Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide.

Abstract

Lenalidomide plus dexamethasone is effective in the treatment of multiple myeloma (MM) but is associated with an increased risk of venous thromboembolism (VTE). This prospective, open-label, randomized substudy of a phase 3 trial compared the efficacy and safety of thromboprophylaxis with low-dose aspirin (ASA) or low-molecular-weight heparin (LMWH) in patients with newly diagnosed MM, treated with lenalidomide and low-dose dexamethasone induction and melphalan-prednisone-lenalidomide consolidation. Overall, 342 patients who did not have clinical indications or contraindications to antiplatelet or anticoagulant therapy were randomly assigned to receive ASA 100 mg/d (n = 176) or LMWH enoxaparin 40 mg/d (n = 166). The incidence of VTE was 2.27% in the ASA group and 1.20% in the LMWH group. Compared with LMWH, the absolute difference in the proportion of VTE was 1.07% (95% confidence interval, -1.69-3.83; P = .452) in the ASA group. Pulmonary embolism was observed in 1.70% of patients in the ASA group and none in the LMWH group. No arterial thrombosis, acute cardiovascular events, or sudden deaths were reported. No major hemorrhagic complications were reported. In previously untreated patients with MM receiving lenalidomide with a low thromboembolic risk, ASA could be an effective and less-expensive alternative to LMWH thromboprophylaxis.

Full text

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doi:10.1182/blood-2011-03-344333
Prepublished online August 11, 2011;




Caravita Di Toritto, Mario Boccadoro, Arnon Nagler and Antonio Palumbo
Siniscalchi, Claudia Crippa, Maria Teresa Petrucci, Dina Ben Yehuda, Eloise Beggiato, Tommaso
Michele Cavo, Jacopo Peccatori, Lucio Catalano, Angelo Michele Carella, Anna Maria Cafro, Agostina
Evangelista, Maide Cavalli, Anfisa Stanevsky, Paolo Corradini, Sara Pezzati, Francesca Patriarca,
Alessandra Larocca, Federica Cavallo, Sara Bringhen, Francesco Di Raimondo, Anna Falanga, Andrea
myeloma patients treated with lenalidomide
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LAROCCA et al ASA OR LMWH FOR NDMM PATIENTS TREATED WITH Rd
1
Aspirin or enoxaparin thromboprophylaxis for newly-diagnosed multiple myeloma patients treated
with lenalidomide

Alessandra Larocca,1 Federica Cavallo,1 Sara Bringhen,1 Francesco Di Raimondo,2 Anna Falanga,3
Andrea Evangelista,4 Maide Cavalli,2 Anfisa Stanevsky,5 Paolo Corradini,6 Sara Pezzati,7 Francesca
Patriarca,8 Michele Cavo,9 Jacopo Peccatori,10 Lucio Catalano,11 Angelo Michele Carella,12 Anna Maria
Cafro,13 Agostina Siniscalchi,14 Claudia Crippa,15 Maria Teresa Petrucci,16 Dina Ben Yehuda,17 Eloise
Beggiato,18 Tommaso Caravita Di Toritto,14 Mario Boccadoro,1 Arnon Nagler,5 and Antonio Palumbo1

1Myeloma Unit, Division of Hematology, University of Torino, AOU S Giovanni Battista, Torino, Italy;
2Divisione di Ematologia, Ospedale Ferrarotto, Università di Catania, Catania, Italy; 3Division of
Immunohematology and Tranfusion Medicine, Ospedali Riuniti, Bergamo, Italy; 4Unità di Epidemiologia
dei Tumori, A.O.U. San Giovannni Battista e CPO, Piemonte, Torino, Italy; 5Hematology Division &
Cord Blood Bank, Chaim Sheba Medical Center, Tel-Hashomer, Israel; 6 Fondazione IRCCS Istituto
Nazionale dei Tumori, Università di Milano, Milano, Italy; 7Centro di Ematologia e Trapianto di Midollo,
Azienda Ospedaliera S. Gerardo, Monza, Italy; 8Clinica Ematologica Dipartimento Scienze Mediche
Sperimentali Cliniche, Università di Udine, Udine, Italy; 9Seràgnoli Institute of Hematology, Bologna
University School of Medicine, Bologna, Italy; 10Myeloma Unit, San Raffaele Scientific Institute, Milano,
Italy; 11Divisione di Ematologia, Università Federico II, Napoli, Italy; 12U.O.C.Ematologia 1, Azienda
Ospedaliera Universitaria san Martino-Genova, Italy; 13 S.C. Ematologia, A.O. Niguarda Ca' Granda,
Milano, Italy; 14 Divisione di Ematologia, Ospedale S.Eugenio, Roma, Italy; 15Divisione di Ematologia
Spedali Civili, Brescia, Italy; 16Hematology, Sapienza University of Roma, Italy; 17Hadassah Medical
Center, Jerusalem, Israel; and 18SSCVD Malattie Trombotiche ed Emorragiche dell’adulto, Ospedale
Molinette, Torino, Italy


