Multiple Myeloma - Prevention of Venous Thromboembolism in Patients Receiving Immunomodulatory Drugs (Thalidomide, Lenalidomide, and Pomalidomide)

20/09/2019 Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pom…
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Multiple myeloma: Prevention of venous

thromboembolism in patients receiving
immunomodulatory drugs (thalidomide, lenalidomide, and
pomalidomide)
Authors: Jeffrey Zonder, MD, Charles A Schiffer, MD
Section Editor: Robert A Kyle, MD
Deputy Editor: Rebecca F Connor, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2019. | This topic last updated: May 24, 2019.
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 "Pathogenesis of the
hypercoagulable state associated with malignancy".)
Patients with multiple myeloma (MM) or the precursor lesion monoclonal gammopathy of
undetermined significance (MGUS) have an increased incidence of venous thromboembolism
(VTE). In addition, a few studies have suggested an increased risk of arterial thromboembolism
(ATE) in these populations as manifested by stroke, transient ischemic attack, myocardial
infarction, or symptomatic peripheral artery disease. The increased rate of VTE appears to be both
a result of the malignancy itself and the therapy given. In particular, the rate of VTE is particularly
high for patients with MM treated with combination chemotherapy that contains thalidomide or a
thalidomide analog such as lenalidomide.
The thrombotic risk associated with the use of thalidomide and its analogues as treatment for MM
will be discussed here. Thrombotic risk following the use of other antineoplastic agents (eg,
tamoxifen, L-asparaginase) and issues related to the treatment of VTE are presented separately.
(See "Drug-induced thrombosis in patients with malignancy", section on 'L-asparaginase' and
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"Treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Overview of the
treatment of lower extremity deep vein thrombosis (DVT)" and "Drug-induced thrombosis in
patients with malignancy", section on 'Tamoxifen'.)
POTENTIAL MECHANISMS
Patients with MM are at increased risk of having comorbidities known to be risk factors for the
development of venous thromboembolism (VTE) in the general population. In addition, treatment
with thalidomide and its analogs has been associated with high rates of VTE. Thalidomide has a
wide spectrum of biological effects, including immune modulation, alteration of adhesion molecule
and cytokine expression, and inhibition of angiogenesis [1]. (See 'General risk factors' below and
"Overview of angiogenesis inhibitors", section on 'Immunomodulatory drugs (IMiDs)'.)
While the exact mechanism by which thalidomide contributes to thrombosis is not known, the
following mechanisms have been postulated:
● Serum levels of the anticoagulant pathway cofactor thrombomodulin transiently drop during
the first month of thalidomide therapy, with gradual recovery over the following two months [2].
It is not known whether surface thrombomodulin expression on endothelial cells is similarly
reduced.
● Thalidomide increases endothelial cell expression of protease activated receptor-1 (PAR-1)

after exposure to doxorubicin or other anthracyclines [3]. This could result in increased
thrombin binding to the vascular endothelium, and explain, in part, the increased risk of
thrombosis seen when thalidomide is used in conjunction with an anthracycline. (See
'Thalidomide plus anthracycline' below.)
● Active treatment for MM has been associated with resistance to activated protein C (APC) in
the absence of factor V Leiden and response to APC appears to normalize following treatment
[4,5]. In one of these reports, the risk of VTE was highest in those patients with both APC
resistance and treatment with thalidomide [4]. However, other investigators have not been
able to confirm this observation [2,6].
● In one study, patients with MM treated with thalidomide had extremely high levels of von
Willebrand factor antigen and factor VIII, factors known to be associated with an increased risk
of VTE in the general population [7]. (See "Overview of the causes of venous thrombosis",
section on 'Factor VIII'.)
● Genetic analysis of single nucleotide polymorphisms (SNPs) noted that the set of SNPs
associated with thalidomide-related VTE events in patients with MM was enriched in genes
and pathways important in drug transport/metabolism, DNA repair, and cytokine balance [8-
10].
● Down-regulation of PU.1 by immunomodulatory derivatives such as thalidomide and

lenalidomide leads to arrest of myeloid maturation with resultant accumulation of
promyelocytes, with high levels of cathepsin G contained in their azurophilic granules [11].
Cathepsin G, a platelet function agonist, may contribute to risk of VTE.
INCIDENCE AND RISK FACTORS
General risk factors — Patients with MM are at increased risk of having comorbidities known to
be risk factors for the development of venous thromboembolism (VTE) in the general population.
These include immobilization related to bone involvement and pathologic fractures, renal disease
due to kidney involvement, diabetes due to glucocorticoid use, acute infection due to
immunosuppression, the use of erythropoietin, and central venous catheter placement for
treatment. 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 multiple myeloma who
have elevated levels of D-dimer and prothrombin fragments 1 and 2 [12,13].
Thalidomide-based therapy — The risk of VTE among patients with MM taking single agent
thalidomide does not appear to be increased over that of patients with myeloma not taking
thalidomide. In contrast, the risk of VTE increases substantially when thalidomide is administered
in conjunction with glucocorticoids [14]. While the majority of thrombotic events described in
patients treated with thalidomide have been venous, arterial thrombotic events have also been
reported [15].
Single agent thalidomide — Treatment with single agent thalidomide is not associated with a
significantly increased risk of thrombosis, as attested to in the following studies [16]:
● In a report in which 84 patients with relapsed or refractory myeloma were treated with 200 to
800 mg/day of thalidomide, no definite thromboembolic events were reported [17].
● Another study reported three nonfatal thromboembolic events and one case of transient
ischemic attacks occurring among 75 patients with MM treated with thalidomide, with or
without concomitant interferon [18].
● A third study observed one thromboembolic event during thalidomide monotherapy in 28

