Epstein-Barr virus-positive multiple myeloma developing after immunosuppressant therapy for rheumatoid arthritis: a case report and review of literature

Abstract

A 61-year-old woman was diagnosed as having rheumatoid arthritis (RA) and began treatment with salazosulfapyridine (SASP) and methotrexate (MTX) in 2008; the administration of concomitant tacrolimus (TAC) was initiated in 2010. She subsequently developed concurrent multiple myeloma (MM), immunoglobulin G (IgG)-κ type, in 2012. A portion of the tumor cells tested positive for Epstein-Barr virus-encoded small RNA (EBER). MTX treatment was discontinued in 2014, and the exacerbation of MM ensued. The patient received two cycles of bortezomib plus dexamethasone (BD) therapy and attained a complete response (CR). She then underwent an autologous peripheral blood stem cell transplantation. The Epstein-Barr (EB) virus infection arising from the increased RA disease activity and immunosuppressant medication might have influenced the development of MM in this case. Most reported patients with EB virus-positive plasmacytoma are in a state of immunosuppression, and this condition may fall within the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders. No other reports of plasmacytoma occurring in a background of RA or after TAC or MTX therapy have been made, and the present case is the first such report.

Introduction

Sporadic reports have documented the frequent concurrence of myeloma in patients with rheumatoid arthritis (RA) [1-7], but other reports have concluded that RA is unrelated to hematologic malignancies, including myeloma [8-10]. It has been suggested that RA is not the only risk factor for myeloma, but that other factors might also be involved, with the Epstein-Barr (EB) virus being one. Our extensive literature search revealed as few as 22 reported cases of EB virus-positive plasmacytoma [11-22]. The rarity of reported cases might be ascribed to the fact that plasma cells are devoid of cluster of differentiation (CD) 21, which is a receptor for EB virus. Whilst the background, pathophysiology, and molecular biologic characteristics of the disorder remain unclear, reports of small-scale studies have suggested an unfavorable prognosis [13]. The median age of the affected patients was as young as 46 years, an extramedullary mass was demonstrable in about 60% of the patients, and the outcome was unfavorable, with a reported mean survival time of approximately 33 months (Tables 2, 3). These findings stress the need for the cautious monitoring of clinical progress.

Table 2.

