OfficialreprintfromUpToDate

www.uptodate.com2016UpToDate

Clinicalfeatures,laboratorymanifestations,anddiagnosisofmultiplemyeloma
Author
SVincentRajkumar,MD

SectionEditor
RobertAKyle,MD

DeputyEditor
RebeccaFConnor,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Dec2015.|Thistopiclastupdated:Jan14,2016.
INTRODUCTIONMultiplemyeloma(MM)ischaracterizedbytheneoplasticproliferationofplasmacells
producingamonoclonalimmunoglobulin.Theplasmacellsproliferateinthebonemarrowandoftenresultsin
extensiveskeletaldestructionwithosteolyticlesions,osteopenia,and/orpathologicfractures.Thediagnosisof
MMisoftensuspectedbecauseofone(ormore)ofthefollowingclinicalpresentations:
Bonepainwithlyticlesionsdiscoveredonroutineskeletalfilms
Anincreasedtotalserumproteinconcentrationand/orthepresenceofamonoclonalproteinintheurineor
serum
Systemicsignsorsymptomssuggestiveofmalignancy,suchasunexplainedanemia
Hypercalcemia,whichiseithersymptomaticordiscoveredincidentally
Acuterenalfailurewithablandurinalysisorrarelythenephroticsyndromeduetoconcurrentprimary
amyloidosis
ItisimportanttodistinguishMMbothfromothercausesoftheclinicalpresentationsaboveandfromotherplasma
celldyscrasiasforthepurposesofprognosisandtreatment.Itisalsoimportanttoevaluatepatientssuspectedof
havingMMinatimelyfashionsinceamajordelayindiagnosishasbeenassociatedwithanegativeimpactonthe
diseasecourse[1].
Theclinicalmanifestations,pathologicfeatures,diagnosis,anddifferentialdiagnosisofMMarediscussedhere.
Thepathogenesisandtreatmentofthisdisorderarediscussedseparately.(See"Pathobiologyofmultiple
myeloma"and"Overviewofthemanagementofmultiplemyeloma".)
EPIDEMIOLOGYMMaccountsforapproximately1percentofallcancersandslightlymorethan10percentof
hematologicmalignanciesintheUnitedStates(US)[2].TheannualincidenceintheUSisapproximately4to5
per100,000.AsimilarincidencehasbeenreportedintheSouthThamesareaoftheUnitedKingdomandinEurope
ingeneral[35].
Theincidenceappearstobestable[6,7].Whilesomereportshavesuggestedanincreaseinincidenceovertime,
thismorelikelyreflectstheenhancedavailabilityanduseofmedicalfacilities,especiallybyolderpersons.Our
databasefromOlmstedCounty,Minnesotahasdocumentedastableincidencefromthe1940stotheearly21st
century[6].
MMoccursinallracesandallgeographiclocations.TheincidencevariesbyethnicitytheincidenceinAfrican
AmericansandblacksfromAfricaistwotothreetimesthatinwhites[810].Incontrast,theriskislowerin
AsiansfromJapanandinMexicans[9,11].MMisalsoslightlymorefrequentinmenthaninwomen
(approximately1.4:1).
MMisadiseaseofolderadults.Themedianageatdiagnosisis66yearsonly10and2percentofpatientsare
youngerthan50and40years,respectively[8,12].
Asmallbutunknownfractionofcasesarefamilial.TheriskofdevelopingMMisapproximately3.7foldhigherfor
personswithafirstdegreerelativewithMM[13].MMhasbeenreportedinclustersoftwoormorefirstdegree

relatives,identicaltwins,andinfourmembersspanningthreegenerationsinonefamily,withanincidenceof
approximatelythreefamilialcasesper1000patientswithmyeloma[1328].Inonereportof15familieswithMM
clustering,10occurredinsiblings[23].ThesameIgGkappamonoclonalpatternwaspresentinallcasesinseven
families.Inaddition,agenomewideassociationstudythatgenotyped1675patientswithMMandcomparedthem
with5903controlsubjectssuggestedthatpersonswithacommonvariationatthe3p22.1or7p15.3geneticloci
areatahigherriskofdevelopingMM(oddsratiosof1.32and1.38,respectively)[29].Whileintriguing,suchcases
wouldbeexpectedtoaccountforlessthan5percentoffamilialrisk.Thelowhazardratiosindicatethatthese
markersdonothaveanydirectclinicalimplications,andreflectthecomplexityofthediseaseandtheetiologic
mechanisminvolved.
CLINICALPRESENTATION
SpectrumofdiseaseMostpatientswithMMpresentwithsignsorsymptomsrelatedtotheinfiltrationof
plasmacellsintotheboneorotherorgansortokidneydamagefromexcesslightchains.Asanexample,a
retrospectiveanalysisof1027sequentialpatientsdiagnosedwithMMatasingleinstitutionfoundthefollowing
symptomsandsignsatpresentation[8]:

Anemia73percent
Bonepain58percent
Elevatedcreatinine48percent
Fatigue/generalizedweakness32percent
Hypercalcemia28percent
Weightloss24percent,onehalfofwhomhadlost9kg

Symptomsandsignspresentin5percentorlessincluded:paresthesias(5percent),hepatomegaly(4percent),
splenomegaly(1percent),lymphadenopathy(1percent),andfever(0.7percent).Pleuraleffusionanddiffuse
pulmonaryinvolvementduetoplasmacellinfiltrationarerareandusuallyoccurinadvanceddisease.Astheuse
of"routine"bloodworkhasbecomemorecommon,patientsarebeingdiagnosedearlierinthediseasecourse.
Extramedullaryplasmacytomas(EP)areseeninapproximately7percentofpatientswithMMatthetimeof
diagnosis,andisbestdiagnosedbyPET/CTscanthepresenceofEPatdiagnosisisassociatedwithinferior
survival.Anadditional6percentofpatientswilldevelopEPlaterinthediseasecourse[25,30].EPcanpresentas
large,purplish,subcutaneousmasses(picture1andimage1).Planexanthomasinvolvingthecreasesofthe
palmsand/orsolesmayrepresentaparaneoplasticphenomenon[31].Cutaneousspicules,composedinpartof
themonoclonalprotein,mayrarelyoccur[26].(See"Diagnosisandmanagementofsolitaryextramedullary
plasmacytoma"and"Cutaneousmanifestationsofinternalmalignancy".)
AnemiaAnormocytic,normochromicanemia(hemoglobin12g/dL)ispresentin73percentatdiagnosisand
in97percentatsometimeduringthecourseofthedisease[8].Thisanemiacanberelatedtobonemarrow
replacement,kidneydamage,and/orcanbeduetodilutioninthecaseofalargeMprotein.Anemiacommonly
resultsincomplaintsoffatigueandpallorseenonphysicalexamination.
Macrocytosis(meancorpuscularvolume>100fL)waspresentin9percentof1027patientsstudied[8].Inthis
study,53patients(11percent)withaMCV>100fLhadavitaminB12level<200ng/L.Thisfindingissimilartoa
prevalenceofvitaminB12deficiencyof14percentseeninaseparatestudyof664consecutivepatientswith
plasmacelldyscrasias[27].WhilethemechanismforlowvitaminB12levelsinthesepatientsisnotknown,
investigationsmustbedonetoruleoutperniciousanemia.
BonepainBonepain,particularlyinthebackorchest,andlessoftenintheextremities,ispresentatthetime
ofdiagnosisinapproximately60percentofpatients[8].Thepainisusuallyinducedbymovementanddoesnot
occuratnightexceptwithchangeofposition.Thepatient'sheightmaybereducedbyseveralinchesbecauseof
vertebralcollapse.Plasmacytomasoftheribsoccurandcanpresenteitherasexpandingcostallesionsorsoft
tissuemasses.

RenaldiseaseTheserumcreatinineconcentrationisincreasedinalmostonehalfofpatientsatdiagnosis(and
is>2mg/dL(177micromol/L)inapproximately20percent)renalfailuremaybethepresentingmanifestationof
MM[8,28].TwomajorcausesofrenalinsufficiencyinpatientswithMMarelightchaincastnephropathy(also
calledmyelomakidney)andhypercalcemia.Patientswhodonotsecretelightchainsarenotatriskformyeloma
kidney.Intheabsenceofothercausesofrenalfailure,apresumptivediagnosisoflightchaincastnephropathy
canbemadeinthesettingofhighinvolvedfreelightchainlevels(typically>1500mg/L).Incontrast,renalbiopsy
shouldbeperformedtodocumenttypicalhistologicchangesinpatientswithsuspectedcastnephropathy,
especiallyiftheseruminvolvedFLClevelis<500mg/L[32].(See"Pathogenesisanddiagnosisofmyelomacast
nephropathy(myelomakidney)".)
Othercausesofrenalfailureinapatientwithmyelomaincludeconcurrentlightchain(AL)amyloidosis,lightchain
depositiondisease,anddruginducedrenaldamage.RenaldiseaseinMMisdiscussedinmoredetailseparately.
(See"Typesofrenaldiseaseinmultiplemyeloma".)
HypercalcemiaHypercalcemiaisfoundin28percentofoneseriesofpatientswithMMatthetimeof
diagnosisserumcalciumwas11mg/dL(2.75mmol/liter)in13percentandcanrequireemergenttreatment[8].
Theionizedcalciumshouldbemeasuredifthepatienthasahighserumcalciumlevelbutnosymptomsof
hypercalcemia.Elevationoftheserumcalciummaybeduetobindingofthemonoclonalproteinwithcalcium[33].
(See"Treatmentofthecomplicationsofmultiplemyeloma",sectionon'Hypercalcemia'and"Treatmentof
hypercalcemia"and"Hypercalcemiaofmalignancy",sectionon'Osteolyticmetastases'.)
Ofnote,severehypercalcemiacanactasanunmeasuredcationandtherebyresultinalowaniongap.A
decreasedaniongapmayalsobeduetothepresenceofacationicIgGmolecule.(See"Serumaniongapin
conditionsotherthanmetabolicacidosis".)
NeurologicdiseaseRadiculopathy,usuallyinthethoracicorlumbosacralarea,isthemostcommon
neurologiccomplicationofMM.Itcanresultfromcompressionofthenervebyaparavertebralplasmacytomaor
rarelybythecollapsedboneitself.
CordcompressionSpinalcordcompressionfromanextramedullaryplasmacytoma(image2)orabone
fragmentduetofractureofavertebralbody(image3)occursinapproximately5percentofpatientsitshould
besuspectedinpatientspresentingwithseverebackpainalongwithweaknessorparesthesiasofthelower
extremities,orbladderorboweldysfunctionorincontinence.
Thissetofsymptomsconstitutesamedicalemergencymagneticresonanceimaging(MRI)orcomputed
tomographicmyelographyoftheentirespinemustbeperformedimmediately,withappropriatefollowup
treatmentbychemotherapy,radiotherapy,orneurosurgerytoavoidpermanentparaplegia.(See"Clinical
featuresanddiagnosisofneoplasticepiduralspinalcordcompression,includingcaudaequinasyndrome"and
"Treatmentandprognosisofneoplasticepiduralspinalcordcompression,includingcaudaequina
syndrome".)
PeripheralneuropathyPeripheralneuropathyisuncommoninMMatthetimeofinitialdiagnosisand,when
present,isusuallyduetoamyloidosis.Anexceptiontothisgeneralruleoccursintheinfrequentsubsetof
patientswithPOEMSsyndrome(osteoscleroticmyeloma)inwhichneuropathyoccursinnearly100percent
ofpatients.Thepathogenesisoftheneuropathyisuncertainbutaparaneoplasticmechanismmaybe
importantthisissueisdiscussedseparately.(See"POEMSsyndrome"and"Paraneoplasticsyndromes
affectingperipheralnerveandmuscle",sectionon'Associationwithplasmacelldyscrasias'.)
CNSinvolvementIntracranialplasmacytomasarerareandalmostalwaysrepresentextensionsof
myelomatouslesionsoftheskullorplasmacytomasinvolvingtheclivusorbaseoftheskull.Leptomeningeal
myelomatosisalongwithabnormalcerebrospinalfluidfindingsisuncommonbutisbeingrecognizedmore
frequently,especiallyinadvancedstagesofthedisease[3439].Whenfounditdenotesapoorprognosis
withsurvivalhistoricallymeasuredinmonthsdespitetreatment[38].Itisusuallyassociatedwithhighrisk
cytogeneticslactatedehydrogenase(LDH)levelsmaybeelevated.Survivalappearstohaveimproved

slightlysincetheincorporationofimmunomodulatorydrugsandproteasomeinhibitorsintofirstlinetherapy
[40,41].
Rarecasesofencephalopathyduetohyperviscosityorhighbloodlevelsofammonia,intheabsenceofliver
involvement,havebeenreported[4245].Myelomacelllinesdevelopedfromsuchpatientsproduceelevated
amountsofammonia,althoughthemechanismisunclear[46].Ammonialevelsandthepatient'sstateof
consciousnessreturntonormalifandwhentheunderlyingmyelomarespondstochemotherapy.
InfectionPatientswithMMareatincreasedriskforinfectionduetoacombinationofimmunedysfunctionand
physicalfactors.Immunedysfunctionresultsfromimpairedlymphocytefunction,suppressionofnormalplasma
cellfunction,andhypogammaglobulinemia.Physicalfactorsincludehypoventilationsecondarytopathologic
fracturesandpaininvolvingtheribcageandspine.Streptococcuspneumoniaeandgramnegativeorganismsare
themostfrequentpathogens.
FurtherdetailsofimmunodeficiencyduetoMMarediscussedseparately.(See"Treatmentofthecomplicationsof
multiplemyeloma",sectionon'Infection'.)
PATHOLOGICFEATURES
MonoclonalproteinsThevastmajority(97percent)ofpatientswithMMwillhaveamonoclonal(M)protein
producedandsecretedbythemalignantplasmacells,whichcanbedetectedbyproteinelectrophoresisofthe
serum(SPEP)and/orofanaliquotofurine(UPEP)froma24hourcollectioncombinedwithimmunofixationofthe
serumandurine[8].
TheMproteinusuallypresentsasasinglenarrowpeak,likeachurchspire,inthegamma,beta,oralpha2region
ofthedensitometertracing(figure1),orasadense,discretebandontheagarosegel(image4).Infrequently,two
Mproteinsarepresent(biclonalgammopathy)(figure2).(See"Recognitionofmonoclonalproteins".)
SerumimmunofixationconfirmsthepresenceofanMproteinanddeterminesitstype(figure3).Themalignant
plasmacellscanproduceimmunoglobulinheavychainspluslightchains,lightchainsalone,orneitherwiththe
followingfrequenciesonserumimmunofixation[8]:

