Autoimmune Disorders and Multiple Myeloma- Two

Rev Colomb Cancerol. 2018;22(2):76---83

www.elsevier.es/cancerologia

CASE REPORT

Illustrative Case Reports and a Literature Review

a,∗ b

Ana María Ávila , Sergio Giralt

La Sabana University School of Medicine, Bogota, Colombia

Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States

of America

Received 17 March 2017; accepted 21 July 2017

Available online 30 August 2017

KEYWORDS Abstract Several autoimmune disorders have been associated with a variety of hematopoietic

Myeloma; malignancies, particularly lympho-proliferative disorders. Multiple myeloma (MM) is one of the

Neoplasia; most common hematologic malignancies and has been described in the context of a variety of

Autoimmunity; autoimmune conditions. Due to their diversity and rarity, the clinical features of autoimmune

Response to self conditions associated with MM have not been elucidated and the pathogenesis remains unclear.

antigen; In this report, we describe two cases of autoimmune conditions in the setting of MM and review

Immunobiology; the current literature.

reserved.

PALABRAS CLAVE Trastornos autoinmunes y Mieloma Múltiple- Dos Reportes de Casos Ilustrativos y una

Mieloma; Revisión de la Literatura

Neoplasia;

Autoinmunidad; Resumen Varios trastornos autoinmunes se han asociado a una variedad de neoplasias malig-

nas hematopoyéticas, particularmente trastornos linfoproliferativos. El mieloma múltiple (MM)

Respuesta a antígeno

propio; es una de las neoplasias malignas hematológicas más comunes y ha sido descrito en el contexto

Inmunobiología; de una variedad de condiciones autoinmunes. Debido a su diversidad y rareza, las caracterís-

Miastenia ticas clínicas de las condiciones autoinmunes asociadas con el MM no han sido aclaradas y la

patogénesis sigue siendo poco clara. En este artículo se describen dos casos de condiciones

autoinmunes en el marco del MM y se realiza una revisión de la literatura actual.

∗

Corresponding author.

E-mail address: anita maria [email protected] (A.M. Ávila).

https://doi.org/10.1016/j.rccan.2017.07.001

Autoimmune Disorders and Multiple Myeloma- Tw o Illustrative Case Reports 77

Introduction inhibitor, C3 complement, C4 complement and C1q comple-

ment. Although there was no direct evidence that could

conﬁrm the association, it has not been effectively ruled

The relationship between autoimmune diseases and

1 --- 4 out either. Patient has not received antimyeloma therapy

myeloma was initially observed in the 1960’s. Multiple ret-

and angioedema episodes have been controlled symptomat-

rospective and cohort studies have shown that the incidence

ically.

of lymphoproliferative diseases is greater in patients carry-

ing autoimmune disorders. Multiple myeloma (MM), a plasma

cell neoplasia and the second most common lymphoprolife-

Patient 2

rative disorder, has been associated with a wide spectrum

5 --- 8

of autoimmune related conditions. A retrospective cohort

A 53 year old African American male presented with a 30

study of more than 4000 white and black male veterans pos-

year history of myasthenia gravis; he initially experienced

tulated that various types of immune-mediated conditions

upper body weakness, ptosis, diplopia, loss of peripheral

such as pernicious anemia, systemic sclerosis and systemic

vision and was treated with pyridostigmine. He was assessed

lupus erythematosus were related to MM development.

in 2011 for a progressive hemoglobin drop from 14.7 to 13

Herein we report on two patients with MM presenting with

with normal levels of serum iron, B12, folic acid and ele-

autoimmune conditions rarely described in conjunction with

vated total protein. Further workup revealed a paraprotein

MM (angioedema and myasthenia gravis) as autoimmune

peak in the blood (IgG of 3786 mg/dl with an IgG Kappa peak

disorders associated with MM and summarize the current

of 2.65 mg/dl), bone marrow with 29% plasma cells, and no

literature regarding autoimmune manifestations of MM.

