Version May 2024
INTRODUCTION — Patients with multiple myeloma (MM) have an increased incidence of venous thromboembolism (VTE) that appears to be related to both the malignancy itself and the therapy given. In particular, the rate of VTE is especially high for patients with MM treated with regimens that contain an immunomodulatory drug such as lenalidomide, pomalidomide, or thalidomide.
Prophylactic strategies to minimize this risk of VTE in patients with MM 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 "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)".)
VTE INCIDENCE AND RISK FACTORS
General risk factors — VTE is the most common form of thrombosis in patients with MM. Arterial thrombotic events have also been reported, although at a lower rate [1,2].
Patients with MM are at an increased risk of having comorbidities known to be risk factors for the development of VTE in the general population, including:
●Immobilization related to bone involvement and pathologic fractures
●Kidney injury, including nephrotic syndrome in some patients
●Diabetes due to glucocorticoid use
●Acute infection due to immunosuppression
●Central venous catheter placement
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 [3,4].
The impact of these and other risk factors in the general population is discussed in more detail separately. (See "Overview of the causes of venous thrombosis".)
Immunomodulatory drugs — The risk of thrombosis among patients with MM taking an immunomodulatory drug (IMiD) varies depending on many factors. In particular, VTE rates are higher when IMiDs are:
●Given as induction therapy (high burden of disease) – The highest risk of VTE is in the first six months following a new diagnosis of MM. In a meta-analysis of >9000 patients treated with lenalidomide, the lowest incidence of VTE was among patients treated with single-agent lenalidomide as maintenance [5]. These individuals had already completed induction therapy and presumably had better disease control than patients receiving combination therapy.
●Given in combination with other agents – VTE rates are higher when an IMiD is given with dexamethasone and/or other agents and lower when used as a single agent.
●Given in combination with an anthracycline – VTE rates are very high when IMiDs are combined with an anthracycline [6-12]. 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 [11].
●Given with higher-dose dexamethasone (>160 mg/month) – The high VTE risk related to induction therapy with lenalidomide plus dexamethasone without mandated thromboprophylaxis was evident in a phase 3 trial (SWOG 0232), in which 9 of the first 12 patients randomized to this combination developed thromboembolic events (8 lower extremity VTEs and 1 ischemic stroke), prompting modification of the trial to require VTE prophylaxis [13]. The precise impact of dexamethasone dose on VTE risk was illustrated in another phase 3 trial (ECOG E4A03), in which 445 patients with previously untreated MM receiving lenalidomide were randomly assigned to higher-dose dexamethasone (total 480 mg/month) versus lower-dose dexamethasone (total160 mg/month) [14]. The trial was stopped prematurely due to higher mortality in the higher-dose dexamethasone arm; VTE rates were also higher in those assigned to higher-dose dexamethasone (26 versus 12 percent).
●Given with erythropoietin – In a multivariable analysis of MM-009 and MM-010, concomitant use of recombinant human erythropoietin was an independent contributor to the risk of development of VTE (odds ratio 3.2; 95% CI 1.7-6.0) [15].
Most of these factors have been incorporated into VTE risk stratification scoring systems. (See 'VTE risk stratification scoring systems' below.)
Lenalidomide — Patients with MM treated with lenalidomide plus dexamethasone have an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as an increased risk of myocardial infarction and stroke. The package insert includes a boxed warning for venous and arterial thromboembolism with a recommendation that all patients receive thromboprophylaxis [16].
The risk of VTE in patients treated with lenalidomide plus dexamethasone is higher than for those treated with either agent alone. In several randomized trials, the incidence of VTE among those treated with lenalidomide plus high-dose dexamethasone was at least threefold higher than that seen with dexamethasone alone [15,17-20].
VTE rates in patients receiving lenalidomide plus low-dose dexamethasone were estimated in a meta-analysis that included data from >9000 patients on clinical trials who received lenalidomide-based treatment regimens that did not contain high-dose dexamethasone [5]. VTE prophylaxis was unspecified but given to most patients. The pooled rate of VTE was 1.2 VTE events per 100 patient cycles where a cycle represents one month of lenalidomide treatment. 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 among 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 recorded VTE in 3 percent [1].
