Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis.

Lenalidomide (LEN) is an immunomodulatory compound with significant activity versus relapsed/refractory multiple myeloma (RRMM).1 In Blood, Rajkumar et al2 reported striking efficacy of LEN plus dexamethasone (DEX) versus newly diagnosed multiple myeloma (NDMM). While structurally similar to thalidomide (THAL), also used to treat MM,3 LEN has a unique activity profile. Both agents appear to increase the risk of thromboembolic events (TEEs), although the actual baseline incidence is unclear. The TEE incidence in NDMM patients receiving THAL DEX without thrombosis prophylaxis is approximately 15%.4,5 An 8.5% incidence of TEE in RRMM patients getting DEX LEN without routine prophylaxis has been reported.1 Rajkumar et al2 described a 3% incidence in NDMM with DEX LEN and daily aspirin (ASA; 80 mg or 325 mg). The Southwest Oncology Group is conducting a double-blind randomized trial comparing DEX (40 mg/day on days 1-4, 9-11, and 17-20 every 35 days for 3 induction cycles, then 40 mg/day on days 1-4 and 15-18 every 28 days as maintenance thereafter) plus placebo versus DEX (same schedule) plus LEN (25 mg/day on days 1-28 every 35 days during induction, then 25 mg/day on days 1-21 every 28 days during maintenance). Crossover from DEX to DEX LEN is permitted for progressive MM. Initially, no thrombosis prophylaxis was mandated. After 21 patients were enrolled, an increased incidence of TEEs in 1 arm became apparent: 9 (75%) of 12 patients receiving DEX LEN developed TEEs (8 lowerextremity deep-vein thromboses with 2 pulmonary embolic events, 1 ischemic stroke) after a median of 50 days, versus 0 (0%) of 9 patients on DEX alone (P .001). The study was modified to require 325 mg ASA daily, based on the low TEE incidence observed by Rajkumar et al,2 as well as a report showing low-dose ASA reduced TEE risk in MM patients receiving chemotherapythalidomide combinations.6 As of October 31, 2005, 76 patients have been enrolled. Since mandating ASA prophylaxis, 6 TEEs have occurred among 55 additional patients: 4 (15%) of 26 randomized to DEX LEN (P .001 for comparison of TEE incidence on DEX LEN before and after aspirin) and 2 (7%) of 29 on DEX alone (P .41 for DEX vs DEX LEN after ASA). Of interest, both of the patients randomized to DEX who developed clots had already crossed over from DEX to DEX LEN due to progressive disease. One of these patients was noncompliant with ASA prophylaxis. Overall, 6 (19%) of 32 patients receiving DEX LEN have developed TEEs since modification of the protocol to include ASA prophylaxis (P .001 before vs after ASA). In summary, although adding ASA markedly reduced the risk of TEEs in NDMM patients receiving DEX LEN, we observed a much higher incidence of TEE than reported by Rajkumar et al.4 Potential reasons include higher DEX dose, longer LEN exposure during induction in our trial, or other factors such as possible differences in the use of recombinant erythropoietin. The 19% TEE incidence we observed is similar to that reported for NDMM patients treated with anthracycline-THAL combinations plus either 81 mg ASA6 or low-dose enoxaparin.7 At present, using one of these prophylaxis strategies during DEX LEN treatment for NDMM is highly recommended. Further research is needed to determine the optimal prophylaxis strategy.