Patients with multiple myeloma (MM) are at an increased risk of venous and arterial thrombosis. The pathogenesis remains unclear, but probably involves several factors such as activation of procoagulant factors, acquired activated protein C resistance, and inflammation. In addition to general risk factors for venous thromboembolism, such as older age, immobility, surgery, and inherited thrombophilia, there are some MM-specific and treatment-related factors that contribute to the increased risk. The risk for venous thromboembolism is high when patients are treated with thalidomide or lenalidomide in combination with dexamethasone or multi-agent chemotherapy. Thromboprophylaxis should be given in these settings. Which agent is the most appropriate is a matter of debate, but aspirin, low-molecular-weight heparin, and warfarin all seem to be effective. This review discusses risk factors for thromboembolism in MM and general, disease-specific and treatment-related mechanisms for thrombosis. Recommendations for thromboprophylaxis are described and treatment choices for venous thrombosis in MM patients are reviewed.

It has been known for more than four decades that patients with multiple myeloma (MM) have an increased risk of venous thromboembolism (VTE).1  During the past decade, the introduction of the oral immunomodulatory drugs (IMiDs) thalidomide and lenalidomide has improved the clinical outcome of patients diagnosed with MM.2–3  However, a high rate of thromboembolic complications has been observed when using these agents, especially in combination with chemotherapy and high-dose corticosteroids,2,4–6  which has led to increased clinical awareness of VTE and research focus on the topic.

We performed two population-based studies on the risk of thrombosis in MM patients. In one study, based on more than 4 million military veterans in the United States, we identified 6192 patients with MM, of whom 2.4% developed deep-vein thrombosis (DVT). MM patients demonstrated a 9.2-fold increase in DVT risk compared with all other patients in the database. The greatest risk was observed during the first year following diagnosis.7  In a study from Sweden, including 18,627 MM patients and 70,991 matched controls, the risk for VTE was found to be 7.5-fold after 1 year of follow-up and 4.1-fold after 10 years (Figure 1). Interestingly, the risk for arterial thrombosis (myocardial infarction, transient ischemic attack, ischemic stroke, and angina) was also significantly increased compared with the controls (Figure 1).8  In a recent clinical study of 195 MM patients, there was a high risk of arterial thrombosis observed both during and following induction chemotherapy, irrespective of treatment type.9 

Figure 1.

Cumulative risk of arterial and venous thrombosis in patients with multiple myeloma and MGUS compared with matched controls.8  This research was originally published in Blood. Kristinsson SY et al. Blood. 2010;115:4991–4999. © the American Society of Hematology.

Figure 1.

Cumulative risk of arterial and venous thrombosis in patients with multiple myeloma and MGUS compared with matched controls.8  This research was originally published in Blood. Kristinsson SY et al. Blood. 2010;115:4991–4999. © the American Society of Hematology.

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Recent studies have shown that MM is consistently preceded by the precursor condition monoclonal gammopathy of undetermined significance (MGUS).10  In the first of our two population-based studies (the U.S. study), we identified 2374 MGUS patients and found a 3-fold increased risk of DVT.7  In the second study (the Swedish study), we found a 2.1-fold increased risk for VTE after 5 and 10 years follow-up among 5326 MGUS patients compared with 20,161 matched controls (Figure 1). Interestingly, only patients with IgG and IgA, and not IgM MGUS, had an increased risk, suggesting that there might be a biological difference between IgG/IgA and IgM MGUS with regard to risk of thromboembolism.8  In both of these studies of MGUS patients, the increased risk of thrombosis was not explained by malignant transformation. These studies show that the increased risk of VTE in MM is present prior to the onset of MM, possibly due to a result of ongoing clonal plasma cell activities.

This review discusses the risk factors for VTE and the mechanisms for VTE in MM, reviews the evidence and current recommendations for thromboprophylaxis in thalidomide- and lenalidomide-treated patients, and summarizes treatment choices for VTE in MM patients.

