CASE REPORT

Increased Risk of Ischemic Stroke in Multiple Myeloma
Associated With Lenalidomide Treatment: A Case Report
and Review of the Literature
Elena de Celis, MD, María Alonso de Leciñana, MD, PhD, Jorge Rodríguez-Pardo, MD,
Blanca Fuentes, MD, PhD, and Exuperio Díez-Tejedor, MD, PhD

Objective: The aim of the study was to illustrate the increased risk of ischemic stroke in the context of multiple myeloma (MM) under treatment
with lenalidomide combined with dexamethasone.
Methods: This is a case report and literature review.
Results: A 62-year-old woman diagnosed with relapsed MM under treatment with lenalidomide and dexamethasone presented with acute onset
disorientation, disturbed behavior, and aphasia. Cranial computed tomography scan revealed an acute cerebral infarction in the left middle cerebral
artery territory, and brain magnetic resonance imaging showed additional
silent ischemic lesions in other arterial territories. Common stroke etiologies were excluded after an extensive study, leading to a final diagnosis
of cerebral infarction of uncommon cause probably related to MM and
treatment with lenalidomide plus dexamethasone. A literature review provided
84 reports from the license holder, 2 more cases of stroke in patients with MM
receiving lenalidomide and a recurrent stroke in a patient experiencing
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy,
and skin changes (POEMS syndrome) treated with lenalidomide.
Conclusions: Our case exemplifies the need to raise awareness about the
risk of ischemic stroke associated with MM that might be increased by
treatment with lenalidomide and to establish consistent recommendations
regarding thromboprophylaxis to reduce comorbidities and mortality in
these patients.
Key Words: lenalidomide, dexamethasone, ischemic stroke,
hypercoagulable state, thromboprophylaxis

M

ultiple myeloma (MM) is one of the most frequent hematologic malignancies, particularly in populations older than
60 years. It is characterized by a proliferation of plasma cells that
cause an elevation of circulating monoclonal immunoglobulin.1
The incidence of MM in the general population is approximately
3 to 4 cases per 100,000 inhabitants, and it accounts for 1% of
all malignancies.2 Fortunately, therapies have increased survival
in patients with MM, although it still remains an incurable disease.
A frequent complication of MM is venous thromboembolic disease (VTD), which occurs up to 28 times more frequently among
these patients than in the general population.3 Increased risk of arterial thrombosis (including coronary and cerebral ischemia) has
also been reported, especially during the first year after diagnosis4;
given that arterial thrombosis is associated with increased mortality,5

Department of Neurology and Stroke Center, La Paz University Hospital, Autonomous University of Madrid, La Paz University Hospital Health Research
Institute (IdiPAZ), Madrid, Spain.
Address correspondence and reprint requests to Elena de Celis, MD, Hospital
Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain;
E‐mail: elenadececelisruiz@gmail.com
Conflicts of Interest and Source of Funding: The authors have no conflicts of
interest to declare.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/WNF.0000000000000310

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METHODS
We present a novel case report and a literature review by a
PubMed search using the keywords “stroke” and “lenalidomide.”
We reviewed resulting articles and their references. We present a
summary of the findings.

RESULTS
Case Report

(Clin Neuropharm 2018;41: 232–235)

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thromboprophylaxis is an important issue in MM management. The
precise mechanisms underlying the increased thrombotic risk in patients with MM are yet unknown, although tumor-related factors,
patient-specific conditions, and effects of antineoplastic treatment
could be considered as potential pathogenic factors.2
Lenalidomide is a highly effective immunomodulatory drug
commonly used in patients with MM. Increased risk of venous
thrombosis with lenalidomide is well known, and arterial thrombosis has also been described.6–8 The use of lenalidomide in combination with dexamethasone has a synergistic antitumoral effect9;
thus, it is usually recommended, although it seems to increase
thrombotic events.10