Pomalidomide — Patients with MM treated with pomalidomide plus dexamethasone have an increased risk of DVT and PE, as well as an increased risk of myocardial infarction and stroke. The package insert includes a boxed warning for venous and arterial thromboembolism with a recommendation that all patients receive thromboprophylaxis [21].
Without prophylaxis, the rate of VTE is high. In a phase 1 study of single-agent pomalidomide in 24 patients with relapsed or refractory MM, no prophylaxis was administered, and four patients (17 percent) developed VTE [22]. 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 have routinely included thromboprophylaxis with aspirin or other agents [23-27]. Rates of VTE in these trials have been approximately 3 percent.
Thalidomide — Patients with MM treated with thalidomide plus dexamethasone have an increased risk of DVT and PE, as well as an increased risk of myocardial infarction and stroke. The package insert includes a boxed warning for venous thromboembolism with a recommendation to consider thromboprophylaxis in all patients [28].
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) [29]. While the majority of thrombotic events described in patients treated with thalidomide have been venous, arterial thrombotic events have also been reported [2].
●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 [6,30-36].
●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) [6,32,37-40]. As an example, in one randomized trial, DVT occurred in 17 of 102 patients (17 percent) treated with TD versus 3 of 102 patients (3 percent) treated with dexamethasone alone [39].
●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 [6,41-45].
●Thalidomide, steroid, plus an anthracycline – Regimens utilizing thalidomide in combination with an anthracycline appear to be associated with the highest risk of VTE [6-12]. 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 (though the mandated VTE surveillance strategy utilized in this trial likely affected the observed rate of VTE) [11].
Proteasome inhibitors — The risk of VTE in patients receiving a proteasome inhibitor appears to depend on the proteasome inhibitor used. The risk appears to be increased with carfilzomib but not with bortezomib or ixazomib. As such, the package insert for carfilzomib includes a recommendation for thromboprophylaxis, whereas the package inserts for bortezomib and ixazomib do not [46-48].
In a meta-analysis that included patients treated with lenalidomide plus low-dose dexamethasone and included VTE prophylaxis, 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 [5]. However, the proteasome inhibitor used in >80 percent of patients in this meta-analysis was carfilzomib or ixazomib.
●Carfilzomib, lenalidomide, and dexamethasone – Randomized trials have reported increased VTE rates when carfilzomib was added to lenalidomide plus dexamethasone (13 versus 6 percent in ASPIRE [49]) and higher VTE rates with carfilzomib plus dexamethasone when compared with bortezomib plus dexamethasone (9 versus 2 percent in ENDEAVOR [50]). A retrospective study reported VTE rates with carfilzomib, lenalidomide, and dexamethasone (KRd) plus aspirin (16.1 percent); bortezomib, lenalidomide, and dexamethasone (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 [51].
●Bortezomib, lenalidomide, and dexamethasone – 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 [52,53].
●Ixazomib, lenalidomide, and dexamethasone – In a placebo controlled trial that mandated thromboprophylaxis, the addition of ixazomib to lenalidomide plus dexamethasone did not increase the rate of thromboembolism (8 percent with ixazomib, lenalidomide, and dexamethasone and 11 percent with lenalidomide and dexamethasone) [54].
Monoclonal antibodies — In patients with MM, the risk of VTE does not appear to increase with the addition of a monoclonal antibody (ie, daratumumab, isatuximab, or elotuzumab).
In one meta-analysis that included six trials, regimens that included daratumumab were associated with a lower risk of VTE compared with regimens that did not include daratumumab (risk ratio 0.60; 95% CI 0.40-0.91) [55].
