International Journal of Myeloma 10(1): 8–12, 2020
©Japanese Society of Myeloma

CASE REPORT

Successful treatment of progressive multifocal leukoencephalopathy
with mirtazapine and mefloquine in refractory myeloma
Kengo UDAKA1, Shingen NAKAMURA1, Shiro FUJII1, Ryosuke MIYAMOTO2, Naoko MATSUI2,Shiyori KAWATA1, Taiki HORI1, Jumpei MURAI1, Ryohei SUMITANI1, Masahiro OURA1,Kimiko SOGABE1, Mamiko TAKAHASHI1, Takeshi HARADA1, Kumiko KAGAWA1,Yuishin IZUMI2, Masahiro ABE1 and Hirokazu MIKI3
We herein describe a 52-year-old man with multiple myeloma (MM) who developed progressive multifocal leuko­
encephalopathy (PML). He was diagnosed with MM in December 20XY, and underwent high-dose chemotherapy
followed by autologous stem cell transplantation. He relapsed in October 20XY+2, and he was treated with the oral
administration of cyclophosphamide and prednisolone (CP). He developed apraxia and visual disturbance in March
20XY+4. Since PML was suspected, we stopped CP and mirtazapine was initiated; however, his neurologicalsymptoms did not improve. He was diagnosed with PML based on John Cunningham virus (JCV) DNA in his­cerebrospinal fluid (CSF). He was treated with therapy involving of mirtazapine, cytarabine, and high-dose­immunoglobulin; however, his neurological disorders did not improve despite the disappearance of JCV DNA
in his CSF. Therefore, we started combination therapy of mirtazapine and mefloquine, which resulted in the­significant improvement of both his neurological symptoms and MRI findings. Although we restarted the anti-MMtreatment, his neurological symptoms remained stable for more than 2 years with the continuation of this com­bination therapy. The present case suggests that combination therapy of mirtazapine and mefloquine is effective
for patients with PML, particularly those requiring immunosuppressive chemotherapy.
Key words:

progressive multifocal leukoencephalopathy, JC virus, multiple myeloma, mirtazapine, mefloquine

Introduction

develops in patients with acquired immunodeficiency syndrome. PML has also been reported in human immuno­

Progressive multifocal leukoencephalopathy (PML) is a rare

deficiency virus (HIV)-negative patients with hematological dis-demyelinating disease caused by John Cunningham virus

ease, such as malignant lymphoma, and acute leukemia [2, 3].

(JCV) infection in oligodendrocytes and astrocytes [1]. Neuro-Of note, PML is associated with immunosuppressive states

logical symptoms correspond to demyelinated lesions in theafter treatments for against hematological malignancies, suchbrain, including sensory disorders, hemianopsia, cognitive

as rituximab therapy or stem cell transplantation [4].

dysfunction, aphasia, and gait disturbance [1]. PML often
Received: December 22, 2019, accepted: February 21, 2020
1
Department of Hematology, Endocrinology and Metabolism,
Institute of Biomedical Sciences, Tokushima University Graduate
School, Tokushima, Japan2
Department of Clinical Neuroscience, Institute of BiomedicalSciences, Tokushima University Graduate School, Tokushima, Japan
3
Division of Transfusion Medicine and Cell Therapy, Tokushima
University Hospital, Tokushima, Japan
Corresponding author: Hirokazu MIKI, M.D., PhD.
Division of Transfusion Medicine and Cell Therapy, Tokushima
University Hospital, Tokushima, 2-50-1, Kuramoto-cho, Tokushima
770-8503, Japan
E-mail: mikihiro@tokushima-u.ac.jp

8International Journal of Myeloma

vol. 10 no. 1 (2020)

PML progresses rapidly to death. Its median overall survival
without treatment was previously reported to be 3.5 months[5]. However, recovery from immune suppression increases thesurvival rate of PML with HIV [6]. There are currently no effective treatments for PML in HIV-negative immunosuppressive
patients.
Multiple myeloma (MM) remains an incurable disease, evenwith the implementation of hematopoietic stem cell transplantation and novel therapeutic modalities. Immunoparesis isassociated with MM; repeated treatment with anti-MM agentsincluding corticosteroids, strongly induces an immuno­
suppressive state in MM patients [7]. As a result, infection isa major cause of morbidity and mortality in patients with MM[8, 9].