Blood First Edition Paper, prepublished online August 11, 2011; DOI 10.1182/blood-2011-03-344333
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Copyright © 2011 American Society of Hematology
For personal use only.

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LAROCCA et al ASA OR LMWH FOR NDMM PATIENTS TREATED WITH Rd
2
Correspondence: Dr Antonio Palumbo, Myeloma Unit, Division of Hematology, University of Torino,
AOU S. Giovanni Battista, Torino, 10126, Italy; e-mail: appalumbo@yahoo.com.
Tel.: +39 011 6336728; fax: +39 011 6963737.

Abstract word count: 200 [limit of 200 words]
Text word count: 3592
No. of figures: 2
No. of tables: 3
No. of references: 27

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Abstract
Lenalidomide plus dexamethasone is effective in the treatment of multiple myeloma (MM) but is
associated with an increased risk of venous thromboembolism (VTE). This prospective, open-label,
randomized substudy of a phase 3 trial compared the efficacy and safety of thromboprophylaxis with low-
dose aspirin (ASA) or low-molecular-weight heparin (LMWH) in newly-diagnosed MM patients, treated
with lenalidomide and low-dose dexamethasone (Rd) induction and melphalan-prednisone-lenalidomide
consolidation. Overall, 342 patients who did not have clinical indications or contraindications to
antiplatelet or anticoagulant therapy, were randomized to receive ASA 100 mg/day (n=176) or LMWH
enoxaparin 40 mg/day (n=166). The incidence of VTE was 2.27% in the ASA group and 1.20% in the
LMWH group. Compared with LMWH, the absolute difference in the proportion of VTE was +1.07%
(95% CI, −1.69 to 3.83; P = 0.452) in the ASA group. Pulmonary embolism was observed in 1.70% of
patients in the ASA group and none in the LMWH group. No arterial thrombosis, acute cardiovascular
events, or sudden deaths were reported. No major hemorrhagic complications were reported. In
previously untreated MM patients receiving lenalidomide with a low thromboembolic risk, ASA could be
an effective and less-expensive alternative to LMWH thromboprophylaxis. This study is registered at
http://www.clinicaltrials.gov as NCT00551928.
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Introduction
The annual incidence of venous thromboembolism (VTE), which encompasses deep-vein thrombosis
(DVT) and pulmonary embolism (PE), is greater than 1‰ in the general population,1 but it increases to
more than 7% in cancer patients.2 The risk of cancer-associated thrombosis depends on the type of cancer
the patient has and is particularly high in patients with hematologic malignancies, especially multiple
myeloma (MM). The baseline risk of developing VTE in cancer patients is increased 28-fold compared
with individuals without cancer.3 The introduction of the oral immunomodulatory drugs, thalidomide and
lenalidomide, has improved myeloma outcomes but these agents are also associated with higher rates of
VTE.4,5 Individual risk factors for VTE associated with thalidomide and lenalidomide therapy include:
advanced age; a history of VTE; an indwelling central venous catheter; comorbid conditions (eg,
infections, diabetes, cardiac disease); current or recent immobilization; recent surgery; and inherited
thrombophilic abnormalities.6
Lenalidomide in combination with high-dose dexamethasone is an effective and well-tolerated
treatment for patients with relapsed and refractory MM,7,8 and is also highly effective in patients with
newly-diagnosed MM (NDMM).9 However, lenalidomide in combination with high-dose dexamethasone
is associated with VTE rates of 26%-67% in NDMM patients.9,10 In contrast, the risk of VTE is
significantly reduced to 12% with low-dose dexamethasone.9 In the relapsed/refractory setting, the risk of
VTE in patients treated with lenalidomide plus high-dose dexamethasone is 11%-15%.7,8
Due to the increasing use of immunomodulatory agent-based treatment combinations, the
prevention of VTE has become an important consideration during myeloma treatment.9-13 Based on the
available data, the current American Society of Clinical Oncology guidelines currently recommend
thromboprophylaxis with low-molecular-weight (LMWH) or adjusted-dose warfarin in patients receiving
combination regimens, including lenalidomide.14 The use of LMWH is limited by factors such as a high
cost of treatment, lower patient compliance due to the need for self-injection, and renal impairment. The
International Myeloma Working Group recommends aspirin (ASA) prophylaxis for patients with one or
no VTE risk factors, and LMWH for those with more than one risk factor for VTE.6 The comparative
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efficacy of different single-agent antithrombotic regimens in myeloma is not established. However, a
recent randomized, open-label study in untreated NDMM patients reported that ASA and fixed low-dose
warfarin were as effective as LMWH in reducing the incidence of serious thrombotic events associated
with thalidomide regimens.15
The aim of this substudy of a phase 3, multicenter, randomized controlled clinical trial was to
compare the efficacy and safety of LMWH and ASA, in preventing VTE in MM patients treated with
lenalidomide as first line therapy.