Similarly, a post-hoc analysis of the phase 2 GRIFFIN study did not show an increase in VTE with the addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (10 percent with daratumumab with lenalidomide, bortezomib, and dexamethasone versus 16 percent with lenalidomide, bortezomib, and dexamethasone) [56]. While the protocol recommended VTE prophylaxis, thromboprophylaxis use and adherence were suboptimal, potentially explaining the higher-than-expected VTE rate.
VTE RISK STRATIFICATION SCORING SYSTEMS — The sections that follow describe several scoring systems that have been developed to incorporate risk factors for VTE in patients with MM and have demonstrated the ability to differentiate risk. In contrast, the International Myeloma Working Group (IMWG) risk stratification score and Khorana scores appear to be poor predictors of VTE risk in patients with MM, so they are less clinically helpful [6,57-59].
The impact of various risk factors on the development of VTE in the general population is discussed in more detail separately. (See "Overview of the causes of venous thrombosis".)
SAVED score — The SAVED score predicts the risk of VTE in patients with MM receiving an immunomodulatory drug (IMiD; ie, lenalidomide, pomalidomide, thalidomide). It has not been validated in other populations. A SAVED score ≥2 points designates high VTE risk (algorithm 1).
The acronym SAVED can assist with remembering the factors included in score calculation:
●S – Surgery within 90 days (+2 points)
●A – Asian population (-3 points)
●V – VTE history (+3 points)
●E – Elders: Age ≥80 years (+1 point)
●D – Dexamethasone >160 mg/month (+2 points) or 120 to 160 mg/month (+1 point)
The SAVED score was derived using data from >2300 patients with MM within the SEER-Medicare database and validated using >1200 patients with MM included in the Veterans Administration Central Cancer Registry [58]. The databases did not include information regarding use of over-the-counter aspirin. Also, the study was limited to patients treated prior to 2014, so they were not exposed to drugs approved after that time (eg, carfilzomib, ixazomib, daratumumab). In the validation cohort, VTE occurred in 9.4 percent within 12 months of starting an IMiD. Patients with a SAVED score ≥2 points had a higher incidence of VTE after starting an IMiD at three months (6 versus 4 percent), six months (11 versus 7 percent), and 12 months (16 versus 8 percent; overall hazard ratio 1.98).
In another validation cohort that included >500 patients starting an IMiD (95 percent received aspirin for thromboprophylaxis), the percent with VTE within six months increased with the SAVED score: 0 points (2.7 percent), 1 point (8.7 percent), 2 points (26.7 percent), and ≥3 points (35.4 percent) [60]. The higher rates of VTE in the validation cohort compared with the derivation cohort likely reflect the study design, including the exclusion of patients on single-agent maintenance therapy and the use of chart review for data extraction.
The SAVED score compared favorably versus the National Comprehensive Cancer Network/IMWG model, which was unable to adequately discriminate VTE risk in this population [6,58]. Interpretation of the SAVED score must take into account its retrospective design, limited data regarding aspirin use, and lack of treatments approved after 2014 (eg, carfilzomib, ixazomib, daratumumab). Also, while ethnicity/race is included in the score, the dataset had few females and persons of Asian descent, limiting interpretation in these populations. However, despite the limitations of the methodology used in the original SAVED score publication, the utility of this scoring system was confirmed by the external validation cohort, which used slightly different methodology for identifying VTEs.
IMPEDE VTE score — The IMPEDE VTE score predicts the risk of VTE in patients with MM treated with or without IMiDs. If the IMPEDE VTE score is used for clinical VTE risk assessment, we propose using a cutoff of ≥8 points to designate high VTE risk (algorithm 1). This cutoff predicts a VTE risk that is similar to that with a SAVED score of ≥2 points and more clearly identifies patients who need prophylaxis that is more intensive than aspirin alone. Some other experts use an IMPEDE VTE score ≥4 points to designate high VTE risk [57,61].