high risk cytogenetic abnormalities with the exception of

deletion of ETV6 stain in 8% of the cells. At that time the

Patient and Methods diagnosis of asymptomatic IgG Kappa multiple myeloma ISS II

(normal albumin and B2 3.7) was conﬁrmed without any evi-

This review is based on information from the Med- dence of anemia, bone disease, hypercalcemia or impaired

line/PubMed and Scopus database using combinations of the renal function.

keywords multiple myeloma, auto antibodies, myasthenia Therefore he continued with close observation; during his

gravis, rheumatoid arthritis, systemic lupus erythematous, nine month follow up he had recurrence of his old symptoms

urticaria, paraneoplastic and autoimmunity. We included of myasthenia gravis (only right eye ptosis) and was treated

reports that were published in English, Spanish and French with pyridostigmine by his neurologist. Tw o months later, he

and speciﬁcally described autoimmune disorders associated demonstrated progression of the disease with an increas-

with MM. Forty-four articles met our selection criteria. ing paraprotein peak, kappa free light chain of 67.21 mg/dl,

kappa:lambda ratio of 93.35 as well as progressive cytope-

nias. He started to have symptoms---- in particular, fatigue

Patient 1

and mild back pain. CT scans revealed punctate lytic lesions

at the vertebral bone and nondisplaced fractures in the

A 70 year old male was seen for initial consultation in 2013

fourth and ﬁfth ribs. A repeat bone marrow biopsy showed

for history of free lambda chain monoclonal gammopathy as

30% plasma cells and complex cytogenetic abnormalities

well as focal episodes of angioedema. He initially developed

including p11 deletion,p12 addition, and additional copies

intermittent episodes of facial swelling involving different

of chromosomes 3, 5, 9 and 15. MLL gene loss was seen in

parts of his face in 2008. He was noted to have proteinuria

35% of the cells.

during one of his angioedema episodes and was referred to a

The patient received 4 cycles of bortezomib, lenalido-

hematologist. Over the next few years, the attacks involved 10

mide, and dexamethasone (RVD) with suboptimal

also his forehead, cheek, tongue and sometimes the bottoms

response. He then underwent stem cell mobilization

of the hands and feet. These episodes occurred without any

with bortezomib, dexamethasone, thalidomide, platinum,

antecedent triggers or associated factors and were relieved

adriamycin, cyclophosphamide and etoposide (VDTPACE)

with Benadryl. Involvement of the upper respiratory or gas- 11

for stem cell mobilization and collection. Subsequently

trointestinal tracts was never observed.

undergoing an autologous stem cell transplantation with

A full workup for multiple myeloma (MM) was then per-

a high dose melphalan based conditioning regimen and

formed, and he was noted to have immune globulins within

achieved a very good partial response (VGPR).

normal limits except for IgG of 648 mg/dl, free lambda ele-

His symptoms of myasthenia gravis recovered completely

vated to 27.85 mg/dl with a decreased kappa lambda ratio

off all treatment, noticing less fatigue and muscular weak-

to 0.02 and serum and urine immunoﬁxation revealing free

ness compared to before his transplant. He discontinued

lambda light chains. The percentage of plasma cells was 15%

pyridostigmine and denies any other symptoms related to

by bone marrow examination with immunohistochemistry

this disease.

demonstrating lambda restriction and a normal karyotype

with an extra copy of 1q25 in 75% of plasma cells.