The cause of VTE is multifactorial and is often a consequence of a combination of risk factors.11  VTE is primarily a disease of the elderly; other patient-related risk factors include previous VTE, inherited thrombophilic abnormalities such as factor V Leiden, prothrombin G20210A mutation, protein C or protein S deficiency, and antithrombin deficiency. Immobilization has repeatedly been observed to be an independent risk factor, as well as trauma and several chronic diseases. Surgery is associated with a very high risk of thrombosis, and central venous catheters (CVCs) increase the risk of VTE. Treatment-specific factors include hormone therapy, chemotherapy, and erythropoietin.11 

Cancer has been shown to increase the risk of thrombosis by 4- to 5-fold.11  Thrombotic complications are frequently observed in patients with solid tumors, such as cancers of the pancreas, lung, stomach, breast, ovaries, and brain. In addition, patients with an unprovoked VTE are more likely to have an underlying occult malignancy than those with a known risk factor for VTE. Recent studies suggest that patients with hematological malignancies have a similar or even higher risk of solid tumors, with the highest risk found in patients with MM, acute leukemia, and central nervous system lymphoma.12  In addition to tumor type, advanced disease is also associated with a higher VTE risk. Chemotherapy for malignancy is associated with a high risk of VTE, ranging from 7% to 11% in patients with solid tumors and up to 12% in acute leukemia in different studies.12  The risk for VTE among patients with cancer is exponentially increased with the simultaneous presence of the general risk factors mentioned above, such as in cancer patients undergoing surgery or having a CVC. The risk of recurrence after a previous VTE is higher in cancer patients than in those without malignancy.13  Despite the traditional division of risk factors for VTE versus arterial thrombosis, the two disorders have many features in common, and patients with VTE have been shown to be at an increased risk for arterial thrombosis.14 

MM and Risk of Thrombosis

Many clinical studies have found an increased risk of VTE in patients with MM; however, most of these studies were retrospective or were not designed to evaluate the risk of VTE. The incidence of VTE in patients treated with melphalan and prednisone is 2% to 6%. MM patients treated with high-dose dexamethasone have a VTE incidence of 3% (Table 1).

In MM patients, the VTE risk is higher at the time of diagnosis than after relapse. Before it became evident that treatment with thalidomide and lenalidomide was associated with an increased risk of VTE, investigators did not require the use of any thromboprophylaxis. Table 1 shows the incidence of VTE in MM patients treated with thalidomide or lenalidomide without thromboprophylaxis. Thalidomide alone does not seem to increase the risk for VTE when used in relapsed or refractory patients. However, the risk of VTE increases when thalidomide is given in combination with dexamethasone, alkylating agents, anthracyclines, or as multi-agent chemotherapy. The highest reported risk was observed in patients treated with the combination of thalidomide, pegylated doxorubicin, vincristine, and dexamethasone (Table 1). Similarly, the risk does not seem to be increased if thalidomide is used as a single-agent therapy in newly diagnosed patients. This risk is increased beyond that observed in relapsed/refractory patients when thalidomide is used in combination with dexamethasone, alkylating agents, as part of a three-agent therapy, and with doxorubicin. In randomized clinical trials combining thalidomide with melphalan and prednisone, the incidence of VTE was 6% to 17% when given without thromboprophylaxis. In most studies, the highest risk was observed during the first few months of therapy; however, VTE still occurs after several months of therapy. Studies on maintenance treatment with thalidomide have not found a high risk for VTE, probably due to low tumor burden.

Clinical studies on the incidence of VTE in patients treated with lenalidomide have shown that single-agent treatment in relapsed/refractory patients does not increase the risk for VTE. However, when lenalidomide was combined with dexamethasone or cyclophosphamide, the risk increased (Table 1). Few studies have been conducted with lenalidomide in newly diagnosed patients without any thromboprophylaxis. In a case-control study comparing newly diagnosed patients treated with lenalidomide + dexamethasone (n = 228) or thalidomide + dexamethasone (n = 183), no statistical difference in VTE incidence between the thalidomide- and the lenalidomide-treated patients was found.15  In two studies on lenalidomide and high-dose dexamethasone with no thromboprophylaxis, 23% to 75% of the patients were diagnosed with VTE. As for thalidomide-treated patients, most lenalidomide-related thromboses occurred within the first few months.

Treatment with bortezomib has not been associated with an increased risk of VTE, alone or in combination with dexamethasone and/or chemotherapy. When bortezomib is given in combination with thalidomide or lenalidomide, the VTE incidence is low. The possibility of a protective role of bortezomib on VTE16  has to be validated in a prospective randomized study.