previously untreated patients with MM [19].
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 [20-23]. As such, VTE prophylaxis is generally reserved for patients taking single agent
thalidomide that also have two or more individual or myeloma-related risk factors [24-26]. (See
'Risk stratification' below.)
Thalidomide plus dexamethasone — The reported frequency of thrombotic events has been
as high as 26 percent when thalidomide is used in combination with high dose dexamethasone
(thal/dex) [16].
● One study reported six thromboembolic events, one of which was fatal, among 40 previously
untreated patients (15 percent) receiving treatment with thal/dex [19]. The same group
reported a deep vein thrombosis (DVT) rate of 8 percent in 28 patients receiving the same
treatment for relapsed myeloma [27].
● A second study observed thrombotic complications in 6 of 50 patients with newly diagnosed

myeloma (12 percent) treated with thal/dex [28].
● Results of a large Eastern Cooperative Oncology Group randomized trial are consistent with
the above findings [29]. Among 102 patients treated with thal/dex, there were 17 episodes of
DVT (17 percent), compared with three such episodes in the 102 patients (3 percent)
receiving dexamethasone alone.
● In another study, 43 previously untreated patients with myeloma received two to three courses
of doxorubicin plus dexamethasone (dox/dex), followed by two months of treatment with
thalidomide and dexamethasone (thal/dex) [30]. All patients received thromboprophylaxis with
81 mg of aspirin/day orally. There were five episodes of VTE documented among 42 evaluable
patients, three during initial treatment with dox/dex, and two during the subsequent treatment
with thal/dex.
Thalidomide plus melphalan and prednisone — Adding thalidomide to melphalan and

prednisone (MPT) in patients with MM results in a risk of thrombosis of up to 20 percent in those
not receiving thromboprophylaxis [16].
● An interim analysis of a randomized French study with 200 accrued patients observed a
higher rate of DVT with MPT treatment (9 percent), compared with 6 percent with MP alone,
and 3.5 percent with high dose intravenous melphalan [31].
● In another French study of similar design in patients 75 years of age or older, the incidence of
VTE in the MP (3 percent) and MPT (6 percent) arms was not statistically different.
Thromboprophylaxis was not pre-specified, but the authors note that heightened vigilance due
to prior trial experience led to greater thromboprophylaxis usage [32].
● A third phase III study reported a 20 percent incidence of DVT in 65 patients randomly
assigned to treatment with MPT and no thromboprophylaxis [33]. In the 126 patients receiving
MP and no thromboprophylaxis, the incidence of VTE was 1.6 percent (see 'Low molecular
weight heparin (LMWH)' below).
● In a trial adding a lower dose of thalidomide (100 to 200 mg/day) to pulses of oral
cyclophosphamide and dexamethasone, only 2 of 62 patients (3 percent) developed DVT [34].
Taken together, the results of these trials suggest that the risk of thrombosis during treatment with
the combination of thalidomide, steroids, and an alkylating agent (melphalan) is similar to that seen
following the use of thalidomide and steroids alone.
Thalidomide plus anthracycline — Regimens utilizing thalidomide in combination with

