INTRODUCTION — The association between cancer and venous thromboembolic events 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 "Risk and prevention of venous thromboembolism in adults with cancer" and "Cancer-associated hypercoagulable state: Causes and mechanisms".)
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 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 an immunomodulatory drug (IMiD) such as thalidomide, lenalidomide, or pomalidomide.
The thrombotic risk associated with the use of IMiDs and prophylactic strategies to minimize this risk will be discussed here. Thrombotic risk following the use of other antineoplastics (eg, tamoxifen, L-asparaginase) and issues related to the treatment of VTE are presented separately.
●(See "Cancer-associated hypercoagulable state: Causes and mechanisms".)
●(See "Cancer-associated hypercoagulable state: Causes and mechanisms".)
●(See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)
●(See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)
POTENTIAL MECHANISMS — While the exact mechanism by which IMiDs contribute to thrombosis in patients with MM is not known, the following mechanisms have been postulated:
●Serum levels of the anticoagulant pathway cofactor thrombomodulin transiently decrease during the first month of thalidomide therapy, with gradual recovery over the following two months [1]. 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 [2]. 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' 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 [3,4]. In one of these reports, the risk of VTE was highest in those patients with both APC resistance and treatment with thalidomide [3]. However, other investigators have not been able to confirm this observation [1,5].
●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 [6]. (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 [7-9].
●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 [10]. Cathepsin G, a platelet function agonist, may contribute to risk of VTE.
INCIDENCE AND RISK FACTORS
General risk factors — Patients with MM are at increased risk of having comorbidities known to be risk factors for the development of 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. The impact of these risk factors in the general population is discussed in more detail separately. (See "Overview of the causes of venous thrombosis".)
Other risk factors for VTE include obesity (body mass index ≥30 kg/m2), previous VTE, pacemaker placement, cardiac disease, hormone therapy, and inherited thrombophilias. Observational studies have also suggested an increased risk of thrombosis among patients with MM who have elevated levels of D-dimer and prothrombin fragments 1 and 2 [11,12].
Lenalidomide in myeloma — The risk of VTE among patients with MM taking lenalidomide varies depending on many factors, the most important of which are whether it is given as a single-agent or in combination, and whether it is being given as induction therapy (high burden of disease) or maintenance (low burden of disease). While VTE is the most common form of thrombosis in this population, arterial thrombotic events have also been reported [13].
Single agent lenalidomide — VTE risk in patients with MM taking single-agent lenalidomide does not appear to be increased over that of patients with MM not taking lenalidomide. No increased risk of clotting events was apparent in phase I and II studies of lenalidomide as monotherapy for MM [14,15]. Randomized trials of lenalidomide maintenance after transplant that included data from >1000 patients have reported VTE rates up to 6 percent without prophylaxis and <1 percent with a risk-adapted approach to prophylaxis [16,17]. (See 'Patients receiving single-agent IMiD as maintenance' below.)
Lenalidomide plus dexamethasone — The use of lenalidomide in combination with high dose glucocorticoids is associated with an at least threefold increased risk of clotting events [18-20]. The risk of VTE appears to be considerably lower when lenalidomide is combined with low dose glucocorticoids. (See 'Risk stratification' below.)
In several randomized trials, the incidence of VTE among those treated with lenalidomide plus high dose dexamethasone (RD) was at least threefold higher than that seen with dexamethasone alone [21-24]. As an example, in a multivariate analysis of MM-009 and MM-010, the odds ratio for development of VTE in patients receiving RD (versus those receiving placebo plus dexamethasone) was 3.5 (95% CI 1.8-7.0) [23]. 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).
The risk of VTE appears to be at least partially associated with the dose of dexamethasone that is combined with lenalidomide therapy. This was illustrated in a phase 3 trial (ECOG E4A03) in which 445 patients with previously untreated MM receiving RD were randomly assigned to higher dose dexamethasone (40 mg/day by mouth on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle) versus lower dose dexamethasone (40 mg by mouth on days 1, 8, 15, and 22 of each cycle) [25]. The trial was stopped prematurely by the data safety monitoring committee because mortality was increased in the higher dose dexamethasone arm. VTE rates were higher in those assigned to higher dose dexamethasone (26 versus 12 percent).