In addition to the increased risk of VTE among patients treated with IMiDs in combination with dexamethasone or chemotherapy, other treatment-related factors have been described. In a study of MM patients treated with lenalidomide and dexamethasone, the addition of erythropoietin increased the incidence from 5% to 23%,17  however, this has not been supported in other studies of MM.2  The dose of dexamethasone has been shown to affect the VTE risk. In a randomized clinical trial comparing lenalidomide and low-dose dexamethasone versus high-dose dexamethasone, the incidence was 12% and 26%, respectively.18  In the Western world, approximately 25% of MM patients are treated with high-dose melphalan with stem-cell support.19  Although an increased risk of VTE has been observed in some studies, most have been CVC related.12 

MM is an independent risk factor for VTE, and treatment with thalidomide and/or lenalidomide increases this risk, particularly in newly diagnosed patients and when combined with dexamethasone or chemotherapy. Furthermore, there is evidence that the higher the dexamethasone dose, the higher the risk of VTE. Erythropoietin treatment and indwelling CVC may also increase the risk for VTE. Patients with MM often have additional transient risk factors, such as infections and immobilization due to skeletal pain and during hospitalization.

The mechanisms for VTE in cancer are heterogeneous, and can include hypercoagulability, vessel wall injury, and stasis. The blood coagulation system is activated in patients with cancer. The prothrombotic mechanisms often relate to the host response to the tumor, including inflammation, necrosis, and hemodynamic factors. These can also be exacerbated by chemotherapy. In addition, tumor-specific clot-promoting mechanisms, such as the expression of procoagulant and fibrinolytic activities by the tumor cells and interaction with endothelial cells and blood cells, play a role in the pathogenesis. Venous vessel wall injury may be caused by cancer surgery and by cell-to-cell interactions. Finally, venous stasis predisposes to VTE by diluting and reducing the clearance of activated coagulation factors and also may cause endothelial cell damage, increasing the risk for thrombosis.

Proposed Mechanisms in MM

In addition to the general mechanisms for thrombosis observed in cancer patients, there are some specific pathogenetic issues in MM. A prothrombotic state has been observed in patients with MM. Increases in von Willebrand factor and factor VIII have been found, and were associated with a more advanced stage of disease, even before the start of treatment.20  The association between the increased level of these factors and VTE is unclear and requires larger prospective studies. The increase in the procoagulant factors can also reflect an inflammatory reaction. A higher incidence of acquired activated protein C resistance has been observed in MM patients, which disappeared during therapy and was associated with an increased risk of VTE.21  The production of paraprotein has also been suggested to have a role in thrombosis in MM patients. The suggested mechanisms are increased blood viscosity, procoagulant antibody formation, and interference with fibrin. High levels of inflammatory cytokines have also been suggested to play a role in the pathogenetic mechanism of VTE in MM, with interleukin-6, C-reactive protein, and tumor necrosis factor being the most important.16 

The observed excess risk for both arterial and venous thrombosis in MM patients suggests that there might be some shared biological features, most probably involving platelet activation.8–9  Arterial thrombi consist mainly of platelets and fibrin, whereas venous thrombi consist mainly of fibrin and red blood cells. However, there are common pathophysiologic features, including activation of endothelium, platelets, leukocytes, and high levels of coagulation factors.14  This is further supported by reports suggesting that aspirin is an effective prophylactic agent in venous thrombosis in MM, as discussed below.22  Additionally, some studies have found evidence of platelet aggregation5  and activation caused by thalidomide, which is also abrogated by aspirin.23 

Thalidomide and its analog lenalidomide have various mechanisms of action, including immunomodulatory, anti-angiogenic, and anti-inflammatory effects, as well as an effect on the bone marrow microenvironment. The exact mechanisms for the underlying thrombogenic effects of these agents are not known. There is evidence that the IMiDs enhance expression of tissue factor and vascular endothelial growth factor, down-regulate thrombospondin, and cause cytokine-mediated, activated protein C resistance.12,16  Thalidomide has been shown to increase the levels of von Willebrand factor and factor VIII.20  In addition, thalidomide regulates the level of the prothrombotic factor COX-2.24  Furthermore, there is some evidence to support an effect on the endothelial cells in patients treated with thalidomide and lenalidomide, possibly via tumor necrosis factor. Interestingly, a study of 1966 MM patients found evidence for an individual genetic variation in thalidomide-mediated VTE.25 

The mechanism for the apparent protective effect of bortezomib on the risk of VTE is not well understood. Some authors have suggested an inhibition of platelet aggregation,26  and others a prevention of the up-regulation of prothrombotic molecules such as thrombomodulin.27  Further research is needed to explore the mechanisms for the treatment-related effects on the risk of VTE with these agents.