IgG52percent
IgA21percent
Kappaorlambdalightchainonly(BenceJones)16percent
IgD2percent
Biclonal2percent
IgM0.5percent
Negative6.5percent

Kappaisthepredominantlightchainisotypecomparedwithlambda,byafactorof2to1withtheexceptionthat
lambdalightchainsaremorecommoninIgDmyelomaandmyelomaassociatedwithamyloidosis(figure4)[47].
TypicalpatternSerumproteinelectrophoresis(SPEP)willdemonstratealocalizedbandorpeakin82
percentofpatientswithmyeloma[8].Additionofserumproteinimmunofixationincreasesthesensitivityto93
percent.If,inaddition,eithertheserumfreelightchain(FLC)assayorurinemonoclonalproteinstudies(urine
proteinelectrophoresisandurineimmunofixation)aredone,thesensitivityincreasesto97percentormore.
PatientswholackdetectableMproteinbyanyofthesetestsareconsideredtohave"nonsecretorymyeloma."
Amongthe20percentwithnolocalizedbandonSPEP,hypogammaglobulinemiaisseeninapproximatelyonehalf
(dueinparttosuppressionofnormalgammaglobulinproduction)andnoapparentabnormalityintheremainder.
Thelevelofoneorbothofthemajoruninvolvedimmunoglobulins(ie,IgMandIgAinthecaseofIgGmyeloma)is
reducedin91percentofpatientsoverall,andbotharereducedin73percent.Normallevelsoftheuninvolved
immunoglobulinswerepresentatdiagnosisin3,8,12,and13percentofourpatientswithIgA,nonsecretory,IgG,

andlightchainmyeloma,respectively[8].Inaretrospectiveanalysis,normallevelsofuninvolvedimmunoglobulins
wereassociatedwithbetterclinicaloutcomes,includinglongerprogressionfreesurvivalandoverallsurvival,
independentoftreatmentreceived[48].Inanotherstudy,patientswithmyelomahadlowermedianlevelsofIgE
(11internationalunits/mL)thannormalsubjects(38internationalunits/mL)[49].
LightchainmyelomaUpto20percentofmyelomaischaracterizedbyonlyalightchainintheserumor
urine,lackingexpressionoftheimmunoglobulinheavychain.ThesepatientsaredetectedreadilybyserumFLC
andUPEPandurineimmunofixation.Theincidenceofrenalfailureismuchhigherinlightchainmyeloma,asthe
serumcreatinineis2mg/dL(177micromol/L)inapproximatelyonethirdofthesepatientsatpresentation.(See
"Treatmentofthecomplicationsofmultiplemyeloma",sectionon'Renalinsufficiency'and"Pathogenesisand
diagnosisofmyelomacastnephropathy(myelomakidney)".)
NonsecretorymyelomaApproximately3percentofpatientswithMMhavenoMproteinintheserumor
urineonimmunofixationatthetimeofdiagnosis[8].Inapproximately60percentofpatientswithmyelomawho
haveanormalserumandurineimmunofixation,monoclonalFLCcanbedetectedintheserumusingFLCassays
[50,51].TheFLCassaymeasuresserumkappaandlambdalightchainlevels,whichcanthenbeexpressedasa
FLCkappatolambdaratio.PatientswithoutproliferativedisordersofplasmacellsorBlymphocyteshavenormal
FLCratios[52].Incomparison,patientswithplasmacelldisorderswillhavegreaterthanexpectedproportionsof
kappaorlambdalightchainsresultinginanabnormalratio.PatientswithmyelomawhohavenoMproteininthe
serumorurineonimmunofixationbuthaveanabnormalserumFLCratioareconsideredtohave"nonmeasurable
FLConlymyeloma"[53].(See'Freelightchainassay'belowand"Recognitionofmonoclonalproteins",sectionon
'Serumfreelightchains'.)
PatientswithmyelomawhohavenormalserumandurineimmunofixationaswellasanormalserumFLCratioare
consideredtohavetruenonsecretorymyeloma[53].Ofthese,themajority(approximately85percent)willhaveM
proteinthatcanbedetectedinthecytoplasmoftheneoplasticplasmacellsbyimmunochemistry,buthave
impairedsecretionofthisprotein.Theother15percentdonothaveimmunoglobulindetectableintheplasmacells
(ie,nonproducermyeloma).Patientswithtruenonsecretorymyelomaneedtobemonitoredmainlyonthebasisof
imagingtestsandbonemarrowstudies.
InaMayoClinicstudy,124patientsdiagnosedwithMMwhohadnomonoclonalproteindetectedonserumand
urineimmunofixationatdiagnosisandonallsubsequentfollowuptestingwerestudied[54].Themedianfollowup
was102months(range,1to204months).Themedianprogressionfreesurvivalwithinitialtherapywas28.6
months,andthemedianoverallsurvival(OS)was49.3months.TheOSofthiscohortwascomparedwithpatients
withsecretorymyeloma.Priorto2001,OSwassimilarinnonsecretorymyeloma(n=86)andsecretorymyeloma
(n=4011),median3.6versus3.5years,respectively.However,amongpatientsdiagnosedbetween2001and
2012,OSwassuperiorinnonsecretorymyeloma(n=36)comparedwithsecretorymyeloma(n=2942),median
8.3versus5.4years,respectively.OSwassuperiorinpatientswithtruenonsecretorymyeloma(n=10)compared
withpatientswithnonmeasurableFLConlymyeloma(n=19),mediansnotreachedinbothgroups.Patientswith
nonsecretoryMMarenotatriskformyelomakidneyaslongaslightchainscannotbedetectedintheurine,but
theyareatriskforothercomplicationsofMM.
OligosecretorymyelomaApproximately5to10percentofpatientswithMMhaveoligosecretory
myelomaatdiagnosis,definedasabsenceofmeasurablediseaseinserumorurinebythefollowingparameters:
SerumMprotein<1g/dL,and
UrineMprotein<200mg/24hours
Monitoringofthesepatientsisdifficultusingthestandardserumandurineelectrophoretictestssinceitwillbe
difficulttodetermineifsmallvariationsarerealorduetoexpectedlaboratoryvariability.Inmostofthesepatients,
theserumfreelightchain(FLC)assaycanbeusedtomonitorthedisease,providedthattheserumFLCratiois
abnormalandtheinvolved(affected)FLClevelis10mg/dL[55].Aswithnonsecretorymyeloma,patientswith
oligosecretorydiseasemayalsoneedtobemonitoredbyimagingandbonemarrowstudies,particularlyifthe

baselineFLClevelsareunmeasurable(<10mg/dL)orifthereisconcernaboutthereliabilityoftheresults.
LaboratoryartifactsCirculatingmonoclonalproteinsmayinterferewithoneormorelaboratorytests
performedonliquidbasedautomatedanalyzers,eitherbyprecipitatingduringtheanalysis,orbyvirtueoftheir
specificbindingproperties.ThemostcommonartifactsarealowvalueforHDLcholesterol,ahighvaluefor
bilirubin,aswellasalteredmeasurementofinorganicphosphate.(See"Recognitionofmonoclonalproteins",
sectionon'Interferencewithlaboratorytests'.)
Althoughnotalaboratoryartifact,monoclonalproteincanincreasetheserumviscosityanderythrocyte
sedimentationrate(ESR).TheESRis>20mm/hourin84percent,and>100mm/hourinonethirdofpatientswith
MM.
UrinalysisAsmentionedabove,patientswithMMfrequentlypresentwithrenalinsufficiencyduetocast
nephropathy.Alternatively,kidneydiseaseassociatedwithMMcanbeduetoamyloidosisorlightchaindeposition
disease.Caremustbetakenininterpretingtheurinalysisresults.Urinedipstickexaminationsprimarilydetect
albumin,notlightchains,whichcanbedetectedbysulfosalicylicacidora24hoururinecollectionincluding
electrophoresisandimmunofixation.(See"Pathogenesisanddiagnosisofmyelomacastnephropathy(myeloma
kidney)"and"Patientinformation:Collectionofa24hoururinespecimen(BeyondtheBasics)".)
FindingsonurinalysisinMMdependupontheetiologyofthekidneydamage:
Myelomacastnephropathyischaracterizedbythepresenceoflarge,waxy,laminatedcastsinthedistaland
collectingtubulesthecastsaremainlycomposedofprecipitatedmonoclonallightchains(picture2AC).The
urinedipstickistypicallynegativeforprotein,sincemostoftheproteinuriaiscomprisedofurinary
monoclonalprotein(BenceJonesproteinuria)ratherthanalbumin.(See"Pathogenesisanddiagnosisof
myelomacastnephropathy(myelomakidney)".)
Incontrasttomyelomacastnephropathy,renalinvolvementinotherrelatedplasmacelldisorders,namely
ALamyloidosisandlightchaindepositiondisease,typicallypresentwithamarkedlypositivedipstickfor
protein,sincemostoftheurinaryproteiniscomprisedofalbumin(nephroticsyndrome).BenceJones
proteinuriaisminimal.
Castnephropathyandamyloidosisrarelyoccurinthesamepatientsbecausethebiochemicalcharacteristicsof
theindividualmonoclonallightchainareanimportantdeterminantofthetypeofrenaldiseasethatmaybeseen.
(See"Typesofrenaldiseaseinmultiplemyeloma".)
PeripheralsmearThemostfrequentfindingsonperipheralsmeararerouleauxformation(>50percent),
leukopenia(20percent),andthrombocytopenia(5percent)[8].Rouleauxformationisthephenomenonwhenred
cellstakeontheappearanceofastackofcoinsindilutedsuspensionsofbloodandisseeninpatientswith
elevatedserumproteinlevels(picture3).Aleukoerythroblasticreactionisuncommonlyseen.(See"Evaluationof
theperipheralbloodsmear",sectionon'Initialapproach'.)
Monoclonalplasmacellsarerarelyseenintheperipheralsmearinpatientswithmyelomaadetectableabsolute
peripheralbloodplasmacellcount100cells/microL(0.1x109/L)isfoundinapproximately10percent(picture4).
Plasmacellleukemia,arare,yetaggressiveformofMMcharacterizedbyhighlevelsofplasmacellscirculatingin
theperipheralblood,shouldbeconsideredwhenevercirculatingplasmacellsarereadilydetectedonconventional
completebloodcountevaluation.(See"Plasmacellleukemia".)
Circulatingmonoclonalplasmacellscanbedetectedusingaslidebasedimmunofluorescenceassay,atwocolor
immunoassaytechnique(ELISPOT),orflowcytometrybygatingonCD38+/CD45cells.Usingthesesensitive
techniques,circulatingmonoclonalplasmacellscanbeidentifiedinthemajorityofpatientswithMMtheabsolute
percentagedependsuponthesensitivityofthetestused.(See"Stagingandprognosticstudiesinmultiple
myeloma",sectionon'Circulatingplasmacells'.)
Bonemarrowexamination