Mirtazapine and mefloquine for PML

We herein report the efficacy of combination therapy ofapraxia, moderate visual agnosia, moderate left-right disori-mirtazapine and mefloquine for PML that developed in aentation, mild motor-dominant aphasia, and forced-grasping.

patient with MM after autologous peripheral blood stem cell

A visual field defect, ataxia, and nuchal rigidity were nottransplantation (ASCT) and the subsequent long-term oral

detected. Mild right arm weakness with a positive Barre’s signadministration of cyclophosphamide and prednisolone (CP).

was noted. The snout reflex was positive, deep tendon reflexes
were normal in the upper and lower limbs, and Babinski’s sign

Case Report

was negative.
Laboratory data on admission in May 20XY+4 were listed in

A 52-year-old man was diagnosed with MM (IgA-λ type,

Table 1. Pancytopenia (hemoglobin: 8.3 g/dL, white blood

International Staging System: 2) in December 20XY. Hecells: 2,200/μL, and platelets: 113 × 103/μL) with a marked

received induction chemotherapy consisting of vincristine,decrease in CD4-positive lymphocytes (24/μL) was observed indoxorubicin, and dexamethasone for three cycles, andthe peripheral blood. His serum IgA level was elevated with aachieved a partial response (PR). He received high-dose

monoclonal spike (695 mg/dL, normal range: 110–410 mg/dL),chemotherapy (melphalan: 200 mg/m2) followed by ASCT
­while IgG decreased (597 mg/dL, normal range: 870–1,7006(CD34 positive cells 2.4 × 10 cells/kg) in February 20XY+2,mg/dL) and β2-microglobulin (4.37 mg/L, normal range

and achieved very good PR. However, he relapsed in October<2.2 mg/L) increased. Magnetic resonance imaging (MRI) of20XY+2, and was treated with CP. His disease status remained

the brain showed a white matter lesion involving the left

stable without progression with continuous CP; however, he­parietal and occipital lobes, exhibiting hyperintense signals on

developed apraxia in March 20XY+4, followed by dysmnesia,

T2-­weighted images and fluid attenuated inversion recovery

visual disturbance, weakness in the right arm, and aphasia. He(FLAIR) images (Fig. 1B, 1C). Lesions were observed as hypo­

was admitted to our hospital in May 20XY+4 (835 days after

intense signals on T1-weighted images and hyperintenseASCT).

­signals on diffusion-weighted images, and were not enhanced

On admission, his body temperature was 36.8°C, bloodby gadolinium (Fig. 1D, 1E). PML was strongly suspected basedpressure 125/89 mmHg, pulse rate 68/minute, and oxygen

on MRI findings. A cerebrospinal fluid (CSF) examination­saturation 99% on room air. He had severe memory impair-showed a normal opening pressure (12 cmH2O), a normal cellment (Mini-Mental State Examination score of 5/30), moderate

count (1/3 mm3), and normal levels of protein (46 mg/dL) andTable 1.
Blood cell countWBC

Results of laboratory examination in May 20XY+4 (at diagnosis of PML)
Blood chemistry

Serological test

2,200/μL

GOT22 U/LCRP

1.18 mg/dLband0.0%

GPT

18 U/LIgG

597 mg/dL

seg

75.0%

T-Bil

0.5 mg/dL

IgA

695 mg/dL

baso

0.0%

ALP

154 U/L

IgM

20 mg/dL

eosino0.0%

LDH

238 U/LsIL-2R

110 U/mL

mono

15.0%

BUN

10.0 mg/dL

β2MG

4.37 mg/L

lymph

10.0%

Cre

0.58 mg/dL

HIV (Ag/Ab)(–)+24/μLNa

142 mEq/L

Vitamin B1

11 ng/mLCD8+133/μL

K

3.9 mEq/L

Vitamin B12>1500 pg/mL

RBC

6

2.4 × 10 /μL

Cl

108 mEq/L

Aspergillus antigen

0.2Hb

8.3 g/dLCa

8.1 mg/dL1-3 β-D-glucan<4.8 pg/mL

Hct25.7%TP

5.6 g/dL

MCV

107.1 fLAlb

2.9 g/dL

Glucose123 mg/dL

CD4PLT

3113 × 10 /μL

Hemostatic test

Cerebrospinal fluid
Opening pressure

12 cmH2O

Cell count

1/3 mm3Protein

46 mg/dLPT

11.0 sec

Glucose50 mg/dL

PT-INR

0.93

Cl

123 mEq/L

APTT

29.5 sec

Fib483 mg/dL

International Journal of Myeloma

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9UDAKA et al.

