EUROPEAN POST-APPROVAL SAFETY STUDY (PASS) OF RELAPSED/ REFRACTORY MULTIPLE MYELOMA (RRMM): VTE INCIDENCE, RISK FACTORS, AND USE OF ANTITHROMBOTIC PROPHYLAXIS IN MM PATIENTS TREATED WITH LENALIDOMIDE

Background
EU PASS is an observational, non-interventional post-authorization study designed to investigate the safety of lenalidomide (LEN) and other agents in the treatment (Tx) of RRMM patients (pts). Venous thromboembolic events (VTEs) are recognized as possible adverse events (AEs) associated with the administration of LEN+dexamethasone (DEX). Larocca (Blood, 2012) reported that the incidence of grade 3/4 deep vein thrombosis (DVT) and pulmonary embolism (PE) during the first 6 mos of Tx was similar in selected newly diagnosed MM pts treated with LEN+low-dose DEX randomized to receive either acetylsalicylic acid (ASA) 100 mg/day (2.3%) or low-molecular-weight heparin (LMWH) enoxaparin 40 mg/day (1.2%; P=0.452). In the observational MELISSE study of pts treated with IMiD immunomodulatory drugs in 52 IFM centers, 443 pts received thromboprophylaxis at therapy initiation: 307 pts (59%) received ASA, 88 pts (17%) received LMWH, and 81 pts (15.5%) did not receive VTE prophylaxis (Leleu, Thromb Haemost. 2013). Through the first year of follow-up, the cumulative incidence of VTEs was 6% (n=31). Overall, VTEs occurred irrespective of whether pts were on ASA or LMWH prophylaxis (P=0.62).

Aims
To describe the incidence of VTE (DVT/PE) among RRMM pts enrolled in the PASS, to identify risk factors for VTE, and to compare the incidence of VTE in pts receiving different types of anti-thrombotic prophylaxis and no prophylaxis. 

Methods
RRMM pts who had received ≥ 1 prior Tx were enrolled at the investigator’s discretion into a LEN or background cohort (other regimens); this analysis focused only on pts who were treated in the LEN cohort. Thromboprophylactic medication was administered per local standard practice. Baseline risk factors for VTE were extracted. Incidence rates of VTE were calculated for events that occurred during the first 6 mos of follow-up based on pt-mos of exposure to single agents (ie, LMWH, ASA) and pt-mos of no exposure.

Results
A total of 2164 pts received LEN therapy for RRMM. Pts in the LEN cohort had a median age of 68 yrs (range, 25-95 yrs), and 54% were male. The proportion of pts prescribed low-dose DEX (≤160 mg) was 74.2%. Among 1529 pts with new or continuing thromboprophylaxis at baseline, 36.5% received ASA, 24.9% received LMWH, 7.1% received other anti-platelet medications, and 5% received warfarin. Over the entire follow-up interval, 123 pts (5.7%) experienced a VTE. Only 2 pts experienced a VTE while receiving warfarin therapy. Baseline risk factors associated with VTE were previous history of VTE (odds ratio [OR]=1.71; 95% CI, 1.06-2.77), age (OR=2.10; 95% CI, 1.36-3.25), and body mass index (OR=1.47; 95% CI, 0.98-2.21). Considering only single thromboprophylaxis agent use during the first 6 mos of IMiD therapy, the incidence of VTE was highest among pts not receiving prophylaxis during the month the VTE occurred: 1.64 per 100 pt-mos. VTE incidence rates were similar among pts treated with either ASA (0.686 per 100 pt-mos) or LMWH (0.636 per 100 pt-mos). In either case, a significant protective effect was noted for use of either ASA (relative risk [RR]=0.42, P=0.003) or LMWH (RR=0.39;P=0.004).

Summary
The incidence of VTE among RRMM pts in the PASS (5.7%) was similar to that previously reported in another large cohort study (MELISSE). Identified VTE risk factors were similar to those previously identified (age, prior VTE, BMI). Similar to previously reported results comparing ASA and LMWH, equivalent reductions in VTE risk were identified for pts receiving thromboprophylaxis with either ASA or LMWH.

Keyword(s): Multiple myeloma, Refractory, Relapse, Thromboembolism

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