423 patients) and 21 new trials from August 2006 to 2008 (2261 patients). In the recent trials, lower doses of both thal and dex were used, which are leading to lower VTE rates. The dosage/use of dex has a direct impact on VTE rates, with recent randomized trials of low dose thal and low dose dex reporting VTE rates as low as 0% (0–5) regardless of the use of anticoagulant prophylaxis. When high thal and no dex were used without prophylaxis, VTE rates were 2%. The benefit of prophylaxis is still unclear because when low dose thal and low dose dex are administered, the effects of prophylaxis are negligible. Len and high dose dex associated VTE rates in MM patients have reached a high of 15% (3–15), which is lower than the 29% maximum VTE rates found in our previous report (JAMA 2006). The lower len and dex-associated VTE rates in recent trials with MM patients is confounded by exclusion of VTE risk MM patients prior to treatment. Both the pre- and post-FDA approval trials do not demonstrate significantly reduced len and high dose dex-associated VTE rates with prophylaxis. As with thal, cogent VTE prophylaxis strategies for MM patients who receive len are unclear. Conclusion: After FDA approval of thal and len in 2006, low thal and low dex dosages were used treat MM patients and have shown to be an effective way to decrease VTE risk. Optimal VTE prophylaxis strategies for MM patients who receive len or thal with dex continue to be uncertain. A formal randomized trial of alternative VTE strategies is needed. Randomized Trial VTE Results Bold: new results 8/06–08/08, Regular: previous results in JAMA 2006 Thal (n=1713) Len (n=548) None ASA LWMH Coumadin None ASA LWMH Coumadin DVT prophylaxis (n=905) (n=961) (n=154) (n=402) (n=252) (n=83) (n=211) (n=846) (n=160) (n=133) (n=177) Dosage Low Thal/Low Dex 2% (0–5) [3/122] n/a n/a n/a 5% [2/38] n/a n/a n/a Len + Dex + DVT screening n/a n/a 9% (3–10) [10/106] n/a n/a n/a n/a n/a n/a n/a Low Thal/No Dex 0% [0/30] 18% [9/49] 8% [4/37] n/a 0% [0/30] n/a 1% [2/202] n/a Len + dex + no DVT screening 10% (6–11) [22/211] 14% (4–28) [86/624] n/a 11% (3–19) [10/88] n/a n/a n/a n/a 15% [26/177] n/a Low Thal/High Dex 16% (6–18) [52/328] 17% (15–20) [35/202] 8% [9/117] 7% [3/45] n/a n/a 14% [7/50] n/a Len + no Dex + no DVT screening n/a 2% [4/222] 6% [3/54] 7% [3/45] n/a n/a n/a n/a n/a n/a High Thal/High Dex 12% [15/124] 7% (0–13%) [7/106] n/a n/a 29% [98/334] n/a n/a 6% [2/33] High Thal/Low Dex n/a 11% (7–26) [21/193] n/a n/a n/a n/a n/a 16% (8–25) [8/50] High Thal/No Dex 2% [6/301] 9% (0–16) n/a n/a n/a n/a n/a n/a