**4. Lenalidomide and thrombosis**

Pathophysiology and Clinical Aspects of 118 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

A meta-analysis of studies of thalidomide in MM, which involved 3,322 patients, showed that patients receiving thalidomide were 2.1 times as likely to have a VTE event compared with those who were not receiving thalidomide (p<0.01). Those receiving thalidomide plus dexamethasone were 3.1 times as likely to have a VTE event (p<0.01), and those receiving thalidomide in addition to other chemotherapy agents were 1.5 times as likely to have a VTE

The pathogenesis of thalidomide-associated thrombosis has not yet been established. Zangari et al. [10] tested for hypercoagulability in 62 newly diagnosed MMs, and found that DVT was more frequent in those patients with acquired APC resistance (36 *vs.* 15%, p<0.04). The pre-existing elevated factor VIII coagulant activity and von Willebrand factor antigen have also been related with thalidomide-associated thrombosis [50]. In an experimental model, Kausahal et al. demonstrated that the addition of thalidomide to uninjured arterial endothelium did not cause any appreciable change, whereas thalidomide added to adriamycin-injured (8–24 h) endothelial cells resulted in endothelial dysfunction by altering

Cases of VTE that began shortly after the initiation of treatment with recombinant human erythropoietin in patients who had been receiving thalidomide for some time have been reported [52]. However, another study found no apparent increased risk of thrombosis in 199 cases of myeloma given thalidomide with or without erythropoietin. Of the 49 patients receiving both drugs, 8.1% developed thrombosis compared with 9.3% of the 150 patients on

The genetic susceptibility to developing a VTE in response to thalidomide therapy has been also evaluated. The lack of a strong association with genetic variations in the coagulation cascade, such as factor V Leiden or G20210A prothrombin mutation, suggests that VTE risk is mediated via alternative mechanisms. Johnson et al [54] identified 18 SNPs, using a custom-built molecular inversion probe (MIP)-based single nucleotide polymorphism (SNP) chip. There were two "response to stress" groups: a response to DNA damage group, including *CHEK1*, *XRCC5*, *LIG1*, *ERCC6*, *DCLRE1B* and *PARP1*, and a cytokine response group containing *NFKB1*, *TNFRSF17*, *IL12B* and *LEP*. A third apoptosis-related group with

Interestingly, no thromboembolic events were observed in a group of 30 patients with relapsed MM treated with a bortezomib, melphalan, prednisone and thalidomide (VMPT) combination despite the absence of any anticoagulant prophylaxis [55]. A recent review of phase 3 trials of bortezomib- and/or IMiD-based therapy in frontline MM, together with other studies of novel combination regimens concluded that bortezomib-based regimens were typically associated with DVT/PE rates of ≤ 5%, similar to those seen with melphalanprednisone and dexamethasone, whereas IMiD-based bortezomib-free regimens were generally associated with higher rates [56]. These results suggested the existence of a protective effect of coadministration of thalidomide or lenalidomide with bortezomib [57- 58]. Zangari et al prospectively described *in vivo* effects of bortezomib from routine tests of blood coagulation and platelet function in treated MM patients. This pilot clinical trial showed *in vivo* that even a short exposure to bortezomib can affect platelet function. Platelet aggregation was reduced after bortezomib infusion with most of the commonly agonists

used (ADP, epinephrine and ristocetin) on both days of treatment [59].

event (p<0.01) [2].

the expression of PAR-1 in injured endothelium [51].

thalidomide who did not receive erythropoietin [53].

*CASP3*, *PPARD* and *NFKB1* was also found.

Lenalidomide, a more potent immunomodulatory derivative of thalidomide, was designed to increase the anti-myeloma efficacy of thalidomide, while possibly reducing side effects like neuropathy and thrombosis. However, although neuropathy is not an important lenalidomide-related side effect, thrombosis continues to be one of the most important side effects, especially when lenalidomide is given in combination with dexamethasone or chemotherapy (*table 2*).


RR: refractory / relapsed; ND: newly diagnosed.

Table 2. Incidence of lenalidomide-associated venous thromboembolism without VTE prophylaxis

In two large phase 3 trials comparing lenalidomide plus dexamethasone to dexamethasone alone without mandated thromboprophylaxis in patients with RRMM, the incidences of VTE in the LD arm were 11.4 and 14.7%, compared with 4.6 and 3.4% in the DEX alone arm [66-67]. The incidence was even higher in patients with newly diagnosed MM (up to 75%) who were treated with lenalidomide plus dexamethasone [68]. In all these trials conducted in RR and newly diagnosed MM patients, dexamethasone was given at high dose (three pulses of 40 mg for 4 days, total amount per cycle: 480 mg). Interestingly, the rate of VTE was significantly lower when lenalidomide was combined

Thrombosis Associated with Immunomodulatory Agents in Multiple Myeloma 121

**Before treatment with IMiDs**

**Evaluating risk factors**

**Aspirin 81 - 325 mg / day HBPM: enoxaparin 40 mg/d**

**More than 4 – 6 months if: persistence of risk factors**

**0 – 1 Risk factor > 1 Risk factor High - dose dexamethasone**

Fig. 1. International Myeloma Working Group consensus statement on VTE prophylaxis in

**risk factor**: Obesity, previous venous thromboembolism, central venous catheter or pacemaker, cardiac disease, chronic renal disease, diabetes, acute infection, immobilization, general surgery, anesthesia, trauma, erythropoietin, blood clotting disorders, myeloma at diagnosis and hyperviscosity

**At least 4 – 6 months**

Adapted from Palumbo A , *et al*. Leukemia. 2008;22:414-423.

**apparition of new risk factors**

**Doxorubicin multi-chemotherapy**

**dalteparin 5000 UI/d fondaparinux 2.5 mg/d**

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

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

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

up (5.0, 6.4 and 8.2%, respectively), and all were considered likely to be effective.

myeloma patients receiving thalidomide or lenalidomide (2008).

1st step

2nd step

Action

lenalidomide [83].

with low-dose dexamethasone (40 mg weekly; total dose per cycle: 160mg) compared with high-dose (26 *vs.* 12%, p=0.0003) [69].

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% overall) [70].

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 [72].