Materials and methods
Study design and treatment
This open-label, multicenter randomized trial was conducted at 62 centers in Italy and Israel from
November 2007 to June 2009, as a substudy of the phase 3 randomized controlled trial RV-MM-PI209.
This study compared the efficacy and safety of the consolidation regimen melphalan-prednisone-
lenalidomide (MPR) with the standard high-dose melphalan 200 mg/m2 (Mel200) regimen followed by
tandem stem-cell transplantation in patients with NDMM. The aim of the substudy was to compare the
effectiveness and safety of ASA and LMWH as antithrombotic prophylaxis in patients receiving
lenalidomide-based induction and consolidation therapy.
The study was approved by the institutional review board at each of the participating centers. All
patients gave written informed consent before entering the study, which was performed in accordance
with the Declaration of Helsinki. The study was designed by the investigators, who were also responsible
for the data collection; A.L., F.C. and A.E. analyzed the data; all authors had access to the primary
clinical trial data.

Patient populations and randomization
Previously untreated NDMM patients, aged between 18 and 65 years, enrolled in the phase 3 trial were
assessed for eligibility to enroll in the substudy. Eligible patients had no history of DVT or arterial
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thromboembolic events within the past 12 months, no clear indication or contraindication for antiplatelet
or anticoagulant therapy, had no active bleeding, and were not considered to be at high risk of bleeding.
Eligible patients were randomly assigned to receive ASA 100 mg/day orally, or LMWH enoxaparin 40
mg/day subcutaneously, using a simple randomization sequence run by a central computer, which
generated an automated assignment procedure that was concealed from the investigators in each study
center.
All patients enrolled in the substudy received induction with lenalidomide plus low-dose
dexamethasone (Rd) treatment comprising four 28-day cycles of lenalidomide (25 mg/day orally for 21-
days) in combination with dexamethasone (40 mg/day orally on days 1, 8, 15 and 22), followed by
cyclophosphamide (4 g/m2) for stem-cell mobilization and collection before entering the consolidation
phase with either MPR or Mel200. The MPR consolidation phase comprised six 28-day cycles of
lenalidomide 10 mg/day for 21-days, melphalan 0.18 mg/kg for 4-days, and prednisone 2 mg/kg for 4
days.

Study interventions
Prophylaxis was administered during the four cycles of Rd therapy and the six cycles of MPR
consolidation. Patients who were assigned to the Mel200 consolidation arm stopped thromboprophylaxis
at this point. Antithrombotic prophylaxis was discontinued in any patient who developed DVT, PE,
arterial thrombosis, any acute cardiovascular or bleeding event, or those who had a platelet count of
≤50 000/μL. Patients attended clinic study visits every 2 weeks during the first two cycles of Rd or MPR,
then every 4 weeks for the last two cycles of Rd and the last four cycles of MPR in order to assess the
effectiveness and safety of treatment; subsequently, patients attended visits at the physician’s discretion,
and the incidence of thromboembolism in the absence of prophylaxis was also evaluated.