Twenty-three reported cases of EB virus-positive plasma cell tumors

Case	Age (y)/gender	Underlying disease	Treatment of underlying disease	Clinical findings	Type of myeloma	Time from onset of underlying disease to onset of myeloma (y)	Treatment of myeloma	Therapeutic response	Outcome	Reference
1	11/F	None	None	Osteolytic lesion	IgA/κ/MM	-	Systemic steroid/RT/DEXA/Thal	Remission	Alive Elective for HSCT	[11]
2	78/M	None	None	Left submaxillary gland mass/osteolytic lesion	Plasmacytoma	-	Ex	Unknown	Unknown	[12]
3	40/M	Unknown	Unknown	Plasmacytoma/no osteolytic lesion	Plasmacytoma Bone marrow invasion plasmablastic	Unknown	Ex/RT	Remission maintained for 75 m	Alive 75 m	[13]
4	27/M	Unknown	Unknown	Osteolytic lesion	IgG/MM nonplasmablastic	Unknown	CT	Remission maintained for 30 m	DOMM 74 m	[13]
5	60/M	Unknown	Unknown	Osteolytic lesion	IgG/MM plasmablastic	Unknown	CT/RT	Remission maintained for 67 m	DOMM 97 m	[13]
6	51/M	Unknown	Unknown	Osteolytic lesion	IgG/MM plasmablastic	Unknown	CT	Not improved	DOMM 5 m	[13]
7	Unknown/Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	[14]
8	Unknown/Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	[14]
9	47/M	Chronic renal failure	Renal transplantation, CsA/AZA/PSL	Extramedullary mass/no osteolytic lesion	IgG-κ type plasmacytoma high-grade anaplastic plasmacytoma	12	Immunosuppressants discont’d/CY/PSL/RT	CR maintained	Died of respiratory tract infection 2 m later	[15]
10	49/F	None	None	Ileum ulcer	Plasmacytoma λ	-	Unknown	Unknown	Unknown	[16]
11	46/M	None	None	Stomach nodular	Plasmacytoma κ	-	Unknown	Unknown	Unknown	[16]
12	Unknown/Unknown	Unknown	Unknown	Head and neck extramedullary mass	Unknown	Unknown	Unknown	Unknown	Unknown	[17]
13	Unknown/Unknown	Unknown	Unknown	Head and neck extramedullary mass	Unknown	Unknown	Unknown	Unknown	Unknown	[17]
14	Unknown/Unknown	Unknown	Unknown	Head and neck extramedullary mass	Unknown	Unknown	Unknown	Unknown	Unknown	[17]
15	52/M	Hepatic failure and renal failure	Hepato-renal transplantation CsA/PSL/ALG/AZA/mPSL	Multiple pelvic soft tissue tumor	IgG-κ type plasmacytoma	1.4	CsA discont’d/RT	Complete remission maintained for 24 m	Alive 24 m	[18]
16	30/M	HIV	None	Gingival mass/maxillary soft tissue mass & destructive bone lesion/skin nodules	Anaplastic plasmacytoma κ	4	RT	Improved	Died 4 m later	[19]
17	34/M	HIV	None	Short breath Abdominal pain Ascites Dementia	Immature plasma cell λ	3	RT	Improved	Died 5 days later	[19]
18	41/M	Hodgkin’s lympho-ma	Curative therapy	Plasmacytoma involving skin and testis	Plasmacytoma κ	7	Unknown	Unknown	Unknown	[20]
19	51/Unknown	Unknown	Liver transplantationCsA	Periumbilical plasmacy-toma	Plasmacytoma κ	Unknown	Unknown	Unknown	Unknown	[20]
20	31/M	HIV	Unknown	Fever/confusion/slurred speech/progressive lethargy/polyuria polydypsia/left tonsillar mass/lung mass	IgG/κ IgM/λ Plasmablast Leukemic visceral and meningeal involvement	Unknown	Unknown	Unknown	Died of aspiration pneumonia	[21]
21	1.2/M	Unknown	Organ transplantation/CsA/PSL/AZA	Purulent rhinorrhea/difficulty breathing/recurrent otitis media/nasopharyngeal mass	Nasopharyngeal mass focal infiltration of plasmacells	0.9	Ex/immunosuppressant dose reduction	Improved	Unknown	[22]
22	61/F	RA	SASP/MTX/TAC/PSL	None	IgG/κ/MM	5.4	MTX discont’d/BD/Auto-PBSCT	CR	Surviving with CR, 12 m	Subject case

y, year; F, female; RT, radiation therapy; DEXA, dexamethasone; Thal, thalidomide; HSCT, hematopoietic stem cell transplantation; M, male; Ex, excision; m, month; CT, chemotherapy; DOMM, dead of multiple myeloma; CsA, cyclosporine; AZA, azathioprine; CY, cyclophosphamide; ALG, antilymphocyte globulin; mPSL, methylprednisolone; Auto-PBSCT, autologous peripheral blood stem cell transplantation.

Table 3.