cytotoxic chemotherapy appear to be associated with the highest risk of VTE [16]. This is
particularly true when thalidomide is used in combination with an anthracycline [35-40]:
● One study treated 31 newly diagnosed patients with myeloma with the combination of
thalidomide (400 mg/day) plus vincristine, epirubicin, and dexamethasone [35]. Eight of 31
patients (26 percent) experienced VTE. The authors postulated that the relatively high dose of
thalidomide may have accounted for part of the excess risk, since, in a separate report, only 4
of 39 patients (10 percent) treated with vincristine, adriamycin, and dexamethasone (VAD)
plus a lower dose of thalidomide (200 mg/day) experienced DVT [36].
● In another report, 100 patients with myeloma underwent four cycles of induction
chemotherapy with or without thalidomide (400 mg daily). Cycles one (VAD) and three
(cyclophosphamide, adriamycin, dexamethasone) included adriamycin, whereas cycles two
and four consisted of dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP).
Fourteen of 50 patients (28 percent) randomly assigned to receive thalidomide had thrombotic
complications compared with only 2 of 50 (4 percent) receiving chemotherapy alone [37].
● Another study compared the frequency of VTE among 40 patients receiving thalidomide plus
DCEP ("T-DCEP") and 192 patients treated with "DT-PACE," a regimen similar to T-DCEP
except for the addition of adriamycin [38]. Thrombosis occurred in 2.5 percent (1 of 40) and 16
percent (31 of 192) in the T-DCEP and DT-PACE groups, respectively. Although this was not a
randomized trial, it provides compelling evidence that the inclusion of anthracyclines may have
more of an impact on risk of thrombosis than the thalidomide dose, which was 400 mg/day in
each regimen.
● A study of 19 patients treated with thalidomide plus DVd (pegylated liposomal doxorubicin,
vincristine, dexamethasone) and no thrombosis prophylaxis reported VTE in 11 of 19 patients
(58 percent) [39].
● In a study employing lower dose thalidomide (100 mg/day), dexamethasone, and pegylated
liposomal doxorubicin, the incidence of VTE was 14 percent despite the use of low dose
warfarin prophylaxis (1.25 mg/day) [41]. (See "Multiple myeloma: Management in resource-
poor settings", section on 'Thalidomide plus dexamethasone'.)
Thalidomide analogues — An increased risk of thrombosis has also been seen when thalidomide
analogues, such as lenalidomide and pomalidomide, are used in combination with steroids. The
thrombogenic potential of these agents is less well-defined than that of thalidomide.
Lenalidomide in myeloma — As with thalidomide, the risk of VTE among patients with MM
taking single agent lenalidomide does not appear to be increased over that of patients with
myeloma not taking lenalidomide. In contrast, the use of lenalidomide in combination with high
dose glucocorticoids is associated with an at least threefold increased risk of clotting events
[14,16,42]. The risk of VTE appears to be considerably lower when lenalidomide is combined with
low dose glucocorticoids or with bortezomib. While VTE is the most common form of thrombosis in
this population, arterial thrombotic events have also been reported [43].
● No increased risk of clotting events was apparent in phase I and II studies of lenalidomide as
monotherapy for MM [44,45] or myelodysplastic syndrome [46]. Similarly, in a post-marketing
study of the use of lenalidomide in 7764 patients with myelodysplasia, VTE was reported in
0.53 percent during the first two years of treatment [47].
● Two large randomized phase III studies (MM-009 and MM-010) compared lenalidomide (25
mg/day orally on days 1 through 21 of a 28-day cycle) plus dexamethasone (40 mg/day orally
on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles then on days 1 to 4 only for
subsequent cycles) versus dexamethasone plus placebo in a total of 704 patients with
relapsed or refractory MM [48,49]. Both studies were stopped by their data safety monitoring
boards due to significantly better response rates and time to progression with lenalidomide
plus dexamethasone compared with dexamethasone alone. However, the lenalidomide plus
dexamethasone group had significantly higher rate of VTE (approximately 11 versus 4
percent).
● In a multivariate analysis of MM-009 and MM-010, the odds ratio for development of VTE in
patients receiving lenalidomide plus dexamethasone (versus those receiving placebo plus
dexamethasone) was 3.5 (95% CI 1.8-7.0) [50]. Concomitant use of recombinant human
erythropoietin was also an independent contributor to the risk of development of VTE (odds
ratio 3.2; 95% CI 1.7-6.0).
● A Southwest Oncology Group (SWOG) study comparing lenalidomide plus high dose
dexamethasone to dexamethasone alone found a significantly increased risk of VTE when
lenalidomide was given with high dose dexamethasone (23.5 versus 5 percent) [51].
The risk of VTE appears to be at least partially associated with the dose of dexamethasone that is
combined with lenalidomide therapy:
● An Eastern Cooperative Oncology Group (ECOG) randomized trial of lenalidomide plus either
high-dose or reduced-dose dexamethasone for newly diagnosed MM patients was temporarily
halted because of an increased incidence of VTE in the absence of routine
thromboprophylaxis with rates of VTE of 18 and 3.7 percent in patients receiving high-dose
and low-dose dexamethasone, respectively [50].
● A randomized trial in 445 patients with newly diagnosed myeloma found a significantly lower
rate of VTE with the use of lenalidomide plus a lower dose of dexamethasone (40 mg orally on
days 1, 8, 15, and 22 of each 28-day cycle) compared with lenalidomide plus the standard
high dose dexamethasone (40 mg days 1 to 4, 9 to 12, 17 to 20 every 28 days) of 12 versus
26 percent, respectively [52].
The use of VTE prophylaxis can decrease the risk of thrombotic disease among patients receiving
lenalidomide plus dexamethasone. As an example, an expanded access program of lenalidomide
plus dexamethasone in 1438 patients with relapsed myeloma that recommended VTE prophylaxis
for all enrollees reported VTE in 3 percent [43]. Similarly, a study of lenalidomide and
dexamethasone plus bortezomib in patients with newly diagnosed MM that required VTE
prophylaxis with at least aspirin reported an incidence of VTE of 6 percent [53].
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 [54]. No
information was provided regarding thrombosis prophylaxis among the patients who
developed clots on this trial.
In a randomized trial comparing lenalidomide to lenalidomide plus rituximab in 91 patients with

