International Journal of Myeloma 8(1): 1–3, 2018
©Japanese Society of Myeloma

LETTER TO THE EDITOR

Development of unexpected severe thrombocytopenia
just after initiating lenalidomide: possible involvementof an immunologic mechanism
Yusuke MEGURI, Yui KAMBARA, Akira YAMAMOTO,
Taro MASUNARI, Nobuo SEZAKI and Toru KIGUCHI

Lenalidomide (Len) is one of the second-generation

with Len (15 mg/body) and dexamethasone (20 mg/body/immuno­modulatory drugs (IMiDs) for treatment of multiple

weekly). On day 5 after the initiation of the treatment, shemyeloma. Len is also known to show an antitumor effectcomplained of skin rash and malaise. Cytopenia due to drug

through a variety of mechanisms, including inhibition oftoxicity had not then severely developed. On day 14, thrombo-­cytokine signaling, angiogenesis, and induction of tumor

cytopenia suddenly progressed to 10,000/μl. Her Hb was 10.9

cell apoptosis [1]. In addition, Len can induce immune dys-g/dl and leukocyte was 7,060/μl, and the percentage ofregulations and cause autoimmunity. Adverse events of Len

immature platelet fraction (IPF) was comparatively increased

are, generally, leukopenia, thrombocytopenia, deep venous

to 14.3%. The number of platelets was too low to measurethrombosis, skin rash, opportunistic infections, and others.

the mean platelet volume. Anti-platelet antibody and PA-IgG

Myocarditis, Basedow disease, autoimmune hemolytic anemia,

were not elevated. Anti-nuclear antibody and ds-DNA anti-

cold agglutinin disease, and acquired hemophilia have also

body were not elevated, and cytomegalovirus C7-HRP wasoccurred; those were thought to be autoimmune disorders.

negative (Table 1). A bone marrow biopsy proved normo­

Similarly, immune thrombocytopenic purpura (ITP) is ancellular with adequate megakaryocytes and there was no

autoimmune disease. Only a few cases were reported of­evidence of dysplasia or neoplasm. Plasma cells in the bone

ITP associated with Len. In this letter, we report the expe­

marrow had rather decreased comparably with the time ofrience of a severe and transient reduction in platelets soon

admission. And there were no signs of disseminated intra­

after administration of Len and the possible involvement

vascular coagulation (DIC) or viral infection. On the otherof an immunological mechanism that prevented excluding

hand, she presented exacerbations of skin rash and tempo­

ITP from the d­ ifferential diagnosis.

rarily increased proteinuria. For the decrease in platelet

A 74-year-old woman was diagnosed with monoclonalcount, platelet transfusion was given. Platelet count did not

gammopathy undetermined significance (MGUS, Bence

respond at all. Anti-HLA antibody screening was performedJones-λ) in July 2005 and MGUS progressed to asymptom-but donor-­specific antibodies were not detected. From theseatic myeloma by November 2012. In December 2017, she wasfindings, we speculated that this severe thrombocytopenia

referred to our hospital for progression of anemia (Hemoglo-could be caused by an immunological mechanism, such asbin (Hb) 9.1 g/dl) and hypercalcemia (12.1 mg/dl). She wasITP. Len was discontinued and the patient was treated withadmitted to our hospital, and bone marrow examination

prednisolone (PSL) at the dose of 0.5 mg/kg. The platelet

showed the increase of plasma cells, which confirmed the pro-count promptly increased to 149,000/μl after 14 days ofgression to symptomatic multiple myeloma. She was treated­steroid therapy and steadily kept on tapering.
One case report [2] and summary of four cases summaries

Received: October 23, 2017, accepted: March 2, 2018
Department of Hematology, Chugoku Central Hospital, Hiroshima,
Japan
Corresponding author: Toru KIGUCHI
Department of Hematology, Chugoku Central Hospital, 148-13
Kamiiwanari, Miyuki-Cho, Fukuyama city, Hiroshima 720-0001, Japan
E-mail: kiguchi-t@umin.ac.jp[3] were previously reported as Lenalidomide-associated ITP(Table 2). No previous cases including the present case had ahistory of autoimmune disorders. Our case occurred ITP in thefirst cycle but in previous cases, it occurred after 3 cycles. Allpatients had been treated with dexamethasone at the dosageof 20–40 mg/weekly for myeloma, and after diagnosis of ITP,
they all were treated with PSL, and Len was discontinued.
Some cases had relapsed after re-treatment with Len, and one

International Journal of Myeloma

vol. 8 no. 1 (2018)

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MEGURI et al.