Outcome measures
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The primary endpoint was a composite measure defined as: the proportion of patients developing a first
episode of objectively confirmed symptomatic DVT, PE, arterial thrombosis, any acute cardiovascular
event (acute myocardial infarction or stroke); or sudden, otherwise unexplained, death (presumed to be
due to PE, acute myocardial infarction, or stroke) in the first 6 months after randomization. Secondary
endpoints included the incidence of major and minor bleeding events and any other complications related
to thromboprophylaxis.
All adverse events were assessed and graded according to the National Cancer Institute Common
Terminology Criteria for Adverse Events (version 3.0).16 Major bleeding was defined as fatal bleeding,
symptomatic bleeding in a crucial area or organ, bleeding causing a reduction in hemoglobin
concentration of at least 2 g/dL, or necessitating transfusion of at least 2 units of whole blood or red blood
cells.17 The incidence of minor bleeding comprised all bleeding events that did not meet the criteria for
major bleeding.
Data on age, gender, performance status according to Karnofsky score, standard prognostic
parameters (serum levels of creatinine, β2-microglobulin, and serum albumin), and comorbidities
(diabetes, cardiovascular disease, orthopedic surgery, dislipidemia, prior thromboembolism, and
concomitant recombinant human erythropoietin administration) were collected.

Statistical analysis
The main planned comparison was ASA versus LMWH during the first 12-months after randomization.
The statistical power and the minimum effect size detectable in this substudy was determined according
to the prevalence of patients without a clear indication to anticoagulant or antiplatelet therapy in the
sample size of the main phase III trial (RV-MM-PI209). Overall, 402 patients treated with lenalidomide-
containing regimens were randomized, with a 1:1 allocation ratio between the two prophylaxis regimens.
The expected rate of thromboembolic events in NDMM patients treated with lenalidomide-containing
regimens was approximately 12-67%.9,10 Of the 402 patients enrolled in the RV-MM-PI209 study, 60
patients were not eligible for this substudy. The sample size of 342 patients reaches statistical power
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ranging from 47% to 80% to detect an absolute difference of 7% to 11%, respectively, between the
groups, with alpha 0.05 (two tailed), assuming a value of 10% for the composite primary end point in the
LMWH group.
The statistical test used to compare the difference between proportions was the two-sided z-test, with
pooled variance. To compare the incidence of the composite primary endpoint in the two intervention
arms through to follow-up, taking into account the competing risk of death due to any other cause, the
cumulative incidence (adjusted for competing risks) was compared between groups using the Gray’s
test.18 All efficacy and safety analyses were performed according to the intention-to-treat principle and
included all randomized patients who received at least one dose of the study drug. Times of observation
were censored on November 30, 2010.
Data were analyzed in December 2010 using SAS software (version 8.2) with SPSS 18.0.2 (SPSS
Inc., Chicago, IL) packages and R software version 2.5.0 (package cmprsk; open source).