The acronym IMPEDE VTE can assist with remembering the factors included in score calculation:
●I – Immunomodulatory drug (+4 points)
●M – Body mass index ≥25 kg/m2 (calculator 1)(+1 point)
●P – Pelvic, hip, or femur fracture (+4 points)
●E – Erythropoiesis-stimulating agent (+1 point)
●D – Doxorubicin or multiagent chemotherapy (+3 points)
●D – Dexamethasone >160 mg/month (+4 points) or <160 mg/month (+2 points)
●E – Ethnicity/race is Asian/Pacific Islander (-3 points)
●V – History of VTE before diagnosis of MM (+5 points)
●T – Tunneled central line or central venous catheter (+2 points)
●E – Existing thromboprophylaxis with prophylactic dose low molecular weight heparin or aspirin (-3 points) or therapeutic dose low molecular weight heparin or warfarin (-4 points)
The IMPEDE VTE score was derived using data from >4400 patients with MM within the Veterans Administration Central Cancer Registry and validated using >4200 patients with MM included in the SEER-Medicare database [57]. The databases did not include data regarding use of over-the-counter aspirin. Also, patients were treated prior to 2014, so they were not exposed to drugs approved after that time (eg, carfilzomib, ixazomib, daratumumab).
The six-month cumulative incidence of VTE after starting therapy in the validation cohort was 5.2 percent, and the hazard ratio for VTE increased by 1.16 per point. Three risk groups could be determined based on the cumulative score with significantly different six-month cumulative incidence rates of VTE from the start of chemotherapy:
●≤3 points – 3.3 percent (95% CI 2.6-4.1)
●4 to 7 points – 8.3 percent (95% CI 7.1-9.8)
●≥8 points – 15.2 percent (95% CI 12.1-19)
This model was able to better discriminate VTE risk when compared with a previous National Comprehensive Cancer Network/IMWG model [6,57]. However, study limitations include its retrospective design and limited data regarding aspirin use. Also, while ethnicity/race is included in the score, the dataset used to derive and validate IMPEDE VTE included few females and persons of Asian or Pacific Islander descent, limiting interpretation in these populations. Finally, it is not known whether VTE risk might be impacted by agents approved after the study period (eg, carfilzomib, ixazomib, daratumumab).
PRISM score — The PRISM score was developed to predict the risk of VTE in outpatients with MM treated with or without immunomodulatory agents. The score was developed based on a relatively small cohort of patients, and we await further validation before incorporating it into routine practice.
The acronym PRISM can assist with remembering the factors included in score calculation:
●P – Prior VTE (+8 points)
●R – Black American (+1 point)
●I – Immunomodulatory drug use (+2 points)
●S – Surgery within 90 days (+5 points), excludes minimally invasive procedures such as kyphoplasty or vertebroplasty
●M – Abnormal metaphase cytogenetics (+2 points)
The PRISM score was derived using individual patient-level data from a cohort of >780 patients with MM diagnosed at the Cleveland Clinic between 2008 and 2018 and validated with a separate cohort of >200 patients with MM from Columbia University [62]. In the derivation and validation cohorts, the most common induction regimen used was bortezomib, lenalidomide, and dexamethasone (41 percent) with a monthly dexamethasone dose of 120 to 160 mg (76 percent). Most patients received thromboprophylaxis with aspirin (60 percent) or prophylactic low molecular weight heparin (4 percent). In the derivation cohort, the cumulative incidence of VTE at 6 and 12 months was 8.2 and 11.5 percent. In contrast, the incidence of VTE in the validation cohort was low (23 events within one year).
The risk of VTE increased with each point by a hazard ratio of 1.28, and patients could be divided into three risk groups with significantly different cumulative VTE incidence at 12 months:
●Low risk (score 0) – 2.7 percent (95% CI 0.7-7.0)
●Intermediate risk (score 1 to 6) – 10.8 percent (95% CI 8.2-13.8)
●High risk (score ≥7) – 36.5 percent (95% CI 23.6-49.6)
In this study, development of a VTE within 12 months of starting therapy did not impact overall survival.