Table 1. Laboratory data of the current case
WBCBandSeg
Eos
BasoMoLyRBC
Hgb
HctMCV
MCH
MCHC
RDW
PltRetIPF

7060 /μl
9 %63 %4 %0 %
13 %11 %278 × 104/μl
10.9 g/dl
24.2 %
87.1 fl30.2 pg34.7 %
15.4 %
1.0 × 104/μl
0.89 %
14.3 %

APTTPT
Fibg
D-dimer
FDP
AT-335 sec
1.09
307 mg/dl
1.3 μg/ml
3.5 μg/ml
64 %Table 2.

TP
ALB
α1
α2
β1β2γ
Alb
T.Bil
D.Bil
I.Bil
AST
ALT
LDH
ALP
ChE
γ-GTPUABUNCre
Na
KCa
Mg
ClCRP

IgG
IgA
IgM

596 mg/dl
38 mg/dl
35 mg/dl

Anti-platelet ab
PAIgG

Negative48 ng/107 cells

ANA
HomogeneousSpeckled
ds-DNA abx40x40x40<10 IU/ml

FLC κ
FLC λFLC (κ/λ ratio)

8.4 mg/d
349 mg/d
0.02

CMV pp65C7-HRP

Negative

Previous reports of Len-associated ITP and the current case2)

case 1case 23)case 33)

case 43)case 53)

Current Case

66

2766

76

78

74

Age (y)Sex

6.3 g/dl
60.9 %
8.2 %
12.6 %
5 %
3.7 %
9.6 %
4 g/dl
1.5 mg/dl
0.5 mg/dl
1.0 mg/dl
12 U/l
21 U/l212 U/l
304 U/l130 IU/l
21 U/l
4.6 mg/dl
22.9 mg/dl
0.79 mg/dl
134 mEq/l
4.44 mEq/l
7.6 mg/dl
3.1 mg/dl
99 mEq/l
3.64 mg/dl

FemaleMale

FemaleFemaleFemaleFemaleMM type

NENE

IgG-κ

IgG-λ

Amyloidosis IgA-λBJ-λDose of Len (mg/body)2525

15 - lower dose

151515

Dose of Dex combinatedwith Len (mg/body)

20020NE (used)2020

3rd cycle

NE (>4 cycle)

5–6th cycle

3rd cycle

6th cycle

1st cycle

Cycle at ITP
Len retreatment after ITP

NANA

3 times

1 timeNA

1 timeRecovered/–

Recovered/–

Recovered/3 times

Recovered/–

Steroid dependent

Recovered/–NE

Mgk normal

Absent of Plasma
cell, MgK++

NE

Mgk++

Mgk; normal

Number of pre-treatment

2nd line

Maintenancetherapy after ASCT

2nd line

2nd line

2nd line

NAPlatelet count at ITP (/μl)

4.4 × 104

0.1 × 104

1.7 × 104

0.5 × 104

1.8 × 104

1.0 × 104

ITP-asosiated symptom

NAPetechiae

NANA

Diffuse pupura

NAOther AesNE

Alopecia

Moderate
hematologic
toxicityNE

Proteinuria

Skin rash,proteinuria,
anorexia

PSL 1 mg/kg

HD-DEX, IVIG

PSL 1 mg/kg, IVIG,
Rituximab

PSL 1 mg/kg

PSL 1 mg/kg

PSL 0.5 mg/kg

PRCRPR

VGPR

PR

PR

Outcome/relapse
BM findings

Treatment for ITP
Effect of Len

NE: Not evaluated, NA: No applicable, MM: Multiple myeloma, Len: Lenalidomide, ITP: immune thrombocytopenia purpura, BM: Bone marrow,
Mgk: Megakaryocyte, AE: adverse event, HD-DEX: high dose dexamethasone, IVIG: intravenous immunoglobulin, PSL: prednisolone, CR: Complete
remission, RP: partial response, VGPR: Very good partial response