Results
A total of 402 patients aged 65 years and younger with NDMM, were enrolled in the study and received
induction with Rd. Of the 402 patients assessed for eligibility, 342 patients were enrolled in this substudy
and were included in the efficacy and safety analyses; 176 were randomly assigned to receive ASA and
166 were randomized to receive LMWH (Figure 1). Sixty patients were excluded from the substudy
because of a clear indication to anticoagulant therapy (n = 37) or anti-platelet therapy (n = 11), or other
comorbidities (n = 12). The main reasons for exclusion were: recent orthopedic surgery or vertebroplasty,
immobilization, allergy to ASA, concomitant thromboembolism at diagnosis, concomitant disseminated
intravascular coagulation, inherited thrombophilic abnormalities, previous history of coronary ischemic
disease or angioplasty, atrial fibrillation and glucose-6-phosphate-dehydrogenase deficiency.
Baseline patient characteristics are summarized in Table 1. The median age of patients at diagnosis
was similar between the two prophylaxis groups (57 years in the ASA group and 58 years in the LMWH
group). Overall, 49% of the patients in the ASA group and 60% in the LMWH group were male (P =
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.058). According to International Staging System criteria, 43% and 54% of patients in the ASA and
LMWH groups, respectively, had stage I myeloma; for stage II disease these percentages were 31% and
27%, respectively, and for stage III the percentages were 26% and 19%, respectively (P = .082). All
enrolled patients in the study had symptomatic disease requiring anti-myeloma therapy. The two
prophylaxis groups were well-balanced in terms of patient characteristics and the number of comorbid
conditions, as assessed by medical history. Overall 48% of patients in both the ASA and LMWH arms
were assigned to consolidation with MPR and 52% to Mel200. Four patients (2%) in the ASA and 2
patients (1%) in the LMWH group had at least 2 risk factors for VTE.
Overall, 88% of patients in the substudy finished the planned Rd induction therapy; the median
follow-up period was 20 months. During the first 6 months from randomization, the incidence of grade
3/4 DVT and PE was 2.27% (4 of 176) in patients receiving ASA and 1.20% (2 of 166) in patients
receiving LMWH prophylaxis (P = .452; Table 2). Symptomatic PE occurred in 1.70% (3 of 176) patients
in the ASA group; there were no reports of PE in the LMWH group. The 3 patients who experienced PE
had all received concomitant recombinant human erythropoietin during Rd induction. Four patients
treated with ASA experienced a superficial thrombophlebitis; no cases of superficial phlebitis were
reported in the LMWH group. No arterial thrombosis, acute cardiovascular events, or sudden deaths were
reported in either the ASA or LMWH groups (Table 2). The absolute difference in the composite primary
endpoint between the ASA and LMWH groups during the first 6 months of follow-up was +1.07% (95%
CI, −1.69 to 3.83; P = .452), the absolute difference in the incidence of DVT was −0.07% (95% CI, −2.35
to 2.21; P = .953), and the absolute difference in the incidence of PE was +1.70% (95% CI, −0.21 to 3.62;
P = .091) for the ASA versus LMWH groups (Table 2). The cumulative proportions of thromboembolic
events, acute cardiovascular events, and sudden deaths adjusted for competing risks at 12 months were
2.3 (95% CI, 0.1-4.5) in the ASA group and 1.8 (95% CI, 0.0-3.9) in the LMWH group (Figure 2).
The characteristics of patients who experienced grade 3/4 thromboembolic events during the
substudy are detailed in Table 3. The median age at onset of VTE was 57 years. The majority of
thrombotic events occurred early during Rd treatment, with a median time to onset of 1.3 months. The
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median times to onset in the two prophylaxis arms were 0.95 months in the ASA group and 2.13 months
in the LMWH group (Figure 2). One patient in the LMWH group and no patients in the ASA group
experienced a thromboembolic event during consolidation treatment with MPR.
The small number of VTE events precluded meaningful analysis of the relationship between
baseline characteristics and VTE occurrence.
No major bleeding complications were detected during thromboprophylaxis with either ASA or
LMWH (Table 2). Only one event of gastrointestinal minor bleeding, which had a complete and
spontaneous resolution, was reported in the LMWH group.
The median duration of prophylaxis was 3.6 and 3.5 months in the ASA and LMWH groups,
respectively. Twelve patients (6.8%) in the ASA group and 5 patients (3%) in the LMWH group
discontinued prophylaxis prematurely, mainly due to progressive disease during Rd induction (6 patients
in the ASA group and 3 patients in the LMWH group) and adverse events (3 patients in the ASA group
and 1 patient in the LMWH group).