At that time the diagnosis of lambda light chain mul- Discussion

tiple myeloma ISS I was conﬁrmed without any evidence

of anemia, bone disease, hypercalcemia or impaired renal Multiple myeloma is a B cell malignancy characterized

function. Nonetheless, the question remained of whether by clonal expansion of malignant plasma cells in bone

the episodes of focal angioedema may be related to marrow. Although the etiology is poorly understood, there

an acquired C1q inhibitor antibody related to multiple is some evidence for immune dysregulation or sustained

myeloma. Further testing noted normal levels of C1 esterase immune stimulation in the pathogenesis of this disease. 78 A.M. Ávila, S. Giralt in

Cases reported the literature 0 0 0 15 0 17 5 5 1

Improved - Resolved Resolved Death Autoimmune symptoms evolution - Resolved Resolved Improved

Favorable Relapse - CR VGPR Death Evolution PR CR CR +

+ +

Physostig- mine HCQ MM treatment FFP Resection physostig- mine - CS Artiﬁcial tears HCQ+CS+ cyclophosphamide AC treatment CS+azathio- prine+cyclophosphamide plasma- pheresis treatment

x2 (AC). +

BTD

x2: x4 x4 treatment

ASCT BD Cyclophos-

lenalidomide

VAD dexamethasone prednisone -> -> -> VAD VAD Dexamethasone + Melphalan Melphalan+ Prednisone - VAD Vincristine VAD CHOP MM phamide conditions

LN and

both

autoimmune

mediastinal LN. inguinal No No Both cervical, paratra- cheal, No No No Abdominal, inguinal, cervical No No Extra medullary involvement

␭

with of

␬ ␬ ␬ ␬ ␬ ␭ ␭

- IgG IgG IgG3/ IgG IgG Type IgA IgG IgA mm

IAS

4 and

associated after after after

MM.

delay

PS and

MM after after after

years years

after years years years months MG MG/PK RA of

5 3 5 Several 24 20 2

years

AIN SLE. months after after deﬁciency Diagnostic MM SS MM SS+SLE MM SLE. MM months Simultaneous MM MM 7 Acquired MM after years cases

58 44 26 63 74 30 25 46 47 Age AC reported

in 40 47 63 47 74 54 45 Age 31 63 MM

46/M 47/M 63/F 47/F 74/F age/sex 31/F 25/F 54/M 63/M

characteristics s ´

(ref)

(21)

´ nska-ry (20) clinical (15)

(17) Tazi Wang Yao Garcia- Fernández (16) Urba Choi(13) Waldron- Lynch(14) Authors Deitcher(18) Ardalan(19) PS

Summary

(AC)

free

1 interstitial

deﬁciency nephritis RA-like polyarthritis

Acquired Acute SS SLE+SS IAS TTP MG+thymoma SLE+MG+PK Table Autoimmune conditions SLE Autoimmune Disorders and Multiple Myeloma- Tw o Illustrative Case Reports 79 in

Cases reported the literature 5 13 0 - - 0 5

Resolved - - Autoimmune symptoms evolution - - Resolved 0 ResolvedImproved 8 Resolved

Death Death - - - PR - Evolution -

gold,

pyri-

- dostigmine prostaglandin E1 Filgastrim HCQ, - Neostigmine and CS treatment Prednisone Prednisone - MTX. Calcium channel blockers and

-> x

treatment AC

cyclophosphamide. carﬁlzomib - - Melphalan MCNU-VMP BTD Mephalan +Prednisone Cyclophosph- amide+BD- >VRD-> BCNU VAD Doxorubicin, carbamustina, melphalan MM >Bortezomide x2

No No - No No No No No No Extra medullary involvement of

␭ ␬ ␬ ␭ ␭ ␬

IgA IgG IgG IgA IgG IgG IgA IgA mm IgG

after after after

delay Type after

years year

months years years year RA MG

27 5 4 2 8 15

after SSc Diagnostic MM Simultaneous MM after Simultaneous Simultaneous MM Urticarial Vasculitis MM pemphigus MM MM urticarial pigmentosa of

74 79 54 57 54 40 35 43 36 Age AC of

44 79 54 57 54 44 37 58 Age 47 MM

44/M 58/M 74/F

(ref) age/sex

(27) 44/M

(26) 54/M (23) 79/M

˜ na(28) 37/M ) Ogg.(30) Highet Shen Rowland(24) 54/M Wada(25)Aryal 57/M Owlia(29) Alexopoulou(22) Espa Authors

Continued ( (AC)

IgA

pigmentosa Vasculitis pemphigus SSc Urticaria Scleromyxedema MG AHA AN Urticarial SPD-type RA Table Autoimmune conditions 80 A.M. Ávila, S. Giralt F

VAD in

Dexa-

and Vindesine,

acquisita,

purpura, Cases reported the literature - - - 7 1 0 11 -

erythematosus, transplantation,

bullosa

cell

lupus

Thalidomide, Ranimustine,

stem

Improved Persisted Resolved Resolved Autoimmune symptoms evolution - Resolved Improved Resolved Systemic

thrombocytopenic

Epidermolysis

SLE MCNU-VMP

Bortezomib, autologous

EBA

BTD node,

ASCT

- - CR - - Evolution Death Relapse Death Thrombotic

Protein

Lymph PS

TTP

LN CS.

nephritis,

+ +

Dermatomyositis,

Dexamethasone CS CS AC treatment - Topics CS - Cepharan- thine CS cyclosporine. cyclophosphamide response, Arthritis,

purpura, DM

and

and interstitial

Partial response.

PR 6

Acute x6-> x

Rheumatoid treatment

partial

AIN Bortezomib

dexamethasone. melphalan ASCT - VAD VAD ASCT-> brotezomib, carﬁlzomib - - Melphalan+ Prednisone Melphalan+ prednisone. MM

Corticosteroids,

BD good

thrombocytopenic

keratoderma, Very

sclerosis,

Immune

neutropenia,

VGPR

Carmustine, No Testicular No No No No No No Extra medullary involvement , ITP remission,

Systemic and of

␭ ␬ ␬ ␬ ␭ Palmoplantar

SSc

PK - IgG IgG Type IgG3 IgG IgA IgA IgG mm

Autoimmune Complete syndrome,

CR AN

Male, Dexamethasone Adriamycin

delay MM M

syndrome,

10 after

months years

MM MM

Anemia, after

5 autoimmune

vasculitis,

Sjögren year months Diagnostic after Simultaneous DM+SLR - Dermatosis EBA after Simultaneous Simultaneous ITP

myeloma,

SS Lenalidomide, Insulin

Hemolytic

IAS

Cyclophosphamide,

75 46 - 50 69 29 79 80 Age AC Multiple

paraneoplastic

of MM

dermatosis,

Bortezomib,

78 46 53 49 64 29 79 Age 75 MM Autoimmune

Melphalan, VRD

gravis,

Cutaneous AHA

pustular

, BCNU

78/M 46/M 53/M 50/M 71/M 29/M 79/M age/sex 75/F Hydroxychloroquine, CPV

HCQ Myasthenia

(32)

condition disease,

Sucorneal

(31)

Dexamethasone,

(ref)

acquisita (35) (36) SPD

plasma, (33)

(34) and

) laxa

Zhang(37) Tw o Tabata(38) Chakraverty Jain Radfar Authors Turner Tokumitsu Willebrand

frozen Autoimmune

Cutis reaction,

Von Prednisolone, AC

Fresh CLA C1q

Doxorubicin Continued

( (AC) and

FFP

1 Acquired

+ Sarcoid-like

erythema dermatosis complete leukocytoclastic vasculitis deﬁciency SLR AvWD CLA Urticarial ITP methasone, Female, Melphalan Vincristine, DM+SLR CPV Eosinophilic EBA Abbreviations: Urticaria Table Autoimmune conditions

Autoimmune Disorders and Multiple Myeloma- Tw o Illustrative Case Reports 81

The concurrence of autoimmuned conditions and MM is rare esterase inhibitor (C1-INH) deﬁciency is a rare disorder usu-

and has not been fully investigated. We herein describe ally identiﬁed as acquired angioedema (AAE). It was ﬁrst

the course of two patients with MM who presented with described in 1972 by Caldwell et al and is characterized

two different autoimmune conditions: myasthenia gravis by episodes of bradykinin-mediated angioedema without

43,45,46

and angioedema. To date, more than 25 different autoim- urticarial. In the acquired form, the deﬁciency results

mune conditions related to MM have been reported in the from markedly increased catabolism of C1 inhibitor due to

13---38

literature, which are summarized in Table 1. In the its consumption by the neoplastic lymphatic tissues (AAE

review of reported cases, the mean age of diagnosis of MM type 1) or by autoantibody mediated inactivation (AAE type

46,47 48

and the autoimmune condition was 55 and 54 years old, 2). Geha et al. presented a patient with IgA MM and

respectively. One third of the cases had the diagnosis of acquired C1-inhibitor deﬁciency who had circulating antiid-

their autoimmune condition before the onset of MM, and 40 iotypic antibodies that reacted with the M component. This

percent (10 of 25 cases) the diagnosis were made simulta- interaction appeared to cause increased consumption of C1-

neously. Among the autoimmune conditions related to MM, inhibitor. There is evidence that the M components detected

SLE was the most common with 17 reported cases, followed frequently correspond to the C1-inhibitor auto antibodies.

42,44

by SS and SSc with 15 and 13 respectively. The autoimmune Castelli et al. study group has shown that patients with

symptoms resolved or improved with MM treatment in the MGUS and C1-inhibitor auto-antibodies frequently have the

majority of cases, as in the case of patient 2. same heavy and light chain histotypes. This suggests that a

B-cell hyperactivity, considered a trademark of autoim- single B cell clonal disorder with different potential clinical

mune conditions, favors the escape of abnormal cell clones evolutions underlies all AAE.

from normal regulatory mechanisms. Therefore, it has In correlation with patient 1, it has been documented

been suggested that immune related conditions can be asso- that C1- INH antigen values can be normal due to elevated

12,21

ciated with an elevated MM risk. In the case of SLE, the amounts of cleaved inactive C1-INH in plasma or normal

mouse lupus model showed an increased prevalence of MM, function levels between angioedema attacks. C1q reduction

and more than 30% of the specimens showed monoclonal conﬁrms the diagnosis of AAE, but a minority of patients

gammopathy. It has been recently reported that plasma can present with normal C1q. In this case, the presence

cell growth factors such as B lymphocyte stimulator (BLyS) of autoantibodies to C1- INH can be investigated. Limits to

are elevated in patients with SLE. these procedures are the inadequate standardization of C1-

Several theories have been proposed to explain the coex- INH functional measurements and the availability to look for

49,50

istence of MM and an immune condition. One hypothesis anti-C1-INH autoantibodies.

suggests that a spontaneous autoreactive clone of B cells In summary, autoimmunity appears to have an associ-

undergoes physiological maturation and produces mono- ation with multiple myeloma. We reviewed several cases

14,39

clonal auto antibodies. of autoimmune conditions related to multiple myeloma

The association of Myasthenia Gravis and MM was ﬁrst documented in the literature. The heterogeneous set of con-

reported by Rowland et al who diagnosed the plasma cell ditions, diversity among presentations and severity explains

dyscrasia in a patient ﬁve months after the diagnosis of MG. the lack of epidemiological data and clinical features. In

Because the protein abnormality was considered to be pos- the majority of cases, the diagnoses were made simultane-

sibly related to the myasthenic syndrome, therapy for MM ously; SLE was the most common AD associated with MM.

was instituted and caused a remission of myasthenic symp- Myeloma treatment in general improved the autoimmune

toms. In this regard, our reported case (patient 2) is similar symptoms. As the pathogenesis is still not clear, different

because treatment of MM resulted in resolution of MG. hypotheses have emerged although none proven. Based on

The incidence of monoclonal gammopathy developing only a few studies, it appears that autoimmunity favors

during the course RA has been estimated to be 1-2%. More- the escape of abnormal clones of B cells from regula-

over, Srinivasulu et al. reported the case of two patients tory mechanisms leading to emergence of neoplastic B cell

who presented with inﬂammatory arthritis as the initial clones. On the other hand, other data suggests a sponta-

manifestation of MM. Reza-Ardalan et al. studied the similar- neous transformation of an autoreactive clone of B cells that

ity in the cytokine milieu of MM and RA. They showed that in later on undergoes physiological maturation and production

the context of MM, an immunologic reaction directed against of autoantibodies, therefore, explaining the autoimmune

light chain molecules and tumoral antigens deposited within manifestations.

the synovium could result in RA-like polyarthritis. Another This association needs further clinical studies in order to

biologically plausible association between autoimmune thy- provide an important foundation in understanding the physi-

roid disease (ATD) and MM has been reported regarding the ology of B cell in MM. In addition, larger retrospective studies

cytokine milieu. IL-6 in particular appears to contribute to could favor the discernment of risk factors, prognosis and

the growth of myeloma cells and has a role in the initiation essential epidemiologic data in the setting of autoimmune

and perpetuation of ATD. conditions related to myeloma.

In a prospective study, less than 4% of AHA cases were

due to MM, and only eight cases of AHA at MM presenta-

40,42 25

tion have been reported in the literature. Wada et al.

demonstrated that the antibody binding to erythrocytes was Ethical responsibilities

similar to myeloma M protein.

Among the paraneoplastic syndromes and cutaneous Protection of human and animal subjects. The authors

manifestations of MM, angioedema is exceptional (only 4 declare that no experiments were performed on humans or

43,44

cases in the literature). Angioedema with acquired C1 animals for this study.

82 A.M. Ávila, S. Giralt

Conﬁdentiality of data. The authors declare that they have case report and literature review. Clin Rheumatol [Internet].

followed the protocols of their work center on the publica- 2010;29:1323---6.

14. Waldron-Lynch F, Inzucchi SE, Menard L, Tai N, Preston-Hurlburt

tion of patient data.

P, Hui P, et al. Relapsing and remitting severe hypoglycemia

due to a monoclonal anti-insulin antibody heralding a case

Right to privacy and informed consent. The authors have

of multiple myeloma. J Clin Endocrinol Metab [Internet].

obtained the written informed consent of the patients or 2012;97:4317---23.

subjects mentioned in the article. The corresponding author

15. Yao H, Monge M, Renou M, Lecaque C, Jauréguy M, Presne

is in possession of this document. C, et al. Thrombotic thrombocytopenic purpura due to anti-

ADAMTS13 antibodies in multiple myeloma. Clin Nephrol

[Internet]. 2014;81:210---5.

Conﬂicto de intereses

16. García Fernández M, Sanz MA, Vilela C, Rafecas J, Yaya Huaman

R. A case of association of myasthenia, thymoma and multi-

The authors have no conﬂicts of interest to declare. ple myeloma. Review of the cases published. Rev Clin Esp.

1979;153:465---9.

Acknowledgments 17. Urbanska-ry´ ´s H, Robak E, Kordek R, Bartkowiak J, Rieske P,

Wo´zniacka A, et al. Multiple Myeloma in a Patient with Systemic

Lupus Erythematosus, Myasthenia Gravis and Non-Familial Dif-

Dr. Avila and Dr. Giralt performed the research, designed

fuse Palmoplantar Keratoderma. Leuk Lymphoma [Internet].

the research study and wrote the paper. We considered the 2004;45:1913---8.

ethical responsibilities dictated by Revista Colombiana de 18. Deitcher SR, Erban JK, Limentani SA. Acquired free protein S

Cancerología and we do not have any conﬂict of interest to deﬁciency associated with multiple myeloma: a case report.

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19. Reza-Ardalan M, Mohajel-Shoja M. Multiple myeloma presented

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