In the first prospective multicenter phase III trial to evaluate the best thromboprophylaxis in thalidomide-treated MM patients (the GIMEMA study), Palumbo et al. randomized 991 newly diagnosed MM patients to bortezomib-thalidomide-dexamethasone (VTD), thalidomide-dexamethasone (TD), bortezomib-melphalan-prednisone-thalidomide (VMPT), or bortezomib-melphalan-prednisone (VMP).28  In a sub-study, patients treated with thalidomide (VTD, TD, and VMPT) were randomized to receive enoxaparin 40 mg/d (n = 223), aspirin 100 mg/d (n = 227), or warfarin 1.25 mg/d (n = 223) for the duration of the induction therapy.28  Patients in the VMP arm (n = 257) did not receive any prophylaxis and served as controls. The results of this study are summarized in Figure 2. There was no significant difference in the incidence of VTE between the three groups, with an incidence of 5%, 6%, and 8% in the low-molecular weight heparin (LMWH), aspirin, and warfarin groups, respectively. Higher doses of thalidomide and dexamethasone were associated with a higher VTE risk. In addition, patients treated with thalidomide in combination with bortezomib had a nonsignificantly lower risk of VTE. The incidence of bleeding was not different in the three arms. The authors concluded that treatment with LMWH conferred the lowest risk of VTE, although this was not statistically different.28  Another study was performed in which 402 patients received four cycles of lenalidomide-dexamethasone as induction, and were then randomized to melphalan-prednisone-lenalidomide or tandem autologous stem-cell transplantation as well as to either aspirin or enoxaparin. In an interim analysis, the incidence of thromboembolic events was similar in both groups, 2% and 1% in the aspirin and enoxaparin groups, respectively (p = 0.42).29 

Figure 2.

A randomized study of 991 newly diagnosed MM patients treated with thalidomide, evaluating the incidence of VTE with low-molecular-weight heparin (enoxaparin 40 mg/d), fixed low-dose warfarin (1.25 mg/d), and aspirin (100 mg/d).28  Patients treated with bortezomib-melphalan-prednisone (no prophylaxis) are shown as controls. P > 0.05 (not significant).

Figure 2.

A randomized study of 991 newly diagnosed MM patients treated with thalidomide, evaluating the incidence of VTE with low-molecular-weight heparin (enoxaparin 40 mg/d), fixed low-dose warfarin (1.25 mg/d), and aspirin (100 mg/d).28  Patients treated with bortezomib-melphalan-prednisone (no prophylaxis) are shown as controls. P > 0.05 (not significant).

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All MM patients who are treated with thalidomide or lenalidomide in combination with dexamethasone and/or chemotherapy should be treated with thromboprophylaxis, with the exception of patients with a major risk of bleeding. Given the results from the two randomized clinical trials, aspirin, LMWH, and warfarin can all be regarded as effective thromboprophylaxis. However, there are still areas of uncertainty; for example, the patients were not stratified according to other known risk factors.

Although aspirin is inferior to LMWH in preventing VTE in general, it does have some protective effects. Earlier studies of patients undergoing orthopedic surgery showed a significant risk reduction in VTEs compared with placebo.30  In their recent guidelines, the American College of Chest Physicians recommend against the use of aspirin for any patient group.31  Conversely, the American Association of Orthopedic Surgeons recommends aspirin as an equal alternative to heparin or warfarin in standard-risk patients undergoing total hip or knee arthroplasty.32  In addition to the two randomized studies cited above,28–29  there is some evidence from before/after studies in MM indicating a protective mechanism of aspirin (Table 2). For example, in newly diagnosed patients treated with thalidomide and anthracycline, the VTE incidence was 58% without any thromboprophylaxis, but decreased to 18% when aspirin was introduced.5  Several clinical studies on MM patients treated with lenalidomide have used aspirin as thromboprophylaxis with encouraging results, with a VTE incidence of 3% to 15% (Table 2). It should be noted that these studies were not designed to evaluate the risk of VTE, and many introduced aspirin after observing a high initial incidence of VTE.