PercentplasmacellsAbonemarrowaspirateandbiopsyareakeycomponenttothediagnosisofMM
(picture5andpicture6).Thebonemarrowplasmacellpercentageshouldbeestimatedfromacorebiopsy
specimen,whenpossible.However,ifthepercentplasmacellsintheaspirateandcorebiopsydiffer,thehigher
valueshouldbeused.Flowcytometryisnotusedtodeterminebonemarrowplasmacellpercentagefordiagnostic
purposes.Clonalitycanbeestablishedbydemonstratingkappa/lambdalightchainrestrictiononflowcytometry,
immunohistochemistry,orimmunofluorescence.
Thebonemarrowofthevastmajorityofpatientscontains10percentormoreclonalplasmacells.However,due
topatchybonemarrowinvolvement,bonemarrowaspirateandbiopsymayshowlessthan10percentplasma
cellsinapproximately4percentofpatients.Asanexample,intheMayoClinicseries,plasmacellsconstituted
morethan10percentofallnucleatedcellsin96percentofpatients,butthisvaluerangedfromlessthan5percent
toalmost100percent,withamedianvalueof50percent[8].
AdiagnosisofMMcanbemadeinpatientswithlessthan10percentclonalplasmacellsonbiopsyifother
diagnosticcriteriaarefulfilledandafterhistopathologicconfirmationofasofttissueorbonyplasmacytoma[11].
Sincebonemarrowinvolvementmaybemorefocalthandiffuse,somepatientsmayrequirebonemarrow
aspirate/biopsyfromseveraldifferentsitesoraguidedbiopsyofafocallesiondiagnosedbyeitherMRIorPET/CT
(integratedpositronemissiontomographyandcomputedtomography)scaninordertoestablishthediagnosis.
Inaddition,asymptomaticpatientswhohave60percentclonalplasmacellsinthebonemarrowhaveariskof
progressiontoendorgandamageinthenexttwoyearsofgreaterthan80percentandamedianprogressionfree
survivalofapproximatelysevenmonths[56,57].Inthissetting,thepercentofclonalplasmacellsinthebone
marrowisdiagnosticofMM[58].(See'Diagnosticcriteria'below.)
MorphologyThemorphologicalfeaturesofplasmacellscandifferdependingupontheirmaturityand,at
times,theymaybemorphologicallyindistinguishablefrommyeloblasts.Matureplasmacellsareovalwith
abundantbasophiliccytoplasm.Thenucleusisroundandeccentricallylocatedwithamarkedperinuclearhof,or
cytoplasmicclearing(picture4).Thenucleuscontains"clockface"or"spokewheel"chromatinwithoutnucleoli.
Immatureplasmacellshavedispersednuclearchromatin,prominentnucleoliandahighnucleartocytoplasmic
ratio.
Thecytoplasmofmyelomacellsmaycontaincondensedorcrystallizedcytoplasmicimmunoglobulinresultingin
thefollowingunusualfindings,whicharenotlimitedtoMM[59]:
Multiplepalebluishwhite,grapelikeaccumulations(eg,Mottcells,Morulacells)
Cherryredrefractiveroundbodies(eg,Russellbodies)
VermilionstainingglycogenrichIgA(eg,Flamecells)
Overstuffedfibrils(eg,Gaucherlikecells,thesaurocytes)
Crystallinerods
ImmunophenotypeImmunohistochemicalstaining,immunofluorescentstudies,andflowcytometrydetect
eitherkappaorlambdalightchains,butnotboth,inthecytoplasmofbonemarrowplasmacellsinpatientswith
myelomasurfaceimmunoglobulinisabsent.Thenormalkappa/lambdaratiointhebonemarrowis2:1.Aratioof
morethan4:1orlessthan1:2isconsideredtomeetthedefinitionofkappaorlambdamonoclonality,respectively.
Thisfindingdistinguishesthemonoclonalgammopathiesfromreactiveplasmacytosisduetoautoimmune
diseases,metastaticcarcinoma,chronicliverdisease,acquiredimmunodeficiencysyndrome(AIDS),orchronic
infection,inwhichtheplasmacellsshowreactivityforbothlightchaintypesandthekappa/lambdaratioiswithin
thenormalrange.ACD138staincanidentifyplasmacellsandaidintheaccuratedeterminationofpercentage
involved.
Muchlikenormalplasmacells,myelomacellsexpressCD79a,VS38c,CD138,andCD38[59].Incontrastto
normalplasmacells,myelomacellsinfrequentlyexpressCD19.Approximately70percentofmyelomacellswill

expressCD56,whichistypicallynegativeinnormalplasmacellsandinplasmacellleukemia.(See"Plasmacell
leukemia".)
CytogeneticsThereisnosinglecytogeneticabnormalitythatistypicalordiagnosticofMM.Themajorityof
myelomatumorshavegeneticabnormalitiesthatcanbedetectedwithsensitivemoleculargenetictechniques,
suchasinterphasefluorescentinsituhybridization(FISH).Incontrast,only20to30percentofpatientswillhave
cytogeneticabnormalitiesdetectedinbonemarrowplasmacellsbyconventionalkaryotyping,duetoalownumber
ofmetaphasesinmyelomacellsinsuchspecimens[60,61].ThegeneticchangesfoundinMMarediscussedin
moredetailseparately.(See"Pathobiologyofmultiplemyeloma",sectionon'Cytogeneticabnormalities'and
"Stagingandprognosticstudiesinmultiplemyeloma",sectionon'Fluorescentinsituhybridization(FISH)'.)
FreelightchainassayThefreelightchain(FLC)assaymeasureskappaandlambdalightimmunoglobulin
chainsthatareunboundtoheavychainsintheserum.Thenormalkappa/lambdaFLCratiois0.26to1.65.
AbnormalFLCratiosareseeninclonalplasmacelldisorderswhenthereisexcessproductionofonetypeoflight
chain(kappaorlambda).AbnormalFLCratiosareseeninapproximately90percentofpatientswithMM[62,63].
Patientswithotherwiseasymptomaticmyelomawhohaveaninvolved/uninvolvedFLCratioof100orgreaterhave
ariskofprogressiontoendorgandamageinthenexttwoyearsofapproximately80percent[6466].Inthese
patients,iftheabsoluteinvolvedFLClevelwasalsoincreasedat100mg/dL(1000mg/L)ormore,theriskof
progressioninthenexttwoyearsincreasedto93percent.Giventhehighrateofprogression,anFLCratioof100
ormoreisnowconsidereddiagnosticofMM[58].(See"Recognitionofmonoclonalproteins",sectionon'Serum
freelightchains'.)
RADIOGRAPHICSTUDIESAmetastaticbonesurveywithplainradiographsincludingthehumeriandfemoral
bonesisakeycomponenttotheevaluationofapatientsuspectedofhavingMM[67].Computerizedtomography
(CT),magneticresonanceimaging(MRI),andpositronemissiontomography(PET)aremoresensitivethanplain
radiographsatdetectingboneinvolvementhowever,ourunderstandingoftheclinicalimportanceofasymptomatic
bonelesionsdetectedbytheseimagingmodalitiesaloneisevolving.Ourapproachisconsistentwiththe
guidelinesproposedbytheInternationalMyelomaWorkingGroup[58,68,69].
WereserveCT,MRI,andPET/CTforselectpatientssuchas:

Patientswithbonepainwithoutanabnormalityonskeletalsurvey
Patientswithcompressionfractures
Patientswithneurologicaldeficitthatmaybeduetospinalcordcompression
Patientsinwhomthereisanyuncertaintyabouttheextentofbonedisease

Inaddition,eitherMRIorPET/CTscanincludingtheskull,pelvis,sternum,shoulders,andthoracolumbarspine
shouldbeperformedroutinelybeforemakingthediagnosisofsolitaryplasmacytomaorsmolderingmyeloma
[58,69,70].Technetium99mbonescanning(whichprimarilydetectsosteoblasticactivity)isinferiortoconventional
radiographyforthedetectionoflyticlesionsandshouldnotbeused[71].Thesetestsarealsoappropriatein
patientsreceivingintensivetherapiestomonitordiseaseresponse.
SkeletalsurveysTheskeletalsurveyforpatientswithMMincludesaposteroanteriorviewofthechest,
anteroposteriorandlateralviewsofthecervicalspine,thoracicspine,lumbarspine,humeriandfemora,
anteroposteriorandlateralviewsoftheskullandanteroposteriorviewofthepelvis[72].Symptomaticareasare
alsoimaged.
Conventionalskeletalsurveysrevealpunchedoutlyticlesions(image5andimage6),diffuseosteopenia(image
7),orfracturesinnearly80percentofpatientswithMMatthetimeofdiagnosis(table1)[8,73,74].Focallytic
lesionsarefoundinnearly60percentosteoporosis,pathologicfractures,orcompressionfracturesofthespine
eachoccurinapproximately20percentofpatients.Themostfrequentsitesofinvolvementincludeareaswith
activehematopoiesis,suchasthevertebralbodies,skull,thoraciccage,pelvis,andproximalhumeriandfemora.
Osteoscleroticlesions(ie,areasofintenseincreasedbonedensity)arerare.(See'POEMSsyndrome'belowand

"POEMSsyndrome".)
CT,MRI,andPETLowdosewholebodyCT,MRI,andPET/CTscansarehelpfulinpatientswhohavebone
painbutnoabnormalitiesonroutineroentgenograms[71,7588].Inaddition,eitherMRIorPET/CTscanshouldbe
performedroutinelybeforemakingthediagnosisofsolitaryplasmacytomaorsmolderingmyeloma[58,69,70].
Patientswithotherwiseasymptomaticmyelomawhohavemorethanonefocalbonelesion(5mm)haveariskof
progressiontoendorgandamageinthenexttwoyearsofgreaterthan80percent[8991].Inthissetting,theMRI
canbediagnosticofMM[58].(See'Diagnosticcriteria'below.)
MRIcandetectdiffuseandfocalbonemarrowlesionsinpatientswithMMwithoutosteopeniaorfocalosteolytic
lesionsonstandardmetastaticbonesurveysandbonesurveyscandetectlesionsnotfoundonMRIoftheaxial
skeleton.Inonestudyinwhich611patientswithmyelomahadbothMRIimaging(limitedtotheaxialbone
marrow)aswellasastandardmetastaticbonesurvey,MRIdetectedfocallesionsin52percentofthosewith
negativebonesurveys,whilebonesurveysdetectedfocallesionsin20percentofthosewithanegativeMRI[82].
SignificantlyhigherproportionsofpatientshadfocallesionsdetectedonMRIinthespine,pelvis,andsternum,
whilebonesurveysoutperformedMRIforlesionsintheribsandlongbones.
Uptohalfofpatientswithoutotherevidenceofendorgandamagewithnormalplainfilmsmaydemonstratetumor
relatedlesionsonMRIofthelowerspine[8284].MRImayalsobeofprognosticvalueinsuchpatientsin
determiningriskofprogression[81,89].Asanexample,theimportanceoffocallesionsidentifiedonwholebody
MRIwasinvestigatedin149patientswithasymptomaticmyeloma[89].Onmultivariateanalysis,thepresenceof
morethanonefocallesionorthepresenceofdiffusemarrowinvolvementweresignificantlyassociatedwithan
increasedlikelihoodofprogressiontosymptomaticendorgandamage.
Amongpatientswithmoderatetoadvancedrenalfailure(dialysisdependentorestimatedGFR<30mL/min),the
administrationofgadoliniumhasbeenassociatedwiththepotentiallyseveresyndromeofnephrogenicsystemic
fibrosis.Insuchpatients,gadoliniumbasedimagingshouldbeavoidedifpossible.Thisissueandtheroleof
hemodialysisaftertheprocedureifgadoliniumbasedimagingmustbeperformedarediscussedseparately.(See
"Nephrogenicsystemicfibrosis/nephrogenicfibrosingdermopathyinadvancedrenalfailure",sectionon'If
gadoliniummustbegiven'.)
PET/CTscanningusingfluorine18labeledFDGappearstocorrelatewithareasofactivelyticbonedisease[85
88,92].Inonesmallseries,PET/CTscanningdetectedsomelesionsmissedbyothertechniqueshowever,false
positiveaswellasfalsenegativeresultswerealsoreported[87].Thespecificityofmyelomalesionsishigherwith
aPET/CTscan,whichsuggestsanactiveosteolyticlesionatthesiteofincreasedtraceruptake.
Theadministrationofradiocontrastmedia,usuallyinconjunctionwithaCTscan,canleadtoausuallyreversible
formofacutekidneyinjurythatbeginssoonafterthecontrastisadministered,calledcontrastinduced
nephropathy.PatientswithMMareatincreasedriskfromacontraststudy,althoughtheincidenceofacuterenal
failureappearstobelessthan1.5percentwiththeuseofmoderncontrastagents[93].Patientswithnearnormal
renalfunctionareatrelativelylowriskandfewprecautionsarenecessaryotherthanavoidanceofvolume
depletion[94].(See"Preventionofcontrastinducednephropathy"and"Pathogenesis,clinicalfeatures,and
diagnosisofcontrastinducednephropathy",sectionon'Epidemiology'.)
DIAGNOSISThediagnosisofMMisoftensuspectedbecauseofone(ormore)ofthefollowingclinical
presentations:
Bonepainwithlyticlesionsdiscoveredonroutineskeletalfilms
Anincreasedtotalserumproteinconcentrationand/orthepresenceofamonoclonalproteinintheurineor
serum
Systemicsignsorsymptomssuggestiveofmalignancy,suchasunexplainedanemia
Hypercalcemia,whichiseithersymptomaticordiscoveredincidentally

