Hematology

Thrombotic complications following treatment of multiple myeloma with thalidomide and its analogues

Thrombotic complications following treatment of multiple myeloma with thalidomide and its analogues
Authors
Jeffrey Zonder, MD
Charles A Schiffer, MD
Section Editors
Stanley L Schrier, MD
Robert A Kyle, MD
Deputy Editor
Rebecca F Connor, MD
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Mon Sep 19 00:00:00 GMT 2011 (More)

INTRODUCTION — The association between cancer and venous thromboembolic events (VTE) has been well documented. There are several possible mechanisms involved, including acquired abnormalities involving clotting factors and the coagulation cascade, extrinsic vessel compression by tumor masses, immobility, surgery, the presence of indwelling central venous catheters, as well as the simultaneous presence of an inherited hypercoagulable state (eg, factor V Leiden). (See “Hypercoagulable disorders associated with malignancy” and “Pathogenesis of the hypercoagulable state associated with malignancy”.)

Patients with multiple myeloma (MM) or the precursor lesion monoclonal gammopathy of undetermined significance (MGUS) have an increased incidence of venous thromboembolism (VTE). In addition, a few studies have suggested an increased risk of arterial thromboembolism (ATE) in these populations as manifested by stroke, transient ischemic attack, myocardial infarction, or symptomatic peripheral artery disease. The increased rate of VTE appears to be both a result of the malignancy itself and the therapy given. In particular, the rate of VTE is particularly high for patients with MM treated with combination chemotherapy that contains thalidomide or a thalidomide analog such as lenalidomide.

The thrombotic risk associated with the use of thalidomide and its analogues as treatment for MM will be discussed here. Thrombotic risk following the use of other antineoplastic agents (eg, tamoxifen, L-asparaginase) and issues related to the treatment of VTE are presented separately. (See “Drug-induced thrombosis and vascular disease in patients with malignancy”, section on ‘L-asparaginase’ and “Drug-induced thrombosis and vascular disease in patients with malignancy”, section on ‘Tamoxifen and raloxifene’ and “Treatment of acute pulmonary embolism” and “Treatment of lower extremity deep vein thrombosis”.)

POTENTIAL MECHANISMS — The association between cancer and venous thromboembolic events (VTE) has been well documented. There are several possible mechanisms involved, including acquired abnormalities involving clotting factors and the coagulation cascade, extrinsic vessel compression by tumor masses, immobility, surgery, the presence of indwelling central venous catheters, as well as the simultaneous presence of an inherited hypercoagulable state (eg, factor V Leiden). (See “Hypercoagulable disorders associated with malignancy” and “Pathogenesis of the hypercoagulable state associated with malignancy”.)

Thalidomide has a wide spectrum of biological effects, including immune modulation, alteration of adhesion molecule and cytokine expression, and inhibition of angiogenesis [1]. (See “Overview of angiogenesis inhibitors”, section on ‘Thalidomide’.)

While the exact mechanism by which thalidomide contributes to thrombosis is not known, the following mechanisms have been postulated:

 

  • Serum levels of the anticoagulant pathway cofactor thrombomodulin transiently drop during the first month of thalidomide therapy, with gradual recovery over the following two months [2]. It is not known whether surface thrombomodulin expression on endothelial cells is similarly reduced.
  • Thalidomide increases endothelial cell expression of protease activated receptor-1 (PAR-1) after exposure to doxorubicin or other anthracyclines [3]. This could result in increased thrombin binding to the vascular endothelium, and explain, in part, the increased risk of thrombosis seen when thalidomide is used in conjunction with an anthracycline (see ‘Thalidomide plus anthracycline’ below).
  • Active treatment for MM has been associated with resistance to activated protein C (APC) in the absence of factor V Leiden and response to APC appears to normalize following treatment [4,5]. In one of these reports, the risk of VTE was highest in those patients with both APC resistance and treatment with thalidomide [4]. However, other investigators have not been able to confirm this observation [2,6].
  • In one study, patients with MM treated with thalidomide had extremely high levels of von Willebrand factor antigen and factor VIII, factors known to be associated with an increased risk of VTE in the general population [7]. (See “Overview of the causes of venous thrombosis”, section on ‘Factor VIII’.)
  • Genetic analysis of single nucleotide polymorphisms (SNPs) noted that the set of SNPs associated with thalidomide-related VTE events in patients with MM was enriched in genes and pathways important in drug transport/metabolism, DNA repair, and cytokine balance [8-10].
  • Down-regulation of PU.1 by immunomodulatory derivatives such as thalidomide and lenalidomide leads to arrest of myeloid maturation with resultant accumulation of promyelocytes, with high levels of cathepsin G contained in their azurophilic granules [11]. Cathepsin G, a platelet function agonist, may contribute to risk of VTE.

