Introduction: Lenalidomide (L) is an immunomodulatory compound, or IMiD®, which has impressive activity against both relapsed/refractory (RRMM) and newly diagnosed MM (NDMM). Although approximately 15% of NDMM patients (pts) treated with thalidomide (another IMiD®) plus dexamethasone (D)(TD) will develop thromboembolic events (TEEs), less is known about the thrombotic risk associated with LD. In 2 large Phase III studies comparing LD to D + placebo (P)(DP) in RRMM, which did not include routine thrombosis prophylaxis, the overall rate of TEEs in the LD groups were 8 and 14% versus 4% for those treated with DP. Here we describe an unexpectedly higher incidence of TEEs among the first 21 pts enrolled in a Southwest Oncology Group (SWOG) double-blinded Phase III study (S0232) comparing LD to DP in NDMM pts.

Methods: Pts received L/P 25 mg/day on days 1–28 plus D 40 mg/day on days 1–4, 9–12, 17–20 for three 35-day induction cycles, followed by L/P 25 mg/day on days 1–21 plus D 40 mg/day on days 1–4, 15–18 in repeating 28-day maintenance cycles. The incidence of TEEs for pts on LD and DP were compared using Fisher’s exact test (two-sided). Baseline clinical data were compared for pts who developed thromboses versus those who did not. Baseline labs, including hemoglobin, platelet count, PT, PTT, D-dimers, fibrinogen, vWF activity, Protein C, Protein S, activated protein C resistance, factor VIII level, and thrombin-antithrombin complexes, were also assessed.

Results: Nine of 12 NDMM pts (75%) randomized to LD developed TEEs, compared to zero of 9 (0%) treated with DP (p = 0.0011). All events were lower extremity deep vein thromboses except for one ischemic stroke. Events occurred after a median of 50 days of therapy. There was no association between myeloma stage, pt age or gender, or M-protein Ig subtype and the risk of thrombosis. Although baseline fVIII and vWF levels were elevated in the majority of pts (median 169 and 164.5, respectively) neither these nor other coagulation lab findings correlated with the risk of thrombosis. In all cases except the one pt who suffered a stroke, LD was resumed after full anticoagulation was instituted.

Discussion: The 75% incidence of thrombosis for the first 12 newly diagnosed pts treated with LD on S0232 was much higher than expected. No other predictive risk factors, including coagulation-related laboratory abnormalities, were identified. The incidence of thrombosis for pts with NDMM treated on a prior Phase II study of LD administered in 28-day cycles with daily ASA prophylaxis (325 mg/day) was extremely low. This experience, plus evidence that ASA (81 mg/day or 325 mg/day) reduces the risk of TEEs in pts treated with TD or T plus chemotherapy, prompted us to amend the protocol to include ASA 325 mg daily for all pts. The impact of ASA prophylaxis on the incidence of TEEs in pts enrolled subsequent to the 21 pts described here will be reported at the meeting.

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