VTE PROPHYLAXIS INDICATIONS AND DURATION — All patients with MM should have an assessment of their VTE risk so that appropriate prophylaxis may be employed (algorithm 1). VTE prophylaxis is a standard part of the treatment of patients with MM unless there are contraindications to anticoagulation agents or antiplatelet agents. We use a risk-stratified approach that is generally consistent with recommendations from the International Myeloma Working Group; the National Comprehensive Cancer Network; the International Initiative on Thrombosis and Cancer; the American Society of Hematology; and the American Society of Clinical Oncology [6,61,63-66].
VTE prophylaxis is generally administered as long as active therapy is continued [6]. It is not known whether VTE prophylaxis can be safely discontinued in patients receiving prolonged therapy with immunomodulatory drug (IMiD)-containing regimens. 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.
VTE rates are increased in patients with MM treated with a regimen that includes an IMiD (eg, lenalidomide, pomalidomide, thalidomide) and/or carfilzomib. Without thromboprophylaxis, VTE rates in these populations can exceed 20 percent. In comparison, the rate of VTE decreases to less than 10 percent when VTE prophylaxis is administered (in the absence of other risk factors for VTE beyond IMiD use). In a meta-analysis that included data from >9000 patients on clinical trials who received thromboprophylaxis along with a lenalidomide-based treatment regimen that did not contain high-dose dexamethasone, the pooled rate of VTE was 1.2 (95% CI 0.9-1.7) VTE events per 100 patient cycles where a cycle represents one month of lenalidomide treatment [5].
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.
CHOICE OF VTE PROPHYLAXIS
During induction therapy
Risk stratification — For patients receiving induction therapy for MM, our preferred thromboprophylaxis depends on (algorithm 1):
●The baseline risk of VTE associated with a given regimen
●The presence or absence of additional risk factors for thromboembolism
●The risk of bleeding complications from VTE prophylaxis
Those already on therapeutic anticoagulation for another indication (eg, atrial fibrillation) should continue their prior anticoagulation. We reassess VTE risk, bleeding risk, and prophylaxis choice periodically. Patients may shift from one group to another if complications arise or treatment is de-escalated.
A validated risk stratification scoring system can be used to estimate VTE risk. Cutoff values to identify high VTE risk include a SAVED score ≥2 or an IMPEDE VTE score ≥8. (See 'VTE risk stratification scoring systems' above.)
For patients treated with an immunomodulatory drug (IMiD), we prefer SAVED for its simplicity and because it more clearly identifies patients who might benefit from prophylaxis that is more intensive than aspirin alone. (See 'SAVED score' above.)
For patients treated without an IMiD, we use IMPEDE VTE as SAVED has not been validated in this population. If the IMPEDE VTE score is used for clinical VTE risk assessment, we propose using a cutoff of ≥8 points to designate high VTE risk. This cutoff predicts a VTE risk that is similar to that with a SAVED score of ≥2 points. (See 'IMPEDE VTE score' above.)
Standard VTE risk (aspirin preferred) — For patients with standard VTE risk (eg, a SAVED score <2 or IMPEDE VTE score <8), we suggest VTE prophylaxis with aspirin 100 to 325 mg daily rather than anticoagulation with warfarin, low molecular weight heparin (LMWH), or a direct oral anticoagulant (algorithm 1). A common example of standard VTE risk is a patient without other risk factors being treated with lenalidomide, bortezomib, and weekly dexamethasone. We reassess VTE risk, bleeding risk, and prophylaxis choice periodically. Patients with standard VTE risk may shift to having a high VTE risk if complications arise.
This preference is largely based on the lower cost and ease of administration of aspirin and randomized trials that demonstrated similar rates of serious thromboembolic events compared with other low-intensity VTE prophylaxis options (namely fixed-dose warfarin or low-dose LMWH) [67,68]. In our practice, almost all patients are able to tolerate aspirin when administered with appropriate gastrointestinal prophylaxis (eg, an H2-blocker or a proton pump inhibitor).