LMWH and fondaparinux are considered the optimal thromboprophylaxis according to clinical guidelines.31  Randomized clinical trials have consistently shown LMWH to be superior to placebo in high-risk patients. Compared with unfractionated heparin, these agents show similar efficacy, but a lower risk of bleeding.31  Studies of MM patients treated with thalidomide or lenalidomide have shown promising results. In the GIMEMA study, the incidence of VTE was 5% in thalidomide-treated patients receiving enoxaparin, and in other studies the incidence was approximately 3% to 15%. In newly diagnosed patients treated with LMWH, the incidence of VTE has varied between 3% and 24% (Table 2).

The data on warfarin as a thromboprophylaxis is controversial. Some studies have used fixed, low-dose warfarin, whereas others have used full-dose warfarin. Using these approaches, the incidence of VTE has been shown to vary from 8% to 31%, with higher risk among patients treated with a fixed, low dose of warfarin (Table 2). In one study, a similar effect with both strategies was found, but a higher risk of bleeding in patients treated with the full-dose warfarin was noted.33 

An expert panel reported on consensus guidelines22  before the data from the GIMEMA study28  were available. The panel recommended the use of LMWH in MM patients treated with IMiDs with high-dose dexamethasone or doxorubicin, or when more than one risk factor for VTE was present (Table 3).22  Aspirin was recommended when one or no other risk factors were present. Additionally, full-dose warfarin was suggested as an alternative to LMWH, despite the lack of corroborating data. Because the risk of VTE in cancer patients with a previous VTE is very high, LMWH should probably be used in MM patients with a previous VTE, despite lack of additional risk factors. Because most VTE events in clinical studies have occurred during the first months, it is reasonable to continue prophylaxis for at least 4 to 6 months. The duration of the thromboprophylaxis should, however, depend on the length of treatment and the number of VTE risk factors.

Despite evidence of an increased risk of VTE among patients with MGUS, there is no evidence to support giving thromboprophylaxis at this point. The same thromboprophylactic strategy should be applied in MGUS patients as in other patients, in accordance with clinical guidelines.31,34 

All MM patients who do not have excess risk of bleeding and are treated with thalidomide or lenalidomide in combination with dexamethasone or chemotherapy, should receive thromboprophylaxis. In light of the recent randomized clinical trials, aspirin, LMWH, and fixed, low-dose warfarin seem to be effective in thalidomide-treated patients. Despite this, an individual risk-based strategy needs to be applied. Patients with MM often have additional transient risk factors, such as immobilization, infections, and surgery. The most appropriate thromboprophylaxis needs to be re-evaluated in these situations. Because 90% of all MM patients have an additional risk factor,35  most patients should be treated with LMWH. Aspirin should be used in patients with no or only one additional risk factor, as outlined in Table 3.

Thromboembolism in Patients with Renal Dysfunction and Thrombocytopenia

No data are available on thromboprophylaxis in MM patients with renal dysfunction. Extrapolating data from other studies, the recommendation for these patients would be LMWH with dose adjustments for patients with creatinine clearance below 30 mL/min. For example, enoxaparin can be given at the dose of 30 mg/d instead of 40 mg/d. In addition, anti-Xa should be monitored closely to minimize risk of over-anticoagulation. Another option is to use warfarin if renal dysfunction is present.31 

MM patients with thrombocytopenia due to tumor burden or treatment are at an increased risk of bleeding from thromboprophylaxis. The risk is highest among patients treated with full-dose warfarin. Low-dose aspirin has been shown to be safe in this setting.5  Furthermore, LMWH has been used without major bleeding risks in patients with thrombocytopenia after stem-cell transplantation, and is thus an alternative agent.36 

Screening for Inherited Thrombophilia in Multiple Myeloma

Cancer patients who carry factor V Leiden or prothrombin G20210A mutations have a high risk of VTE. Analyses by the Multiple Environmental and Genetic Assessment study showed that testing for inherited thrombophilia did not reduce the recurrence of venous thrombosis.37  Some studies have observed a high prevalence of inherited thrombophilia among MM patients; however, no large study has evaluated its association with VTE incidence. Currently, there is no role for screening for inherited thrombophilia in MM patients treated with thalidomide or lenalidomide.