 Acuterenalfailurewithablandurinalysisorrarelythenephroticsyndromeduetoconcurrentprimary
amyloidosis
EvaluationPatientssuspectedofhavingMMshouldinitiallyundergoacompletehistoryandphysical
examination.Thehistoryshouldpayspecificattentiontocomplaintsofbonepain,constitutionalsymptoms,
neurologicalsymptoms,andinfections.Thephysicalexaminationshouldincludeadetailedneurologicexam.
Inaddition,weperformthefollowinglaboratorystudiesasaninitialscreentolookforMM[68,9597]:
Acompletebloodcountanddifferentialwithexaminationoftheperipheralbloodsmear.
Achemistryscreenthatincludesmeasurementsofserumcalcium,creatinine,albumin,lactate
dehydrogenase,beta2microglobulin,andCreactiveprotein.(See"Stagingandprognosticstudiesinmultiple
myeloma".)
Serumfreemonoclonallightchain(FLC)analysis.
Aserumproteinelectrophoresis(SPEP)withimmunofixationandquantitationofimmunoglobulins.(See
"Recognitionofmonoclonalproteins".)
Aroutineurinalysisanda24hoururinecollectionforelectrophoresis(UPEP)andimmunofixation.Serum
FLCanalysismaybeusedinplaceofa24hoururinecollectioninconjunctionwithSPEPand
immunofixationforscreeningpurposesonly[98].However,ifaplasmacellproliferativedisorderisidentified,
theUPEPandimmunofixationarenecessary.(See"Recognitionofmonoclonalproteins".)
SerumviscosityshouldbemeasurediftheMproteinconcentrationishigh(ie,>5g/dL)orthereare
symptomssuggestiveofhyperviscosity.(See"Epidemiology,pathogenesis,clinicalmanifestationsand
diagnosisofWaldenstrmmacroglobulinemia",sectionon'Hyperviscositysyndrome'.)
Bonemarrowaspirationandbiopsywithimmunophenotyping,conventionalcytogenetics,andfluorescencein
situhybridization(FISH).AlthoughabonemarrowevaluationisindicatedforallpatientswithMMat
diagnosis,itmaybedeferredforpersonsthatareclinicallysuspectedofhavingMGUSwithasmall
monoclonalprotein(lessthan1.5g/100mL),minimalornoabnormalitiesinserumfreelightchains,andno
endorgandamage.
Ametastaticbonesurveywithplainradiographsincludingthehumeriandfemoralbonesshouldbeperformed
inallpatients.Ifpatientshaveanormalbonesurveyinthesettingofbonepain,orhaveneurologicaldeficits
thatmaybeduetospinalcordcompression,additionalimagingsuchasMRI,CT,orPET/CTshouldbe
performedtoruleoutmyelomabonedisease.MRIandPET/CTareusefulinpatientsinwhomthereis
uncertaintyabouttheextentofbonedisease,andtheroleoftheseimagingmodalitiesisevolving.PET/CTor
MRIshouldbeperformedtoconfirmtheabsenceofmorethanonefocallyticlesioninallpatientsotherwise
suspectedofhavingsmolderingmyelomaorsolitaryplasmacytoma.
DiagnosticcriteriaTheInternationalMyelomaWorkingGroupcriteriaforthediagnosisofMMemphasizethe
importanceofendorgandamageinmakingthediagnosis(table2)[58].
ThediagnosisofMMrequiresthefulfillmentofthefollowingcriterion:
Clonalbonemarrowplasmacells10percentorbiopsyprovenbonyorsofttissueplasmacytoma
Clonalityshouldbeestablishedbyshowingakappa/lambdalightchainrestrictiononflowcytometry,
immunohistochemistry,orimmunofluorescence.Bonemarrowplasmacellpercentageshouldbeestimated
fromacorebiopsyspecimen,whenpossible.Ifthereisdisparitybetweentheaspirateandcorebiopsy,the
highestvalueshouldbeused.Approximately4percentofpatientsmayhavefewerthan10percentbone
marrowplasmacellssincemarrowinvolvementmaybefocal,ratherthandiffuse.Repeatbonemarrow
biopsyshouldbeconsideredinsuchpatients.
PLUSoneofthefollowing:

 Presenceofrelatedorganortissueimpairment(oftenrecalledbytheacronymCRAB)Endorgan
damageissuggestedbyincreasedplasmacalciumlevel,renalinsufficiency,anemia,andbonelesions.In
ordertobeincludedasdiagnosticcriteria,changesinthesefactorsmustbefelttoberelatedtothe
underlyingplasmacellproliferativedisorder.(See"Overviewofthemanagementofmultiplemyeloma",
sectionon'Verificationofthediagnosis'.)
Forthesepurposes,thefollowingdefinitionsareused:
AnemiaHemoglobin<10g/dL(<100g/L)or>2g/dL(>20g/L)belownormal
HypercalcemiaSerumcalcium>11mg/dL(>2.75mmol/liter).Considerothercausesof
hypercalcemia(eg,hyperparathyroidism).(See"Diagnosticapproachtohypercalcemia".)
RenalinsufficiencyEstimatedormeasuredcreatineclearance<40mL/min(calculator1and
calculator2)orserumcreatinine>2mg/dL(177mol/liter).Ofthese,creatinineclearanceisthe
preferredmeasureofrenalinsufficiencybecausenormalserumcreatininelevelsvarybyage,sex,and
race.Usingcreatinineclearanceensuresthatasimilarlevelofrenaldysfunctionisrequiredtoend
organdamage.
BonelesionsOneormoreosteolyticlesions5mminsizeonskeletalradiography,MRI,CT,or
PET/CT.Intheabsenceofosteolyticlesions,thefollowingarenotsufficientmarkersofbonelesions:
increasedFDGuptakeonPET,osteoporosis,orvertebralcompressionfracture.Whenadiagnosisisin
doubt,biopsyofthebonelesionshouldbeconsidered.
ManifestationsofnonCRABendorgandamage(eg,hyperviscosity,recurrentbacterialinfections,AL
amyloidosis,peripheralneuropathy)arenonspecificandnotdiagnosticofMM.
Presenceofabiomarkerassociatedwithnearinevitableprogressiontoendorgandamage60
percentclonalplasmacellsinthebonemarrowinvolved/uninvolvedfreelightchain(FLC)ratioof100or
more(providedinvolvedFLClevelisatleast100mg/L)orMRIwithmorethanonefocallesion(involving
boneorbonemarrow).
MostbutnotallpatientswillhaveanMproteininserum(figure1andfigure3)and/orurine(figure5andfigure6).
Approximately40percentofpatientswithsymptomaticMMwillhaveanMproteinoflessthan3g/dL.Intruenon
secretoryMM(approximately3percentofMM),anMproteinwillnotbedetectableintheserumorurinewith
immunofixation(see"Recognitionofmonoclonalproteins").
DIFFERENTIALDIAGNOSISItisimportanttodistinguishMMbothfrombenigncauses,whichcanpresent
withsimilarmanifestations,andfromotherplasmacelldyscrasiasforthepurposesofprognosisandtreatment.
Thediagnosticapproachestopatientswithhypercalcemiaoracuterenalfailurearediscussedseparately.(See
"Diagnosticapproachtohypercalcemia"and"Diagnosticapproachtothepatientwithsubacutekidneyinjuryinan
outpatientsetting".)
ThemainconditionstoconsiderinthedifferentialdiagnosisofMMaremonoclonalgammopathyofundetermined
significance(MGUS),smolderingmultiplemyeloma(SMM)[99],Waldenstrmmacroglobulinemia(WM),solitary
plasmacytoma,primaryamyloidosis(AL),POEMSsyndrome,andmetastaticcarcinoma(table3andtable4).
Distinguishingfeaturesoftheseconditionsarelistedbelow.
MonoclonalgammopathyofundeterminedsignificanceMonoclonalgammopathyofundetermined
significance(MGUS)isdiagnosedinpersonswhomeetthefollowingthreecriteria(table2andalgorithm1):
Serummonoclonalprotein(whetherIgA,IgG,orIgM)<3g/dL
Clonalbonemarrowplasmacells<10percent
Absenceoflyticlesions,anemia,hypercalcemia,andrenalinsufficiency(endorgandamage)thatcanbe
attributedtotheplasmacellproliferativedisorder

MGUScarriesariskofprogressiontoMMofapproximately1percentperyear[100].DifferentiationofMGUSfrom
MMcanbedifficultandisprimarilybasedonpresenceorabsenceofrelatedendorgandamage.Incomparisonto
overtMMorplasmacellleukemia,mostpatientswithMGUSorSMMhavefewornocirculatingmonoclonal
plasmacells.Theuseofotherclinicalandlaboratoryfactorstodifferentiatebetweenthesetwoentitiesis
discussedinmoredetailseparately.(See"Diagnosisofmonoclonalgammopathyofundeterminedsignificance",
sectionon'Multiplemyeloma'.)
SmolderingmultiplemyelomaSmolderingmultiplemyeloma(SMM)isdefinedas:
Mprotein3g/dLand/or10to60percentbonemarrowplasmacells,plus
Noendorgandamageorothermyelomadefiningevents,andnoamyloidosis(table2)[58]
Thus,forthediagnosisofSMM,patientsshouldnothaveanyofthefollowingmyelomadefiningevents:
Endorgandamage(lyticlesions,anemia,renaldisease,orhypercalcemia)thatcanbeattributedtothe
underlyingplasmacelldisorder
60percentclonalplasmacellsinthebonemarrow[56,57]
Involved/uninvolvedfreelightchain(FLC)ratioof100ormore[6466]
Magneticresonanceimaging(MRI)withmorethanonefocallesion(involvingboneorbonemarrow)[8991]
AsymptomaticpatientswithoneormoreofthemyelomadefiningeventslistedaboveareconsideredtohaveMM
ratherthanSMMbecausetheyhaveariskofprogressionwithcomplicationsofgreaterthan80percentwithintwo
years[58](see'Diagnosticcriteria'above).
ThemanagementofSMMispresentedinmoredetailseparately.(See"Smolderingmultiplemyeloma".)
IftherearedoubtsaboutthedifferentiationofMGUS/SMMfrommyeloma,andwhethertobeginchemotherapy
immediately,oneshouldwithholdtreatmentandreevaluateintwoorthreemonths.PatientswithSMMmayremain
stableforprolongedperiods.
WaldenstrmmacroglobulinemiaandIgMmultiplemyelomaWaldenstrmmacroglobulinemia(WM)isa
distinctclinicopathologicentitydemonstratinglymphoplasmacyticlymphoma(LPL)inthebonemarrowwithanIgM
monoclonalgammopathyintheblood.Patientsmaypresentwithsymptomsrelatedtotheinfiltrationofthe
hematopoietictissuesortheeffectsofmonoclonalIgMintheblood.(See"Epidemiology,pathogenesis,clinical
manifestationsanddiagnosisofWaldenstrmmacroglobulinemia".)
Inmostcases,thedistinctionbetweenWMandMMisstraightforwardsincetheclinicalfeaturesaredifferent,and
thetypeofMproteinseeninWMisunique(IgM).Thelymphoplasmacyticlymphomaseeninthebonemarrowof
patientswithWMcanbedistinguishedfromplasmacellsseeninthebonemarrowofpatientswithMMbythe
absenceofCD56andthepresenceofasubstantialsmalllymphocyticcomponentthatexpressesaclonalsurface
immunoglobulin,CD19,andCD20.SomepatientswithMMandt(1114)mayhavelymphoplasmacyticorsmall
matureplasmacellmorphology,alongwithCD20expressionthatmayresembleWM.However,thet(1114)
translocationisnotseeninWM.(See"Stagingandprognosticstudiesinmultiplemyeloma",sectionon
'Fluorescentinsituhybridization(FISH)'.)
ClassicMMwithanIgMparaprotein(IgMmultiplemyeloma)isextremelyrare,comprisingonly0.5percentofthe
MayoClinicseries[8].TheMayoCliniccriteriafordiagnosisofIgMmyeloma(anditsdifferentiationfromWM)
requirepresenceofeitherlyticbonelesionsfeltsecondarytotheplasmacelldisorderand/orevidenceofthe
t(1114)translocation[101].Thecriteriaareconservativeanddesignedtoemphasizespecificityoversensitivity,
andensurethatpatientswithWMarenotmisclassifiedandtreatedasmyelomapatientsbasedonlessreliable
andsubjectivemeasuressuchasCD20expressionormorphology.
SolitaryplasmacytomaPlasmacytomasaretumorscomposedofplasmacellsofvariablematurity,whichare
histologicallyidenticaltothoseseeninMM.Iftheyoccursolelyinthebone,theyaredesignatedsolitary
plasmacytomaofbone.Iftheyariseoutsideboneinsofttissues,theyarecalledsolitaryextramedullary

plasmacytoma.(See"Diagnosisandmanagementofsolitaryplasmacytomaofbone"and"Diagnosisand
managementofsolitaryextramedullaryplasmacytoma".)
Tomakethediagnosisofsolitaryplasmacytoma,thefollowingfourcriteriamustbemet:
Biopsyprovensolitarylesionoftheboneorsofttissuethatdemonstratesclonalplasmacells.
Normalbonemarrowwithnoevidenceofclonalplasmacells.
SkeletalsurveyandMRIofthespineandpelvisarenormalexceptfortheprimarysolitarylesion.
Absenceoflyticlesions,anemia,hypercalcemia,andrenalinsufficiency.
Notethatpatientswhohaveabiopsyprovensolitarymedullaryorextramedullarylesionwithevidenceofclonal
plasmacellsinthebonemarrowareusuallytreatedinasimilarfashiontothosewithsolitaryplasmacytoma,but
technicallyareconsideredtohaveeither"solitaryplasmacytomawithminimalmarrowinvolvement"ifclonalbone
marrowplasmacellsare<10percent,orMM(typicallyDurieSalmonstage1)ifclonalbonemarrowplasmacells
are10percent.(See"Stagingandprognosticstudiesinmultiplemyeloma".)
ALamyloidosisAswithMM,AL(amyloidlightchain)amyloidosis(previouslyreferredtoasprimary
amyloidosis)andlightchaindepositiondiseaseareplasmacellproliferativedisordersassociatedwiththe
overproductionofmonoclonallightchains.However,patientswithprimaryamyloidosisorlightchaindeposition
diseasedeveloptissuedepositsofamyloidfibrilsornonfibrillarmaterialthatcanproducethenephroticsyndrome,
heartfailure,hepatomegaly,andotherfindingsthatarenotseeninMM.
IncontrasttopatientswithMM,patientswithALamyloidosisusuallydemonstratelessthan20percentbone
marrowplasmacells,nolyticbonelesionsonimaging,andamodestamountofBenceJonesproteinuria.The
diagnosisofprimaryamyloidosisisestablishedbydemonstratingamyloidonabiopsyofaffectedtissue,suchas
abdominalfat,bonemarrow,rectum,orkidney.(See"Pathogenesisofimmunoglobulinlightchain(AL)amyloidosis
andlightandheavychaindepositiondiseases"and"Clinicalpresentation,laboratorymanifestations,anddiagnosis
ofimmunoglobulinlightchain(AL)amyloidosis(primaryamyloidosis)".)
Rarely,MMcandevelopinpatientswithprimaryamyloidosis.Inaseriesof1596patientswithprimary
amyloidosisseenattheMayoClinicbetween1960and1994,onlysix(0.4percent)showeddelayedprogression
(at10to81months)toovertMM[102].Thisusuallyoccursinpatientswithoutcardiacorhepaticamyloidwholive
longenoughtodevelopMM.Ontheotherhand,thedevelopmentofdipstickpositiveproteinuria,hypoalbuminemia,
andedemaorheartfailureinapatientwithknownMMsuggestssuperimposedamyloidosisorlightchain
depositiondisease.
POEMSsyndromePOEMSsyndrome(osteoscleroticmyeloma:Polyneuropathy,Organomegaly,
Endocrinopathy,Monoclonalprotein,Skinchanges)isamonoclonalplasmacelldisorderaccompaniedby
symptomsand/orsignsofperipheralneuropathy,osteoscleroticlesions,Castleman'sdisease,organomegaly,
endocrinopathy(excludingdiabetesmellitusorhypothyroidism),edema,typicalskinchanges,and/orpapilledema.
ThesepatientstypicallyhaveelevatedserumVEGF(vascularendothelialgrowthfactor)levels.(See"POEMS
syndrome".)
PolyneuropathyisuncommoninclassicalMMand,whenpresent,isusuallyduetothepresenceofamyloidosis.
Thepresenceofanemia,hypercalcemia,renalfailure,pathologicfractures,andahighpercentofplasmacellsin
thebonemarrowallservetodistinguishclassicalMMfromPOEMSsyndrome.
Inrareinstances,MMmaybeassociatedwiththepresenceofdiffuseandnotfocalosteoscleroticbonelesions.
SuchpatientshavethetypicalclinicalandlaboratoryfeaturesofMManddonothavetheothercharacteristicsof
POEMSsyndrome.
MetastaticcarcinomaThepresenceoflyticbonelesionsinapatientwithamonoclonalgammopathysuggests
thepossibilityofMM.However,metastaticcarcinoma(eg,kidney,breast,nonsmallcelllungcancer)canproduce