Discussion
This is the first large prospective randomized study comparing ASA and LMWH thromboprophylaxis in
NDMM patients treated with an Rd induction regimen. Our findings show that in NDMM patients
without a high individual risk of VTE, and without a clear indication to anticoagulant or antiplatelet
therapy, prophylaxis with either ASA or LMWH during lenalidomide-based induction treatment is
associated with a low VTE incidence. The incidence of VTE was 2.27% in the ASA group and 1.20% in
the LMWH group. No acute cardiovascular events and sudden deaths were reported. In our study the
majority of thromboembolic events occurred early during the first months of lenalidomide therapy.
Treatment was delayed in patients experiencing a VTE, but no discontinuations or treatment interruptions
due to thromboembolic events were reported. No evidence of early or late deaths due to
thromboembolism was seen during lenalidomide treatment.
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In patients receiving Rd at diagnosis, and for whom antithrombotic prophylaxis was not mandatory,
the incidence of VTE was 12%.9 The VTE rate observed during Rd induction and MPR consolidation in
our study was much lower than previously reported in NDMM patients. Due to the fixed sample size of
the main trial RV-MM-PI209 it was not possible to increase the power of the substudy.
Prevention of VTE is an important consideration during myeloma treatment because of the
increasing use of immunomodulatory agent-based treatment combinations. The development of
thrombotic events is a potentially life-threatening complication that may lead to treatment
discontinuations, increases in patient morbidity, and increased healthcare costs. A recent population-based
study found that the rate of hospitalization due to VTE in a large cohort of cancer patients was more than
double that in a cohort of the general population (1.8% vs 0.8%, respectively).19 The risk of VTE in
cancer patients was increased eight-fold during the first year after cancer diagnosis, declining thereafter
but remaining twice as high as in individuals without cancer.19
In our trial, no significant differences in VTE incidence and safety profile were found between
patients treated with ASA and LMWH, but our study includes in myeloma patients who had a standard
risk of VTE, in other words in those whose risk was not increased due to the presence of individual
factors such as advanced age, inherited thrombophilic abnormalities, recent surgery, or a history of VTE.
Three PE events were observed in patients receiving ASA, whereas no PE was detected in the LMWH
group. These findings are comparable with the results of another study carried out by our group on
thromboprophylaxis in NDMM patients treated with thalidomide-based regimens. We reported that ASA
and low-dose warfarin were as effective as LMWH in reducing the incidence of VTE, acute
cardiovascular events and sudden deaths, with the exception of elderly patients for whom warfarin
showed less efficacy than LMWH.15 Further clinical studies are required to evaluate the role of initial
short-term treatment with LMWH, followed by long-term ASA to reduce the risk of PE, regardless of
baseline individual thrombotic risk.
In the present study, the concomitant use of erythropoietin is the only risk factor reported in
patients who experienced PE. A previous trial has also reported an increased incidence of VTE in cancer
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patients treated with erythropoiesis-stimulating agents, compared with patients who did not receive this
support (7% vs 1%, respectively).20 In our trial, no direct correlation between the use of erythropoietin
and the incidence of VTE can be suggested due to the limited number of events reported, but further
evaluations are warranted.
Although arterial thrombotic events are rare and little is known about the underlying mechanisms,
they are increasingly recognized as a complication of hematologic cancer. A recent report, including
population-based data from 18 627 patients with MM, found an increased risk of both arterial thrombosis
and VTE compared with matched controls.21 Case reports of patients treated with thalidomide also
suggest that arterial thrombosis may be an adverse effect of this drug. In one study, including 195
previously untreated young patients, the incidence of arterial thrombosis was 5.6%, independent of
induction treatment and was strongly associated with well-known risk factors, including hypertension and
smoking.22 Therefore, we included both venous and arterial events as endpoints in the present study.
However, no arterial thromboses were reported, probably due to the exclusion of patients receiving long-
term antithrombotic treatment. Furthermore, our study population comprised of young patients, with a
relatively low incidence of risk factors for arterial thrombosis, such as hypertension.
Patients with MM are at higher risk of developing thrombocytopenia due to disease infiltration of
the bone marrow and as an adverse effect of cytotoxic therapy. This may increase the risk of bleeding
associated with thromboprophylaxis in myeloma. In the present study no major bleeding events were
reported in association with low-dose ASA, indicating that this may be a safe prophylactic option in
patients with NDMM. Other studies on thromboprophylaxis in cancer patients have, however, reported
conflicting results regarding the risk of bleeding associated with ASA prophylaxis,23-25 and further