If a patient with MM is being treated with thalidomide or lenalidomide and is subsequently diagnosed with VTE, then lenalidomide/thalidomide treatment should be withheld until full anticoagulation has been established. This usually takes a few days, and then thalidomide or lenalidomide can be reintroduced.38  In patients with cancer, LMWH has been shown to be superior to warfarin in terms of efficacy, safety, and possibly survival.39  However, this issue has not been addressed in randomized studies of patients with MM. LMWH can be considered an appropriate choice in patients with MM, due to lower risk of bleeding compared with warfarin. MM patients with a low risk of thrombocytopenia or bleeding can also be treated with oral warfarin. LMWH should be reduced if thrombocytopenia occurs; a 50% reduction can be performed with platelet counts below 50,000/μL, and a discontinuation of LMWH if the platelet count is less than 20,000 /μL. Patients should continue treatment as long as they are being treated with thalidomide or lenalidomide, or for a minimum of 6 months.12 

The occurrence of DVT or pulmonary embolism in the general population is associated with an inferior survival rate. Additionally, patients with cancer have a 2-fold higher mortality if diagnosed with VTE. Two independent studies have been published on this topic in MM. In a retrospective study on 668 MM patients treated with or without thalidomide, patients with VTE had similar survival rates as those without MM.40  In a study on 353 MM patients treated with lenalidomide, no survival difference was observed in patients with a thromboembolic episode.41  The reason for this finding is not clear. It is possible that the occurrence of thrombosis is partly related to the response to the treatment, and that patients with VTE have a better response than others. This could partly explain why newly diagnosed patients have the highest risk, because they usually have the most therapy-sensitive tumors. This has to be studied in a large prospective study.

MM patients have an increased risk of thrombosis, particularly when treated with thalidomide and lenalidomide in combination with other agents. The two available randomized clinical trials suggest that aspirin, LMWH, and warfarin are effective in lowering the VTE risk. Individually based risk stratification should be taken into account when choosing the agent. Future studies will hopefully help us to gain more insight into the pathogenesis of thromboembolism in MM. Also, new, orally available anticoagulants, such as thrombin inhibitors and FXa inhibitors, have shown efficacy in preventing VTE.42  In addition to the advantage of being taken orally, these agents have predictable effects, which eliminates the need for monitoring; however, they need to be tested in MM patients.

Conflict-of-interest disclosure: The author declares no competing financial interests. Off-label drug use: None disclosed.

Sigurdur Yngvi Kristinsson, MD, PhD, Department of Medicine, Division of Hematology, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden; Phone: 46–7-36696116; Fax: 46–8-318264; e-mail: sigurdur.kristinsson@karolinska.se