follicular NHL, nine patients developed a grade 3/4 thrombosis [55]. 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. Most VTEs occurred within one year from diagnosis of AL amyloidosis,
and the incidence related to immunomodulatory agent (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 [56].
Smaller non-randomized 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 [57,58]. All patients in both trials received at least daily aspirin as VTE prophylaxis.
● Ovarian cancer – In a phase 2 trial of 45 patients with ovarian cancer treated with
lenalidomide, five (11 percent) developed DVTs [59]. All five were among the 30 patients who
did not receive any thrombosis prophylaxis as part of their therapy.
Pomalidomide — There is relatively less data regarding the risk of VTE among patients with
MM 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/refractory MM, no prophylaxis was administered and four patients (17
percent) developed VTE [60]. One clot occurred three weeks into therapy in the lower extremity of
a patient subsequently recognized as having malignant melanoma-associated adenopathy,
whereas the others occurred after four, nine, and 11 months of pomalidomide therapy.
Subsequent trials investigating the use of pomalidomide plus low dose dexamethasone (Pd) have
routinely included thromboprophylaxis with aspirin or other agents [61-65]. 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)
[66]. 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) [67].
VENOUS THROMBOEMBOLISM PROPHYLAXIS
Choice of agent — As described above, patients with MM treated with immunomodulatory drugs
(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. In comparison, the rate of VTE decreases to less than 10 percent when VTE prophylaxis
is administered. As a result, we recommend the routine use of VTE prophylaxis for patients with
MM who are treated with a combination therapy regimen that contains an immunomodulatory drug.
Our approach is consistent with recommendations from the International Myeloma Working Group
and the American Society of Clinical Oncology [16,68]. (See 'Thalidomide-based therapy' above.)
There are no randomized trials comparing treatment with these agents 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 [12,42,50,69,70]:
● The incidence of thrombosis in myeloma is higher during treatment of newly diagnosed

disease compared with relapsed or refractory disease.
● The risk of thrombosis is also influenced by other medications administered; the risk is higher
when immunomodulatory drugs are combined with higher doses of corticosteroids [42,70].
Some, but not all, analyses have also suggested an increased thrombosis risk in patients
receiving recombinant human erythropoietin in addition to immunomodulatory drugs
[12,42,50,69].
● The incidence of VTE is almost certainly affected by the degree of physician vigilance in
identifying such events (eg, mandatory ultrasound monitoring versus clinical observation
alone).
Despite the above caveats, the incidence of thrombotic complications appears to be reduced in
patients receiving combination therapy that contains an immunomodulatory drug, using one of the
following three strategies [68,71]:
● Warfarin, either fixed dose or full dose with a target INR of 2.0 to 3.0
● Therapeutic or prophylactic dose of low molecular weight heparin
● Aspirin (81 to 325 mg/day)
A choice among these strategies may be based on the baseline risk of VTE associated with a
given regimen and patient risk factors. 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 immunomodulatory agents are used in combination with aspirin, corticosteroids, and/or
chemotherapy.
Risk stratification — The decision to give one of the above drugs and the choice of drug for
thromboprophylaxis needs to consider the baseline risk of VTE associated with a given regimen
and the presence or absence of risk factors for thromboembolism. Our approach is similar to that
proposed by the International Myeloma Working Group [16].
Patients should be assessed for the following risk factors:
● Body mass index ≥30 kg/m2 (calculator 1)