evaluation is needed. Myeloma patients require regular and continued monitoring of platelet counts
during MM treatment and during thromboprophylaxis. If thrombocytopenia develops, ASA should be
withheld when the platelet count falls to 50 000/µL and the dose of the LMWH reduced. A 50% reduction
in LMWH dose is recommended for patients with a platelet count below 50 000/µL, with LMWH
treatment discontinued if the platelet count is less than 20 000/µL.26
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A major strength of the study is the prospective and randomized design that enabled us to analyse a
well-defined group of previously untreated myeloma patients; almost all the randomized patients were
included in the efficacy and safety analysis. However, the study had several limitations. Firstly, only a
small number of VTE events were detected which limited our analysis of the associations between patient
risk factors and the development of VTE. However, thrombotic events did not appear to be associated
with well-known risk factors for VTE, including infections, diabetes, cardiac disease, immobilization,
surgery, and inherited thrombophilia. Patient selection was the second significant limitation of our study
because only patients with standard risk of VTE aged less than 65 years were included. Patients with high
risk of VTE, such as those with a history of thromboembolism, severe cardiovascular disease,
uncontrolled diabetes, infections, immobilization or surgery, were excluded from the substudy because
they had a clear indication or contraindication to a specific anticoagulant or antiplatelet therapy. Finally, a
placebo comparison was not possible for ethical reasons because of the known high VTE risk associated
with lenalidomide and dexamethasone treatment regimens.
The 2008 International Myeloma Working Group consensus statement on the prevention of
thrombosis associated with thalidomide and lenalidomide recommends specific thromboprophylaxis
strategies according to the type of therapy and the individual risk of patients, taking into account bleeding
and clotting risks.6 Our results support the use of VTE risk stratification-based prophylactic strategies,
and may suggest a new consensus for antithrombotic prophylaxis. With the exception of clear indications
or contraindications, the use of ASA and LMWH could be optimized by adopting the following approach.
Following an individualized thrombotic risk assessment, prophylaxis with LMWH should be mandatory
in patients at high risk of VTE during induction therapy with lenalidomide. However, ASA could be a
safe and effective option during induction therapy with lenalidomide for standard-risk patients with no or
only one VTE risk factor, and for prophylaxis during long-term treatment, such as consolidation and
maintenance with lenalidomide, in order to reduce the occurrence of late thromboembolic events.
The potential benefit and the safety profile of next generation oral anticoagulants, including direct
thrombin inhibitors (dabigatran etexilate), Xa inhibitors (rivaroxaban, apixaban) and defibrotide, could be
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LAROCCA et al ASA OR LMWH FOR NDMM PATIENTS TREATED WITH Rd
14
assessed in patients with MM receiving immunomodulatory drugs. In a phase I/II study, only one VTE
event was detected with defibrotide in combination with MPT, in relapsed/refractory MM patients
without further thromboprophylaxis. 27 Defibrotide exerts a spectrum of pleiotropic effects on
endothelium, hemostasis and stroma, that makes it a potential protective agent against thromboembolism.
In conclusion, this study demonstrates that the risk of VTE in patients with NDMM receiving
lenalidomide is low upon prophylaxis. LMWH demonstrated a clear benefit in reducing lenalidomide-
associated VTE complications, whereas ASA was not as effective in preventing PE. ASA could be
considered an alternative option to LMWH for prophylaxis in untreated NDMM patients, with low
individual risk of thrombosis, with the advantages of oral administration, safe use in comorbid conditions
(eg, renal insufficiency), no need for regular coagulation monitoring, being inexpensive and the
possibility of long-term administration. However, the small number of events detected makes it difficult
to draw general conclusions and further evaluations to optimize patient care are still needed.

Acknowledgements
We thank the patients who agreed to participate in this study, the nurses, in particular Elena Ponticelli and
Maria Marcella Lionetti, the data managers Maria Josè Fornaro, Jessica Mastrovito, Giulia Lupparelli,
and Debora Caldarazzo, and the editorial assistant Giorgio Schirripa. The study RV-MM-PI209 was
funded by Fondazione Neoplasie Sangue Onlus. Celgene supplied free Lenalidomide for the study RV-
MM-PI209. Celgene had no role in the study design, data analysis, data interpretation, or writing of the
report. The authors would like to acknowledge Excerpta Medica for linguistic improvement, formatting of
the manuscript, and artwork.

Authorship
Contribution: M.B. and A.P. designed the research; A.L. and F.C. collected, analyzed, and interpreted
data; A.E. performed statistical analysis; A.L., F.C., M.B., and A.P. wrote the manuscript; S.B., F.D.R.,
A.F., M.C., A. Stanevsky., P.C., S.P., F.P., M.C., J.P., L.C., A.M.Carella, A.M. Cafro, A. Siniscalchi,
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