1
Catovsky
D
Ikoku
NB
Pitney
WR
Galton
DA
Thromboembolic complications in myelomatosis
Br Med J
1970
3
438
439
2
Dimopoulos
M
Spencer
A
Attal
M
et al
Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma
N Engl J Med
2007
357
2123
2132
3
Singhal
S
Mehta
J
Desikan
R
et al
Antitumor activity of thalidomide in refractory multiple myeloma
N Engl J Med
1999
341
1565
1571
4
Osman
K
Comenzo
R
Rajkumar
SV
Deep venous thrombosis and thalidomide therapy for multiple myeloma
N Engl J Med
2001
344
1951
1952
5
Baz
R
Li
L
Kottke-Marchant
K
et al
The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma
Mayo Clin Proc
2005
80
1568
1574
6
Rajkumar
SV
Blood
E
Vesole
D
Fonseca
R
Greipp
PR
Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group
J Clin Oncol
2006
24
431
436
7
Kristinsson
SY
Fears
TR
Gridley
G
et al
Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma
Blood
2008
112
3582
3586
8
Kristinsson
SY
Pfeiffer
R
Björkholm
M
et al
Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study
Blood
2010
115
4991
4998
9
Libourel
EJ
Sonneveld
P
van der Holt
B
de Maat
MP
Leebeek
FW
High incidence of arterial thrombosis in young patients treated for multiple myeloma: results of a prospective cohort study
Blood
2010
7
8
116
1
22
26
10
Landgren
O
Kyle
RA
Pfeiffer
RM
et al
Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study
Blood
2009
113
5412
5417
11
Heit
JA
Silverstein
MD
Mohr
DN
Petterson
TM
O'Fallon
WM
Melton
LJ
3rd
Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study
Arch Intern Med
2000
160
809
815
12
Falanga
A
Marchetti
M
Venous thromboembolism in the hematologic malignancies
J Clin Oncol
2009
27
4848
4857
13
Prandoni
P
Lensing
AW
Prins
MH
et al
Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism
Ann Intern Med
2002
137
955
960
14
Green
D
Risk of future arterial cardiovascular events in patients with idiopathic venous thromboembolism
Hematology Am Soc Hematol Educ Program
2009
259
266
15
Gay
F
Hayman
SR
Lacy
MQ
et al
Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients
Blood
2010
115
1343
1350
16
Eby
C
Pathogenesis and management of bleeding and thrombosis in plasma cell dyscrasias
Br J Haematol
2009
145
151
163
17
Knight
R
DeLap
RJ
Zeldis
JB
Lenalidomide and venous thrombosis in multiple myeloma
N Engl J Med
2006
354
2079
2080
18
Rajkumar
SV
Jacobus
S
Callander
NS
et al
Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial
Lancet Oncol
2010
11
29
37
19
Kristinsson
SY
Landgren
O
Dickman
PW
Derolf
AR
Bjorkholm
M
Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003
J Clin Oncol
2007
25
1993
1999
20
van Marion
AM
Auwerda
JJ
Lisman
T
et al
Prospective evaluation of coagulopathy in multiple myeloma patients before, during and after various chemotherapeutic regimens
Leuk Res
2008
32
1078
1084
21
Elice
F
Fink
L
Tricot
G
Barlogie
B
Zangari
M
Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism
Br J Haematol
2006
134
399
405
22
Palumbo
A
Rajkumar
SV
Dimopoulos
MA
et al
Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma
Leukemia
2008
22
414
423
23
Dunkley
S
Gaudry
L
Thalidomide causes platelet activation, which can be abrogated by aspirin
J Thromb Haemost
2007
5
1323
1325
24
Fujita
J
Mestre
JR
Zeldis
JB
Subbaramaiah
K
Dannenberg
AJ
Thalidomide and its analogues inhibit lipopolysaccharide-mediated induction of cyclooxygenase-2
Clin Cancer Res
2001
7
3349
3355
25
Johnson
DC
Corthals
S
Ramos
C
et al
Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping
Blood
2008
112
4924
4934
26
Avcu
F
Ural
AU
Cetin
T
Nevruz
O
Effects of bortezomib on platelet aggregation and ATP release in human platelets, in vitro
Thromb Res
2008
121
567
571
27
Sohn
RH
Deming
CB
Johns
DC
et al
Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated by activation of nuclear factor-kappa B
Blood
2005
105
3910
3917
28
Palumbo
A
Cavo
M
Bringhen
S
et al
A phase III study of enoxaparin vs aspirin vs low-dose warfarin as thromboprophylaxis for newly diagnosed myeloma patients treated with thalidomide based-regimens
Blood
2009
114
29
Palumbo
A
Cavallo
O
Yehuda
DB
et al
A prospective, randomized study of melphalan, prednisone, lenalidomide (MPR) versus Melphalan (200 Mg/M2) and autologous transplantation (Mel200) in newly diagnosed myeloma patients: an interim analysis [abstract]
Blood
2009
114
350
30
Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial
Lancet
2000
355
1295
1302
31
Geerts
WH
Bergqvist
D
Pineo
GF
et al
Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Chest
2008
133
381S
453S
32
Johanson
NA
Lachiewicz
PF
Lieberman
JR
et al
American academy of orthopaedic surgeons clinical practice guideline on. Prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty
J Bone Joint Surg Am
2009
91
1756
1757
33
Ikhlaque
N
Seshadri
V
Kathula
S
Baumann
MA
Efficacy of prophylactic warfarin for prevention of thalidomide-related deep venous thrombosis
Am J Hematol
2006
81
420
422
34
Berenson
JR
Anderson
KC
Audell
RA
et al
Monoclonal gammopathy of undetermined significance: a consensus statement