Summary of 23 reported cases of EB virus-positive plasma cell tumors

Patients	n = 22
Age (y)/gender	n = 17
	1.2-78 (46)
	Unknown: 5
	n = 16
	M:F = 13:3
	Unknown: 6
Underlying disease	n = 11
	None: 4
	Chronic renal failure: 2
	Hepatic failure: 1
	HIV: 3
	Hodgkin’s lymphoma: 1
	RA: 1
	Unknown: 11
Treatment	n = 12
	None: 6
	Organ transplantation: 4
	CsA: 4
	AZA: 3
	PSL: 5
	ALG: 1
	SASP: 1
	MTX: 1
	TAC: 1
	Unknown: 10
Clinical findings	n = 20
	Extramedullary mass: 12
	Bone lesion: 5
	Ileum ulcer: 1
	Shortness of breath: 1
	Abdominal pain: 1
	Ascites: 1
	Dementia: 1
	Fever: 1
	Clouding of consciousness: 1
	Lethargy: 1
	Polyuria: 1
	Polydysplasia: 1
	Slurred speech: 1
	Purulent rhinorrhea: 1
	Dyspnea: 1
	Otitis media: 1
	None: 1
	Unknown: 2
Type of myeloma	n = 17
	IgA: 1
	IgG: 7
	IgM: 1
	κ: 9
	λ: 3
	Plasmacytoma: 11
	Plasmablastic: 4
	Non-plasmablastic: 1
Time from onset of underlying disease to that of myeloma (yr)	n = 7
	0.9-12 (median: 4)
	No underlying disease: 4
	Unknown: 11
Treatment of myeloma	n = 12
	Corticosteroids (incl. PSL): 2
	DEXA: 2
	RT: 7
	Ex: 3
	CT: 4
	Thal: 1
	BD: 1
	Auto-PBSCT: 1
	Immunosuppressants discont’d or dose reduced: 4
	Unknown: 10
Therapeutic response	n = 11
	Remission (improved): 10
	Not improved: 1
	Unknown: 11
Outcome	n = 11
	Surviving: 4
	DOMM: 3
	Died of infection: 2
	Died, cause unknown: 2
	Unknown: 11

Case report

The patient, a 61-year-old woman, with a chief complaint of M protein leukemia had been known to be affected with RA and indolent thyroiditis since the age of 55 years. Her family history was noncontributory. Figure 1 illustrates the clinical course. Regarding the present illness, the patient began to experience right wrist joint pain in 2005 and, as the pain became gradually exacerbated, sought medical advice at the Department of Collagen Diseases of this hospital in July 2008. She was diagnosed as having RA and began receiving salazosulfapyridine (SASP) at a dosage of 1000 mg/day. As the drug regimen failed to afford a sufficient therapeutic response, concomitant methotrexate (MTX) therapy at a dosage of 6 mg/week was initiated in December of the same year, and SASP was discontinued in May 2009 on account of her favorable clinical progress. In March 2010, an RA relapse was noted and concurrent tacrolimus (TAC) medication was started. TAC was discontinued in April 2011 because the RA disease activity had diminished. There was a gradual increase of immunoglobulin G (IgG) (1171 mg/dL) in June 2012 and thereafter, and the IgG level exceeded the upper limit of the reference range in April 2013 (IgG: 1716 mg/dL). As a re-elevation of the RA disease activity was also evident (rheumatoid factor [RF]: 55 IU/mL), concurrent prednisolone (PSL) was begun at a dosage of 2 mg/day. The RA disease activity subsequently decreased while the IgG level continued to be elevated, reaching 3393 mg/dL in December 2013. At this time, the patient consulted our department. An immunoelectrophoretic analysis of serum and urine samples revealed the occurrence of IgG-κ paraprotein. A bone marrow examination showed normoplasia, with 10.8% anisocytotic immature plasma cells with a slightly increased nuclear-cytoplasmic (N/C) ratio (Figure 2A, 2B). A bone marrow biopsy disclosed Epstein-Barr virus-encoded small RNA (EBER)-positive plasma cells (solid arrows, Figure 2C, 2D). The mindbomb E3 ubiquitin protein ligase 1 (MIB-1) index was low (Figure 2E, 2F). Using flow cytometry, the cells were found to be positive for CD138, mature plasma cell-1 (MPC-1), cytoplasmic κ, and CD54 (Figure 3A-C) and negative for CD20, CD45, CD49e, and cytoplasmic λ (Figure 3B-D). A chromosome analysis revealed G-banding to be of normal karyotype for females, and a fluorescent in situ hybridization (FISH) test demonstrated the presence of a 13q deletion and t(4;14) (Table 1). F18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET-CT) did not show any osseous lesions but disclosed an FDG accumulation in the upper region of the right lobe of the thyroid (SUVmax, 5.6) (Figure 4A, red arrow; Figure 4B, white arrow). This finding was thought to be ascribable to the patient’s history of indolent thyroiditis. The disorder was thus diagnosed as a multiple myeloma (MM), IgG-κ type, Durie & Salmon stage 1 and International Staging System (ISS) stage 1. The maturity of the tumor was considered to be intermediate, since marrow plasma cells were positive for MPC-1 and negative for CD45 and CD49e (Figure 3B, 3D). As the cells were found to be EBER-positive, MTX was discontinued and the dosage of PSL was increased to 5 mg/day in April 2014. However, the patient was admitted to this hospital in late May because of an increased IgG level (4694 mg/dL). The laboratory findings obtained on admission are summarized in Table 1.