● Previous VTE
● Central venous catheter or pacemaker
● Cardiac disease (eg, symptomatic coronary artery disease, congestive heart failure, or history
of stent placement/CABG)
● Chronic kidney disease (eg, estimated glomerular filtration rate less than 30 mL/min)
● Diabetes mellitus
● Acute infection
● Immobilization
● Use of erythropoietin
● Inherited thrombophilia
● Elevated D-dimer levels
Using these risk factors, patients can be divided into three categories:
● Patients receiving either thalidomide or a thalidomide analogue as a single agent are at lower
risk for VTE and do not require VTE prophylaxis if the risks of daily aspirin are felt to outweigh
the small absolute reduction in expected risk of thrombosis. Support for this approach is based
predominantly on publications involving thalidomide or lenalidomide. Pomalidomide trials have
routinely employed some form of thromboprophylaxis. (See 'Single agent thalidomide' above
and 'Lenalidomide in myeloma' above.)
● Patients with no or one VTE risk factor who are not being treated with doxorubicin, multiagent
chemotherapy, or high-dose dexamethasone are considered to be at standard risk for VTE
and should receive VTE prophylaxis. (See 'Standard risk setting' below.)
● Patients with two or more risk factors and any patients being treated with doxorubicin,
multiagent chemotherapy, or high dose dexamethasone (≥480 mg per month) are considered
at higher risk for VTE and require VTE prophylaxis. (See 'High risk setting' below.)
Specific recommendations for the prevention of VTE in cancer patients who are hospitalized or are
undergoing surgery are discussed separately. (See "Prevention of venous thromboembolic disease
in adult nonorthopedic surgical patients" and "Prevention of venous thromboembolic disease in
acutely ill hospitalized medical adults", section on 'Selection of method of prophylaxis'.)
Lower risk setting — The incidence of thrombosis in patients at lower risk, defined as those
treated with single agent thalidomide or lenalidomide, is approximately 1 to 5 percent, which is
similar to the background rate of VTE in patients with multiple myeloma not receiving treatment
with one of these agents [20-23]. Thus, in the absence of other indications for VTE prophylaxis,
patients taking single agent thalidomide or lenalidomide do not require VTE prophylaxis if the risks
of daily aspirin are felt to outweigh the small absolute reduction in expected risk of thrombosis [16].
Support for this approach is based predominantly on publications involving thalidomide or
lenalidomide. Pomalidomide trials have routinely employed some form of thromboprophylaxis.
Standard risk setting — Patients with no or one VTE risk factor who are not receiving high-
dose dexamethasone, doxorubicin, or multiagent chemotherapy are considered to be at standard
risk for VTE. 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 aspirin rather than warfarin or prophylactic dose low molecular
weight heparin (LMWH). This preference is largely based upon the lower cost and ease of
administration of aspirin and randomized trials that demonstrated similar rates of serious
thromboembolic events with each of these agents, as described below.
An open-label phase III trial included 667 patients with previously untreated myeloma who received
thalidomide-containing induction therapy and had no clinical indication or contraindication to
specific antiplatelet or anticoagulant therapy; the patients were randomly assigned to aspirin (100
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mg daily), fixed low-dose warfarin (1.25 mg daily), or LMWH (enoxaparin 40 mg once daily) [71].
The following findings were noted:
● The rate of a composite endpoint of serious thromboembolic events (symptomatic DVT,