An open-label phase 3 trial of 667 patients receiving thalidomide-containing induction therapy randomly assigned VTE prophylaxis with aspirin 100 mg daily, fixed low-dose warfarin 1.25 mg daily, or LMWH (enoxaparin 40 mg once daily) [67]. 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 3 trial, 342 adults were randomly assigned to VTE prophylaxis with either aspirin 100 mg/day or LMWH (enoxaparin 40 mg daily) during treatment with lenalidomide plus dexamethasone or melphalan, prednisone, and lenalidomide [68]. 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 patients with standard VTE risk. 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 (international normalized ratio [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 VTE risk' below.)
High VTE risk
Anticoagulation versus aspirin — For most patients with high VTE risk (eg, a SAVED score ≥2 or an IMPEDE VTE score ≥8), we suggest VTE prophylaxis with LMWH, a direct oral anticoagulant (DOAC), or warfarin rather than aspirin (algorithm 1). However, data on VTE prophylaxis in this setting are limited, and clinical practice varies widely. Aspirin is an acceptable alternative, especially for patients at high risk of bleeding complications with anticoagulation. We reassess VTE risk, bleeding risk, and prophylaxis choice periodically. Patients with a high VTE risk may transition to having a low VTE risk as treatment is de-escalated and disease control is achieved.
Details regarding the specific agents are described below:
●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 more intensive anticoagulation over aspirin is largely based upon data suggesting efficacy of full-dose warfarin and LMWH and the 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, DOAC, and warfarin is made based upon the clinical circumstances. As examples:
●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.
●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 kidney impairment, dose reduction is suggested (table 1).
●Both warfarin and DOACs have drug interactions that may necessitate dose adjustments, as detailed in the drug interactions program within UpToDate.
●Warfarin and DOACs differ in their dosing frequency, dietary restrictions, need for monitoring, drug interactions, and availability of antidotes in the case of excessive bleeding (table 2).
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. Dosing for thromboprophylaxis, including adjustments for body weight and kidney 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 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) [69].
●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 [43]. 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 developed VTE within two months of discontinuation of enoxaparin.
●In a randomized trial of induction chemotherapy with vincristine, doxorubicin, and dexamethasone, followed by 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) [70]. 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 1 in 45 patients with relapsed refractory MM treated with lenalidomide and dexamethasone given in conjunction with LMWH developed VTE [71].
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. Warfarin has drug interactions that may necessitate dose adjustments, as detailed in the drug interactions program within UpToDate.
Support for the use of warfarin 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-dose warfarin 1 mg/day [33,70].
●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) [32].
●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) [72]. The effectiveness of low-dose warfarin in this report may be explained by the lower mean/median dose of thalidomide (average 200 mg/day) used in these patients, although there are no data clearly demonstrating a dose-effect relationship for thalidomide and thrombosis risk.
There are limited data on the use of therapeutic-dose warfarin in patients treated with IMiDs other than thalidomide. In one small, retrospective study, there were no clinically significant VTEs among a cohort of 13 patients with lenalidomide-treated MM who developed asymptomatic VTE of the lower extremity and were treated with therapeutic-dose warfarin [73]. While this was a very small cohort, such patients would be at a higher risk for clinically significant VTE than unselected patients.
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 [74-77]. DOACs have drug interactions that may necessitate dose adjustments, as detailed in the drug interactions program within UpToDate.
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 for relapsed disease [74]. Two DVTs were observed; both were in patients treated with lenalidomide and dexamethasone, and one occurred while apixaban was being held for thrombocytopenia. There was one nonfatal major hemorrhage and 11 clinically relevant, nonmajor bleeding events.
Only 15 patients with MM (2.6 percent) were included in the randomized AVERT trial that compared apixaban versus placebo in ambulatory patients with cancer [78]; apixaban decreased rates of VTE (4.2 versus 10.2 percent) and increased major bleeding (3.5 versus 1.8 percent). Patients with MM were excluded from the CASSINI trial of rivaroxaban, another trial involving ambulatory cancer patients at high risk for VTE [79].
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".)