Figure 1.

Clinical course. The patient started treatment with SASP in July 2008. As the response was insufficient, concomitant MTX at a dosage of 6 mg/week was started in December of the same year. The patient had a satisfactory clinical progress, and SASP was discontinued in May 2009. Concomitant TAC was begun in March 2010 and was discontinued in April 2011. The plasma IgG level began to increase from June 2012 onwards, and the concurrent administration of PSL at 2 mg/day was prescribed. MM was diagnosed in December 2013; the MTX regimen was terminated, and the PSL dosage was raised to 5 mg/day in April 2014. BD therapy was performed after no improvement in the MM was observed. A CR was attained after 2 cycles of therapy. An autologous peripheral blood stem cell transplantation was performed early in October. The patient has been progressing favorably with respect to both MM and RA. HD-CY, high-dose cyclophosphamide; HD-MEL, high-dose melphalan; Auto-PBSCT, autologous peripheral blood stem cell transplantation.

Figure 2.

Findings of bone marrow examination. A. (Smear, ×40): Normoplastic and 10.8% anisocytotic plasma cells with a slightly high N/C ratio were noted. B. (Smear, ×600): Slightly immature plasma cells were noted. C. (EBER, ×40): The tumor cells were positive. D. (EBER, ×600): The tumor cells were positive. E. (MIB-1, ×40): Low occurrence. F. (MIB-1, ×600): Low occurrence.

Figure 3.

Marrow blood flow cytometry. A. Positive for CD54 and CD138. B. Positive for MPC-1 and negative for CD45. C. Positive for cytoplasmic κ and negative for cytoplasmic λ. D. Negative for CD49e and CD20.

Table 1.