We present the case of a 62-year-old woman diagnosed with
MM type IgG κ stage IIIA 4 years earlier, with a relapse on treatment with lenalidomide 25 mg daily, dexamethasone 40 mg a
week, darbepoetin 150 mg per month, and simvastatin 20 mg a
day. She suddenly presented disorientation, disturbed behavior,
and aphasia. On admission, a computed tomography (CT) scan
showed an acute cerebral infarction in the left parietal lobe. After
an extensive work-up study, including laboratory tests (hemogram,
coagulation profiles with anticardiolipin antibodies, lipids, glycated
hemoglobin), chest x-ray, transthoracic echocardiogram, 24-hour
Holter electrocardiogram, and ultrasonographic study of intracranial and extracranial arteries, we ruled out significant atheromatosis
and cardiac arrhythmias. We found no signs of deep vein thrombosis, neither did there appear to be reasons to suspect a paradoxical
embolism or other cardiac source of embolism on transthoracic
echocardiogram. Brain magnetic resonance imaging showed the
infarct previously observed in the CT scan and 2 additional ischemic lesions at the left occipital and right frontal cortex, suggesting
silent infarctions in the left posterior cerebral artery and right
middle cerebral artery territories (Fig. 1). After excluding other
etiologies, we diagnosed the patient with cerebral infarctions of
uncommon etiology probably secondary to a hypercoagulable
state induced by MM and lenalidomide plus dexamethasone treatment. We interrupted chemotherapy and the patient was treated
with aspirin 300 mg after hospital discharge. One month after, she
still presented cognitive alterations, although language disturbances
had clearly improved.

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Clinical Neuropharmacology • Volume 41, Number 6, November/December 2018

Stroke in Lenalidomide-Treated Multiple Myeloma

FIGURE 1. Brain magnetic resonance imaging. A, FLAIR sequence showing a left middle cerebral artery infarct and laminar necrosis in the
bilateral frontal cortex and left occipital cortex, suggesting silent infarctions in multiple vascular territories. B, Diffusion-weighted sequence
shows restriction in middle cerebral artery territory, suggesting an acute infarction.

Literature Review
Postmarketing data published by the Medicines and Healthcare Products Regulatory Agency in 2011 included 493 reports of
arterial thrombosis in patients with MM treated with lenalidomide,
representing a 0.5% rate. Most of the events were myocardial
infarctions (65%), followed by cerebrovascular disease (17%),
although no description of the stroke cases was provided.11 The
PubMed search displayed 2 more case reports: a 54-year-old woman
with MM and without any other vascular risk factors who developed
a fatal bilateral cerebral infarction under lenalidomide treatment
without thromboprophylaxis8 and a 34-year-old woman with
polyneuropathy, organomegaly, endocrinopathy, monoclonal
gammopathy, and skin changes (POEMS syndrome) experiencing
recurrent transient ischemic events with a clear temporal relationship with lenalidomide and dexamethasone treatment despite thromboprophylaxis.12 In a recent phase II trial in which
lenalidomide was administered together with rituximab and ibrutinib,
1 case of fatal stroke is also described.13 A summary of the case
reports in the literature review is found in Table 1.

DISCUSSION
Multiple myeloma is a known risk factor for ischemic stroke,
although the exact mechanisms underlying the increased risk are
not yet well known.4 Patient-dependent factors such as immobilization and advanced age, tumor-related factors such as increased plasma viscosity and hypercoagulable state and effects
© 2018 Wolters Kluwer Health, Inc. All rights reserved.

of antineoplastic treatments are considered potential pathogenic
factors. The risk of arterial thrombotic events is higher in the first
stages of the disease and seems to be increased with lenalidomide
plus high-dose dexamethasone. The incidence of cerebral vascular events in 2 multicenter, randomized, double-blind, placebocontrolled, parallel-group studies of lenalidomide plus dexamethasone
versus dexamethasone alone performed on 704 patients was 3.4%
for those treated with lenalidomide and dexamethasone compared
with 1.7% of those treated only with dexamethasone with placebo.11 Lenalidomide alone is rarely used in MM treatment, given
that concomitant use of dexamethasone has proven a synergistic
antineoplastic effect. However, in vitro studies with endothelial
cells have shown different results regarding prothrombotic effects;
Valsami et al14 have demonstrated increased expression of tissue
factor (TF) with lenalidomide use alone, whereas Isozumi et al10
did not observe significant overexpression of TF with the use of
lenalidomide. In this same study, dexamethasone alone as well
as in combination with lenalidomide increased TF expression on
endothelial cells. Other studies15,16 comparing patients with MM
treated with lenalidomide plus high-dose or low-dose dexamethasone
report higher rates of VTD in the high dexamethasone group. Increased risk of thrombotic events with the use of erythropoietic therapy along with lenalidomide plus dexamethasone is controversial; its
effect on risk of ischemic stroke in our patient remains unclear.15,17
An associated hypercoagulable state has been suggested to
be the underlying mechanism of thrombotic events in MM. An increase of inflammatory cytokines (especially interleukin 6), von
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Clinical Neuropharmacology • Volume 41, Number 6, November/December 2018

de Celis et al

TABLE 1. Case Reports of Stroke in Patients Treated With Lenalidomide
Sex
8

Woman
Woman11
Woman*11
Woman (actual case)

