RevColombCancerol.2018;22(2):76---83
www.elsevier.es/cancerologia
CASE
REPORT
Autoimmune
Disorders
and
Multiple
Myeloma-
Two
Illustrative
Case
Reports
and
a
Literature
Review
Ana
María
Ávila
a,∗,
Sergio
Giralt
baLaSabanaUniversitySchoolofMedicine,Bogota,Colombia
bDepartmentofMedicine,MemorialSloanKetteringCancerCenter,WeillCornellMedicalCollege,NewYork,NY,UnitedStates
ofAmerica
Received17March2017;accepted21July2017 Availableonline30August2017
KEYWORDS Myeloma; Neoplasia; Autoimmunity; Responsetoself antigen; Immunobiology; Myasthenia
Abstract Severalautoimmunedisordershavebeenassociatedwithavarietyofhematopoietic malignancies,particularlylympho-proliferativedisorders.Multiplemyeloma(MM)isoneofthe mostcommonhematologicmalignanciesandhasbeendescribedinthecontextofavarietyof autoimmuneconditions.Duetotheirdiversityandrarity,theclinicalfeaturesofautoimmune conditionsassociatedwithMMhavenotbeenelucidatedandthepathogenesisremainsunclear. Inthisreport,wedescribetwocasesofautoimmuneconditionsinthesettingofMMandreview thecurrentliterature.
© 2017 Instituto Nacional de Cancerolog´ıa. Published by Elsevier Espa˜na, S.L.U. All rights reserved.
PALABRASCLAVE Mieloma;
Neoplasia; Autoinmunidad; Respuestaaantígeno propio;
Inmunobiología; Miastenia
TrastornosautoinmunesyMielomaMúltiple-DosReportesdeCasosIlustrativosyuna RevisióndelaLiteratura
Resumen Variostrastornosautoinmunessehanasociadoaunavariedaddeneoplasias malig-nashematopoyéticas,particularmentetrastornoslinfoproliferativos.Elmielomamúltiple(MM) esunadelasneoplasiasmalignashematológicasmáscomunesyhasidodescritoenelcontexto deunavariedaddecondicionesautoinmunes.Debidoasudiversidadyrareza,las caracterís-ticasclínicasdelascondicionesautoinmunes asociadasconelMMnohansidoaclaradasyla patogénesissiguesiendopococlara.Enesteartículose describendoscasosde condiciones autoinmunesenelmarcodelMMyserealizaunarevisióndelaliteraturaactual.
© 2017Instituto Nacional deCancerolog´ıa. Publicado por Elsevier Espa˜na, S.L.U. Todoslos derechosreservados.
∗Correspondingauthor.
E-mailaddress:[email protected](A.M.Ávila).
https://doi.org/10.1016/j.rccan.2017.07.001
The relationship between autoimmune diseases and myelomawasinitiallyobservedinthe1960’s.1---4Multiple
ret-rospectiveandcohortstudieshaveshownthattheincidence oflymphoproliferativediseasesisgreaterinpatients carry-ingautoimmunedisorders.Multiplemyeloma(MM),aplasma cellneoplasiaandthesecondmostcommon lymphoprolife-rativedisorder, hasbeenassociatedwithawidespectrum ofautoimmunerelatedconditions.5---8Aretrospectivecohort
studyofmorethan4000whiteandblackmaleveterans pos-tulatedthatvarioustypesof immune-mediatedconditions suchasperniciousanemia,systemicsclerosisandsystemic lupuserythematosuswererelatedtoMMdevelopment.9
HereinwereportontwopatientswithMMpresentingwith autoimmuneconditionsrarelydescribedinconjunctionwith MM (angioedema and myasthenia gravis) as autoimmune disorders associated with MM and summarize the current literatureregardingautoimmunemanifestationsofMM.
Patient
and
Methods
This review is based on information from the Med-line/PubMedandScopusdatabaseusingcombinationsofthe keywords multiple myeloma, auto antibodies, myasthenia gravis,rheumatoidarthritis,systemiclupuserythematous, urticaria, paraneoplastic and autoimmunity. We included reportsthatwerepublishedinEnglish,SpanishandFrench andspecificallydescribedautoimmunedisordersassociated withMM.Forty-fourarticlesmetourselectioncriteria.