pulmonary embolism, or arterial thrombosis), acute cardiovascular events (myocardial
infarction or stroke), and sudden death during the first six months of therapy was not
significantly different in the three groups (6.4, 8.2, and 5.0 percent, respectively), 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
myeloma 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 [72]. 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 'Thalidomide-based therapy' above.)
High risk setting — Patients receiving immunomodulatory drugs who have two or more risk
factors or are receiving concomitant high-dose dexamethasone (≥480 mg per month), doxorubicin,
or multiagent chemotherapy are considered at higher risk of VTE. The ideal agent for VTE
prophylaxis in this setting is unknown and clinical practice varies widely. For patients at higher risk
of VTE treated with thalidomide-, lenalidomide-, or pomalidomide-containing therapy, we suggest
the use of prophylactic dose of low molecular weight heparin (LMWH) or therapeutic
anticoagulation with either LMWH or adjusted-dose warfarin with a target INR of 2.0 to 3.0 rather
than aspirin. This preference is largely based upon the data suggesting efficacy of full dose
warfarin and LMWH and the uncertainty of the efficacy of aspirin in this setting. The choice of
prophylactic LMWH versus full anticoagulation in this setting may be based in part on the patient’s
risk for bleeding complications (see 'Patients at high risk of bleeding' below).
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 in this setting, dose reduction is
suggested.
There have been no randomized trials comparing VTE prophylaxis strategies in this higher risk
population. Single-arm studies suggest that the use of either full-dose warfarin or prophylactic dose
LMWH reduces the incidence of VTE associated with thalidomide or lenalidomide therapy. Data on
the efficacy of aspirin in this setting have been mixed.
Warfarin — Full-dose warfarin, with a target INR of 2.0 to 3.0, may be used for VTE
prophylaxis in high-risk patients with multiple myeloma being treated with thalidomide or
lenalidomide combinations. The potential benefit of full-intensity anticoagulation with warfarin, in
comparison to a fixed low-dose warfarin, is suggested by the following studies:
● In one study, VTE prophylaxis with a fixed, low dose of warfarin (1 mg/day) was inadequate to
prevent VTE in patients undergoing myeloma induction therapy with chemotherapy plus
thalidomide (400 mg/day) [20]. Eleven of 35 patients (31 percent) treated in this fashion
developed VTE. In an update of the experience from this center, the incidence of VTE among
162 patients receiving low dose warfarin as prophylaxis during combined chemotherapy and
thalidomide induction therapy was 34 percent [73].
● In a second report, prophylaxis with low dose warfarin (1 mg/day) was not effective in
preventing VTE in myeloma patients being treated with thalidomide plus dexamethasone [19].
Six of 24 patients given low dose warfarin developed VTE (25 percent), compared with none
of 16 patients treated with full-dose warfarin (target INR 2.0 to 3.0) or LMWH.
● In a retrospective review in 131 patients treated with thalidomide, VTE was noted in 18 of 76
patients (24 percent) not receiving anticoagulation and 3 of 55 patients (5 percent) receiving
either low-dose warfarin (1 of 37, 3 percent) or conventional-dose warfarin (2 of 18, 11
percent) [24]. The effectiveness of low dose warfarin in this report may be explained by the
lower mean/median dose of thalidomide (200 mg/day) used in these patients, although there
are no data clearly demonstrating a dose-effect relationship for thalidomide and thrombosis
risk.
In summary, full dose prophylactic anticoagulation with warfarin appears effective in reducing the
incidence of VTE associated with thalidomide or lenalidomide therapy, although only a small
number of patients have been evaluated. More data are needed to determine the relative efficacies
of low-dose versus full-dose warfarin prophylaxis.
Low molecular weight heparin (LMWH) — The use of prophylactic doses of the LMWH
enoxaparin (40 mg/day subcutaneously [SQ]) appears to reduce the frequency of thrombotic
events in myeloma patients receiving immunomodulatory therapy with thalidomide or lenalidomide.
● In the context of a randomized trial of more than 400 patients, the incidence of VTE among
patients at high risk for VTE treated with a thalidomide containing regimen plus daily LMWH
prophylaxis was not statistically different from that seen in patients treated with a
chemotherapy regimen that did not contain thalidomide and who were not given VTE
prophylaxis (9 versus 5 percent) [74].
● 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 [33]. Because of this high incidence, the next 64 patients
received thromboprophylaxis with enoxaparin (40 mg/day SQ) for the first four cycles (months)
of therapy, with an incidence of VTE of 3.1 percent (two patients). These two patients
developed VTE within two months of discontinuation of enoxaparin.
● In a randomized trial of high dose melphalan with autologous hematopoietic cell rescue with or
without thalidomide therapy, VTE was diagnosed in 34 percent of the initial 162 patients
randomly assigned to receive thalidomide in the absence of VTE prophylaxis [73]. The
subsequent 152 patients randomly assigned to thalidomide received prophylactic LMWH, but
still demonstrated an incidence of VTE of 24 percent, a concerning rate of thrombosis.
Therapeutic anticoagulation might be considered during induction therapy with the intensive,
anthracycline-containing regimen used in this particular report.
● A single institution retrospective study reported that only one in 45 patients with relapsed
refractory myeloma treated with lenalidomide and dexamethasone given in conjunction with
LMWH developed VTE [75].
Although the data are mixed, these results suggest that LMWH decreases the rate of VTE among
the patients treated with thalidomide or lenalidomide-containing regimens to less than 10 percent.
Aspirin — Aspirin appears to be an acceptable form of VTE prophylaxis among patients with
multiple myeloma at standard risk of developing VTE during treatment with thalidomide or
lenalidomide-containing combination therapy. However, low dose aspirin has not been directly
compared with warfarin or LMWH in the treatment of patients at high risk of developing VTE. (See
'Standard risk setting' above.)
Investigators at the Cleveland Clinic evaluated the effectiveness of low dose aspirin (81 mg/day) in
reducing the risk of thrombosis following the use of thalidomide [39]. 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 non-randomized comparison (ie, 18 versus 58 percent), it was not
completely protective against the development of thrombosis.
It is not clear whether the risk of thrombosis can be further reduced using a higher dose of aspirin
(eg, 325 mg/day) or whether aspirin may be sufficient for patients receiving lenalidomide plus
dexamethasone. Prospective studies of lenalidomide plus high dose dexamethasone reported VTE
rates in the range of 20 percent when aspirin was used as thromboprophylaxis during therapy
regimens containing high dose dexamethasone [51,70]. 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 [76].
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, such as LMWH,
as soon as the bleeding risk becomes acceptably low or when the bleeding lesion or bleeding risk
has been reversed [77]. (See "Prevention of venous thromboembolic disease in acutely ill
hospitalized medical adults", section on 'Mechanical methods of thromboprophylaxis'.)
Length of prophylaxis — It is not known whether VTE prophylaxis can be safely discontinued in
patients receiving prolonged therapy with thalidomide or lenalidomide-containing regimens. VTE
prophylaxis is generally administered as long as active therapy is continued [16]. The risk of VTE
appears to be greatest in the first 6 to 12 months of treatment. The risk appears to decrease after
this and is lower among patients treated for relapsed disease than for patients with previously
untreated myeloma.
DIAGNOSIS AND MANAGEMENT OF VENOUS THROMBOEMBOLISM
The diagnosis of venenous thromboembolism (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 general
population. Therapeutic (full dose) anticoagulation is indicated for patients with VTE and should be
started immediately. There have been no studies investigating whether the immunomodulatory
drug (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
immunomodulatory drug 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 been receiving
therapeutic anticoagulation for a minimum of three months. This differs somewhat from general
recommendations related to the duration of anticoagulation for VTE in cancer patients, in which
longer (or indefinite) anticoagulation is common. Since stoppage of the immunomodulatory drug
modifies the overall VTE risk of the patient, we feel that indefinite anticoagulation should be
considered only in myeloma patients who have recurrent VTE. (See "Rationale and indications for
indefinite anticoagulation in patients with venous thromboembolism".)
Patients who have developed a immunomodulatory drug-associated VTE and are receiving
therapeutic anticoagulation, as well as patients who are receiving anticoagulation for other reasons
(eg, atrial fibrillation, prior VTE), can be cautiously treated with an immunomodulatory drug, with an
acceptable risk of subsequent episodes of VTE (approximately 10 percent).
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".)
SUMMARY AND RECOMMENDATIONS
● Patients with multiple myeloma (MM) treated with thalidomide or its analogues lenalidomide
and pomalidomide in combination with other agents (eg, glucocorticoids, doxorubicin, or
erythropoietin) have a rate of venous thromboembolism (VTE) greater than 20 percent. (See
'Thalidomide-based therapy' above.)
● For patients with MM treated with a combination chemotherapy regimen that contains
thalidomide, lenalidomide, or pomalidomide, we recommend the routine use of VTE
prophylaxis (Grade 1B). VTE prophylaxis should be continued for as long as the patient is
receiving treatment with thalidomide, lenalidomide, or pomalidomide. Although the evidence is
weaker, we use the same approach for patients with AL amyloidosis treated with myeloma-like
immunomodulatory drug-containing regimens, particularly in the context of disease-associated
nephrotic range proteinuria.
● 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 10 risk factors (body mass index ≥30 kg/m2, previous VTE, central venous
catheter or pacemaker, cardiac disease, chronic renal disease, diabetes, acute infection,
immobilization, use of erythropoietin, and inherited thrombophilia) (see 'Risk stratification'
above):
• Patients being treated with immunomodulatory drugs who have two or more risk factors or
are receiving concomitant high dose dexamethasone (≥480 mg per month), doxorubicin,
or multiagent chemotherapy are considered to be at higher risk for VTE. For patients at
higher risk of VTE treated with thalidomide-, lenalidomide-, or pomalidomide-containing
therapy, we suggest the use of prophylactic dose low molecular weight heparin (LMWH)
or therapeutic adjusted-dose warfarin with a target INR of 2.0 to 3.0 rather than aspirin
(Grade 2B). (See 'High risk setting' above.)
• Patients with no or one risk factor who are not receiving high dose dexamethasone,
doxorubicin, or multiagent chemotherapy are considered to be at standard risk for VTE.
For patients at standard risk for VTE, we suggest VTE prophylaxis with aspirin rather than
warfarin or prophylactic dose LMWH (Grade 2B). (See 'Standard risk setting' above.)
• Patients receiving either thalidomide or a thalidomide analogue as a single agent are at