lyticlesions,andasubsetofpatientspresentinginthiswaywillhavemetastaticcancerwithanassociated,
unrelatedmonoclonalgammopathy(eg,MGUS).Personspresentingwithlyticbonelesions,constitutional
symptoms,asmallMcomponent,andfewerthan10percentclonalplasmacellsinthebonemarrowaremore
likelytohavemetastaticcarcinomawithanunrelatedMGUSratherthanMM.Thiscanbeconfirmedwithabiopsy
ofthebonelesion.(See"Overviewoftheepidemiology,clinicalpresentation,diagnosis,andmanagementofadult
patientswithbonemetastasis".)
Similarly,forpatientswithlyticlesionsinwhomnoMproteinisfoundintheserumorurine,metastaticcarcinoma
shouldbeexcludedbeforethediagnosisofnonsecretorymyelomaisseriouslyconsidered,byperformingabiopsy
ofoneofthelyticlesions(table1).
PROGNOSISMMisaheterogeneousdiseasewithsomepatientsprogressingrapidlydespitetreatmentand
othersnotrequiringtherapyforanumberofyears.Distinctionbetweenthesetwogroupsisimportantsothat
treatmentcanbeinitiatedinappropriatepatientsandpostponedinthosewhodonotneedit.TheprognosisofMM
ispresentedseparately.(See"Stagingandprognosticstudiesinmultiplemyeloma".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Multiplemyeloma(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Multiplemyelomasymptoms,diagnosis,andstaging
(BeyondtheBasics)"and"Patientinformation:Bonemarrowtransplantation(stemcelltransplantation)
(BeyondtheBasics)")
SUMMARY
Multiplemyeloma(MM)ischaracterizedbytheneoplasticproliferationofimmunoglobulinproducingplasma
cells.MostpatientswithMMpresentwithsignsorsymptomsrelatedtotheinfiltrationofplasmacellsinto
theboneorotherorgansortokidneydamagefromexcesslightchains.Commonpresentationsinclude
anemia,bonepain,elevatedcreatinineorserumprotein,fatigue,andhypercalcemia.Lesscommon,but
emergentpresentationsincludespinalcordcompressionandseverehypercalcemia.(See'Clinical
presentation'above.)
Inpatientswithsuspectedmyelomaorrelateddisorders,appropriateinitialscreeningtestsincludeaserum
proteinelectrophoresisalongwithimmunofixation,andaserumfreelightchainassay.A24hoururine
collectionforelectrophoresisandimmunofixationmustbedoneifadiagnosisofMMismade.(See
'Evaluation'aboveand'Pathologicfeatures'above.)
FurtherevaluationtoconfirmthediagnosisofMMincludesabonemarrowaspirationandbiopsy,a
metastaticbonesurvey,acompletebloodcountwithdifferentialandachemistryscreen.(See'Evaluation'
above.)
ThediagnosisofMMrequires10percentclonalplasmacellsinthebonemarroworbiopsyprovenbonyor
softtissueplasmacytomaplusoneofthefollowing(table2)(see'Diagnosticcriteria'above):
Presenceofrelatedorganortissueimpairmentthatcanbeattributedtotheplasmacellproliferative

disorder(eg,increasedcalcium,renalinsufficiency,anemia,lyticbonelesions)
Presenceofabiomarkerassociatedwithnearinevitableprogressiontoendorgandamage(ie,60
percentclonalplasmacellsinthebonemarrowinvolved/uninvolvedfreelightchainratioof100ormore
[theinvolvedFLClevelmustalsobeatleast100mg/Lormore]ormagneticresonanceimaging[MRI]
withmorethanonefocallesion).
Infiltrationwithmalignantplasmacellsmaybefocal,requiringaspiration/biopsyatmultiplesites.Imaging
withMRIand/orpositronemissiontomography(PET)scancanbehelpfulinlocatingfocaldisease.(See
'Bonemarrowexamination'aboveand'Radiographicstudies'above.)
ThedifferentialdiagnosisforMMincludesmonoclonalgammopathyofundeterminedsignificance(MGUS),
smolderingmultiplemyeloma(SMM),Waldenstrmmacroglobulinemia(WM),solitaryplasmacytoma,AL
amyloidosis,POEMSsyndrome,andmetastaticcarcinoma(table3).(See'Differentialdiagnosis'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1. KariyawasanCC,HughesDA,JayatillakeMM,MehtaAB.Multiplemyeloma:causesandconsequencesof
delayindiagnosis.QJM2007100:635.
2. SiegelRL,MillerKD,JemalA.Cancerstatistics,2016.CACancerJClin201666:7.
3. PhekooKJ,ScheySA,RichardsMA,etal.Apopulationstudytodefinetheincidenceandsurvivalof
multiplemyelomainaNationalHealthServiceRegioninUK.BrJHaematol2004127:299.
4. SantM,AllemaniC,TereanuC,etal.IncidenceofhematologicmalignanciesinEuropebymorphologic
subtype:resultsoftheHAEMACAREproject.Blood2010116:3724.
5. SmithA,HowellD,PatmoreR,etal.Incidenceofhaematologicalmalignancybysubtype:areportfromthe
HaematologicalMalignancyResearchNetwork.BrJCancer2011105:1684.
6. KyleRA,TherneauTM,RajkumarSV,etal.IncidenceofmultiplemyelomainOlmstedCounty,Minnesota:
Trendover6decades.Cancer2004101:2667.
7. TuressonI,VelezR,KristinssonSY,LandgrenO.Patternsofmultiplemyelomaduringthepast5decades:
stableincidenceratesforallagegroupsinthepopulationbutrapidlychangingagedistributionintheclinic.
MayoClinProc201085:225.
8. KyleRA,GertzMA,WitzigTE,etal.Reviewof1027patientswithnewlydiagnosedmultiplemyeloma.
MayoClinProc200378:21.
9. WaxmanAJ,MinkPJ,DevesaSS,etal.Racialdisparitiesinincidenceandoutcomeinmultiplemyeloma:a
populationbasedstudy.Blood2010116:5501.
10. ShirleyMH,SayeedS,BarnesI,etal.Incidenceofhaematologicalmalignanciesbyethnicgroupin
England,20017.BrJHaematol2013163:465.
11. HuangSY,YaoM,TangJL,etal.EpidemiologyofmultiplemyelomainTaiwan:increasingincidenceforthe
past25yearsandhigherprevalenceofextramedullarymyelomainpatientsyoungerthan55years.Cancer
2007110:896.
12. BladJ,KyleRA.Multiplemyelomainyoungpatients:clinicalpresentationandtreatmentapproach.Leuk
Lymphoma199830:493.
13. LynchHT,SangerWG,PirruccelloS,etal.Familialmultiplemyeloma:afamilystudyandreviewofthe
literature.JNatlCancerInst200193:1479.
14. LynchHT,WatsonP,TarantoloS,etal.Phenotypicheterogeneityinmultiplemyelomafamilies.JClin
Oncol200523:685.
15. LynchHT,FerraraK,BarlogieB,etal.Familialmyeloma.NEnglJMed2008359:152.
16. CampNJ,WernerTL,CannonAlbrightLA.Familialmyeloma.NEnglJMed2008359:1734.
17. JainM,AscensaoJ,SchechterGP.Familialmyelomaandmonoclonalgammopathy:areportofeight

AfricanAmericanfamilies.AmJHematol200984:34.
18. LandgrenO,KristinssonSY,GoldinLR,etal.Riskofplasmacellandlymphoproliferativedisordersamong
14621firstdegreerelativesof4458patientswithmonoclonalgammopathyofundeterminedsignificancein
Sweden.Blood2009114:791.
19. VachonCM,KyleRA,TherneauTM,etal.Increasedriskofmonoclonalgammopathyinfirstdegree
relativesofpatientswithmultiplemyelomaormonoclonalgammopathyofundeterminedsignificance.Blood
2009114:785.
20. BrownLM,LinetMS,GreenbergRS,etal.Multiplemyelomaandfamilyhistoryofcanceramongblacksand
whitesintheU.S.Cancer199985:2385.
21. MaldonadoJE,KyleRA.Familialmyeloma.Reportofeightfamiliesandastudyofserumproteinsintheir
relatives.AmJMed197457:875.
22. DeshpandeHA,HuXP,MarinoP,etal.Anticipationinfamilialplasmacelldyscrasias.BrJHaematol1998
103:696.
23. GrosboisB,JegoP,AttalM,etal.Familialmultiplemyeloma:reportoffifteenfamilies.BrJHaematol1999
105:768.
24. SobolH,VeyN,SauvanR,etal.Re:familialmultiplemyeloma:afamilystudyandreviewoftheliterature.
JNatlCancerInst200294:461.
25. VarettoniM,CorsoA,PicaG,etal.Incidence,presentingfeaturesandoutcomeofextramedullarydisease
inmultiplemyeloma:alongitudinalstudyon1003consecutivepatients.AnnOncol201021:325.
26. SattaR,CasuG,DoreF,etal.Follicularspiculesandmultipleulcers:cutaneousmanifestationsofmultiple
myeloma.JAmAcadDermatol200349:736.
27. BazR,AlemanyC,GreenR,HusseinMA.PrevalenceofvitaminB12deficiencyinpatientswithplasma
celldyscrasias:aretrospectivereview.Cancer2004101:790.
28. WinearlsCG.Acutemyelomakidney.KidneyInt199548:1347.
29. BroderickP,ChubbD,JohnsonDC,etal.Commonvariationat3p22.1and7p15.3influencesmultiple
myelomarisk.NatGenet201244:58.
30. BladJ,FernndezdeLarreaC,RosiolL,etal.Softtissueplasmacytomasinmultiplemyeloma:
incidence,mechanismsofextramedullaryspread,andtreatmentapproach.JClinOncol201129:3805.
31. SzalatR,ArnulfB,KarlinL,etal.Pathogenesisandtreatmentofxanthomatosisassociatedwithmonoclonal
gammopathy.Blood2011118:3777.
32. HutchisonCA,BatumanV,BehrensJ,etal.Thepathogenesisanddiagnosisofacutekidneyinjuryin
multiplemyeloma.NatRevNephrol20128:43.
33. AnnesleyTM,BurrittMF,KyleRA.Artifactualhypercalcemiainmultiplemyeloma.MayoClinProc1982
57:572.
34. PetersenSL,WagnerA,GimsingP.Cerebralandmeningealmultiplemyelomaafterautologousstemcell
transplantation.Acasereportandreviewoftheliterature.AmJHematol199962:228.
35. FassasAB,MuwallaF,BerrymanT,etal.Myelomaofthecentralnervoussystem:associationwithhigh
riskchromosomalabnormalities,plasmablasticmorphologyandextramedullarymanifestations.BrJ
Haematol2002117:103.
36. SchlutermanKO,FassasAB,VanHemertRL,HarikSI.Multiplemyelomainvasionofthecentralnervous
system.ArchNeurol200461:1423.
37. ChangH,SloanS,LiD,KeithStewartA.Multiplemyelomainvolvingcentralnervoussystem:high
frequencyofchromosome17p13.1(p53)deletions.BrJHaematol2004127:280.
38. ChamberlainMC,GlantzM.Myelomatousmeningitis.Cancer2008112:1562.
39. LeeD,KalffA,LowM,etal.Centralnervoussystemmultiplemyelomapotentialrolesforintrathecal
therapyandmeasurementofcerebrospinalfluidlightchains.BrJHaematol2013162:371.
40. GozzettiA,CeraseA,LottiF,etal.Extramedullaryintracraniallocalizationofmultiplemyelomaand
treatmentwithnovelagents:aretrospectivesurveyof50patients.Cancer2012118:1574.
41. ChenCI,MasihKhanE,JiangH,etal.Centralnervoussysteminvolvementwithmultiplemyeloma:long
termsurvivalcanbeachievedwithradiation,intrathecalchemotherapy,andimmunomodulatoryagents.BrJ
Haematol2013162:483.