2International Journal of Myeloma

vol. 8 no. 1 (2018)

Lenalidomide inducing severe thrombocytopenia

case was refractory to PSL. The present case presentedof Len inducing severe thrombocytopenia from aberrant­proteinuria and the exacerbation of skin rash caused by Len.

immunologic status. One is the immunoglobulin production

These findings suggested immune dysregulation from Len.

from the myeloma cells, which were selected by the anti-Similar findings, such as proteinuria and alopecia, were also

tumor effect of Len. And another is the production from theobserved in previous cases. Therefore, careful attention mustnormal plasma cells, which were activated by immune dys-

be paid to serious thrombocytopenia when adverse events

regulation effect of Len after Len killed myeloma cells.

induced by Len are suddenly exacerbated in any cycle ofLenalidomide will be used more widely, because this drug

treatment. Such immune dysregulation might induce thehas been found to be effective for many hematological disor-auto-reactive immunoglobulin. Our case did not have a highders and situations, e.g. like some kinds of lymphoma, adultlevel of PA-IgG and we could not detect the immunoglobulin

T-cell leukemia, and initial therapy of multiple myeloma. Whenas the pathogen of ITP. PA-IgG is not the specific marker of

unexpected severe thrombocytopenia is encountered during

ITP, and the relationship between the type of immunoglobu-Len therapy, ITP is one of the important differential diagnoses,

lin and pathogenesis of ITP is the very difficult problem. Inand it is preferable to discontinue Len, and commence treat-some reports, the warm-reacting platelet-associated IgM

ment by intravenous immunoglobulin or steroid therapy.

(PA-IgM) was presented in some patients with ITP [4], and­others reported the waldenström macroglobulinemia patient

Referencesof ITP who had the anti-platelet IgM [5]. PA-IgM has not beentested in the current case, but IgM has tended to recover fromtreatment. Perhaps, the platelet reduction might have arisenin the process of the treatment’s being responded, and therebuilding of the immunity.
Another mechanism, which induced ITP, was the associationof monoclonal gammopathy. In this case, Len therapy was very
effective, and 24-hours urine protein before treatment was
9.25 g/day, but it decreased to 0.85 g/day after 1 course of Len
and dexamethasone therapy. This means plasma cells weresuccessfully reduced and thereafter some pathogenic cloneof plasma cells might be selected at the presentation of ITP.
Actually, both MGUS [6] and MM-associated ITP [7] werereported previously. All previous cases were IgG, IgA or IgMtype, but there are no cases which present Bence-jones type.
In this point of view, our case is the first report of Bence-jones
type MM that developed ITP.
In summary, there are two possibilities for the mechanism

1. Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, Smyth MJ,
et al. Mechanism of action of immunomodulatory drugs (IMiDS)
in multiple myeloma. Leukemia. 2010;24(1):22–32.
2. Herold CI, Gasparetto C, Arepally GM. Lenalidomide-Associated
ITP. Case Rep Hematol. 2011;2011:638020.
3. Pompa A, Guidotti F, Gregorini AI, Goldaniga MC, Rossi FG, Baldini
L, et al. Four cases of Lenalidomide-associated immune thrombocytopenia. Blood. 2016;128:4927.
4. Cines DB, Wilson SB, Tomaski A, Schreiber AD. Platelet antibodiesof the IgM Class in immune thrombocytopenic purpura. J Clin
Invest. 1985;75(4):1183–90.
5. Varticovski L, Pick AI, Schattner A, Shoenfeld Y. Anti-platelet andanti-DNA IgM in Waldenström macroglobulinemia and ITP. Am JHematol. 1987;24(4):351–5.
6. Rossi D, De Paoli L, Franceschetti S, Capello D, Vendramin C,Lunghi M, et al. Prevalence and clinical characteristics of immune
thrombocytopenic purpura in a cohort of monoclonal gammop­
athy of uncertain significance. Br J Haematol. 2007;138:249–52.
7. Itoh T. Multiple myeloma developing in a patient with immune
thrombocytopenia. Rinsho Ketsueki. 2016;57(5):630–3.

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