 

INCIDENCE AND RISK FACTORS

General risk factors — Patients with multiple myeloma are at increased risk of having comorbidities known to be risk factors for the development of venous thromboembolism (VTE) in the general population. These include immobilization related to bone involvement and pathologic fractures, renal disease due to kidney involvement, diabetes due to glucocorticoid use, acute infection due to immunosuppression, the use of erythropoietin, and central venous catheter placement for treatment. Other risk factors for VTE include obesity (body mass index ≥30 kg/m2), previous VTE, pacemaker placement, cardiac disease, hormone therapy, and inherited thrombophilias. The impact of these risk factors in the general population is discussed in more detail separately. (See “Overview of the causes of venous thrombosis”.)

Thalidomide-based therapy — The risk of VTE among patients with multiple myeloma taking single-agent thalidomide does not appear to be increased over that of patients with myeloma not taking thalidomide. In contrast, the risk of VTE increases substantially when thalidomide is administered in conjunction with glucocorticoids [12]. While the majority of thrombotic events described in patients treated with thalidomide have been venous, arterial thrombotic events have also been reported [13].

Single agent thalidomide — Treatment with single agent thalidomide is not associated with a significantly increased risk of thrombosis, as attested to in the following studies [14]:

 

  • In a report in which 84 patients with relapsed or refractory myeloma were treated with 200 to 800 mg/day of thalidomide, no definite thromboembolic events were reported [15].
  • Another study reported three nonfatal thromboembolic events and one case of transient ischemic attacks occurring among 75 patients with multiple myeloma treated with thalidomide, with or without concomitant interferon [16].
  • A third study observed one thromboembolic event during thalidomide monotherapy in 28 previously untreated patients with multiple myeloma [17].

 

The thrombosis incidence of approximately 1 to 5 percent in trials using single agent thalidomide is similar to the background rate of such events in patients with multiple myeloma not receiving treatment with this agent [18-21]. As such, VTE prophylaxis is generally reserved for patients taking single agent thalidomide that also have two or more individual or myeloma-related risk factors [22-24]. (See ‘Risk stratification’ below.)

Thalidomide plus dexamethasone — The reported frequency of thrombotic events has been as high as 26 percent when thalidomide is used in combination with high-dose dexamethasone (thal/dex) [14].

 

  • One study reported six thromboembolic events, one of which was fatal, among 40 previously untreated patients (15 percent) receiving treatment with thal/dex [17]. The same group reported a DVT rate of 8 percent in 28 patients receiving the same treatment for relapsed myeloma [25].
  • A second study observed thrombotic complications in 6 of 50 patients with newly diagnosed myeloma (12 percent) treated with thal/dex [26].
  • Results of a large Eastern Cooperative Oncology Group randomized trial are consistent with the above findings [27]. Among 102 patients treated with thal/dex, there were 17 episodes of deep vein thrombosis (17 percent), compared with three such episodes in the 102 patients (3 percent) receiving dexamethasone alone.
  • In another study, 43 previously untreated patients with myeloma received two to three courses of doxorubicin plus dexamethasone (dox/dex), followed by two months of treatment with thalidomide and dexamethasone (thal/dex) [28]. All patients received thromboprophylaxis with 81 mg of aspirin/day PO. There were five episodes of VTE documented among 42 evaluable patients, three during initial treatment with dox/dex, and two during the subsequent treatment with thal/dex.

 

Thalidomide plus melphalan and prednisone — Adding thalidomide to melphalan and prednisone (MPT) in patients with multiple myeloma results in a risk of thrombosis of up to 20 percent in those not receiving thromboprophylaxis [14].

 

  • An interim analysis of a randomized French study with 200 accrued patients observed a higher rate of DVT with MPT treatment (9 percent), compared with 6 percent with MP alone, and 3.5 percent with high-dose IV melphalan [29].
  • In another French study of similar design in patients 75 years of age or older, the incidence of VTE in the MP (3 percent) and MPT (6 percent) arms was not statistically different. Thromboprophylaxis was not pre-specified, but the authors note that heightened vigilance due to prior trial experience led to greater thromboprophylaxis usage [30].
  • A third phase III study reported a 20 percent incidence of DVT in 65 patients randomly assigned to treatment with MPT and no thromboprophylaxis [31]. In the 126 patients receiving MP and no thromboprophylaxis, the incidence of VTE was 1.6 percent (see ‘Low molecular weight heparin’ below).
  • In a trial adding a lower dose of thalidomide (100 to 200 mg/day) to pulses of oral cyclophosphamide and dexamethasone, only 2 of 62 patients (3 percent) developed DVT [32].

