**6. Prophylaxis of TEE-related IMiDs**

Patients with MM being treated with IMiDs-based combinations should receive thromboprophylaxis [79-80]. There are data showing benefit of using low-molecular-weight heparin (LMWH), full-dose warfarin and daily aspirin in myeloma patients receiving IMiDs drugs [3, 44, 81]. However, fixed-dose warfarin (1 mg/d) was ineffective in reducing the VTE rate [3, 36]. Currently, outpatient VTE prophylaxis is recommended by the Italian Association of Medical Oncology, the National Comprehensive Cancer Network, the American Society of Clinical Oncology, the French National Federation of the League of Centers Against Cancer and the European Society of Medical Oncology only for medical oncology patients receiving highly thrombogenic thalidomide- or lenalidomide-based combination chemotherapy regimens [80].

The 2008 International Myeloma Working Group consensus statement on VTE prophylaxis in myeloma patients receiving thalidomide or lenalidomide [81], recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for VTE associated with thalidomide and lenalidomide therapy include: advanced age, a history of VTE, an indwelling central venous catheter, comorbid conditions (e.g, infections, diabetes, cardiac disease, etc), current or recent immobilization, recent surgery and inherited thrombophilic abnormalities. Myeloma-related risk factors include diagnosis and hyperviscosity. Therapyrelated risk factors include high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with ≤1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although little has been published about this strategy (see *figure 1 below ).* 

Pathophysiology and Clinical Aspects of 120 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

with low-dose dexamethasone (40 mg weekly; total dose per cycle: 160mg) compared with

Similar to thalidomide, low rates of VTE have been reported in MM patients treated with lenalidomide in combination with bortezomib. In a phase 1/2 study of lenalidomide plus dexamethasone and bortezomib without thromboprophylaxis, thrombosis was rare (6%

The role of ESA and lenalidomide in thrombotic risk is controversial. An increased thrombotic risk has been observed in patients who received concomitant ESA with lenalidomide plus dexamethasone [71], although a third study showed no impact of ESA

Pomalidomide (CC4047) is a new IMiD with high *in vitro* potency. In a phase 1 trial evaluating CC-4047 alone in 24 patients with RRMM, 4 (17%) developed a TEE during the first year of therapy [73]. Thromboprophylaxis was given in the phase 2 studies of

Patients with MM being treated with IMiDs-based combinations should receive thromboprophylaxis [79-80]. There are data showing benefit of using low-molecular-weight heparin (LMWH), full-dose warfarin and daily aspirin in myeloma patients receiving IMiDs drugs [3, 44, 81]. However, fixed-dose warfarin (1 mg/d) was ineffective in reducing the VTE rate [3, 36]. Currently, outpatient VTE prophylaxis is recommended by the Italian Association of Medical Oncology, the National Comprehensive Cancer Network, the American Society of Clinical Oncology, the French National Federation of the League of Centers Against Cancer and the European Society of Medical Oncology only for medical oncology patients receiving highly thrombogenic thalidomide- or lenalidomide-based

The 2008 International Myeloma Working Group consensus statement on VTE prophylaxis in myeloma patients receiving thalidomide or lenalidomide [81], recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for VTE associated with thalidomide and lenalidomide therapy include: advanced age, a history of VTE, an indwelling central venous catheter, comorbid conditions (e.g, infections, diabetes, cardiac disease, etc), current or recent immobilization, recent surgery and inherited thrombophilic abnormalities. Myeloma-related risk factors include diagnosis and hyperviscosity. Therapyrelated risk factors include high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with ≤1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although little has been published about

high-dose (26 *vs.* 12%, p=0.0003) [69].

**5. Pomalidomide and thrombosis** 

**6. Prophylaxis of TEE-related IMiDs** 

combination chemotherapy regimens [80].

this strategy (see *figure 1 below ).* 

pomalidomide and low-dose dexamethasone [74-78].

overall) [70].

[72].

Fig. 1. International Myeloma Working Group consensus statement on VTE prophylaxis in myeloma patients receiving thalidomide or lenalidomide (2008).

Two direct comparison trials between thromboprophylaxis agents have recently been conducted. In the first phase 3 Italian Myeloma Network GIMEMA study [82], which prospectively assessed the impact of LMWH, aspirin or low-dose warfarin in newly diagnosed patients receiving thalidomide as part of either VMPT, VTD or TD regimens, the risk of VTE was similar in all three thromboprophylactic therapies after 6 months of follow up (5.0, 6.4 and 8.2%, respectively), and all were considered likely to be effective.

The second phase 3 trial compared the efficacy and safety of thromboprophylaxis with lowdose aspirin (ASA) or low-molecular-weight heparin (LMWH) in newly diagnosed MM patients, treated with lenalidomide and low-dose dexamethasone induction and melphalanprednisone lenalidomide consolidation. The incidence of VTE was 2.27% in the ASA group and 1.20% in the LMWH group. The authors concluded that aspirin could be an effective and less expensive alternative to LMWH thromboprophylaxis during treatment with lenalidomide [83].

However, some questions remain unanswered: the outcome of the use of thromboprophylaxis in patients already in remission receiving thalidomide or lenalidomide as maintenance therapy during prolong periods of time is not well understood. A recent meta-analysis of the use of thalidomide as maintenance after autologous transplantation found the incidence of thromboembolic events to be 4–6%, and the risk of thromboembolism

Thrombosis Associated with Immunomodulatory Agents in Multiple Myeloma 123

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**8. References** 

was 1.95 times that of patients who did not receive thalidomide [84]. The use of ASA for a longer period may reduce the risk of late thromboembolism. Future studies should address this possibility.