lower risk for VTE and do not require VTE prophylaxis if the risks of daily aspirin are felt to
outweigh the small absolute reduction in expected risk of thrombosis. Support for this
approach is based predominantly on publications involving thalidomide or lenalidomide.
Pomalidomide trials have routinely employed some form of thromboprophylaxis. (See
'Lower risk setting' above.)
● VTE prophylaxis is generally administered as long as combination therapy with thalidomide or

a thalidomide analogue is continued. (See 'Length of prophylaxis' above.)
● The diagnosis and management of VTE in patients with MM is similar to the diagnosis and
management of VTE in the general population. (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" and "Overview of the treatment of lower extremity deep vein
thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in
adults".)
● For patients who develop VTE and continue treatment with thalidomide, lenalidomide, or
pomalidomide, we suggest that therapeutic anticoagulation continue for the duration of their
treatment with these agents (Grade 2C). If there have been no further VTE episodes while
receiving thalidomide or thalidomide analogue plus therapeutic anticoagulation, we suggest
that anticoagulation be stopped one month after these agents have been discontinued,
provided that the patient has been receiving therapeutic anticoagulation for a minimum of
three months and has no other indication for anticoagulation (Grade 2C). (See 'Diagnosis and
management of venous thromboembolism' above.)
● Given the potential for gastric irritation with or without thrombocytopenia, we suggest
concurrent use of either an H2-blocker or a proton pump inhibitor when pomalidomide,
lenalidomide, or thalidomide is used in combination with aspirin, corticosteroids, and/or
chemotherapy.
ACKNOWLEDGMENT
The editors of UpToDate 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.
Use of UpToDate is subject to the Subscription and License Agreement.
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73. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for
multiple myeloma. N Engl J Med 2006; 354:1021.
74. Minnema MC, Breitkreutz I, Auwerda JJ, et al. Prevention of venous thromboembolism with
low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and
chemotherapy. Leukemia 2004; 18:2044.
75. Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications

with low molecular weight heparin in relapsed multiple myeloma patients treated with
lenalidomide and dexamethasone. Ann Hematol 2009; 88:67.
76. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus
dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 106:4050.
77. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
2008; 133:381S.
Topic 1332 Version 22.0
Contributor
Disclosures
Jeffrey
Zonder,
MD Grant/Research/Clinical Trial Support: Celgene [amyloidosis (lenalidomide,
thalidomide, pomalidomide [IMiDs])]. Consultant/Advisory Boards: Alnylam [Amyloidosis (patisiran)]; Celgene
[myeloma, amyloidosis (IMiDs)]; Janssen [myeloma, amyloidosis (daratumumab)]; BMS [myeloma,
amyloidosis (elotuzumab)]; Seattle Genetics [myeloma, amyloidosis (investigational mAb)]; Takeda [myeloma,
amyloidosis (bortezomib, ixazomib)]; Prothena [myeloma, amyloidosis (NEOD001)]; Amgen [myeloma,
amyloidosis (carfilzomib)]; Caelum [amyloidosis (CAEL-101)]; Oncopeptides [myeloma (melflufen)]. Other
Financial Interest (contributor and spouse): MMRF travel grant supported by Takeda and CURE magazine
[Moving Mountains for Multiple Myeloma Fundraising team for the MMRF]. Charles
A
Schiffer,
MD Grant/Research/Clinical Trial Support: Takeda [CML (ponatinib)]. Consultant/Advisory Boards: Celgene
[AML, thrombotic complications (5-azacytidine, lenalidomide)]; Takeda [DSMB, advisory board AML]; Astellas
[DSMB and advisory board related to AML]; Juno (now Celgene) [DSMB related to CAR-T cells]; NCRI -
United Kingdom [DSMB CML]; Leukemia/Lymphoma Society [DSMB AML]. Robert
A
Kyle,
MD Consultant/Advisory Boards: Celgene Disease Monitoring Committee [Dysproteinemias (lenalidomide,
pomalidomide)]; Bristol-Myers Squibb Independent Monitoring Committee [Dysproteinemias (elotuzumab)];
Onyx Pharma (Amgen) Data Monitoring Committee [Dysproteinemias (carfilzomib)]; Pharmacyclics Data
Safety Monitoring Board [Dysproteinemias (ibrutinib)]. Other Financial Interest: Pfizer [Lecture on therapy of
multiple myeloma, made comments concerning a new Pfizer product and received an honorarium]. Rebecca
F
Connor,
MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

Multiple Myeloma - Prevention of Venous Thromboembolism in Patients Receiving Immunomodulatory Drugs (Thalidomide, Lenalidomide, and Pomalidomide)

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20/09/2019 Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pom…

Official reprint from UpToDate®

Multiple myeloma: Prevention of venous

● Thalidomide increases endothelial cell expression of protease activated receptor-1 (PAR-1)

● Down-regulation of PU.1 by immunomodulatory derivatives such as thalidomide and

INCIDENCE AND RISK FACTORS

● A third study observed one thromboembolic event during thalidomide monotherapy in 28

● A second study observed thrombotic complications in 6 of 50 patients with newly diagnosed

Thalidomide plus melphalan and prednisone — Adding thalidomide to melphalan and

Thalidomide plus anthracycline — Regimens utilizing thalidomide in combination with

Lenalidomide in other conditions — Prospective studies have also suggested an increased

● Non-Hodgkin lymphoma (NHL) – In a phase 2 trial, thromboses developed in 5 of 110 patients

In a randomized trial comparing lenalidomide to lenalidomide plus rituximab in 91 patients with

● AL amyloidosis – In a large retrospective analysis of approximately 900 patients with AL

VENOUS THROMBOEMBOLISM PROPHYLAXIS

● The incidence of thrombosis in myeloma is higher during treatment of newly diagnosed

Patients should be assessed for the following risk factors:

● Body mass index ≥30 kg/m2 (calculator 1)

● The rate of a composite endpoint of serious thromboembolic events (symptomatic DVT,

● A similar incidence of the primary composite endpoint of confirmed symptomatic DVT,

DIAGNOSIS AND MANAGEMENT OF VENOUS THROMBOEMBOLISM

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

• Patients receiving either thalidomide or a thalidomide analogue as a single agent are at

● VTE prophylaxis is generally administered as long as combination therapy with thalidomide or

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1. Dimopoulos MA, Anagnostopoulos A, Weber D. Treatment of plasma cell dyscrasias with

2. Corso A, Lorenzi A, Terulla V, et al. Modification of thrombomodulin plasma levels in

4. Zangari M, Saghafifar F, Anaissie E, et al. Activated protein C resistance in the absence of

10. Cini M, Zamagni E, Valdré L, et al. Thalidomide-dexamethasone as up-front therapy for

21. Srkalovic G, Cameron MG, Rybicki L, et al. Monoclonal gammopathy of undetermined

22. Glasmacher A, Hahn C, Hoffmann F, et al. A systematic review of phase-II trials of

Haematol 2005; 74:40.

38. Zangari M, Siegel E, Barlogie B, et al. Thrombogenic activity of doxorubicin in myeloma

47. Yang X, Brandenburg NA, Freeman J, et al. Venous thromboembolism in myelodysplastic

59. Selle F, Sevin E, Ray-Coquard I, et al. A phase II study of lenalidomide in platinum-sensitive

67. Sanchorawala V, Shelton AC, Lo S, et al. Pomalidomide and dexamethasone in the

71. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis

randomized trial. J Clin Oncol 2011; 29:986.

72. Larocca A, Cavallo F, Bringhen S, et al. Aspirin or enoxaparin thromboprophylaxis for

75. Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications

Topic 1332 Version 22.0

Conﬂict of interest policy

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