The use of VTE prophylaxis can decrease the risk of thrombotic disease among patients receiving lenalidomide plus dexamethasone. This issue was addressed in a meta-analysis that included data from more than 9000 patients on clinical trials who received lenalidomide-based treatment regimens that did not contain high dose dexamethasone [26]. The pooled rate of VTE was 1.2 VTE events per 100 patient cycles (95% CI 0.9-1.7 VTE events per 100 patient cycles), which corresponds to one month of lenalidomide. The rate differed by regimen and was:
●Lowest with single-agent lenalidomide maintenance (0.0, 95% CI 0.0-0.7 events per 100 patient cycles)
●Low with lenalidomide and low dose dexamethasone (0.2, 95% CI 0.1-0.6 events per 100 patient cycles)
●Higher with lenalidomide, low dose dexamethasone, and a proteasome inhibitor (>80 percent of patients received carfilzomib or ixazomib) (1.3, 95% CI 0.7-2.3 events per 100 patient cycles)
The lowest incidence of VTE was amongst patients who had already completed induction therapy and presumably had better disease control than patients receiving combination therapy. In another report, 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 [13].
Lenalidomide plus dexamethasone and a proteasome inhibitor — The risk of VTE in patients treated with lenalidomide, dexamethasone, and a proteasome inhibitor may be increased compared with lenalidomide plus dexamethasone alone, and this risk likely differs depending upon the proteasome inhibitor used.
In the meta-analysis described above, the addition of a proteasome inhibitor increased the rate of VTE events from 0.2 events per 100 patient cycles to 1.3 events per 100 patient cycles [26]. However, the proteasome inhibitor used in >80 percent of patients in this meta-analysis was carfilzomib or ixazomib. In contrast, bortezomib does not appear to be prothrombotic.
●Bortezomib, lenalidomide, and dexamethasone (VRd) – Randomized trials evaluating the addition of bortezomib to lenalidomide plus dexamethasone or thalidomide plus dexamethasone did not demonstrate an increase in VTE rates over that seen with the doublets alone [27,28].
●Carfilzomib, lenalidomide, and dexamethasone (KRd) – Randomized trials have reported increased VTE rates when carfilzomib was added to lenalidomide plus dexamethasone (13 versus 6 percent in ASPIRE [29]) and higher VTE rates with carfilzomib plus dexamethasone when compared with bortezomib plus dexamethasone (9 versus 2 percent in ENDEAVOR [30]). A retrospective study reported VTE rates with KRd plus aspirin (16.1 percent); VRd plus aspirin (4.8 percent); and KRd plus rivaroxaban (4.8 percent) suggesting that KRd is more prothrombotic than VRd and that more intensive prophylaxis with rivaroxaban may be able to counteract this increased VTE rate [31].
Lenalidomide in other conditions — Prospective studies have also suggested an increased risk of thrombosis when lenalidomide is used in patients with some neoplasms other than MM. As examples:
●Non-Hodgkin lymphoma (NHL) – In a phase 2 trial, thromboses developed in 5 of 110 patients with relapsed low grade NHL who were treated with lenalidomide plus rituximab [32]. No information was provided regarding thrombosis prophylaxis among the patients who developed clots on this trial.
In a randomized trial comparing lenalidomide versus lenalidomide plus rituximab in 91 patients with follicular NHL, 9 patients developed a grade 3 or 4 thrombosis [33]. This trial recommended but did not require thrombosis prophylaxis, but the incidence of clots developing in patients receiving aspirin prophylaxis appeared similar to that in patients who did not get prophylaxis.
●AL amyloidosis – In a large retrospective analysis of approximately 900 patients with AL amyloidosis who received various therapies at one large referral center, the overall incidence of VTE was 7 percent [34]. Most VTEs occurred within one year from diagnosis of AL amyloidosis, and the incidence related to IMiD-based therapy seemed similar to that documented during other therapies such as autologous hematopoietic cell transplant. No specific information is provided regarding VTE prophylaxis during IMiD therapy. The authors cite low serum albumin levels, usually in association with nephrotic-range proteinuria as the main identified risk factor for developing VTE.
Smaller nonrandomized trials do little to clarify the actual VTE risk in this population. As an example, long-term follow-up of two small trials of lenalidomide, cyclophosphamide, and dexamethasone-like regimens for AL amyloidosis reported VTE incidence rates of 5 and 10 percent [35,36]. All patients in both trials received at least daily aspirin as VTE prophylaxis.