 

Taken together, the results of these trials suggest that the risk of thrombosis during treatment with the combination of thalidomide, steroids, and an alkylating agent (melphalan) is similar to that seen following the use of thalidomide and steroids alone.

Thalidomide plus anthracycline — Regimens utilizing thalidomide in combination with cytotoxic chemotherapy appear to be associated with the highest risk of VTE [14]. This is particularly true when thalidomide is used in combination with an anthracycline [33-38]:

 

  • One study treated 31 newly diagnosed patients with myeloma with the combination of thalidomide (400 mg/day) plus vincristine, epirubicin, and dexamethasone [33]. Eight of 31 patients (26 percent) experienced VTE. The authors postulated that the relatively high dose of thalidomide may have accounted for part of the excess risk, since, in a separate report, only 4 of 39 patients (10 percent) treated with vincristine, adriamycin, and dexamethasone (VAD) plus a lower dose of thalidomide (200 mg/day) experienced DVT [34].
  • In another report, 100 patients with myeloma underwent four cycles of induction chemotherapy with or without thalidomide (400 mg daily). Cycles one (VAD) and three (cyclophosphamide, adriamycin, dexamethasone) included adriamycin, whereas cycles two and four consisted of dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP). Fourteen of 50 patients (28 percent) randomly assigned to receive thalidomide had thrombotic complications compared with only 2 of 50 (4 percent) receiving chemotherapy alone [35].
  • Another study compared the frequency of VTE among 40 patients receiving thalidomide plus DCEP (“T-DCEP”) and 192 patients treated with “DT-PACE,” a regimen similar to T-DCEP except for the addition of adriamycin [36]. Thrombosis occurred in 2.5 percent (1 of 40) and 16 percent (31 of 192) in the T-DCEP and DT-PACE groups, respectively. Although this was not a randomized trial, it provides compelling evidence that the inclusion of anthracyclines may have more of an impact on risk of thrombosis than the thalidomide dose, which was 400 mg/day in each regimen.
  • A study of 19 patients treated with thalidomide plus DVd (pegylated liposomal doxorubicin, vincristine, dexamethasone) and no thrombosis prophylaxis reported VTE in 11 of 19 patients (58 percent) [37].
  • In a study employing lower dose thalidomide (100 mg/day), dexamethasone, and pegylated liposomal doxorubicin, the incidence of VTE was 14 percent despite the use of low-dose warfarin prophylaxis (1.25 mg/day) [39]. (See “Initial chemotherapy for symptomatic multiple myeloma in patients who are candidates for transplantation”, section on ‘Thalidomide with or without dexamethasone’.)

 

Thalidomide analogues — An increased risk of thrombosis has also been seen when thalidomide analogues, such as lenalidomide and pomalidomide, are used in combination with steroids. The thrombogenic potential of these agents is less well-defined than that of thalidomide.

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Lenalidomide — As with thalidomide, the risk of venous thromboembolism (VTE) among patients with multiple myeloma taking single-agent lenalidomide does not appear to be increased over that of patients with myeloma not taking lenalidomide. In contrast, the use of lenalidomide in combination with high-dose glucocorticoids is associated with an at least threefold increased risk of clotting events [12,14]. While VTE is the most common form of thrombosis in this population, arterial thrombotic events have also been reported [40].

 

  • No increased risk of clotting events was apparent in phase I and II studies of lenalidomide as monotherapy for multiple myeloma [41,42] or myelodysplastic syndrome [43]. Similarly, in a post-marketing study of the use of lenalidomide in 7764 patients with myelodysplasia, VTE was reported in 0.53 percent during the first two years of treatment [44].
  • Two large randomized phase III studies (MM-009 and MM-010) compared lenalidomide (25 mg/day PO on days 1 through 21 of a 28-day cycle) plus dexamethasone (40 mg/day PO on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles then on days 1 to 4 only for subsequent cycles) versus dexamethasone plus placebo in a total of 704 patients with relapsed or refractory multiple myeloma [45,46]. Both studies were stopped by their data safety monitoring boards due to significantly better response rates and time to progression with lenalidomide plus dexamethasone compared with dexamethasone alone. However, the lenalidomide plus dexamethasone group had significantly higher rate of VTE (approximately 11 versus 4 percent).
  • In a multivariate analysis of MM-009 and MM-010, the odds ratio for development of VTE in patients receiving lenalidomide plus dexamethasone (versus those receiving placebo plus dexamethasone) was 3.5 (95% CI 1.8-7.0) [47]. Concomitant use of recombinant human erythropoietin was also an independent contributor to the risk of development of VTE (odds ratio 3.2; 95% CI 1.7-6.0).
  • A Southwest Oncology Group (SWOG) study comparing lenalidomide plus high-dose dexamethasone to dexamethasone alone found a significantly increased risk of VTE when lenalidomide was given with high-dose dexamethasone (23.5 versus 5 percent) [48].

