**2. Multiple myeloma and thrombosis**

The risk of developing venous thrombotic complications for patients with cancer is approximately five times that of the general population (0.5 *vs.* 0.1%) [4]. Multiple myeloma (MM), characterized by the malignant proliferation of clonal plasma cells, accounts for approximately 10% of hematologic malignancies and affects older individuals (median age, 70 years) [5]. Thromboembolic events are a key concern in clonal plasma cells disorders, such as monoclonal gammopathy of undetermined significance (MGUS) as well as in MM. The exact incidence of VTE in MGUS is difficult to determine since reported VTE rates probably vary according to the level of diagnostic vigilance. The underlying medical problems that prompted laboratory testing for monoclonal may also increase the risk of VTE. Srkalovic et al [1] noted an increased incidence of VTE among patients with MGUS. They reported that 7.5% (13 of 174 patients) of patients with MGUS developed VTE at a median of 4 months (range, 0–67 months) after diagnosis. The cumulative VTE rate was 16% after 8 years of follow-up. A medical history of VTE, family history of VTE, immobility, low serum albumin level and an increase in leukocyte count were found to be correlated with increased incidence of VTE in patients with MGUS. In another retrospective study (310 patients with MGUS) the incidence of VTE was 6.1% after a median follow-up of 44 months [6]. Univariate analysis showed that age ≥ 65 years, M protein ≥ 16 g/l and disease progression to symptom MM were the significant risk factors for VTE. A retrospective review of U.S. Veterans Affairs hospital records from 1980–1996 reported an incidence of VTE of 0.9, 3.1 and 8.7% in veterans without a plasma cell dyscrasia, diagnosed to have

Thrombosis Associated with Immunomodulatory Agents in Multiple Myeloma 117

two phase 3 trials confirmed the preliminary observations of increased incidence of VTE in newly diagnosed MM treated with thalidomide plus dexamethasone (16 and 17% of VTEs).

Regimen n Status of disease Incidence (%)

 Barlogie, 2001 26 169 RR < 2 Bennet, 2001 27 326 RR 4.6 Rajkumar, 2002 28 31 RR 3.4 Tosi, 2002 29 65 RR 1.5 Weber, 2002 30 28 ND 3

 Cavo, 2004 32 71 ND 16 Rakjumar, 2006 33 103 ND 17 Palumbo, 2004 34 120 RR 2 Dimopoulos, 2001 35 44 RR 7

 Palumbo, 2006 36 129 ND 20 Facon, 2007 37 125 ND 12

Dimopoulos 2006 38 50 ND 9

 Sidra, 2006 39 62 ND / RR 3.2 García-Sanz, 2004 40 71 RR 7 Dimopoulos, 2004 41 53 RR 4 Kropff, 2003 42 60 RR 9 Moehler, 2003 43 56 RR 7

 Baz, 2005 44 35 ND/RR 58 Zangari, 2004 3 87 ND 34 Zangari, 2002 45 232 RR 16 Barlogie, 2006 46 323 ND 34 Schutt, 2005 47 31 ND 26 Zervas, 2004 48 39 ND 10

Table 1. Incidence of thalidomide-associated venous thromboembolism without VTE

Similarly, when thalidomide was combined with melphalan and steroids, the incidence of VTE was 9–20% in newly diagnosed elderly patients [36-38]. In all of these studies, the major risk of thrombosis occurs early after initiation of the treatment, when the tumor load is maximal. Thus, this complication may be related to the release of thrombogenic factors from

(*table 1 below*).

**Thalidomide in monotherapy** 

**Thalidomide / Dexamethasone** 

**Thalidomide / Melphalan /** 

**Thalidomide / Chemotherapy** 

**Dexamethasone**

prophylaxis

**Thalidomide / Melphalan / Prednisone** 

**Thalidomide / Dexamethasone / CTX** 

RR: refractory / relapsed; ND: newly diagnosed.

myeloma cells rather than to cumulative drug exposure [49].

MGUS, and MM, respectively [7]. The incidence of VTE in MM patients is difficult to estimate and varies from 3–10%. On the other hand, the recent introduction of the antimyeloma therapy class called immunomodulatory drugs (IMiDs), substantially increased risk of VTE in multiple myeloma.

The exact pathogenesis of thrombosis in plasma cell dyscrasia is multifactorial and poorly understood. Prothrombotic coagulation abnormalities are found in patients with newly diagnosed multiple myeloma, including elevated levels of von Willebrand antigen factor, factor VIII and tissue factor, as well as decreased protein S and thrombosposndin [8]. Proinflammatory and angiogenic cytokines such as interleukin-6, tumor necrosis factor and vascular endothelial growth factor (VEGF) are elevated in MM and could activate the coagulation system [9]. A recently described mechanism of hypercoagulability in cancer patients, including MM patients, is acquired activated protein C resistance (APC-R). APC-R, in the absence of factor V Leiden mutation, was present in almost one-quarter of newly diagnosed myeloma patients and significantly increased the risk of VTE [10]. The possible production of auto-antibodies against protein C in these patients could explain the transient APC resistance phenotype. However, to date, we know of no single prothrombotic abnormality that can be used to predict which patients with plasma cell dyscrasia will develop VTE. Other risk factors of MM-associated thrombosis are involved, such as older age, immobility, prior or family history of VTE and the presence of other medical comorbidities, immobility due to pain and/or surgery, indwelling central venous catheters, extrinsic venous compression by plasmacytomas, and the presence of inherited factors such as factor V Leiden. However, the dominant risk factor for VTE in MM is the type of drug administered.