●Myelodysplastic syndrome – No increased risk of clotting events was apparent in a phase I study of lenalidomide as monotherapy for myelodysplastic syndrome (MDS) [37]. In a three-arm phase 3 trial comparing two doses of lenalidomide versus placebo in 205 patients with MDS, grade 3 or 4 VTE occurred in 5 patients (3.6 percent) treated with lenalidomide and 1 patient (1.5 percent) treated with placebo [38]. No information was provided regarding thrombosis prophylaxis among the patients who developed clots on this trial. 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 [39]. MDS is frequently associated with thrombocytopenia, which may complicate the administration of VTE prophylaxis.
●Ovarian cancer – In a phase 2 trial of 45 patients with ovarian cancer treated with lenalidomide, five (11 percent) developed DVTs [40]. All five were among the 30 patients who did not receive any thrombosis prophylaxis as part of their therapy.
Pomalidomide — There are relatively fewer data regarding the risk of VTE among patients treated with pomalidomide.
Without prophylaxis, the rate of VTE is high. In a phase I study of single-agent pomalidomide in 24 patients with relapsed or refractory MM, no prophylaxis was administered and four patients (17 percent) developed VTE [41]. 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 4, 9, and 11 months of pomalidomide therapy.
Subsequent trials investigating the use of pomalidomide plus low dose dexamethasone (Pd) have routinely included thromboprophylaxis with aspirin or other agents [42-46]. Rates of VTE in these trials have been approximately 3 percent.
In a randomized phase II trial of 34 patients with relapsed MM, the VTE rate was higher with pomalidomide, dexamethasone, and cyclophosphamide than with Pd alone (6 versus 0 percent) [47]. All patients were on at least 81 mg of aspirin daily as thromboprophylaxis.
A phase I/II trial of Pd in patients with AL amyloidosis revealed no incidents of VTE amongst 27 patients on aspirin thromboprophylaxis (325 mg/day) [48].
Thalidomide — The risk of VTE among patients with MM taking single-agent thalidomide does not appear to be increased over that of patients with MM not taking thalidomide. In contrast, the risk of VTE increases substantially when thalidomide is administered in conjunction with glucocorticoids or other agents (eg, doxorubicin, erythropoietin) [18]. While the majority of thrombotic events described in patients treated with thalidomide have been venous, arterial thrombotic events have also been reported [49].
●Single-agent thalidomide – 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 MM not receiving treatment with this agent [19,50-56].
●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 (TD) [19,52,57-60]. As an example, in one randomized trial, deep vein thrombosis (DVT) occurred in 17 of 102 patients (17 percent) treated with TD, versus 3 of 102 patients (3 percent) treated with dexamethasone alone [59].
●Thalidomide, steroid, plus an alkylating agent – The risk of VTE during treatment with the combination of thalidomide, steroids, and an alkylating agent (melphalan, cyclophosphamide) is similar to that seen following the use of thalidomide and steroids alone [19,61-65].
●Thalidomide, steroid, plus an anthracycline – Regimens utilizing thalidomide in combination with an anthracycline appear to be associated with the highest risk of VTE [19,66-71]. As an example, one study of thalidomide, pegylated liposomal doxorubicin, vincristine, and dexamethasone reported VTE in 11 of 19 patients (58 percent) not receiving prophylaxis [70].
VTE PROPHYLAXIS
Length of prophylaxis — It is not known whether VTE prophylaxis can be safely discontinued in patients receiving prolonged therapy with IMiD-containing regimens. VTE prophylaxis is generally administered as long as active therapy is continued [19]. 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 MM.
Choice of prophylaxis
Patients receiving single-agent IMiD as maintenance — For patients with MM receiving an IMiD (thalidomide, lenalidomide, or pomalidomide) as a single agent for maintenance therapy, we suggest low dose aspirin prophylaxis (ie, 81 to 100 mg daily) rather than no prophylaxis or the use of other agents (algorithm 1). In our practice, almost all patients are able to tolerate low dose aspirin when administered with appropriate gastrointestinal prophylaxis (eg, an H2-blocker or a proton pump inhibitor). (See 'Aspirin' below.)