Age

Underlying disease

Dexamethasone

Vascular risk factors

Thromboprophylaxis

54
34
34
62

MM
POEMS syndrome
POEMS syndrome
MM

Yes (40 mg/wk)
Yes (dose not specified)
Yes (dose not specified)
Yes (40 mg/wk)

None
None
None
Hyperlipidemia

None
Aspirin
LMWH
None

*Two different cerebrovascular events occurred to the same patient in a brief period of time (<3 weeks) while on lenalidomide plus dexamethasone treatment even though thromboprophylaxis with aspirin was initiated.

Willebrand factor, and coagulation factor VIII (FVIII) along with
hyperviscosity has been reported in MM.2 In addition, lenalidomide
has been related to the increased levels of fibrinogen, P-selectin,
TF, VFP, and FVIII. A prospective study found that combining
lenalidomide with dexamethasone (especially pulsed dexamethasone) might increase endothelial stress.18
In the latest American Society of Clinical Oncology guidelines19,20 and the guidelines of management of VTD from the International Myeloma Working Group,3 thromboprophylaxis for VTD
is recommended for patients with MM receiving lenalidomide. For
low-risk patients (ie, those with no other prothrombotic risk factors),
aspirin (81–325 mg) is recommended, whereas high-risk patients
(2 or more thrombotic risk factors, such as previous thrombotic
events, obesity, associated disease, or immobilization) should receive low–molecular-weight heparin (LMWH) in prophylactic
doses or even vitamin K antagonists with target international normalized ratio of 2 to 3. High-dose dexamethasone, doxorubicin,
or multiagent chemotherapy in combination with lenalidomide
are considered additional risk factors, for which the use of LMWH
or vitamin K antagonists should be considered. Individual risk
factors for hemorrhage should be taken into account to decide
the optimal treatment (high risk for thrombocytopenia, acquired
von Willebrand disease, use of LWMH in patients with renal failure, international normalized ratio instability in patients treated
with dexamethasone). Risk of thromboembolic events is higher
during the first 6 months after starting treatment; thus, it is reasonable to maintain thromboprophylaxis for primary prevention of
VTD during this time and to individualize further treatment based
on thrombotic risk factors. There are no recommendations established for primary prevention of arterial thrombotic events due to
the paucity of data in this regard. A recent study documented that
only approximately 20% of patients receiving treatment with
lenalidomide for MM were under correct thromboprophylaxis following recommendations of these guidelines.21
Similarly, in cases of established VTD, LMWH or vitamin K
antagonist should be indicated for at least 6 months. Beyond that
time, it could be maintained in high-risk patients. Treatment with
LMWH has demonstrated fewer relapses of thrombotic events
than vitamin K antagonists.19,22 Again, no recommendations exist
for secondary prevention of arterial thrombotic events.
The patient we present did not receive any prophylactic treatment before stroke; afterward, she was maintained on long-term
aspirin (300 mg/d).

CONCLUSIONS
This case report adds new information to the current evidence of the increased risk of arterial thrombosis in patients with
MM receiving treatment with lenalidomide and dexamethasone,
given that no other cause of stroke was found after an extensive diagnostic work-up. No concomitant thromboprophylaxis was being used at the time of the event. Lenalidomide alone seems able

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to cause increased risk of thrombotic events in patients with MM;
however, its combination with dexamethasone (especially in high
doses) can raise this risk even more. Although arterial thrombotic
events have been reported previously in clinical trials and in
postmarketing data, actual guidelines establish thromboprophylactic
recommendations only for venous thrombotic events. Given one
of the optimal treatments for MM seems to be lenalidomide in
combination with dexamethasone, this case highlights the need
to increase awareness about its thrombotic risks and to encourage
prescription of the best thromboprophylactic regime based on individual patient risk factors. More studies with an adequate
follow-up time should be performed concerning the best prophylactic strategy to prevent stroke among these patients.

Highlights
□ Multiple myeloma is related to higher thrombotic risk, especially when treated with lenalidomide and dexamethasone.
□ Cases of arterial thrombosis have been described in these patients.
□ Numerous mechanisms could be responsible of the hypercoagulable state in MM and lenalidomide treatment.
□ Thromboprophylaxis is recommended to prevent venous
thrombotic events.

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