42. ChangH,BartlettES,PattersonB,etal.TheabsenceofCD56onmalignantplasmacellsinthe
cerebrospinalfluidisthehallmarkofmultiplemyelomainvolvingcentralnervoussystem.BrJHaematol
2005129:539.
43. KwanL,WangC,LevittL.Hyperammonemicencephalopathyinmultiplemyeloma.NEnglJMed2002
346:1674.
44. MatsuzakiH,HataH,SonokiT,etal.Serumaminoaciddisturbanceinmultiplemyelomawith
hyperammonemia.IntJHematol199561:131.
45. TalamoG,CavalloF,ZangariM,etal.Hyperammonemiaandencephalopathyinpatientswithmultiple
myeloma.AmJHematol200782:414.
46. OtsukiT,YamadaO,SakaguchiH,etal.Invitroexcessammoniaproductioninhumanmyelomacelllines.
Leukemia199812:1149.
47. BladJ,LustJA,KyleRA.ImmunoglobulinDmultiplemyeloma:presentingfeatures,responsetotherapy,
andsurvivalinaseriesof53cases.JClinOncol199412:2398.
48. KastritisE,ZagouriF,SymeonidisA,etal.Preservedlevelsofuninvolvedimmunoglobulinsare
independentlyassociatedwithfavorableoutcomeinpatientswithsymptomaticmultiplemyeloma.Leukemia
201428:2075.
49. MattaGM,BattaglioS,DibelloC,etal.PolyclonalimmunoglobulinElevelsarecorrelatedwithhemoglobin
valuesandoverallsurvivalinpatientswithmultiplemyeloma.ClinCancerRes200713:5348.
50. DraysonM,TangLX,DrewR,etal.Serumfreelightchainmeasurementsforidentifyingandmonitoring
patientswithnonsecretorymultiplemyeloma.Blood200197:2900.
51. SinghalS,VickreyE,KrishnamurthyJ,etal.Therelationshipbetweentheserumfreelightchainassayand
serumimmunofixationelectrophoresis,andthedefinitionofconcordantanddiscordantfreelightchainratios.
Blood2009114:38.
52. KatzmannJA,AbrahamRS,DispenzieriA,etal.Diagnosticperformanceofquantitativekappaandlambda
freelightchainassaysinclinicalpractice.ClinChem200551:878.
53. DimopoulosMA,KastritisE,TerposE.Nonsecretorymyeloma:one,two,ormoreentities?Oncology
(WillistonPark)201327:930.
54. ChawlaSS,KumarSK,DispenzieriA,etal.Clinicalcourseandprognosisofnonsecretorymultiple
myeloma.EurJHaematol201595:57.
55. LarsonD,KyleRA,RajkumarSV.Prevalenceandmonitoringofoligosecretorymyeloma.NEnglJMed
2012367:580.
56. RajkumarSV,MerliniG,SanMiguelJF.Haematologicalcancer:Redefiningmyeloma.NatRevClinOncol
20129:494.
57. RajkumarSV,LarsonD,KyleRA.Diagnosisofsmolderingmultiplemyeloma.NEnglJMed2011365:474.
58. RajkumarSV,DimopoulosMA,PalumboA,etal.InternationalMyelomaWorkingGroupupdatedcriteriafor
thediagnosisofmultiplemyeloma.LancetOncol201415:e538.
59. SwerdlowSH,CampoE,HarrisNL,etal.WorldHealthOrganizationClassificationofTumoursof
HaematopoieticandLymphoidTissues,IARCPress,Lyon2008.
60. JemalA,SiegelR,WardE,etal.Cancerstatistics,2009.CACancerJClin200959:225.
61. FonsecaR,BergsagelPL,DrachJ,etal.InternationalMyelomaWorkingGroupmolecularclassificationof
multiplemyeloma:spotlightreview.Leukemia200923:2210.
62. KyrtsonisMC,VassilakopoulosTP,KafasiN,etal.Prognosticvalueofserumfreelightchainratioat
diagnosisinmultiplemyeloma.BrJHaematol2007137:240.
63. SnozekCL,KatzmannJA,KyleRA,etal.Prognosticvalueoftheserumfreelightchainratioinnewly
diagnosedmyeloma:proposedincorporationintotheinternationalstagingsystem.Leukemia200822:1933.
64. MikhaelJR,DingliD,RoyV,etal.Managementofnewlydiagnosedsymptomaticmultiplemyeloma:
updatedMayoStratificationofMyelomaandRiskAdaptedTherapy(mSMART)consensusguidelines2013.
MayoClinProc201388:360.
65. LarsenJT,KumarSK,DispenzieriA,etal.Serumfreelightchainratioasabiomarkerforhighrisk
smolderingmultiplemyeloma.Leukemia201327:941.
66. DispenzieriA,KyleRA,KatzmannJA,etal.Immunoglobulinfreelightchainratioisanindependentrisk

factorforprogressionofsmoldering(asymptomatic)multiplemyeloma.Blood2008111:785.
67. D'SaS,AbildgaardN,TigheJ,etal.Guidelinesfortheuseofimaginginthemanagementofmyeloma.BrJ
Haematol2007137:49.
68. DimopoulosM,KyleR,FermandJP,etal.Consensusrecommendationsforstandardinvestigativeworkup:
reportoftheInternationalMyelomaWorkshopConsensusPanel3.Blood2011117:4701.
69. DimopoulosMA,HillengassJ,UsmaniS,etal.Roleofmagneticresonanceimaginginthemanagementof
patientswithmultiplemyeloma:aconsensusstatement.JClinOncol201533:657.
70. KimPJ,HicksRJ,WirthA,etal.Impactof18Ffluorodeoxyglucosepositronemissiontomographybefore
andafterdefinitiveradiationtherapyinpatientswithapparentlysolitaryplasmacytoma.IntJRadiatOncol
BiolPhys200974:740.
71. TrycieckyEW,GottschalkA,LudemaK.Oncologicimaging:interactionsofnuclearmedicinewithCTand
MRIusingthebonescanasamodel.SeminNuclMed199727:142.
72. DimopoulosM,TerposE,ComenzoRL,etal.Internationalmyelomaworkinggroupconsensusstatement
andguidelinesregardingthecurrentroleofimagingtechniquesinthediagnosisandmonitoringofmultiple
Myeloma.Leukemia200923:1545.
73. KyleRA.Multiplemyeloma:reviewof869cases.MayoClinProc197550:29.
74. LahtinenR,LaaksoM,PalvaI,etal.Randomised,placebocontrolledmulticentretrialofclodronatein
multiplemyeloma.FinnishLeukaemiaGroup.Lancet1992340:1049.
75. AngtuacoEJ,FassasAB,WalkerR,etal.Multiplemyeloma:clinicalreviewanddiagnosticimaging.
Radiology2004231:11.
76. KyleRA,SchreimanJS,McLeodRA,BeaboutJW.Computedtomographyindiagnosisandmanagementof
multiplemyelomaanditsvariants.ArchInternMed1985145:1451.
77. MoulopoulosLA,DimopoulosMA.Magneticresonanceimagingofthebonemarrowinhematologic
malignancies.Blood199790:2127.
78. MahnkenAH,WildbergerJE,GehbauerG,etal.MultidetectorCTofthespineinmultiplemyeloma:
comparisonwithMRimagingandradiography.AJRAmJRoentgenol2002178:1429.
79. BaurMelnykA,BuhmannS,BeckerC,etal.WholebodyMRIversuswholebodyMDCTforstagingof
multiplemyeloma.AJRAmJRoentgenol2008190:1097.
80. BaurA,StblerA,NagelD,etal.Magneticresonanceimagingasasupplementfortheclinicalstaging
systemofDurieandSalmon?Cancer200295:1334.
81. MarietteX,ZagdanskiAM,GuermaziA,etal.Prognosticvalueofvertebrallesionsdetectedbymagnetic
resonanceimaginginpatientswithstageImultiplemyeloma.BrJHaematol1999104:723.
82. WalkerR,BarlogieB,HaesslerJ,etal.Magneticresonanceimaginginmultiplemyeloma:diagnosticand
clinicalimplications.JClinOncol200725:1121.
83. BuerleT,HillengassJ,FechtnerK,etal.Multiplemyelomaandmonoclonalgammopathyofundetermined
significance:importanceofwholebodyversusspinalMRimaging.Radiology2009252:477.
84. AilawadhiS,AbdelhalimAN,DerbyL,etal.Extentofdiseaseburdendeterminedwithmagneticresonance
imagingofthebonemarrowispredictiveofsurvivaloutcomeinpatientswithmultiplemyeloma.Cancer
2010116:84.
85. DurieBG,NguyenK,JoselsonM,etal.Technetium99MIBIscanninginmultiplemyeloma:Comparison
withPET(FDG)scanning.CancerResTherControl19986:93.
86. elShirbinyAM,YeungH,ImbriacoM,etal.Technetium99mMIBIversusfluorine18FDGindiffuse
multiplemyeloma.JNuclMed199738:1208.
87. BredellaMA,SteinbachL,CaputoG,etal.ValueofFDGPETintheassessmentofpatientswithmultiple
myeloma.AJRAmJRoentgenol2005184:1199.
88. ShorttCP,GleesonTG,BreenKA,etal.WholeBodyMRIversusPETinassessmentofmultiplemyeloma
diseaseactivity.AJRAmJRoentgenol2009192:980.
89. HillengassJ,FechtnerK,WeberMA,etal.Prognosticsignificanceoffocallesionsinwholebodymagnetic
resonanceimaginginpatientswithasymptomaticmultiplemyeloma.JClinOncol201028:1606.
90. KastritisE,MoulopoulosLA,TerposE,etal.Theprognosticimportanceofthepresenceofmorethanone
focallesioninspineMRIofpatientswithasymptomatic(smoldering)multiplemyeloma.Leukemia2014

28:2402.
91. MerzM,HielscherT,WagnerB,etal.Predictivevalueoflongitudinalwholebodymagneticresonance
imaginginpatientswithsmolderingmultiplemyeloma.Leukemia201428:1902.
92. vanLammerenVenemaD,RegelinkJC,RiphagenII,etal.Ffluorodeoxyglucosepositronemission
tomographyinassessmentofmyelomarelatedbonedisease:asystematicreview.Cancer2012118:1971.
93. McCarthyCS,BeckerJA.Multiplemyelomaandcontrastmedia.Radiology1992183:519.
94. PahadeJK,LeBedisCA,RaptopoulosVD,etal.Incidenceofcontrastinducednephropathyinpatientswith
multiplemyelomaundergoingcontrastenhancedCT.AJRAmJRoentgenol2011196:1094.
95. SmithA,WisloffF,SamsonD,etal.Guidelinesonthediagnosisandmanagementofmultiplemyeloma
2005.BrJHaematol2006132:410.
96. InternationalMyelomaWorkingGroup.Criteriafortheclassificationofmonoclonalgammopathies,multiple
myelomaandrelateddisorders:areportoftheInternationalMyelomaWorkingGroup.BrJHaematol2003
121:749.
97. KyleRA,RajkumarSV.Criteriafordiagnosis,staging,riskstratificationandresponseassessmentof
multiplemyeloma.Leukemia200923:3.
98. DispenzieriA,KyleR,MerliniG,etal.InternationalMyelomaWorkingGroupguidelinesforserumfreelight
chainanalysisinmultiplemyelomaandrelateddisorders.Leukemia200923:215.
99. KyleRA,GreippPR.Smolderingmultiplemyeloma.NEnglJMed1980302:1347.
100. KyleRA,TherneauTM,RajkumarSV,etal.Alongtermstudyofprognosisinmonoclonalgammopathyof
undeterminedsignificance.NEnglJMed2002346:564.
101. SchusterSR,RajkumarSV,DispenzieriA,etal.IgMmultiplemyeloma:diseasedefinition,prognosis,and
differentiationfromWaldenstrom'smacroglobulinemia.AmJHematol201085:853.
102. RajkumarSV,GertzMA,KyleRA.Primarysystemicamyloidosiswithdelayedprogressiontomultiple
myeloma.Cancer199882:1501.
Topic6649Version50.0

GRAPHICS
Extramedullaryplasmacytoma

Largeredpurpleappearingplasmacytomaonlowerbackinpatient
withrelapsedmultiplemyeloma.
Graphic79555Version3.0

Extramedullaryplasmacytoma

TheCTscanthroughthemidchestregionofan80yearoldmale
patientrevealsadestructivesofttissuemassinananteriorleftrib
(redarrow).AcorebiopsyperformedunderCTguidance(B)confirmed
adiagnosisofplasmacytoma.
Graphic83143Version2.0

Extraduralplasmacytoma

Thisstudyisfromapatientwithknownmultiplemyeloma.TheMRIof
thethoracicspineinthemidsagittalplanerevealsanextradural
massinthemidthoracicspine.OntheT2weightedimages(AandB)
thespindleshapedmassisoverlaidingreen(B).Themassinterrupts
theposteriorCSFcolumn(redarrow).ThegadoliniumenhancedT1
weightedimages(CandD)revealamoreprominentareaof
involvementduetotheassociatedhyperemiaintheregion(salmon
overlayinD).
Graphic83141Version1.0

Multiplemyeloma:LyticbonediseaseandPETpositivescan

Thismalepatientis81yearsoldandhasmultiplemyeloma.TheCTscan(AandC)inthe
regionofthecervicothoracicjunctionrevealsanexpansileandlyticprocessintheregion
ofT1(yellowarrow).ThecorrelativePETscan(BandD)showsamoderatelyhotarea
(redarrow).
Graphic83142Version1.0

Monoclonalpatternonserumprotein
electrophoresis(SPEP)