Br J Haematol
2010
7
150
1
28
38
35
Klein
U
Kosely
F
Hillengass
J
et al
Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone
Ann Hematol
2009
88
67
71
36
Ibrahim
RB
Peres
E
Dansey
R
et al
Safety of low-dose low-molecular-weight-heparins in thrombocytopenic stem cell transplantation patients: a case series and review of the literature
Bone Marrow Transplant
2005
35
1071
1077
37
Coppens
M
Reijnders
JH
Middeldorp
S
Doggen
CJ
Rosendaal
FR
Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis
J Thromb Haemost
2008
6
1474
1477
38
Zangari
M
Barlogie
B
Anaissie
E
et al
Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation
Br J Haematol
2004
126
715
721
39
Lee
AY
Levine
MN
Baker
RI
et al
Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer
N Engl J Med
2003
349
146
153
40
Zangari
M
Barlogie
B
Cavallo
F
Bolejack
V
Fink
L
Tricot
G
Effect on survival of treatment-associated venous thromboembolism in newly diagnosed multiple myeloma patients
Blood Coagul Fibrinolysis
2007
18
595
598
41
Zangari
M
Tricot
G
Polavaram
L
et al
Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone
J Clin Oncol
2010
28
132
135
42
Schulman
S
New aspects on treatment modalities for thromboembolic episodes
J Intern Med
2010
8
268
2
109
119
43
Facon
T
Mary
JY
Hulin
C
et al
Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial
Lancet
2007
370
1209
1218
44
Palumbo
A
Bringhen
S
Caravita
T
et al
Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial
Lancet
2006
367
825
831
45
Hulin
C
Facon
T
Rodon
P
et al
Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial
J Clin Oncol
2009
27
3664
3670
46
Weber
D
Rankin
K
Gavino
M
Delasalle
K
Alexanian
R
Thalidomide alone or with dexamethasone for previously untreated multiple myeloma
J Clin Oncol
2003
21
16
19
47
Rajkumar
SV
Gertz
MA
Lacy
MQ
et al
Thalidomide as initial therapy for early-stage myeloma
Leukemia
2003
17
775
779
48
Barlogie
B
Desikan
R
Eddlemon
P
et al
Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients
Blood
2001
98
492
494
49
Prince
HM
Mileshkin
L
Roberts
A
et al
A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma
Clin Cancer Res
2005
11
5504
5514
50
Rajkumar
SV
Hayman
S
Gertz
MA
et al
Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma
J Clin Oncol
2002
20
4319
4323
51
Cavo
M
Zamagni
E
Tosi
P
et al
First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma
Haematologica
2004
89
826
831
52
Palumbo
A
Bertola
A
Falco
P
et al
Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma
Hematol J
2004
5
318
324
53
Offidani
M
Corvatta
L
Marconi
M
et al
Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma
Hematol J
2004
5
312
317
54
Wu
P
Davies
FE
Horton
C
et al
The combination of cyclophosphomide, thalidomide and dexamethasone is an effective alternative to cyclophosphamide - vincristine - doxorubicin - methylprednisolone as induction chemotherapy prior to autologous transplantation for multiple myeloma: a case-matched analysis
Leuk Lymphoma
2006
47
2335
2338
55
Zervas
K
Dimopoulos
MA
Hatzicharissi
E
et al
Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study
Ann Oncol
2004
15
134
138
56
Zangari
M
Siegel
E
Barlogie
B
et al
Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy
Blood
2002
100
1168
1171
57
Richardson
PG
Schlossman
RL
Weller
E
et al
Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma
Blood
2002
100
3063
3067
58
Zonder
JA
Barlogie
B
Durie
BG
McCoy
J
Crowley
J
Hussein
MA
Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis
Blood
2006
108
403
author reply 404
59
Wang
M
Dimopoulos
MA
Chen
C
et al
Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure
Blood
2008
112
4445
4451
60
Weber
DM
Chen
C
Niesvizky
R
et al
Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America
N Engl J Med
2007
357
2133
2142
61
Morgan
GJ
Schey
SA
Wu
P
et al
Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma patients
Br J Haematol
2007
137
268
269
62
Harousseau
JL
Attal
M
Leleu
X
et al
Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study
Haematologica
2006
91
1498
1505
63
Niesvizky
R
Martinez-Banos
D
Jalbrzikowski
J
et al
Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma
Leuk Lymphoma
2007
48
2330
2337
64
Wang
M
Weber
DM
Delasalle
K
Alexanian
R
Thalidomide-dexamethasone as primary therapy for advanced multiple myeloma
Am J Hematol
2005
79
194
197
65
Minnema
MC
Breitkreutz
I
Auwerda
JJ
et al
Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy
Leukemia
2004
18
2044
2046
66
Offidani
M
Corvatta
L
Piersantelli
MN
et al
Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma
Blood
2006
108
2159
2164
67
Barlogie
B
Tricot
G
Anaissie
E
et al
Thalidomide and hematopoietic-cell transplantation for multiple myeloma
N Engl J Med
2006
354
1021
1030
68
Rajkumar
SV
Hayman
SR
Lacy
MQ
et al
Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma
Blood
2005
106
4050
4053
69
Baz
R
Walker
E
Karam
MA
et al
Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy
Ann Oncol
2006
17
1766
1771