Figure 1. Brain MRI findings of the patient at the diagnosis of PML. A: T1-weighted image (T1WI). Note that the lesion basically demonstrates
hypointense signals but there is subtle hyper­intense signals in the advancing edge. B: T2-weighted image (T2WI). C: Fluid attenuated inversion recovery (FLAIR) image. D: Diffusion-weighted image (DWI). E: T1-weighted image of the brain after the gadolinium injection (Gd-T1).

glucose (50 mg/dL). A polymerase chain reaction (PCR) analy-tunately, a laboratory examination showed an increase insis for JCV in CSF showed positive results (JCV-DNA 1.39 × 102

M-­protein, and an anti-MM treatment, involving CP, thalido-copies/mL) and the HIV antibody test was negative (Table 1).

mide, and high-dose dexamethasone, was started along withTherefore, he was diagnosed with HIV-negative PML. We

mirtazapine and mefloquine in October 20XY+4. His neuro­

stopped CP and started mirtazapine (15 mg/day) with thelogical symptoms remained stable without progression,­continuous infusion of cytarabine (100 mg/day for 5 days)

and MRI showed a marked reduction in white matter lesions

and high-dose intravenous immunoglobulin. After this combi-(Fig. 2C, 2D). He died due to MM progression in Augustnation therapy, the PCR test for JCV in CSF became negative

20XY+6 (Fig. 3).

with the recovery of CD4-positive lymphocyte counts (176/μL).
However, his neurological symptoms worsened, and theDiscussion

hyperintense lesion on the FLAIR image expanded to the left
frontal and right parietal lobes (Fig. 2B). After obtaining

The present case demonstrated that PML may occur in

informed consent from the patient and his wife under theimmunocompromised MM patients after ASCT. PML must beapproval of the Ethics Committee/Internal Review Board of theconsidered in immunodeficient patients after ASCT with

Tokushima University Hospital (permission # 1012), oral admin-­neurological symptoms, and relevant diagnostic examinations

istration of mefloquine (275 mg/week) was initiated 3 months

need to be performed. In addition to the discontinuation

after the diagnosis of PML. His neurological symptomsof immunosuppressive therapy, several drugs have been

­gradually improved after the combination of mefloquine andattempted in the treatment of HIV-negative PML. However,­mirtazapine without apparent adverse events, and he wasno specific antiviral treatment for JCV has been established.

­discharged in August 20XY+4 (940 days after ASCT). Unfor­

Cytarabine, a chemotherapeutic drug, has been demonstrated

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Mirtazapine and mefloquine for PML

Figure 2. Follow-up brain MRI imaging of the patient (FLAIR). A: MRI of the brain in May 20XY+4 (at the diagnosis of PML). B: MRI in June 20XY+4.
C: MRI in May 20XY+5. D: MRI in April 20XY+6.

Figure 3. Clinical course of the patient. IVIG: intravenous immunoglobulin. HD-Mel: high-dose melphalan. ASCT: autologous peripheral blood
stem cell transplantation. Thal: thalidomide. CPA: cyclophosphamide. PSL: prednisolone. DEX: dexamethasone. CSF: cerebrospinal fluid.
PB: peripheral blood.

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UDAKA et al.

to exert in vitro anti-viral activities against JCV [1, 10]. It inhibits
both DNA and RNA polymerases and nucleotide reductase
enzymes, which confers anti-viral activity [6, 10]. Aksamit et al.
reported that five out of 19 HIV-negative PML patients treatedwith cytarabine showed neurological improvement [11].
­Mirtazapine is an α-2-adrenergic, 5HT2A, and 5HT3-receptor
antagonist that crosses the blood-brain barrier. It functions as
is an antidepressant; that binds to 5HT2A, a cellular receptor
for JCV, and may prevent the spread of JCV infection to adjacent glial cells [12]. Mefloquine, an anti-malarial drug, is able
to enter the CSF and is expected to inhibit JCV replication invitro [13]. Epperla et al. reported that combination therapy
with mefloquine and mirtazapine achieved a clinical response
for PML in a patient with chronic lymphocytic leukemia [14].
Yoshida et al. also showed that combination therapy of
mefloquine and mirtazapine induced significant clinicalimprovements in PML after allogenic peripheral blood celltransplantation with continuing immunosuppressive therapy
for severe acute graft-versus-host disease [15]. The present
case was also simultaneously treated with anti-MM and antiJCV therapies. However, optimal dosages for these drugs
should be established.
Anderson et al. found only 9 case reports of PML in patientswith MM in the literature [16]. Five out of 9 MM patients developed PML after ASCT and two after bortezomib-combined
therapy [16]. However, limited information is currently available on PML in MM patients. The association of novel anti-MMagents, such as proteasome inhibitors and immunomodulatory drugs, with PML development and progression remains
largely unknown. Although restoration of the immune
response is integral to the management of PML [16], discontinuation of immunosuppressive anti-MM therapy often causesregrowth and progression of MM. The present case suggeststhat combination therapy of mirtazapine and mefloquine iseffective with the long-term suppression of PML, even inpatients receiving immunosuppressive chemotherapy. Because
PML is a fatal complication in severe immunosuppressivestates, the efficacy of this combination treatment for HIV-­negative PML patients on immunosuppressive treatment
should be warranted in well-designed clinical studies.

Conflicts of Interest
The authors state that they have no Conflicts of Interest(COI).

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