Laboratory findings on admission

Peripheral blood	WBC	5300/μL
	Neut	48.9%
	Ly	39.0%
	Mono	7.7%
	Eo	1.6%
	Ba	0.1%
	RBC	422 × 104/μL
	Hb	12.0 g/dL
	Ht	38.3%↓
	MCV	90.8 fl
	MCH	28.6 pg
	Plt	18.7 × 104/μL
	Reti	1.3%
Urinalysis	pH	6.5
	Specific gravity	1.019
	Protein	-
	Occult blood	3+
Biochemistry	T.P	9.1 g/dL
	Alb	2.9 g/dL↓
	AST	15 IU/L
	ALT	16 IU/L
	LDH	183 IU/L
	ALP	295 IU/L
	g-GTP	15 IU/L
	T-Bil	0.5 mg/dL
	BUN	15 mg/dL
	Cr	0.57 mg/dL
	Uric acid	4.4 mg/dL
	CRP	0.3 mg/dL
Thyroid function test	TSH	≤ 0.010 μIU/mL↓
	FT3	7.46 pg/mL
	FT4	2.83 ng/dL
	Thyroglobulin	18.1 ng/mL
	I-PTH	50 pg/mL
Immunoserological findings	IgG	4694 mg/dL
	IgA	53 mg/dL↓
	IgM	63 mg/dL
	IgD	2.1 mg/dL
	Serum b2MG	2.1 mg/dL
	Immunoelectrophoresis (specific antiserum)	IgG-κ positive
	Immunoelectrophoresis (urine)	IgG-κ positive
	ANA	160 ×
	Homogen	40 ×
	Speckle	160 ×
	Anti-DNA antibody	≤ 2.0
	RF	24 IU/mL
	MMP-3	38.7 ng/mL
	Antithyroglobulin antibody	104 IU/mL
	TRACP-5b	104 mU/dL↓
	TSAB (RIA)	109%
	Antibody to TSH receptor	3.7 IU/L
	Anti-TPO antibody (ECLIA)	122 IU/mL
	Anti-HIV antibody	Negative
	EBV VCA IgG	20 ×
	EBV VCA IgM	< 10 ×
	EBV EBNA	10 ×
	EBV DNA	Negative
Findings in bone marrow smear examination	No. of nucleated cells	70.5 × 104/μL
	Megakaryocyte count	72/mL
	M:E ratio	2.02
	Plasma cell	76.4%
Marrow blood flow cytometry	CD19	1.3%
	CD20	14.5%
	CD45	4.2%
	CD49e	2.7%
	CD52	6.9%
	CD54	24.3%
	CD56	97.3%
	CD126	1.8%
	CD138	59.7%
	MPC-1	56.6%
	κ	88.7%
	λ	0.2%
Marrow blood chromosomes	G-banding	46, XX 20/20
	FISH	13q deletion, 27%
	FISH	t(4;14), 23%

Denotes above the upper limit of the reference range;

^↓denotes below the lower limit of the reference range.

Figure 4.

A, B. FDG-PET-CT findings. FDG accumulation was confined solely to the upper part of the right lobe of the thyroid (SUVmax, 5.6) (a: red arrow; b: white arrow). This finding was thought to be due to indolent thyroiditis. No abnormal accumulation in the osseous tissues was seen.

BD therapy (bortezomib at 1.3 mg/m² subcutaneous injection on days 1, 4, 8, and 11, followed by a 7-day withdrawal, along with dexamethasone at 20 mg/day given orally on days 1, 2, 4, 5, 8, 9, 11, and 12; each cycle lasting 3 weeks) was initiated. The patient was discharged after the completion of the first cycle of therapy in late June. She received the second cycle of BD therapy at the outpatient service of this hospital, during which a complete response (CR) was attained. In late August, she was re-admitted to this hospital for the collection of autologous peripheral blood stem cells preceded by high-dose cyclophosphamide therapy (2 g/m²). Early in October, an autologous peripheral blood stem cell transplantation was performed with pretreatment consisting of high-dose melphalan (200 mg/m²). As of November 2014, she has been progressing satisfactorily with a sustained CR in respect to the MM. She also remains asymptomatic for RA and negative for RF, with an uneventful course.

Discussion

In the case documented herein, EBER-positive (EB virus-positive) MM (plasmacytoma) developed following treatment with the immunosuppressants MTX and TAC for RA. Hence, the case falls in the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders.

Regarding reports dealing with concurrent malignant tumors in RA patients, the American College of Rheumatology (ACR) Drug Safety Committee has reported high incidences of malignant lymphoma, lung cancer, skin cancer, and cancer death and low incidences of colorectal cancer and breast cancer, yet the report did not refer to myeloma [23]. However, there have been sporadic reports documenting the frequent concurrence of myeloma in patients with RA [1-7]. Monoclonal hypergammaglobulinemia [24] and a long-sustained disease activity of RA [6] are thought to constitute risk factors. These factors are considered to chronically affect the RA antibody production system, thereby stimulating cells of the reticuloendothelial and lymphoid systems and eventually giving rise to tumorous monoclonal proliferation [25,26]. The average time from the onset of RA until that of MM is, in fact, reportedly as long as 34 and 13.6 years [26,27]. The time in the present case was 5.4 years, which was relatively short.