Our approach is different from that presented in a 2008 IMWG guideline on the prevention of thalidomide- and lenalidomide-associated thrombosis in MM, which allows for the omission of VTE prophylaxis in this population if the risks of daily aspirin are felt to outweigh the small absolute reduction in expected risk of thrombosis [19]. Our preference for aspirin places a higher value on a potentially small absolute decrease in the rate of VTE and less concern about the potential for aspirin-related toxicity. There is uncertainty regarding the safety of aspirin omission since VTE prophylaxis has been incorporated into most modern trials containing IMiDs, including all trials of pomalidomide.
These patients are at lower risk for VTE than patients receiving combination therapy for active MM, and the absolute benefit from prophylaxis is likely to be smaller. Estimates suggest the rate of thrombosis in this population is similar to the background rate of VTE in patients with MM not receiving treatment with one of these agents (1 to 5 percent) [53-56]. In the meta-analysis discussed above, patients who were taking single-agent lenalidomide maintenance had low estimated rates of VTE (0.0 VTE events per 100 patient cycles, 95% CI 0.0-0.7) [26]. VTE prophylaxis was unspecified in this study but given to the majority of patients.
Patients receiving combination therapy — For patients with MM who are treated with a combination therapy regimen that contains an IMiD, we recommend the routine use of VTE prophylaxis (algorithm 1). Our approach is generally consistent with recommendations from the International Myeloma Working Group (IMWG), the National Comprehensive Cancer Network, the International Initiative on Thrombosis and Cancer, the American Society of Hematology, and the American Society of Clinical Oncology [19,72-76].
As described above, patients with MM treated with IMiDs in combination with other agents (eg, glucocorticoids, doxorubicin, or erythropoietin) have a rate of VTE greater than 20 percent. In comparison, the rate of VTE decreases to less than 10 percent when VTE prophylaxis is administered.
There are no randomized trials comparing 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 examples [11,20,23,25,77]:
●The incidence of thrombosis in MM is higher during treatment of newly diagnosed disease compared with relapsed or refractory disease. The meta-analysis discussed above supports this point in that the lowest incidence of VTE was amongst patients who had already completed induction therapy and presumably had better disease control than patients receiving either lenalidomide plus dexamethasone or bortezomib, lenalidomide, and dexamethasone [26]. (See 'Lenalidomide in myeloma' above.)
●The risk of thrombosis is also influenced by other medications administered; the risk is higher when IMiDs are combined with higher doses of corticosteroids [20,25]. Some, but not all, analyses have also suggested an increased thrombosis risk in patients receiving recombinant human erythropoietin in addition to IMiDs [11,20,23,77].
●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).
Risk stratification — For patients with MM who are treated with a combination therapy regimen that contains an IMiD, the choice of thromboprophylaxis is dependent upon the baseline risk of VTE associated with a given regimen and the presence or absence of risk factors for thromboembolism (algorithm 1). Our approach is similar to that proposed by the IMWG [19].
Any patient treated with an anthracycline-containing chemotherapy regimen, or high dose dexamethasone (≥480 mg per month) is considered to be at high risk for VTE. In contrast, in the absence of other risk factors, we consider patients receiving combinations of IMiDs and proteosome inhibitors to be at standard risk for VTE. (See 'High risk' below.)
In addition, any patient with two or more of the following risk factors are considered to be at high risk for VTE:
●Previous VTE
●Known inherited thrombophilia
●Central venous catheter or pacemaker
●Cardiac disease (eg, symptomatic coronary artery disease, congestive heart failure, or history of stent placement/coronary artery bypass graft surgery [CABG])
●Diabetes mellitus
●Acute infection
●Immobilization
●Use of erythropoietin
●Obesity (body mass index ≥30 kg/m2) (calculator 1)
●Chronic kidney disease (eg, estimated glomerular filtration rate <30 mL/min)
●Elevated D-dimer levels
While this risk stratification schema weighs each of these factors equally, their expected impact on VTE likely differs. As examples, prior VTE and known inherited thrombophilia are stronger risk factors for VTE than obesity and chronic kidney disease. With these caveats, we apply this stratification loosely in our practices. We do not routinely measure D-dimer for the purpose of risk stratification. Patients may shift from one group to another if complications arise or treatment is de-escalated.
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 adult nonorthopedic surgical patients" and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Selection of method of prophylaxis'.)