Patient1
A70yearoldmalewasseenforinitialconsultationin2013 forhistoryoffreelambdachainmonoclonalgammopathyas wellasfocalepisodesofangioedema.Heinitiallydeveloped intermittentepisodesof facialswellinginvolving different partsofhisfacein2008.Hewasnotedtohaveproteinuria duringoneofhisangioedemaepisodesandwasreferredtoa hematologist.Overthenextfewyears,theattacksinvolved alsohisforehead,cheek,tongueandsometimesthebottoms ofthehandsandfeet.Theseepisodesoccurredwithoutany antecedenttriggersorassociatedfactorsandwererelieved withBenadryl.Involvementoftheupperrespiratoryor gas-trointestinaltractswasneverobserved.
Afullworkupformultiplemyeloma(MM)wasthen per-formed,andhewasnotedtohaveimmuneglobulinswithin normallimitsexceptforIgGof648mg/dl,freelambda ele-vatedto27.85mg/dlwithadecreasedkappalambdaratio to0.02andserumandurineimmunofixationrevealingfree lambdalightchains.Thepercentageofplasmacellswas15% by bone marrow examination with immunohistochemistry demonstrating lambdarestriction anda normal karyotype withanextracopyof1q25in75%ofplasmacells.
At that time the diagnosis of lambda light chain mul-tiple myeloma ISS I was confirmed without any evidence ofanemia,bonedisease,hypercalcemiaorimpaired renal function. Nonetheless,the question remained of whether the episodes of focal angioedema may be related to an acquired C1q inhibitor antibody related to multiple
confirm the association, it has not been effectively ruled outeither.Patient has notreceived antimyeloma therapy andangioedemaepisodeshavebeencontrolled symptomat-ically.
Patient2
A53year oldAfrican Americanmalepresented witha30 yearhistoryof myastheniagravis;heinitiallyexperienced upper body weakness, ptosis, diplopia, loss of peripheral visionandwastreatedwithpyridostigmine.Hewasassessed in2011foraprogressivehemoglobindropfrom14.7to13 withnormal levelsof serumiron,B12,folicacidand ele-vatedtotalprotein.Furtherworkuprevealedaparaprotein peakintheblood(IgGof3786mg/dlwithanIgGKappapeak of2.65mg/dl),bonemarrowwith29%plasmacells,andno high risk cytogenetic abnormalities with the exception of deletionof ETV6stainin8%of thecells.Atthattimethe diagnosisofasymptomaticIgGKappamultiplemyelomaISSII (normalalbuminandB23.7)wasconfirmedwithoutany evi-denceofanemia,bonedisease,hypercalcemiaorimpaired renalfunction.
Thereforehecontinuedwithcloseobservation;duringhis ninemonthfollowuphehadrecurrenceofhisoldsymptoms ofmyastheniagravis(onlyrighteyeptosis)andwastreated withpyridostigminebyhisneurologist.Twomonthslater,he demonstratedprogression of the disease withan increas-ingparaproteinpeak,kappafreelightchainof67.21mg/dl, kappa:lambdaratioof93.35aswellasprogressive cytope-nias.He startedtohave symptoms----inparticular, fatigue andmildbackpain.CTscansrevealedpunctatelyticlesions at the vertebral bone and nondisplaced fractures in the fourthandfifthribs.Arepeatbonemarrowbiopsyshowed 30% plasma cells and complex cytogenetic abnormalities includingp11deletion,p12 addition,andadditionalcopies ofchromosomes3,5,9and15.MLLgenelosswasseenin 35%ofthecells.
The patientreceived 4 cyclesof bortezomib, lenalido-mide, and dexamethasone (RVD)10 with suboptimal
response. He then underwent stem cell mobilization withbortezomib, dexamethasone, thalidomide, platinum, adriamycin, cyclophosphamide and etoposide (VDTPACE) for stem cell mobilization and collection.11 Subsequently
undergoing an autologous stem cell transplantation with a high dose melphalan based conditioning regimen and achievedaverygoodpartialresponse(VGPR).
Hissymptomsofmyastheniagravisrecoveredcompletely offalltreatment,noticinglessfatigueandmuscular weak-ness compared to before his transplant. He discontinued pyridostigmineand deniesany other symptomsrelated to thisdisease.
Discussion
78
A.M.
Ávila,
S.
Giralt
Table1 Summaryofclinicalcharacteristicsin26reportedcasesofMMassociatedwithautoimmuneconditions(AC).
Autoimmune
conditions(AC)
Authors(ref) age/sex Ageof
MM
Ageof
AC
Diagnosticdelay Typeof
mm
Extra medullary involvement
MMtreatment AC
treatment
Evolution Autoimmune
symptoms evolution
Cases
reportedin
the literature
SLE Choi(13) 31/F 31 26 MM5yearsafter
SLE.
IgA Both
cervical,
paratra-cheal,both
inguinalLN
VADx2:BTDx2
->ASCT
HCQ VGPR - 17
IAS
Waldron-Lynch(14)
63/M 63 63 MMSeveral
monthsafterIAS
IgG3/ No Dexamethasone
+lenalidomide
->BD
MM treatment
Favorable Resolved 5
TTP Yao(15) 74/F 74 74 Simultaneous IgG No Melphalan+
dexamethasone
FFP+
plasma-pheresis
CR Resolved 5
MG+thymoma
Garcia-Fernández (16)
54/M 54 30 MM24years
afterMG
IgG No Melphalan+
Prednisonex2
->
Cyclophos-phamide+
Vincristine+
prednisone
Resection+
physostig-mine
Relapse Improved 1
SLE+MG+PK Urba´nska-ry´s
(17)
25/F 45 25 MM20years
afterMG/PKand
7yearsafter
SLE.
IgG Abdominal,
inguinal,
cervicaland
mediastinal LN.
VADx4->
CHOPx6
Physostig-mine+
CS+azathio- prine+cyclo-phosphamide
PR Improved 0
AcquiredfreePS
deficiency
Deitcher(18) 46/M 40 46 AcquiredPS
deficiency6
yearsafterMM.
IgG No - - - - 0
Acuteinterstitial
nephritis+
RA-like polyarthritis
Ardalan(19) 47/M 47 47 MM2months
afterRAand4
monthsafter
AIN
- No VADx4 CS CR Resolved 0
SS Tazi(20) 63/F 63 58 MM5yearsafter
SS
IgA No VAD Artificial
tears+MM
treatment
CR Resolved 15
SLE+SS Wang(21) 47/F 47 44 MM3yearsafter
SS+SLE
IgG No VAD HCQ+CS+
cyclophosp-hamide
Disorders
and
Multiple
Myeloma-Tw
o
Illustrative
Case
R
eports
Table1 (Continued)
Autoimmune
conditions(AC)
Authors(ref) age/sex Ageof
MM
Ageof
AC
Diagnosticdelay Typeof
mm
Extra medullary involvement
MMtreatment AC
treatment
Evolution Autoimmune
symptoms evolution
Cases
reportedin
the literature
RA Alexopoulou(22) 74/F 47 74 MM27years
afterRA
IgG - - HCQ,gold,
MTX.
- -
-Scleromyxedema Shen(23) 79/M 79 79 Simultaneous IgA No - - - -
-MG Rowland(24) 54/M 54 54 MM5months
afterMG
IgG No Melphalan Neostigmine
and
pyri-dostigmine
Death Resolved 0
AHA Wada(25) 57/M 57 57 Simultaneous IgG No MCNU-VMP CS - Resolved 8
AN Aryal(26) 54/M 54 54 Simultaneous IgG No BTD->
carfilzomib
Filgastrim PR Improved 0
Urticarial Vasculitis
Highet(27) 44/M 44 40 MM4yearsafter
Urticarial Vasculitis
IgA No Mephalan
+Prednisone
Prednisone - Resolved 5
SPD-typeIgA
pemphigus
Espa˜na(28) 37/M 37 35 MM2yearsafter
pemphigus
IgA No
Cyclophosph- amide+BD->VRD-> BCNU
Prednisone - Resolved 5
SSc Owlia(29) 58/M 58 43 MM15yearafter
SSc
IgA No VADx
2->Bortezomide x2
Calcium channel
blockers+
prostaglandin E1
Death - 13
Urticaria pigmentosa
Ogg.(30) 44/M 44 36 MM8yearafter
urticarial pigmentosa
IgG No Doxorubicin,
carbamustina,
melphalanand
cyclophos-phamide.
80
A.M.
Ávila,
S.
Giralt
Table1 (Continued)
Autoimmune
conditions(AC)
Authors(ref) age/sex Ageof
MM
Ageof
AC
Diagnosticdelay Typeof
mm
Extra medullary involvement
MMtreatment AC
treatment
Evolution Autoimmune
symptoms evolution
Cases
reportedin
the literature
Urticaria+
completeC1q
deficiency
Tokumitsu(31) 75/F 75 75 Simultaneous IgG3 No - - - - 1
DM+SLR Chakraverty(32) 46/M 46 46 DM+SLR10
monthsafterMM
IgG Testicular VADx6->
melphalan ASCT
CS CR Resolved 0
CPV Jain(33) 53/M 53 - - IgG No VADx6 TopicsCS. - Improved 11
Eosinophilic dermatosis
Two(34) 50/M 49 50 Dermatosis1
yearafterMM
- No ASCT->
brotezomib,
carfilzomiband
dexametha-sone.
CS - Resolved
-EBA Radfar(35) 71/M 64 69 EBA5years
afterMM
IgG No - CS+
cyclosporine.
Relapse Improved
-CLA+
leukocytoclastic vasculitis
Turner(36) 29/M 29 29 Simultaneous IgA No - CS+
cyclophos-phamide
Death Persisted
-Urticarial erythema
Zhang(37) 79/M 79 79 Simultaneous IgA No Melphalan+
Prednisone
- - Resolved
-ITP Tabata(38) 78/M 78 80 ITP23months
afterMM
IgG No Melphalan+
prednisone.
Cepharan-thine
Death Resolved 7
Abbreviations:ACAutoimmunecondition,AHAAutoimmuneHemolyticAnemia,ANAutoimmuneneutropenia,AINAcuteinterstitialnephritis,ASCTautologousstemcelltransplantation,
AvWDAcquiredVonWillebranddisease,BCNUMelphalan,Cyclophosphamide,AdriamycinandCarmustine,BDBortezomibandDexamethasone,BTDBortezomib,Thalidomide,and
Dexa-methasone,CLACutislaxaacquisita,CPVCutaneousparaneoplasticvasculitis,CRCompleteremission,CSCorticosteroids,DMDermatomyositis,EBAEpidermolysisbullosaacquisita,F
Female,FFPFreshfrozenplasma,HCQHydroxychloroquine,IASInsulinautoimmunesyndrome,ITPImmunethrombocytopenicpurpura,LNLymphnode,MCNU-VMPRanimustine,Vindesine,
MelphalanandPrednisolone,MGMyastheniagravis,MMMultiplemyeloma,MMale,PKPalmoplantarkeratoderma,PRPartialresponse,PSProteinS,SLESystemiclupuserythematosus,
SLRSarcoid-likereaction,SPDSucornealpustulardermatosis,SSSjögrensyndrome,SScSystemicsclerosis,RARheumatoidArthritis,TTPThromboticthrombocytopenicpurpura,VAD
the course of two patients with MM who presented with two different autoimmune conditions: myasthenia gravis andangioedema.Todate,morethan 25different autoim-muneconditionsrelatedtoMMhave beenreportedin the literature, which are summarized in Table 1.13---38 In the
reviewofreportedcases,themeanageofdiagnosisofMM and the autoimmune condition was 55 and 54 years old, respectively. One third of the cases had the diagnosis of theirautoimmuneconditionbeforetheonsetofMM,and40 percent(10of25cases)thediagnosisweremade simulta-neously.AmongtheautoimmuneconditionsrelatedtoMM, SLEwasthemostcommonwith17reportedcases,followed bySSandSScwith15and13respectively.Theautoimmune symptomsresolvedorimproved withMM treatmentin the majorityofcases,asinthecaseofpatient2.
B-cell hyperactivity,consideredatrademarkof autoim-muneconditions,favorstheescapeofabnormalcellclones from normal regulatory mechanisms.13 Therefore, it has
beensuggestedthatimmunerelatedconditionscanbe asso-ciatedwithanelevatedMMrisk.12,21InthecaseofSLE,the
mouselupusmodelshowedanincreasedprevalenceofMM, and more than 30% of the specimens showedmonoclonal gammopathy.13 It has been recentlyreported thatplasma
cellgrowthfactorssuchasBlymphocytestimulator(BLyS) areelevatedinpatientswithSLE.
Severaltheorieshavebeenproposedtoexplainthe coex-istence of MM and an immune condition. One hypothesis suggests thata spontaneous autoreactive cloneof Bcells undergoes physiological maturation and produces mono-clonalautoantibodies.14,39
The association of Myasthenia Gravis and MM was first reportedbyRowlandetal24 whodiagnosedtheplasmacell
dyscrasiainapatientfivemonthsafterthediagnosisofMG. Becausetheproteinabnormalitywasconsideredtobe pos-siblyrelatedtothemyasthenicsyndrome,therapy for MM wasinstitutedandcausedaremissionofmyasthenic symp-toms.Inthisregard,ourreportedcase(patient2)issimilar becausetreatmentofMMresultedinresolutionofMG.