 

The risk of VTE appears to be at least partially associated with the dose of dexamethasone that is combined with lenalidomide therapy:

 

  • An Eastern Cooperative Oncology Group (ECOG) randomized trial of lenalidomide plus either high-dose or reduced-dose dexamethasone for newly-diagnosed multiple myeloma patients was temporarily halted because of an increased incidence of VTE in the absence of routine thromboprophylaxis with rates of VTE of 18 and 3.7 percent in patients receiving high-dose and low-dose dexamethasone, respectively [47].
  • A randomized trial in 445 patients with newly diagnosed myeloma found a significantly lower rate of VTE with the use of lenalidomide plus a lower dose of dexamethasone (40 mg PO on days 1, 8, 15, and 22 of each 28-day cycle) compared with lenalidomide plus the standard high-dose dexamethasone (40 mg days 1 to 4, 9 to 12, 17 to 20 every 28 days) of 12 versus 26 percent, respectively [49].

 

The use of VTE prophylaxis can decrease the risk of thrombotic disease among patients receiving lenalidomide plus dexamethasone. As an example, an expanded access program of lenalidomide plus dexamethasone in 1438 patients with relapsed myeloma that recommended VTE prophylaxis for all enrollees reported VTE in 3 percent [40]. Similarly, a study of lenalidomide and dexamethasone plus bortezomib in patients with newly diagnosed multiple myeloma that required VTE prophylaxis with at least aspirin reported an incidence of VTE of 6 percent [50].

Pomalidomide — There is a paucity of data regarding the risk of venous thromboembolism (VTE) among patients with multiple myeloma treated with the thalidomide-analog pamalidomide (CC-4047). In a phase I study of pomalidomide involving 24 patients with relapsed/refractory multiple myeloma, four patients (17 percent) developed VTE [51]. One clot occurred three weeks into therapy in the lower extremity of a patient subsequently recognized as having malignant melanoma-associated adenopathy, whereas the others occurred after four, nine, and 11 months of pamalidomide therapy. In a study conducted at the Mayo Clinic, only one of 60 patients treated with pomalidomide plus dexamethasone developed VTE [52].

VENOUS THROMBOEMBOLISM PROPHYLAXIS

Choice of agent — As described above, patients with multiple myeloma treated with thalidomide or lenalidomide in combination with other agents (eg, glucocorticoids, doxorubicin, or erythropoietin) have a rate of venous thromboembolism (VTE) greater than 20 percent. In comparison, the rate of VTE decreases to less than 10 percent when VTE prophylaxis is administered. As a result, we recommend the routine use of VTE prophylaxis for patients with multiple myeloma who are treated with a combination therapy regimen that contains thalidomide or lenalidomide. (See ‘Thalidomide-based therapy’ above.)

There are no randomized trials comparing thalidomide or lenalidomide treatment with or without VTE prophylaxis; most of the data consist of comparisons of single arm trials with historical controls in which prophylaxis was not used. Numerous variables can influence such nonrandomized studies. As an example, the incidence of thrombosis in myeloma is higher during treatment of newly diagnosed disease compared with relapsed or refractory disease. Other risk factors have been identified, such as the use of recombinant human erythropoietin and high doses of corticosteroids [47,49,53]. In addition, the incidence of VTE is almost certainly affected by the degree of physician vigilance in identifying such events (eg, mandatory ultrasound monitoring versus clinical observation alone).

Despite the above caveats, the incidence of thrombotic complications appears to be reduced in patients receiving combination therapy that contains thalidomide or lenalidomide, using one of the following three strategies [54]:

 

  • Warfarin, either fixed dose or full dose with a target INR of 2.0 to 3.0
  • Therapeutic or prophylactic dose of low molecular weight heparin
  • Aspirin (81 to 325 mg/day)

 

A choice among these strategies is based upon the baseline risk of VTE associated with a given regimen and patient population. Given the potential for gastric irritation with or without thrombocytopenia, we suggest concurrent use of either an H2-blocker or a proton pump inhibitor when lenalidomide or thalidomide is used in combination with aspirin, corticosteroids, and/or chemotherapy.

Risk stratification — The decision to give one of the above drugs and the choice of drug for thromboprophylaxis needs to consider the baseline risk of VTE associated with a given regimen and the presence or absence of risk factors for thromboembolism. Our approach is similar to that proposed by the International Myeloma Working Group [14].

Patients should be assessed for the following risk factors:

 

  • Body mass index ≥30 kg/m2 (calculator 1)
  • Previous VTE
  • Central venous catheter or pacemaker
  • Cardiac disease (eg, symptomatic coronary artery disease, congestive heart failure, or history of stent placement/CABG)
  • Chronic kidney disease (eg, estimated glomerular filtration rate less than 30 mL/min)
  • Diabetes mellitus
  • Acute infection
  • Immobilization
  • Use of erythropoietin
  • Inherited thrombophilia

 

Using these risk factors, patients can be divided into three categories:

 

  • Patients receiving either thalidomide or a thalidomide analogue as a single agent are at lower risk for VTE and do not require VTE prophylaxis. (See ‘Single agent thalidomide’ above and ‘Lenalidomide’ above.)
  • Patients with no or one VTE risk factor who are not being treated with doxorubicin, multiagent chemotherapy, or high-dose dexamethasone are considered to be at standard risk for VTE and should receive VTE prophylaxis. (See ‘Standard risk setting’ below.)
  • Patients with two or more risk factors and any patients being treated with doxorubicin, multiagent chemotherapy, or high-dose dexamethasone (≥480 mg per month) are considered at higher risk for VTE and require VTE prophylaxis. (See ‘High risk setting’ below.)

 

Specific recommendations for the prevention of VTE in cancer patients who are hospitalized or are undergoing surgery are discussed separately. (See “Prevention of venous thromboembolic disease in medical patients”, section on ‘VTE prevention in medical patients’ and “Prevention of venous thromboembolic disease in surgical patients”.)

Lower risk setting — The incidence of thrombosis in patients at lower risk, defined as those treated with single agent thalidomide or lenalidomide, is approximately 1 to 5 percent, which is similar to the background rate of VTE in patients with multiple myeloma not receiving treatment with one of these agents [18-21]. Thus, in the absence of other indications for VTE prophylaxis, patients taking single agent thalidomide or lenalidomide do not require VTE prophylaxis [14].

Standard risk setting — Patients with no or one VTE risk factor who are not receiving high-dose dexamethasone, doxorubicin, or multiagent chemotherapy are considered to be at standard risk for VTE. In such patients, we suggest VTE prophylaxis with aspirin rather than warfarin or prophylactic dose low molecular weight heparin (LMWH). This preference is largely based upon the lower cost and ease of administration of aspirin and a randomized trial that demonstrated similar rates of serious thromboembolic events with each of these agents, as described below.

An open-label phase III trial included 667 patients with previously untreated myeloma who received thalidomide-containing induction therapy and had no clinical indication or contraindication to specific antiplatelet or anticoagulant therapy; the patients were randomly assigned to aspirin (100 mg daily), fixed low-dose warfarin (1.25 mg daily), or LMWH (enoxaparin 40 mg once daily) [55]. The following findings were noted:

 

  • The rate of a composite endpoint of serious thromboembolic events (symptomatic DVT, pulmonary embolism, or arterial thrombosis), acute cardiovascular events (myocardial infarction or stroke), and sudden death during the first six months of therapy was not significantly different in the three groups (6.4, 8.2, and 5.0 percent, respectively). The lack of statistical significance means that the trial was not powered to detect a difference as large as 3.2 percent.
  • There was no statistically or clinically significant difference in adverse events. Major bleeding occurred during the first six months in three patients who received aspirin, but in no patients who received warfarin or LMWH. Minor bleeding occurred in 2.7, 0.5, and 1.4 percent of patients, respectively.
  • The rate of serious thromboembolic events was lower with aspirin and low-dose warfarin than rates reported with these agents in other trials. In comparison, the rate of thromboembolism with LMWH was similar to that reported in other trials.

 

This trial suggests that low, fixed-dose warfarin, prophylactic dose LMWH, and low-dose aspirin are all acceptable choices of VTE prophylaxis in standard risk patients. All three options lowered the incidence of VTE to less than 10 percent compared with an expected rate of more than 20 percent. It is unknown how these regimens would compare with VTE prophylaxis with therapeutic adjusted-dose warfarin (INR 2.0 to 3.0) or therapeutic dose LMWH. Of importance, the trial excluded patients thought to be at higher risk of thromboembolic events due to a history of VTE, severe cardiac disease, immobilization, uncontrolled diabetes, recent surgery, or ongoing infections. Such patients should be considered for more intensive VTE prophylaxis. (See ‘Thalidomide-based therapy’ above.)

High risk setting — Patients with two or more risk factors and any patients receiving high-dose dexamethasone (≥480 mg per month), doxorubicin, or multiagent chemotherapy are considered at higher risk of VTE. The ideal agent for VTE prophylaxis in this setting is unknown and clinical practice varies widely. For patients at higher risk of VTE treated with thalidomide- or lenalidomide-containing therapy, we suggest the use of prophylactic dose of low molecular weight heparin (LMWH) or therapeutic anticoagulation with either LMWH or adjusted-dose warfarin with a target INR of 2.0 to 3.0 rather than aspirin. This preference is largely based upon the data suggesting efficacy of full dose warfarin and LMWH and the uncertainty of the efficacy of aspirin in this setting. The choice of prophylactic LMWH versus full anticoagulation in this setting may be based in part on the patient’s risk for bleeding complications (see ‘Patients at high risk of bleeding’ below).

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The choice between LMWH and warfarin is made based upon the clinical circumstances. As an example, LMWH may be preferred in patients who are likely to develop thrombocytopenia (such as those receiving chemotherapy) because of its short half-life and suggested lower risk of secondary bleeding. In contrast, warfarin might be preferred in patients with an estimated glomerular filtration rate below 30 mL/min. If LMWH is given, dose reduction is suggested. (See “Enoxaparin: Drug information”.)

There have been no randomized trials comparing VTE prophylaxis strategies in this higher risk population. Single-arm studies suggest that the use of either full-dose warfarin or prophylactic dose LMWH reduces the incidence of VTE associated with thalidomide or lenalidomide therapy. Data on the efficacy of aspirin in this setting have been mixed.

Warfarin — Full-dose warfarin, with a target INR of 2.0 to 3.0, may be used for VTE prophylaxis in high-risk patients with multiple myeloma being treated with thalidomide or lenalidomide combinations. The potential benefit of full-intensity anticoagulation with warfarin, in comparison to a fixed low-dose warfarin, is suggested by the following studies:

 

  • In one study, VTE prophylaxis with a fixed, low dose of warfarin (1 mg/day) was inadequate to prevent VTE in patients undergoing myeloma induction therapy with chemotherapy plus thalidomide (400 mg/day) [18]. Eleven of 35 patients (31 percent) treated in this fashion developed VTE. In an update of the experience from this center, the incidence of VTE among 162 patients receiving low-dose warfarin as prophylaxis during combined chemotherapy and thalidomide induction therapy was 34 percent [56].
  • In a second report, prophylaxis with low-dose warfarin (1 mg/day) was not effective in preventing VTE in myeloma patients being treated with thalidomide plus dexamethasone [17]. Six of 24 patients given low-dose warfarin developed VTE (25 percent), compared with none of 16 patients treated with full dose warfarin (target INR 2.0 to 3.0) or low molecular weight heparin.
  • In a retrospective review in 131 patients treated with thalidomide, VTE was noted in 18 of 76 patients (24 percent) not receiving anticoagulation and 3 of 55 patients (5 percent) receiving either low-dose warfarin (1 of 37, 3 percent) or conventional-dose warfarin (2 of 18, 11 percent) [22]. The effectiveness of low-dose warfarin in this report may be explained by the lower mean/median dose of thalidomide (200 mg/day) used in these patients, although there are no data clearly demonstrating a dose-effect relationship for thalidomide and thrombosis risk.

 

In summary, full dose prophylactic anticoagulation with warfarin appears effective in reducing the incidence of VTE associated with thalidomide or lenalidomide therapy, although only a small number of patients have been evaluated. More data are needed to determine the relative efficacies of low-dose versus full-dose warfarin prophylaxis.

Low molecular weight heparin — The use of prophylactic doses of the low molecular weight heparin (LMWH) enoxaparin (40 mg/day SQ) appears to reduce the frequency of thrombotic events in myeloma patients receiving immunomodulatory therapy with thalidomide or lenalidomide.

 

  • In the context of a randomized trial of more than 400 patients, the incidence of VTE among patients at high risk for VTE treated with a thalidomide containing regimen plus daily LMWH prophylaxis was not statistically different from that seen in patients treated with a chemotherapy regimen that did not contain thalidomide and who were not given VTE prophylaxis (9 versus 5 percent) [57].
  • In a randomized trial of melphalan and prednisone with or without thalidomide, the first 65 patients assigned to treatment with thalidomide did not receive prophylaxis and had an incidence of VTE of 20 percent [31]. Because of this high incidence, the next 64 patients received thromboprophylaxis with enoxaparin (40 mg/day SQ) for the first four cycles (months) of therapy, with an incidence of VTE of 3.1 percent (two patients). These two patients developed VTE within two months of discontinuation of enoxaparin.
  • In a randomized trial of high-dose melphalan with autologous hematopoietic cell rescue with or without thalidomide therapy, VTE was diagnosed in 34 percent of the initial 162 patients randomly assigned to receive thalidomide in the absence of VTE prophylaxis [56]. The subsequent 152 patients randomly assigned to thalidomide received prophylactic LMWH, but still demonstrated an incidence of VTE of 24 percent, a concerning rate of thrombosis. Therapeutic anticoagulation might be considered during induction therapy with the intensive, anthracycline-containing regimen used in this particular report.
  • A single institution retrospective study reported that only one in 45 patients with relapsed refractory myeloma treated with lenalidomide and dexamethasone given in conjunction with LMWH developed VTE [58].