(A)Densitometertracingofthesefindingsrevealsatall,narrow
basedpeak(redasterisk)ofgammamobilityandhasbeenlikenedto
achurchspire.Themonoclonalbandhasadensitometricappearance
similartothatofalbumin(alb)andareductioninthenormal
polyclonalgammaband.
(B)Adense,localizedband(redasterisk)representingamonoclonal
proteinofgammamobilityisseenonserumproteinelectrophoresison
agarosegel(anodeonleft).
Reproducedwithpermissionfrom:KyleRA,RajkumarSV.Plasmacell
disorders.In:Ceciltextbookofmedicine,22nded,GoldmanL,AusielloDA
(Eds),WBSaunders,Philadelphia2004.p.1184.Copyright2004Elsevier.
Graphic67685Version7.0

Immunoglobulinsinmultiplemyeloma

Theelectrophoreticpatternofserumproteinsinanormalsubjectis
showninpanelA.Theareacontainingproteinsof"gamma"mobilityis
shownintheblueboxedarea.Thisareacontainsmostofthe
immunoglobulins.Forthepatientwithmultiplemyeloma(panelB),
thereisamonoclonalimmunoglobulinbandinthegammamobility
region(asterisk),butlittleornoproteinstainingintherestofthe
gammamobilityregion,suggestingthepresenceofreducedamounts
ofnormalpolyclonalimmunoglobulins.
Reproducedwithpermissionfrom:KyleRA,RajkumarSV.Plasmacell
disorders.In:Ceciltextbookofmedicine,22nded,GoldmanL,AusielloDA
(Eds),WBSaunders,Philadelphia2004.p.1184.Copyright2004Elsevier.
Graphic62500Version4.0

Biclonalgammopathy

PanelB:Abiclonalpattern,withtwosmall,discretegammabands,is
seenonserumproteinelectrophoresisonagarosegel(anodeonleft).
PanelA:Densitometertracingofthesefindingsshowsthetwoprotein
peakswithgammamobility.
Graphic54186Version1.0

Monoclonalgammopathyonimmunofixation

Thisfigureshowstheserumproteinelectrophoreticpattern(SPEP)
andimmunofixationpatternofasingleserumsamplewithantiserato
heavychaindeterminantsofIgG,IgA,andIgM,andtokappaand
lambdalightchains.ItshowsadiscretebandonSPEP(redasterisk)
andabandwithsimilarmobilityreactingonlywiththeantiseratoIgG
(blueasterisk)andthekappalightchain(blackasterisk),indicative
ofanIgGkappamonoclonalprotein.
Reproducedwithpermissionfrom:KyleRA,RajkumarSV.Plasmacell
disorders.In:Ceciltextbookofmedicine,22nded,GoldmanL,AusielloDA
(Eds),WBSaunders,Philadelphia2004.p.1184.Copyright2004Elsevier.
Graphic55916Version4.0

Serumfreelightchains

Thisfigureshowssimultaneousmeasurementsoffreeserumkappa(horizontal
axis)andlambda(verticalaxis)lightchains.Thedashedlineindicatesa1:1
kappa/lambdaratio(weightbasis).Resultsareshownfor282normalsubjects
(+),120patientswithkappalightchainmyeloma(closedcircles),140patients
withlambdalightchainmyeloma(closedtriangles),31patientswithrenal
impairmentfromnonlightchaindisorders(opensquares),and28subjectswith
nonsecretorymyeloma(opencircles).Notethatmonoclonalitycouldbedetected
inmanyofthelattergroupusingthistechnique.
Datafrom:BradwellAR,CarrSmithHD,MeadGP,etal.Serumtestforassessmentof
patientswithBenceJonesmyeloma.Lancet2003361:489.
Graphic56523Version2.0

Myelomacast:Lightmicroscopy

HighpowerlightmicrographshowsPASstainoftubularcastsin
myelomakidney.Thebottomtwotubulescontaincastscomposedof
PASnegativeimmunoglobulinlightchains(smallarrows).In
comparison,thecastinthemiddletubule(probablyhyaline)is
primarilycomposedofPASpositiveTammHorsfallmucoprotein,the
matrixofallcasts(largearrow).MyelomaproteinsarePASnegative
becausetheycontainfewoftheneutralsugarsthataredetectedby
thisstain.
PAS:periodacidSchiff.
CourtesyofHelmutRennke,MD.
Graphic57572Version4.0

Myelomacast:Lightmicroscopy

Lightmicrographshowingclassicfeaturesofcastnephropathy
including:1)obstructedtubulewithafractureddensecast2)giant
cellreactioninthelowerleftpartofthetubuleand3)interstitial
infiltratewithmacrophages.
CourtesyofHelmutRennke,MD.
Graphic70405Version3.0

Myelomakidneyimmunofluorescencemicroscopy

Immunofluorescencemicroscopywithantihumanlambdaantiserum
showingvariablestainingofintratubularimmunoglobulinlightchain
castsfromapatientwithmultiplemyelomaexcretingmonoclonal
lambdalightchains.Theweakerstainingcastspresumablycontain
moreTammHorsfallmucoprotein.
CourtesyofHelmutRennke,MD.
Graphic82327Version2.0

Rouleauxformationinmultiplemyeloma

Peripheralbloodsmearfromapatientwithmultiplemyelomashows
redbloodcellrouleaux(arrows),givingtheappearanceofstacked
coins.
CourtesyofCarolavonKapff,SH(ASCP).
Graphic74369Version2.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Several
platelets(blackarrows)andanormallymphocyte(bluearrow)can
alsobeseen.Theredcellsareofrelativelyuniformsizeand
shape.Thediameterofthenormalredcellshouldapproximatethat
ofthenucleusofthesmalllymphocytecentralpallor(redarrow)
shouldequalonethirdofitsdiameter.
CourtesyofCarolavonKapff,SH(ASCP).
Graphic59683Version2.0

Plasmacell

Smearoftheperipheralblooddemonstratesacirculatingplasmacell
thatisovalwithabundantbasophiliccytoplasm.Thenucleusisround
andeccentricallylocatedwithamarkedperinuclearhof,or
cytoplasmicclearing.Thenucleuscontains"clockface"or"spoke
wheel"chromatinwithoutnucleoli.
Reproducedwithpermissionfrom:AndersonSC,PhD.Anderson'sAtlasof
Hematology.Copyright2003,WoltersKluwerHealth/LippincottWilliams&
Wilkins.Copyright2003LippincottWilliams&Wilkins.
Graphic63684Version3.0

Multiplemyeloma

Bonemarrowaspiratesmearsfromtwodifferentpatientswithmultiplemyeloma,
illustratingapreponderanceofmostlymatureappearingplasmacellswith
eccentricallyplacednucleiandprominentGolgizones(arrow)(WrightGiemsa
stain).
From:BrunningRD,McKennaRW.Tumorsofthebonemarrow.Atlasoftumorpathology
(electronicfascicle),Thirdseries,fascicle9,1994,Washington,DC.ArmedForcesInstitute
ofPathology.
Graphic61145Version2.0

Flamecellinmultiplemyeloma

Highpowerviewofabonemarrowaspiratefromapatientwith
multiplemyelomaoftheIgAtype.Multipleabnormalplasmacellscan
beseeninthisview,includingabinucleateform(smallarrows).The
largecellontherighthasanabnormalnucleusandacytoplasmwith
areddish(flamelike)tint,duetothepresenceofIgAprotein(arrow).
CourtesyofDavidSRosenthal,MDandWilliamCMoloney,MD.
Graphic72153Version2.0

Multiplemyelomalyticlesions

Inthisradiographoftheskullinmultiplemyeloma,the"punchedout"
radiolucentlesionsaretheresultofdestructionbynodulesofplasma
cells.
Reproducedwithpermissionfrom:RubinE.Pathology.4thed.Philadelphia.
LippincottWilliamsandWilkins,2005.Copyright2005LippincottWilliams&
Wilkins.
Graphic78569Version3.0

Multiplemyeloma:Lyticlesionsintheradius

(A)TheplainfilmofrightradiusintheAPprojectionisfromapatientwith
multiplemyeloma.Theimagerevealscharacteristicmultiplepunchedoutlesions
intheproximaldiaphysisoftherightradius.
(B)Amagnifiedviewoftheproximalradius.
(C)Amagnifiedandenhancedviewtoexemplifythepunchedout,welldefined
natureofthelesionswithnoovertreactionbythesurroundingbone.
Graphic83023Version1.0

Multiplemyeloma:Osteopenia,compression
fracture,andlyticdisease

(A)Theplainfilmoflumbarspineinthelateralprojectionisfroma
38yearoldmanwithmultiplemyeloma.Theimagerevealsevidence
ofdecreasedbonedensity,compressionofL4andT11(arrows),and
lyticdiseasewithasofttissuemassoftheposteriorelementsofL2
(arrowhead).
(B)AcorrelativeCTreconstructioninthesagittalprojectionofthe
thoracolumbarspinerevealsmultiplelyticchangesinallofthe
visualizedvertebralbodies,andrevealstobettereffectthe
destructivesofttissueprocessintheposteriorelementsofL2
(arrowhead).
Reproducedwithpermissionfrom:FrymoyerJW,WieselSW,AnHS,etal.The
AdultandPediatricSpine.Philadelphia:LippincottWilliams&Wilkins,2004.
Copyright2004LippincottWilliams&Wilkins.
Graphic83026Version2.0

Typicalradiographicpresentationtoselecttumorsinbone*
Predominantlyosteoblastic
Prostate
Carcinoid
Smallcelllungcancer
Hodgkinlymphoma
Medulloblastoma
POEMSsyndrome

Predominantlyosteolytic
Renalcellcancer
Melanoma
Multiplemyeloma
Nonsmallcelllungcancer
Thyroidcancer
NonHodgkinlymphoma
Langerhanscellhistiocytosis

Mixedosteoblasticandosteolytic
Breastcancer
Gastrointestinalcancers
Squamouscancersatmostprimarysites
*Theserepresentthemostcommonpatternsofmetastaticinvolvementindividualvariationsmay
occur.
Graphic54124Version5.0

RevisedInternationalMyelomaWorkingGroupdiagnosticcriteriafor
multiplemyelomaandsmolderingmultiplemyeloma
Definitionofmultiplemyeloma
Clonalbonemarrowplasmacells10%ofbiopsyprovenbonyorextramedullary
plasmacytoma*andanyoneormoreofthefollowingmyelomadefiningevents:
Evidenceofendorgandamagethatcanbeattributedtotheunderlyingplasmacell
proliferativedisorder,specifically:
Hypercalcemia:serumcalcium>0.25mmol/L(>1mg/dL)higherthantheupperlimitof
normalor>2.75mmol/L(>11mg/dL)
Renalinsufficiency:creatinineclearance<40mLpermin orserumcreatinine>177
mol/L(>2mg/dL)
Anemia:hemoglobinvalueof>20g/Lbelowthelowerlimitofnormal,orahemoglobin
value<100g/L
Bonelesions:oneormoreosteolyticlesionsonskeletalradiography,CT,orPETCT
Anyoneormoreofthefollowingbiomarkersofmalignancy:
Clonalbonemarrowplasmacellpercentage*60%
Involved:uninvolvedserumfreelightchainratio 100
>1focallesionsonMRIstudies

Definitionofsmolderingmultiplemyeloma
Bothcriteriamustbemet:
Serummonoclonalprotein(IgGorIgA)30g/Lorurinarymonoclonalprotein500mgper
24hoursand/orclonalbonemarrowplasmacells10to60%
Absenceofmyelomadefiningeventsoramyloidosis

Definitionofmonoclonalgammopathyofundeterminedsignificance
Allthreecriteriamustbemet:
Serummonoclonalprotein<30g/L
Bonemarrowplasmacells<10%
Absenceofmyelomadefiningeventsoramyloidosis(orWaldenstrmmacroglobulinemiain
thecaseofIgMMGUS)
PETCT: 18Ffluorodeoxyglucosepositronemissiontomographywithcomputedtomography.
*Clonalityshouldbeestablishedbyshowingkappa/lambdalightchainrestrictiononflowcytometry,
immunohistochemistry,orimmunofluorescence.Bonemarrowplasmacellpercentageshouldpreferably
beestimatedfromacorebiopsyspecimenincaseofadisparitybetweentheaspirateandcorebiopsy,
thehighestvalueshouldbeused.
Measuredorestimatedbyvalidatedequations.
Ifbonemarrowhaslessthan10%clonalplasmacells,morethanonebonelesionisrequiredto
distinguishfromsolitaryplasmacytomawithminimalmarrowinvolvement.
ThesevaluesarebasedontheserumFreeliteassay(TheBindingSiteGroup,Birmingham,UK).The
involvedfreelightchainmustbe100mg/L.
Eachfocallesionmustbe5mmormoreinsize.