The incidence of monoclonal gammopathy developing duringthecourseRAhasbeenestimatedtobe1-2%.22
More-over,Srinivasuluetal.40 reportedthecaseoftwopatients
who presented with inflammatory arthritis as the initial manifestationofMM.Reza-Ardalanetal.studiedthe similar-ityinthecytokinemilieuofMMandRA.Theyshowedthatin thecontextofMM,animmunologicreactiondirectedagainst lightchainmoleculesandtumoralantigensdepositedwithin thesynoviumcouldresultinRA-likepolyarthritis.19Another
biologicallyplausibleassociationbetweenautoimmune thy-roiddisease(ATD)andMMhasbeenreportedregardingthe cytokinemilieu.IL-6inparticularappearstocontributeto thegrowthofmyelomacellsandhasaroleintheinitiation andperpetuationofATD.41
In aprospectivestudy,less than4% ofAHAcases were due toMM, and only eight casesof AHA at MM presenta-tionhavebeenreportedintheliterature.40,42Wadaetal.25
demonstratedthattheantibodybindingtoerythrocyteswas similartomyelomaMprotein.
Among the paraneoplastic syndromes and cutaneous manifestations of MM, angioedema is exceptional (only 4
described in 1972 by Caldwell et al and is characterized by episodes of bradykinin-mediated angioedema without urticarial.43,45,46Intheacquiredform,thedeficiencyresults
frommarkedlyincreasedcatabolismofC1inhibitor dueto itsconsumption by the neoplastic lymphatic tissues (AAE type1)orbyautoantibodymediatedinactivation(AAEtype 2).46,47 Geha etal.48 presenteda patientwithIgA MMand
acquiredC1-inhibitordeficiencywhohadcirculating antiid-iotypicantibodiesthatreactedwiththeMcomponent.This interactionappearedtocauseincreasedconsumptionof C1-inhibitor.ThereisevidencethattheMcomponentsdetected frequentlycorrespondtotheC1-inhibitor autoantibodies. Castellietal.42,44studygrouphasshownthatpatientswith
MGUSandC1-inhibitorauto-antibodiesfrequentlyhavethe sameheavyandlightchainhistotypes.Thissuggeststhata singleBcellclonaldisorderwithdifferentpotentialclinical evolutionsunderliesallAAE.49
In correlation with patient1, it has been documented thatC1-INHantigenvaluescanbenormalduetoelevated amounts of cleaved inactive C1-INH in plasma or normal functionlevelsbetweenangioedemaattacks.C1qreduction confirmsthe diagnosis of AAE, but a minority of patients can present with normal C1q. In this case, the presence ofautoantibodiestoC1-INHcanbeinvestigated.Limitsto theseproceduresaretheinadequatestandardizationof C1-INHfunctionalmeasurementsandtheavailabilitytolookfor anti-C1-INHautoantibodies.49,50
In summary, autoimmunity appears to have an associ-ationwith multiple myeloma. We reviewed several cases of autoimmune conditions related to multiple myeloma documentedintheliterature.Theheterogeneoussetof con-ditions,diversityamongpresentationsandseverityexplains the lack of epidemiological data and clinical features. In themajorityofcases,thediagnosesweremade simultane-ously;SLE wasthe mostcommon AD associatedwithMM. Myeloma treatment in general improved the autoimmune symptoms.As thepathogenesisis stillnot clear,different hypotheseshaveemergedalthoughnoneproven.Basedon only a few studies, it appears that autoimmunity favors the escape of abnormal clones of B cells from regula-torymechanismsleadingtoemergenceofneoplasticBcell clones.On the other hand, other data suggests a sponta-neoustransformationofanautoreactivecloneofBcellsthat lateronundergoesphysiologicalmaturationandproduction of autoantibodies, therefore, explaining the autoimmune manifestations.
Thisassociationneedsfurtherclinicalstudiesinorderto provideanimportantfoundationinunderstandingthe physi-ologyofBcellinMM.Inaddition,largerretrospectivestudies couldfavor thediscernment ofrisk factors,prognosisand essentialepidemiologicdatainthesettingofautoimmune conditionsrelatedtomyeloma.
Ethical
responsibilities
82 A.M.Ávila,S.Giralt
Confidentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdata.
Righttoprivacyandinformedconsent.Theauthorshave obtainedthe written informed consentof the patients or subjectsmentionedinthearticle.Thecorrespondingauthor isinpossessionofthisdocument.
Conflicto
de
intereses
Theauthorshavenoconflictsofinteresttodeclare.
Acknowledgments
Dr.Avila andDr. Giraltperformed the research,designed theresearchstudyandwrotethepaper.Weconsideredthe ethicalresponsibilities dictatedby RevistaColombiana de Cancerologíaandwedonothaveanyconflictofinterestto declare.
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