Standard risk — Patients with no or one VTE risk factor who are being treated with combination therapy that does not include high dose dexamethasone (≥480 mg per month), doxorubicin, or multiagent chemotherapy are considered to be at standard risk for VTE. For example, a patient without risk factors being treated with lenalidomide, bortezomib, and weekly dexamethasone would be considered "standard risk." In such patients, we suggest VTE prophylaxis with low dose aspirin (100 mg daily) rather than warfarin or prophylactic dose low molecular weight heparin (LMWH) (algorithm 1). (See 'Aspirin' below.)
This preference is largely based upon the lower cost and ease of administration of aspirin and the following randomized trials that demonstrated similar rates of serious thromboembolic events with each of these agents:
An open-label phase III trial that included 667 patients with previously untreated MM who received thalidomide-containing induction therapy and had no clinical indication or contraindication to specific antiplatelet or anticoagulant therapy randomized patients to aspirin (100 mg daily), fixed low dose warfarin (1.25 mg daily), or LMWH (enoxaparin 40 mg once daily) [78]. The following findings were noted:
●The rate of a composite endpoint of serious thromboembolic events (symptomatic deep vein thrombosis [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), although 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.
In a second phase III trial, 342 younger adults (median age 58 years) with previously untreated MM received lenalidomide plus low dose dexamethasone (Rd) for four cycles followed by cyclophosphamide for stem cell mobilization and collection before consolidation with either melphalan, prednisone, and lenalidomide (MPR) or melphalan 200 mg/m2 [79]. Patients with no clinical indication or contraindication to specific VTE prophylaxis were randomly assigned to receive either low dose aspirin (100 mg/day) or LMWH (enoxaparin 40 mg daily) during treatment with Rd and MPR. When compared with LMWH, low dose aspirin resulted in:
●A similar incidence of the primary composite endpoint of confirmed symptomatic DVT, pulmonary embolism, arterial thrombosis, any acute cardiovascular event, or sudden otherwise unexplained death in the first six months after random assignment (2.27 versus 1.20 percent, respectively).
●A similar rate of confirmed symptomatic DVT (1.14 versus 1.20 percent). All three cases of pulmonary embolism occurred in the aspirin treated group.
●There were no acute cardiovascular events, arterial thromboses, or sudden deaths in either group.
●There were no major bleeding episodes in either group. The one minor bleeding episode (gastrointestinal bleeding) was seen in a patient receiving LMWH.
These trials suggest 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 5 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. Use of aspirin is simpler and less expensive than LMWH. Of importance, these trials 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 'High risk' below.)
High risk — Patients receiving IMiDs who have two or more risk factors or are receiving concomitant high dose dexamethasone (≥480 mg per month), or an anthracycline-containing chemotherapy regimen are at higher risk for VTE. The ideal agent for VTE prophylaxis in this setting is unknown and clinical practice varies widely. 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 IMiDs. Data on the efficacy of aspirin in this setting have been mixed. There is the least experience with direct oral anticoagulants (DOACs). (See 'Direct oral anticoagulants' below.)
For higher-risk patients, we suggest the use of LMWH or warfarin rather than aspirin (algorithm 1). Options include:
●Prophylactic or therapeutic dose LMWH (see 'Low molecular weight heparin' below)
●Therapeutic dose warfarin with a target INR of 2.0 to 3.0 (see 'Warfarin' below)
●Prophylactic dose DOAC (see 'Direct oral anticoagulants' below)
Our preference for LMWH or warfarin over aspirin is largely based upon data suggesting efficacy of full dose warfarin and LMWH and the greater uncertainty regarding the efficacy of aspirin in this setting. Prophylactic dose LMWH may be preferred over full anticoagulation in patients at higher risk for bleeding complications, whereas therapeutic doses may be preferred for those receiving intensive, anthracycline-containing therapy in conjunction with an IMiD. (See 'Patients at high risk of bleeding' below.)
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 (eg, enoxaparin) is given to patients with renal insufficiency, dose reduction is suggested. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Dosing'.)
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 hospitalized 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 when the bleeding risk becomes acceptably low or when the bleeding lesion or bleeding risk has been reversed [80]. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Mechanical methods of thromboprophylaxis'.)
Specific agents
Low molecular weight heparin — The use of prophylactic doses of LMWH (eg, enoxaparin 40 mg/day subcutaneously [SQ]) appears to reduce the frequency of thrombotic events in patients with MM receiving immunomodulatory therapy. A number of LMWH preparations are available, none of which have proven superiority over the other. Studies that have evaluated LMWH in patients with MM have used different preparations. Dosing for thromboprophylaxis, including adjustments for body weight and renal function, is discussed in detail separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Dosing'.)
●In 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) [81].
●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 [63]. 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. These two patients developed VTE within two months of discontinuation of enoxaparin.
●In a randomized trial of induction VAD chemotherapy, autologous hematopoietic cell rescue, and maintenance interferon, each phase given with or without thalidomide therapy, the addition of thalidomide without prophylaxis increased the incidence of VTE (34 versus 18 percent) [82]. The rate of VTE was still concerningly high after protocol adjustments included prophylactic LMWH for those receiving thalidomide (24 percent). These results suggest a role for therapeutic dose LMWH in patients undergoing such intensive, anthracycline-containing therapy in conjunction with an IMiD.
●A single institution retrospective study reported that only one in 45 patients with relapsed refractory MM treated with lenalidomide and dexamethasone given in conjunction with LMWH developed VTE [83].
Although the data are mixed, these results suggest that, in the absence of intensive, anthracycline-containing therapy, LMWH decreases the rate of VTE among the patients treated with IMiD-containing regimens to less than 10 percent.
Warfarin — Full dose warfarin, with a target INR of 2.0 to 3.0, may be used for VTE prophylaxis in patients with MM being treated with IMiD combinations who are at high risk of VTE. Support for this approach comes from small observational studies and retrospective reviews that suggest a potential benefit of full-intensity anticoagulation with warfarin, in comparison to a fixed low dose warfarin:
●In one study, VTE developed in 34 percent of 162 patients receiving induction chemotherapy plus thalidomide despite VTE prophylaxis with fixed, low dose warfarin (1 mg/day) [53,82].
●In a second report, the incidence of VTE with thalidomide plus dexamethasone decreased when VTE prophylaxis was changed from fixed, low dose warfarin (6 of 24 patients, 25 percent) to full dose warfarin or LMWH (none of 16 patients) [52].
●In a retrospective review of 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) [84]. 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.
Other experts consider fixed low-dose warfarin an alternative for selected patients based on the randomized trial described above that suggested similar efficacy to low-dose aspirin with potentially lower bleeding risk [76,78]. (See 'Standard risk' above.)
Direct oral anticoagulants — There are limited data regarding the use of DOACs (direct thrombin inhibitors or factor Xa inhibitors) as VTE prophylaxis in patients receiving IMiD-containing therapy [85,86]. We await further study prior to routinely incorporating these agents into our standard prophylaxis strategies.
A nonrandomized phase 2 study evaluated the use of prophylactic dose apixaban in 104 patients with MM receiving melphalan, prednisone, and thalidomide as initial therapy or lenalidomide and dexamethasone (Rd) for relapsed disease [85]. Two DVTs were observed. Both were in patients treated with Rd and one occurred while apixaban was being held for thrombocytopenia. There was one nonfatal major hemorrhage and 11 clinically relevant, nonmajor bleeding events.
The use of DOACs for VTE prophylaxis in other settings is discussed separately. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Outpatients (VTE prophylaxis)' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)
Aspirin — Low dose aspirin (ie, 81 to 100 mg daily) is our preferred VTE prophylaxis for patients with MM at lower or standard risk for developing VTE during treatment with IMiD-containing therapy (algorithm 1). In contrast, we prefer LMWH or warfarin for higher risk patients. Low dose aspirin has not been directly compared with warfarin or LMWH in the treatment of patients at high risk of developing VTE. It is also not clear whether the risk of thrombosis can be further reduced using a higher dose of aspirin (eg, 325 mg/day). (See 'Standard risk' above.)
●Low dose aspirin – 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 [70]. 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 of aspirin daily developed DVT. While the risk of DVT using low dose aspirin was lower in this nonrandomized comparison (ie, 18 versus 58 percent), it was not completely protective against the development of thrombosis.
●Higher dose aspirin – There are limited data regarding the use of a higher dose of aspirin (eg, 325 mg/day). Prospective studies of lenalidomide plus high dose dexamethasone reported VTE rates in the range of 20 percent when aspirin 325 mg/day was used as thromboprophylaxis during therapy regimens containing high dose dexamethasone [24,25]. 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 [87].
DIAGNOSIS AND MANAGEMENT OF VTE — 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 "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)
The management of VTE in patients with MM is similar to the management of VTE in the cancer population. Therapeutic (full dose) anticoagulation is indicated for patients with VTE and should be started immediately. Agent selection and dosing is described in detail separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)
There have been no studies investigating whether the IMiD (thalidomide, lenalidomide, pomalidomide) should be temporarily held at the time of VTE diagnosis while therapeutic anticoagulation is being achieved. Given their prothrombotic effects, we suggest holding these agents until therapeutic anticoagulation is achieved.
For patients with VTE, therapeutic anticoagulation should be continued for the total duration of IMiD therapy. If there have been no further VTE episodes while receiving one of these agents plus therapeutic anticoagulation, we suggest that anticoagulation be stopped one month after these agents have been discontinued, provided that the patient has received therapeutic anticoagulation for a minimum of three to six 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 IMiD 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 "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)
Patients who developed a prior IMiD-associated VTE being started on another IMiD-containing regimen ought to be considered to be at higher risk for developing another thromboembolic event. As such, in our own practice, such patients generally receive at least prophylactic LMWH, with some patients being treated with full dose anticoagulation. The choice between these approaches is made on a case-by-case basis, taking into account perceived bleeding risk and whether there are other risk factors for thrombosis.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma" and "Society guideline links: Anticoagulation".)
SUMMARY AND RECOMMENDATIONS
●Scope of risk and importance of prophylaxis – Patients with multiple myeloma (MM) treated with an immunomodulatory drug (IMiD) such as thalidomide, lenalidomide, or pomalidomide in combination with other agents (eg, glucocorticoids, doxorubicin, or erythropoietin) have a rate of venous thromboembolism (VTE) greater than 20 percent. (See 'Incidence and risk factors' above.)
For patients with MM treated with an IMiD containing combination chemotherapy regimen, we recommend the routine use of VTE prophylaxis (Grade 1B). VTE prophylaxis is continued for as long as the patient is receiving an IMiD. Although the evidence is weaker, we use the same approach for patients with AL amyloidosis treated with myeloma-like IMiD-containing regimens, particularly in the context of disease-associated nephrotic range proteinuria.
●Choice of prophylaxis – 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 on risk factors (eg, previous VTE, inherited thrombophilia, central venous catheter or pacemaker, cardiac disease, diabetes, acute infection, immobilization, use of erythropoietin, chronic renal disease, and obesity) (algorithm 1):
•Patients treated with IMiDs who have two or more risk factors or are receiving concomitant high dose dexamethasone (≥480 mg per month), or an anthracycline-containing chemotherapy regimen are considered to be at higher risk for VTE. For such patients, we suggest the use of prophylactic or therapeutic dose low molecular weight heparin (LMWH) or therapeutic dose warfarin rather than aspirin (Grade 2C). (See 'High risk' above.)
•Patients with no or one risk factor who are not receiving high dose dexamethasone, or an anthracycline-containing chemotherapy regimen are considered to be at standard risk for VTE. For such patients, we suggest VTE prophylaxis with aspirin rather than warfarin or LMWH (Grade 2B). This includes patients without other risk factors being treated with an IMiD in combination with a proteosome inhibitor. (See 'Standard risk' above.)
•Patients receiving an IMiD as a single agent are at lower risk for VTE. For these patients, we suggest prophylaxis with aspirin rather than no prophylaxis or the use of other agents (Grade 2C). (See 'Patients receiving single-agent IMiD as maintenance' above.)
VTE prophylaxis is generally administered as long as combination therapy with an IMiD is continued. (See 'Length of prophylaxis' above.)
●Patients with VTE – The diagnosis and initial management of VTE in patients with MM is similar to that in the larger cancer population. (See 'Diagnosis and management of VTE' above.)
For patients who develop VTE and continue treatment with an IMiD, 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 the IMiD plus therapeutic anticoagulation, we stop anticoagulation one month after these agents have been discontinued, provided that the patient has been receiving therapeutic anticoagulation for a minimum of three to six months and has no other indication for anticoagulation. (See 'Diagnosis and management of VTE' above.)
●Gastric prophylaxis – 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 an IMiD is used in combination with aspirin, corticosteroids, and/or an anthracycline-containing chemotherapy regimen (Grade 2C).
ACKNOWLEDGMENTS
The editors of UpToDate gratefully acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
The UpToDate editorial staff also acknowledges extensive contributions of Robert A Kyle, MD to earlier versions of this topic review.