 

Although the data are mixed, these results suggest that LMWH decreases the rate of VTE among the patients treated with thalidomide or lenalidomide-containing regimens to less than 10 percent.

Aspirin — Aspirin appears to be an acceptable form of VTE prophylaxis among patients with multiple myeloma at standard risk of developing VTE during treatment with thalidomide or lenalidomide-containing combination therapy. However, low dose aspirin has not been directly compared with warfarin or LMWH in the treatment of patients at high risk of developing VTE. (See ‘Standard risk setting’ above.)

Investigators at the Cleveland Clinic evaluated the effectiveness of low-dose aspirin (81 mg/day) in reducing the risk of thrombosis following the use of thalidomide [37]. In contrast to the high rate of VTE (58 percent) in myeloma patients treated with DVd (pegylated liposomal doxorubicin, vincristine, dexamethasone) plus thalidomide alone, only 15 of 84 patients (18 percent) treated with the same regimen plus 81 mg or aspirin daily developed DVT. While the risk of DVT using low-dose aspirin was lower in this non-randomized comparison (ie, 18 versus 58 percent), it was not completely protective against the development of thrombosis.

It is not clear whether the risk of thrombosis can be further reduced using a higher dose of aspirin (eg, 325 mg/day) or whether aspirin may be sufficient for patients receiving lenalidomide plus dexamethasone. Prospective studies of lenalidomide plus high-dose dexamethasone reported VTE rates in the range of 20 percent when aspirin was used as thromboprophylaxis during therapy regimens containing high-dose dexamethasone [48,59]. In contrast, in a report of a phase II trial of lenalidomide plus high-dose dexamethasone induction therapy in 34 patients with newly-diagnosed myeloma, there was one thrombotic event (3 percent) when 80 to 325 mg/day of aspirin (physicians’ discretion) was used as thrombosis prophylaxis [60].

Patients at high risk of bleeding — Patients who are at high risk of complications due to bleeding on anticoagulation may not be candidates for pharmacologic VTE prophylaxis. This includes patients with a known bleeding lesion, such as a peptic ulcer, or a recent intracranial hemorrhage. Mechanical methods of thromboprophylaxis, such as graduated compression stockings, intermittent pneumatic compression devices and the venous foot pump reduce stasis within the leg veins and reduce the frequency of VTE in other patient populations. Such methods may be considered for patients at standard or high risk of VTE who are also at high risk of complications from bleeding on anticoagulation. When used in all of these circumstances, it is recommended that consideration be given to the use of a pharmacologic agent, such as LMWH, as soon as the bleeding risk becomes acceptably low or when the bleeding lesion or bleeding risk has been reversed [61]. (See “Prevention of venous thromboembolic disease in medical patients”, section on ‘Mechanical methods of thromboprophylaxis’.)

Length of prophylaxis — It is not known whether VTE prophylaxis can be safely discontinued in patients receiving active therapy with thalidomide or lenalidomide-containing regimens. VTE prophylaxis is generally administered as long as active therapy is continued [14]. The risk of VTE appears to be greatest in the first 6 to 12 months of treatment. The risk appears to decrease after this and is lower among patients treated for relapsed disease than for patients with previously untreated myeloma.

DIAGNOSIS AN MANAGEMENT OF VENOUS THROMBOEMBOLISM — The diagnosis of VTE is suspected in patients who develop calf or thigh pain, unilateral edema, or swelling with a difference in calf diameters; warmth, tenderness, or erythema of the skin, and/or superficial venous dilation; a palpable cord; chest pain, shortness of breath, or tachycardia. The diagnosis of VTE is described in detail separately. (See “Diagnosis of suspected deep vein thrombosis of the lower extremity” and “Diagnosis of acute pulmonary embolism”.)

The management of VTE in patients with multiple myeloma is similar to the management of VTE in the general population. Therapeutic (full dose) anticoagulation is indicated for patients with VTE and should be started immediately. There have been no studies investigating whether thalidomide or lenalidomide should be temporarily held at the time of VTE diagnosis while therapeutic anticoagulation is being achieved. Given the prothrombotic effects of thalidomide and lenalidomide, we suggest holding these agents until therapeutic anticoagulation is achieved.