During maintenance therapy — For patients with MM receiving an IMiD (lenalidomide, pomalidomide, or thalidomide) as a single agent for maintenance therapy, including those post-autologous transplantation, we suggest low-dose aspirin prophylaxis (ie, 81 to 325 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 'VTE prophylaxis indications and duration' above.)
A 2008 International Myeloma Working Group guideline on the prevention of thalidomide- and lenalidomide-associated thrombosis in MM 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 [6]. 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 less information about 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 a 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) [6,30-36]. 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 prophylaxis (mostly aspirin) [80,81]. In one meta-analysis of studies in which the majority of patients received VTE prophylaxis, 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) [5].
Adjustments for hospitalization or surgery — Patients with MM who are hospitalized or undergoing surgery may need modifications to their VTE prophylaxis regimen. 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".)
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, we advise frequent reassessment of risk so that pharmacologic agents can be used when the bleeding risk becomes acceptably low or when the bleeding lesion or bleeding risk has been reversed [82]. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Mechanical methods of thromboprophylaxis'.)
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 immunomodulatory drug (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 to three months 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 should be considered at higher risk for developing another thromboembolic event. As such, in our own practice, such patients generally receive at least prophylactic low molecular weight heparin, 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/were other risk factors for thrombosis in each instance of IMiD use.
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) have an increased risk of venous thromboembolism (VTE) related to both the malignancy itself and the therapy given. VTE prophylaxis is a standard part of treatment unless there are contraindications to anticoagulation agents or antiplatelet agents. (See 'VTE prophylaxis indications and duration' above.)
●During induction therapy
•Risk stratification – For patients receiving induction therapy for MM, our preferred thromboprophylaxis depends on (algorithm 1):
-The baseline risk of VTE associated with a given regimen
-The presence or absence of additional risk factors for thromboembolism
-The risk of bleeding complications from VTE prophylaxis
We use a SAVED score ≥2 or an IMPEDE VTE score ≥8 to identify patients with high VTE risk. (See 'VTE risk stratification scoring systems' above.)
For patients treated with an immunomodulatory drug (IMiD), we prefer SAVED for its simplicity and because it more clearly identifies a higher risk population. (See 'SAVED score' above.)
For patients treated without an IMiD, we use IMPEDE VTE, as SAVED has not been validated in this population. (See 'IMPEDE VTE score' above.)
We reassess VTE risk, bleeding risk, and prophylaxis choice periodically. Patients may shift from one group to another if complications arise or treatment changes.
•Standard VTE risk (aspirin preferred) – For patients with standard VTE risk (eg, a SAVED score <2 or IMPEDE VTE score <8), we suggest VTE prophylaxis with aspirin 100 to 325 mg daily rather than anticoagulation with warfarin, low molecular weight heparin (LMWH), or a direct oral anticoagulant (DOAC) (algorithm 1) (Grade 2C).
Aspirin is simple and inexpensive and appears to result in similar rates of serious thromboembolic events in this population. In our practice, almost all patients are able to tolerate aspirin when administered with appropriate gastrointestinal prophylaxis (eg, an H2-blocker or a proton pump inhibitor). (See 'Standard VTE risk (aspirin preferred)' above.)
•High VTE risk (anticoagulation preferred) – For patients with high VTE risk (eg, a SAVED score ≥2 or an IMPEDE VTE score ≥8), we suggest VTE prophylaxis with LMWH, a DOAC, or warfarin rather than aspirin (algorithm 1) (Grade 2C). A choice among these is based on clinical circumstances. (See 'Anticoagulation versus aspirin' above.)
This preference is based on data suggesting efficacy of full-dose warfarin and LMWH and the uncertainty regarding the efficacy of aspirin in this setting. However, aspirin is an acceptable alternative, especially for patients at high risk of bleeding complications with anticoagulation.
●During maintenance therapy – Patients receiving an IMiD as a single agent are at a 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 'During maintenance therapy' 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 at least one to three months after completion of treatment with the IMiD (Grade 2C). If there have been no further VTE episodes while receiving the IMiD plus therapeutic anticoagulation, we stop anticoagulation one to three months 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.)
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.
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