On the other hand, there have also been reports purporting that RA is unrelated to hematologic malignancies, including myeloma [8-10]; therefore, RA might not be the only risk factor, and other factors such as EB virus or multifactorial involvement are likely.

Many reports have implied the irrelevance of drugs, including MTX, to the development of concurrent MM in RA patients [3,28-30]. Further long-term pursuit of a large-scale study is needed.

In the present case, we noted the EB virus-positive plasmacytoma because the tumor cells were positive for EBER. The development of EB virus-positive plasmacytoma has been reported, including the present case, in 22 cases according to our extensive literature search (Table 2). The rarity of pertinent cases may be ascribed to the fact that plasma cells are devoid of CD21, which is a receptor for the EB virus. The characteristics of the reported cases are summarized in Table 3. The median age of the patients was relatively young, at 46 years (1.2 to 78 years), and the disease was more common in men (male:female = 13:3), and the underlying disease was RA in only the present case, whereas cases with immunodeficiency in their clinical background, such as human immunodeficiency virus (HIV), chronic renal failure, hepatic insufficiency, and Hodgkin’s lymphoma, accounted for about 1/3 (7 cases) of all the cases. As for the treatment of underlying diseases, organ transplantation was involved in as many as 4 cases, and the administration of various immunosuppressants was relatively common (16 cases). It would be reasonable to assume that an immunodeficiency state following organ transplantation or that is associated with immunosuppressant therapy exists in the background. The involvement of other factors seemed likely, nevertheless, inasmuch as there was no treatment or unknown treatment of the underlying disease in as many as 70% (15 cases) of patients. A variety of symptoms were noted as to the clinical findings, and about 60% (12 cases) of the patients had an extramedullary mass, which is a poor prognostic factor. The most frequent type of MM was IgG type (7 cases). The median time from the onset of the underlying disease to that of MM was relatively short, at 4 years (0.9-12 years), and coincided with that in the present case. Regarding the treatment for MM, there were no cases in which a clinical improvement was attained with immunosuppressant discontinuance or dosage re-duction alone [15,18,22], and the same held true for the present case as well. Various treatments were provided, producing an improvement in the MM in 10 of the 11 cases, but only 4 patients survived, and the mean survival time for the 11 cases was about 33 months; hence, the outcome was not considered favorable. In fact, according to a report with only 4 cases, the possibility of a poor prognosis was suggested given the plasmablastic cytomorphologic features with high labeling indices and the high MIB-1 index that were observed [13].

To date, there has been no report of a case of plasmacytoma occurring with an underlying disease of RA or after TAC or MTX therapy and falling under the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) [31]; thus, the present case is the first to be reported.

The present case was considered to be MTX-LPD, as the patient was maintained on MTX. MTX-LPD usually results in lymphoma, and its disappearance after the discontinuation of MTX therapy is not uncommon, although many reported cases were EBV-related LPD [31]. In the present EBV-related LPD case, however, spontaneous remission did not occur following the discontinuation of MTX medication. No cases have been reported in which a clinical improvement followed dose reduction or the discontinuation of immunosuppressant medication [15,18,22]. Further studies of accumulated cases of post-immunosuppressant therapy for EB virus-positive plasmacytoma are needed.

The RA disease activity increased despite MTX therapy, and an elevation of the IgG level occurred about 1 year later (estimated to be the onset phase of MM) in the present case. The likelihood that MM developed as a result of the increased RA disease activity as well as the immunosuppression (EBER-positive status) was considered. Such a situation might account for the shorter period from the onset of RA until that of the plasmacytoma (5.4 years) in this case, compared with previously reported averages of 34 and 13.6 years [26,27].

Disclosure of conflict of interest

None.