For patients with VTE, therapeutic anticoagulation should be continued for the total duration of thalidomide or lenalidomide therapy. If there have been no further VTE episodes while receiving thalidomide or lenalidomide plus therapeutic anticoagulation, we suggest that anticoagulation be stopped one month after these agents have been discontinued, provided that the patient has been receiving therapeutic anticoagulation for a minimum of three months. This differs somewhat from general recommendations related to the duration of anticoagulation for VTE in cancer patients, in which longer (or indefinite) anticoagulation is common. Since stoppage of the immunomodulatory drug modifies the overall VTE risk of the patient, we feel that indefinite anticoagulation should be considered only in myeloma patients who have recurrent VTE. (See “Treatment of lower extremity deep vein thrombosis”, section on ‘Length of treatment’.)

Patients who have developed a thalidomide- or lenalidomide-associated venous thromboembolism (VTE) and are receiving therapeutic anticoagulation, as well as patients who are receiving anticoagulation for other reasons (eg, atrial fibrillation, prior VTE), can be cautiously treated with thalidomide or lenalidomide, with an acceptable risk of subsequent episodes of VTE (approximately 10 percent).

SUMMARY AND RECOMMENDATIONS

 

  • Patients with multiple myeloma treated with thalidomide or a thalidomide analogue such as lenalidomide in combination with other agents (eg, glucocorticoids, doxorubicin, or erythropoietin) have a rate of venous thromboembolism (VTE) greater than 20 percent. (See ‘Thalidomide-based therapy’ above.)
  • For patients with multiple myeloma treated with a combination chemotherapy regimen that contains thalidomide or lenalidomide, we recommend the routine use of VTE prophylaxis (Grade 1B). VTE prophylaxis should be continued for as long as the patient is receiving treatment with thalidomide or lenalidomide.
  • The choice of thromboprophylaxis needs to consider the baseline risk of VTE associated with a given regimen and patient population. Our approach stratifies patients into one of three groups based upon 10 risk factors (body mass index ≥30 kg/m2, previous VTE, central venous catheter or pacemaker, cardiac disease, chronic renal disease, diabetes, acute infection, immobilization, use of erythropoietin, and inherited thrombophilia) (see ‘Risk stratification’ above):

 

 

  • Patients with two or more risk factors and any patients receiving high-dose dexamethasone (≥480 mg per month), doxorubicin, or multiagent chemotherapy are considered to be at higher risk for VTE. For patients at higher risk of VTE treated with thalidomide- or lenalidomide-containing therapy, we suggest the use of prophylactic dose low molecular weight heparin (LMWH) or therapeutic adjusted-dose warfarin with a target INR of 2.0 to 3.0 rather than aspirin. (See ‘High risk setting’ above.)
  • Patients with no or one risk factor who are not receiving high-dose dexamethasone, doxorubicin, or multiagent chemotherapy are considered to be at standard risk for VTE. For patients at standard risk for VTE, we suggest VTE prophylaxis with aspirin rather than warfarin or prophylactic dose LMWH (Grade 2B). (See ‘Standard risk setting’ above.)
  • Patients receiving either thalidomide or a thalidomide analogue as a single agent are at lower risk for VTE and do not require VTE prophylaxis. (See ‘Lower risk setting’ above.)
SEE MORE:  Treatment of venous thromboembolism in patients with malignancy

 

 

  • VTE prophylaxis is generally administered as long as combination therapy with thalidomide or lenalidomide is continued. (See ‘Length of prophylaxis’ above.)
  • The diagnosis and management of VTE in patients with multiple myeloma is similar to the diagnosis and management of VTE in the general population. (See “Diagnosis of suspected deep vein thrombosis of the lower extremity” and “Diagnosis of acute pulmonary embolism” and “Treatment of lower extremity deep vein thrombosis” and “Treatment of acute pulmonary embolism”.)
  • For patients who develop VTE and continue treatment with thalidomide or lenalidomide, we suggest that therapeutic anticoagulation continue for the duration of their treatment with these agents (Grade 2C). If there have been no further VTE episodes while receiving thalidomide or lenalidomide plus therapeutic anticoagulation, we suggest that anticoagulation be stopped one month after these agents have been discontinued, provided that the patient has been receiving therapeutic anticoagulation for a minimum of three months and has no other indication for anticoagulation (Grade 2C). (See ‘Diagnosis an management of venous thromboembolism’ above.)
  • Given the potential for gastric irritation with or without thrombocytopenia, we suggest concurrent use of either an H2-blocker or a proton pump inhibitor when lenalidomide or thalidomide is used in combination with aspirin, corticosteroids, and/or chemotherapy.

 

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