Originalfiguremodifiedforthispublication.RajkumarSV,DimopoulosMA,PalumboA,etal.International
MyelomaWorkingGroupupdatedcriteriaforthediagnosisofmultiplemyeloma.LancetOncol2014
15:e538.TableusedwiththepermissionofElsevierInc.Allrightsreserved.
Graphic57627Version13.0

Urinarymonoclonalprotein

PanelB:Thisfigureillustratesthecelluloseacetateelectrophoretic
patternofaurinesample.Itrevealsadensebandofproteinwithbeta
mobility.PanelA:Densitometertracingshowsatall,narrowbased
peakofbetamobility.Thesefindingsareconsistentwithaurine
monoclonalprotein(BenceJonesprotein)confirmationofthe
diagnosisrequiresdemonstrationthattheproteincontainsonlya
lambdaorkappalightchainwithnoheavychainreactivity.
Graphic55073Version1.0

Urinarymonoclonalprotein

Immunofixationofaconcentratedurinespecimenfromtheprevious
patientwithantiseratokappaandlambdalightchainsshowsa
discretelambdaband,indicatingamonoclonallambdalightchain(ie,
BenceJonesproteinoflambdaspecificity).
Graphic75044Version1.0

Diseasedefinitionsforthemonoclonalgammopathies:MGUSand
relateddisorders

Typeof
monoclonal
gammopathy

Premalignancy
withlowriskof
progression(1to
2percentper
year)

Premalignancy
withhighriskof
progression(10
percentperyear)

Malignancy

IgGandIgA

NonIgMMGUS

SmolderingMM

MM

(nonIgM)*

Allcriteriamustbemet:

Bothcriteriamustbe
met:

ClonalBMplasmacells10percent

1. Serummonoclonal
protein<3g/dL
2. ClonalBMplasma
cells<10percent
3. Absenceofend
organdamagesuch
asCRABthatcanbe
attributedtothe
PCPDandabsence
ofmyelomadefining
biomarkers

1. Serummonoclonal
protein(IgGorIgA)
3g/dLand/or
clonalBMplasma
cells10percent

Plusoneofthefollowing:

1. Evidenceofendorgandamag
beattributedtotheunderlyin
specificallyoneormoreofthe

Hypercalcemia:serumcalc
mg/dL

2. Absenceofend
organdamagesuch
asCRABthatcanbe
attributedtoaPCPD
andabsenceof

Renalinsufficiency:serum
>2mg/dLorestimatedcre
clearance<40mL/min

Anemia:normochromic,no
withhemoglobin>2g/dLb
limitofnormalorhemoglo
g/dL

myelomadefining
biomarkers

Bonelesions:lyticlesions
attributedtoaPCPDonske
radiography,MRI,CT,orPE

2. Presenceofoneofthefollowin
biomarkers:

60percentclonalplasma
bonemarrow

Involved/uninvolvedFLCra

MRIwith>1focalboneles
IgM

IgMMGUS

SmolderingWM

WM

IgMm

Allcriteriamustbemet:

Bothcriteriamustbe
met:

Allcriteriamustbemet:

Allcrite
met:

1. Serummonoclonal
protein<3g/dL
2. ClonalBM
lymphoplasmacytic
cells<10percent
3. Absenceofend
organdamagesuch
asanemia,
constitutional
symptoms,
hyperviscosity,

1. SerumIgM
monoclonalprotein
3g/dLand/orBM
lymphoplasmacytic
infiltration10
percent

1. IgMmonoclonal
gammopathy
(regardlessofsizeof
Mprotein)

2. Noevidenceof
anemia,
constitutional

2. 10percentBM
lymphoplasmacytic
infiltration(usual
intertrabecular)by
smalllymphocytes
thatexhibit

symptoms,

plasmacytoidor

lymphadenopathy,
or
hepatosplenomegaly
thatcanbe
attributedtothe
underlying
lymphoproliferative

hyperviscosity,
lymphadenopathy,
or
hepatosplenomegaly
thatcanbe
attributedtothe
underlying

plasmacell
differentiationanda
typical
immunophenotype
(eg,surfaceIgM +,
CD5 ,CD10 ,
CD19 +,CD20 +,

disorder

lymphoproliferative
disorder

CD23 )that
satisfactorily
excludesother
lymphoproliferative
disordersincluding
chroniclymphocytic
leukemiaand
mantlecell
lymphoma

3. Evidenceofanemia,
constitutional
symptoms,
hyperviscosity,
lymphadenopathy,
or
hepatosplenomegaly
thatcanbe
attributedtothe
underlying
lymphoproliferative
disorder
Lightchain

LightchainMGUS

IdiopathicBenceJones

LightchainMM

Allcriteriamustbemet:

proteinuria

SameasMMexceptnoevidenceof

Allcriteriamustbemet:

immunoglobulinheavychainexpres
immunofixation

1. AbnormalFLCratio
(<0.26or>1.65)
2. Increasedlevelof
theappropriate
involvedlightchain
(increasedFLCin
patientswithratio
>1.65and
increasedFLCin
patientswithratio
<0.26)
3. Noimmunoglobulin
heavychain
expressionon
immunofixation
4. ClonalBMplasma
cells<10percent
5. Absenceofend
organdamagesuch

1. Urinarymonoclonal
proteinonurine
protein
electrophoresis
500mg/24h
and/orclonalBM
plasmacells10
percent
2. Noimmunoglobulin
heavychain
expressionon
immunofixation
3. Absenceofend
organdamagesuch
asCRABthatcanbe
attributedtothe
PCPD

asCRABthatcanbe
attributedtothe
PCPD
BM:bonemarrowCRAB:hypercalcemia,renalinsufficiency,anemia,andbonelesionsFISH:
fluorescentinsituhybridizationFLC:freelightchainMGUS:monoclonalgammopathyofundetermined
significanceMM:multiplemyelomaPCPD:plasmacellproliferativedisorderWM:Waldenstrm
macroglobulinemia.
*Occasionally,patientswithIgDandIgEmonoclonalgammopathieshavebeendescribedandwillbe
consideredpartofthiscategoryaswell.
NotethatconventionallyIgMMGUSisconsideredasubtypeofMGUS,andsimilarlylightchainMMis
consideredasubtypeofMM.Unlessspecificallydistinguished,whenthetermsMGUSandMMareusedin
general,theyincludeIgMMGUSandlightchainMM,respectively.
Modifiedwithpermissionfrom:RajkumarSV,KyleRA,BuadiFK.Advancesinthediagnosis,classification,
riskstratification,andmanagementofmonoclonalgammopathyofundeterminedsignificance:
implicationsforrecategorizingdiseaseentitiesinthepresenceofevolvingscientificevidence.MayoClin
Proc201085:945.Copyright2010QuadrantHealthCom,Inc.
Graphic67431Version6.0

InternationalMyelomaWorkingGroupdiagnosticcriteriaand
classificationformonoclonalgammopathyofundetermined
significanceandrelatedplasmacelldisorders

NonIgM
monoclonalgammopathy
ofundetermined
significance

Definition
Serummonoclonalprotein
(nonIgMtype)<30g/L

Progression
rate
1%peryear

Multiplemyeloma,
solitary
plasmacytoma,
immunoglobulin
relatedamyloidosis
(AL,AHL,AH)

1.5%peryear

Waldenstrm
macroglobulinemia,
immunoglobulin
relatedamyloidosis
(AL,AHL,AH)

0.3%peryear

Lightchain
multiplemyeloma,
immunoglobulin
lightchain
amyloidosis

Clonalbonemarrowplasma
cells<10%*
Absenceofendorgandamage
suchashypercalcemia,renal
insufficiency,anemia,andbone
lesions(CRAB)oramyloidosis
thatcanbeattributedtothe
plasmacellproliferativedisorder

IgMmonoclonal
gammopathyof
undetermined
significance

SerumIgMmonoclonalprotein
<30g/L

Primary
progression
events

Bonemarrow
lymphoplasmacyticinfiltration
<10%
Noevidenceofanemia,
constitutionalsymptoms,
hyperviscosity,
lymphadenopathy,
hepatosplenomegaly,orother
endorgandamagethatcanbe
attributedtotheunderlying
lymphoproliferativedisorder

Lightchainmonoclonal
gammopathyof
undetermined
significance

AbnormalFLCratio(<0.26or
>1.65)
Increasedlevelofthe
appropriateinvolvedlightchain
(increasedkappaFLCin
patientswithratio>1.65and
increasedlambdaFLCin
patientswithratio<0.26)
Noimmunoglobulinheavy
chainexpressionon
immunofixation
Absenceofendorgandamage
suchashypercalcemia,renal
insufficiency,anemia,andbone
lesions(CRAB)oramyloidosis

thatcanbeattributedtothe
plasmacellproliferativedisorder
Clonalbonemarrowplasma
cells<10%
Urinarymonoclonalprotein
<500mg/24hours
Solitaryplasmacytoma

Biopsyprovensolitarylesionof
boneorsofttissuewith
evidenceofclonalplasmacells

About10%
withinthree
years

Multiplemyeloma

60%(bone)or
20%(soft
tissue)within
threeyears

Multiplemyeloma

NA

NA

Normalbonemarrowwithno
evidenceofclonalplasmacells
NormalskeletalsurveyandMRI
(orCT)ofspineandpelvis
(exceptfortheprimarysolitary
lesion)
Absenceofendorgandamage
suchashypercalcemia,renal
insufficiency,anemia,orbone
lesions(CRAB)thatcanbe
attributedtoalymphoplasma
cellproliferativedisorder
Solitaryplasmacytoma
withminimalmarrow
involvement

Biopsyprovensolitarylesionof
boneorsofttissuewith
evidenceofclonalplasmacells
Clonalbonemarrowplasma
cells<10%
NormalskeletalsurveyandMRI
(orCT)ofspineandpelvis
(exceptfortheprimarysolitary
lesion)
Absenceofendorgandamage
suchashypercalcemia,renal
insufficiency,anemia,orbone
lesions(CRAB)thatcanbe
attributedtoalymphoplasma
cellproliferativedisorder

POEMSsyndrome

Polyneuropathy
Monoclonalplasmacell
proliferativedisorder(almost
alwayslambda)
Anyoneofthefollowingthree
othermajorcriteria:
Scleroticbonelesions
Castleman'sdisease
ElevatedlevelsofVEGFA
Anyoneofthefollowingsix

minorcriteria:
Organomegaly
(splenomegaly,
hepatomegaly,or
lymphadenopathy)
Extravascularvolume
overload(edema,pleural
effusion,orascites)
Endocrinopathy(adrenal,
thyroid,pituitary,gonadal,
parathyroid,pancreatic)
Skinchanges
(hyperpigmentation,
hypertrichosis,glomeruloid
hemangiomata,plethora,
acrocyanosis,flushing,white
nails)
Papilledema
Thrombocytosis/polycythemia
SystemicAL
amyloidosis

Presenceofanamyloidrelated
systemicsyndrome(eg,renal,
liver,heart,gastrointestinal
tract,orperipheralnerve
involvement)

NA

Somepatients
mightdevelop
multiplemyeloma

Positiveamyloidstainingby
Congoredinanytissue(eg,fat
aspirate,bonemarrow,or
organbiopsy)
Evidencethatamyloidislight
chainrelatedestablishedby
directexaminationofthe
amyloidusingmass
spectrometrybasedproteomic
analysis,or
immunoelectronmicroscopy,
and
Evidenceofamonoclonal
plasmacellproliferativedisorder
(serumorurinemonoclonal
protein,abnormalfreelight
chainratio,orclonalplasma
cellsinthebonemarrow)
IgM:immunoglobulinMAL:immunoglobulinlightchainamyloidosisAHL:immunoglobulinheavyand
lightchainamyloidosisAH:immunoglobulinheavychainamyloidosisFLC:freelightchain.MRI:
magneticresonanceimagingCT:computedtomographyPOEMS:polyneuropathy,organomegaly,
endocrinopathy,monoclonalprotein,skinchangesVEGFA:vascularendothelialgrowthfactorANA:not
applicable.
*Bonemarrowcanbedeferredinpatientswithlowriskmonoclonalgammopathyofundetermined

significance(IgGtype,monoclonalprotein<15g/L,normalfreelightchainratio)inwhomthereareno
clinicalfeaturesconcerningformyeloma.
Solitaryplasmacytomawith10%ormoreclonalplasmacellsisregardedasmultiplemyeloma.
NoteverypatientmeetingthesecriteriawillhavePOEMSsyndromethefeaturesshouldhavea
temporalassociationwitheachotherandnootherattributablecause.Anemiaorthrombocytopeniaare
distinctivelyunusualinthissyndromeunlessCastleman'sdiseaseispresent.
ThesourcedatadonotdefineanoptimalcutoffvalueforconsideringelevatedVEGFAlevelasamajor
criterion.WesuggestthatVEGFAmeasuredintheserumorplasmashouldbeatleastthreetofour
timeshigherthanthenormalreferencerangeforthelaboratorythatisdoingthetestingtoberegarded
asamajorcriterion.
Toregardendocrinopathyasaminorcriterion,anendocrinedisorderotherthandiabetesor
hypothyroidismisrequiredbecausethesetwodisordersarecommoninthegeneralpopulation.
PatientswithALamyloidosiswhoalsomeetcriteriaformultiplemyelomaareconsideredtohaveboth
diseases.
Approximately2to3%ofpatientswithALamyloidosiswillnotmeettherequirementforevidence.
Reproducedfrom:RajkumarSV,DimopoulosMA,PalumboA,etal.InternationalMyelomaWorkingGroup
updatedcriteriaforthediagnosisofmultiplemyeloma.LancetOncol201415:e538.Tableusedwiththe
permissionofElsevierInc.Allrightsreserved.
Graphic98065Version1.0

Algorithmforthediagnosisofmonoclonalgammopathyofundeterminedsign

MGUS:monoclonalgammopathyofundeterminedsignificanceSPEP:serumproteinelectrophoresisUPEP:urinepro
fluorescenceinsituhybridizationLDH:lactatedehydrogenaseCRP:CreactiveproteinMRI:magneticresonanceim

anemia,bonelesions.
*TheserumFLCassaycanbeusedinplaceofurinestudieshowever,ifamonoclonalproteinisseenonserumstud
immunofixationneedtobeperformed.
ConsiderMRIifmetastaticbonesurveyisnegativeinpatientwithbonepain.
Graphic94388Version4.0

Disclosures
Disclosures:SVincentRajkumar,MDNothingtodisclose.RobertAKyle,MDConsultant/AdvisoryBoards:Celgene[myelomaand
relateddisorders(lenalidomide,pomalidomide)]BristolMyersSquibb[multiplemyeloma(elotuzumab)]Onyx[multiplemyeloma
(carfilzomib)]Pharmacyclics[Waldenstrmmacroglobulinemia(ibrutinib)]Novartis[multiplemyeloma(panobinostat)]AeternaZentaris
[multipleMyeloma(perifosine)].RebeccaFConnor,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy