26.06.

2017 MultipleMyelomaandOtherPlasmaCellDyscrasias

PublishedonCancerNetwork(http://www.cancernetwork.com)
Home>MultipleMyelomaandOtherPlasmaCellDyscrasias

MultipleMyelomaandOtherPlasmaCellDyscrasias
June01,2016|CancerManagement[1]
BySundarJagannath,MD[2] ,PaulG.Richardson,MD[3] ,andNikhilC.Munshi,MD[4]
Thismanagementguidecoversthesymptoms,diagnosis,screening,staging,andtreatmentof
multiplemyeloma,smolderingmyeloma,andotherplasmacelldyscrasias.

MultipleMyeloma
Multiplemyelomaisadisseminatedmalignancyofmonoclonalplasmacellsthataccountsfor1.3%
ofallmalignanciesand15%ofhematologiccancers.Theincidencehasbeenincreasingby0.7%
eachyearforthelast10yearswhilemortalityhascomedownby1.7%eachyearoverthesame
period.Theincidenceratewas6.1(7.4inmenand4.7inwomen)andthenumberofdeathswas
3.4per100,000personsperyear(4.3inmenand2.7inwomen).Widespreaduseofthe
immunomodulatorydrugsandproteasomeinhibitorsoverthepastdecadehasresultedinimproved
lifeexpectancy,withamediansurvivaljustunder5years.Theprevalenceofmultiplemyelomahas
increased,andcurrentlyanestimated83,367peopleintheUnitedStateslivewithmyeloma.In
2016,therewillbeanestimated30,330newcasesofmyeloma,and12,650estimateddeaths.

Epidemiology

Gender

Menareaffectedmorefrequentlythanwomen(1.6:1ratio).

Age

Themedianageofdiagnosisis69years,with75%ofdiagnosedpatientsbetweentheagesof55
and84.

Race

Theannualincidenceper100,000population,amongwhitemenandwomen,is7.2and4.3,
respectively,andamongblackmenandwomen,14.8and10.5,respectively.Thisracialdifference
isnotexplainedbysocioeconomicorenvironmentalfactorsandispresumablyduetounknown
geneticfactors.

Geography

Thereisnocleargeographicdistributionofmultiplemyeloma.InEurope,thehighestratesare
notedintheNordiccountries,theUnitedKingdom,Switzerland,Spain,Greece,Italy,Ireland,and
Israel.France,Germany,Austria,andSloveniahavealowerincidence,anddevelopingcountries
havethelowestincidence.Thishigherrelativeincidenceinmoredevelopedcountriesprobably

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resultsfromthecombinationofalongerlifeexpectancyandmorefrequentmedicalsurveillance,
althoughotherfactorsmaybeinvolved.

Survival

Relativesurvivalratemeasuresthesurvivalofcancerpatientsincomparisontothegeneral
population,toestimatetheeffectofthecancerinquestion.Therehasbeenimprovementinthe5
yearrelativesurvivalrateforpatientswithmultiplemyeloma,from29%in1990to45%in2009.
Therehasbeenimprovementinsurvivalinallagegroups,withmedialsurvivalestimatesnow
between5and7years,andmorerecentdatasuggesting7to10yearsoverallsurvivalisachieved
inpatientsreceivingnoveltherapiesbothaspartofinitialtherapyandatrelapse.

EtiologyandRiskFactors

Nopredisposingfactorsforthedevelopmentofmultiplemyelomahavebeenconfirmed,although
possiblecontributingcausesincludecertaintoxicexposuresandpotentialunderlyinggenetic
vulnerability.

Environment

Somecausativefactorsthathavebeensuggestedincluderadiationexposure(radiologistsand
radiumdialworkers),occupationalexposure(agricultural,chemical,metallurgical,rubberplant,
pulp,woodandpaperworkers[includingcarpentersandfurnituremakers],andleathertanners),
andchemicalexposuretoformaldehyde,epichlorohydrin,AgentOrange,hairdyes,paintsprays,
andasbestos.Noneoftheseassociationshasproventobehighlystatisticallysignificant,andsome
havebeencontradictedbynegativecorrelations.Theinitialreportthatsurvivorsoftheatomic
bombingsinJapanhadanincreasedriskofdevelopingmyelomahasbeenrefutedbylongerfollow
up,althoughtheunderlyingrateofmyelomaintheJapanesepopulationisrelativelylowcompared
toothercountries,andisnowincreasing.

Viruses

Apreliminaryreportinalimitednumberofpatientsnotedthepresenceofherpesvirus8inthe
dendriticcellsofpatientswithmultiplemyeloma.However,furtherevaluationbyanumberof
investigatorshasfailedtoconfirmthisresult.

Cytogenetics

Oneofthetwoprimarygeneticevents,eitherhyperdiploidyoraberrantclassswitchrecombination
(CSR),occurringinantigenselectedpostgerminalcenterBcellsultimatelyleadstothe
developmentofmultiplemyeloma.TheaberrantCSRresultsinanonfunctionalimmunoglobulin
heavychaingeneat14q32involvedintranslocationwithpartnerchromosomes4,6,8,11,16,and
20(Table1).Translocationsinvolvingchromosomes4,14,and16aswellassecondarygenetic
eventssuchasdel17p13oramplificationof1q21areassociatedwithpoorprognosis.Hyperdiploidy
generallyconsistsoftrisomiesofchromosomes,3,5,7,9,11,15,19,and21.Multiplemyeloma
presentswithmultiplesubclonesatdiagnosis,whichhavebeenshowntoappearanddisappear
withtreatmentoverthecourseofthediseaseandaccountfortheultimatefailuretoeradicatethe
disease.Betterunderstandingofthebiologyofmultiplemyelomaisunderwaywiththeuseof
wholegenomesequencing,exonsequencing,RNAsequencing,studiesofaberrantmicroRNA
expression,andgeneexpressionprofiling.Suchstudiesmayultimatelyhelpintailoringtherapyin
thenearfutureandsobettercharacterizethephenomenonofclonalheterogeneity,aswellasthe

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challengingphenomenologyofclonaltides,whichlikelyrepresentthecomplexintegrityof
genotypic,phenotypic,andmicroenvironmentalfactors.

Geneticfactors

Multiplemyelomaisnotaninheriteddisease,buttherehavebeennumerous
reportsofmultiplecasesinthesamefamily.However,acasecontrolstudy
revealednosignificantincreaseinitsincidenceamongrelativesofpatients
whohadmultiplemyeloma,otherhematologicmalignancies,orother TABLE1:Oncogenes
involvedinmultiplemyeloma,
cancers.Nonetheless,thisremainsanareaofactiveinvestigation,ascase andtheirlocations
studiescontinuetodescribeassociationsbothwithinfamiliesandwithcertain
othercancers,suchasrenalcellcarcinoma.

Pathophysiology

Interactionsbetweenmultiplemyelomacellsandtheirmicroenvironment(theextracellularmatrix
andthebonemarrowstroma)allowmultiplemyelomacellstosurvive,grow,migrate,andresist
apoptosisinducedbytraditionalchemotherapies.Theseeffectsarepartiallymediatedthrough
adhesionmediatedsignallingandpartlythroughvariouscytokines,includingIL6,vascular
endothelialgrowthfactor,insulinlikegrowthfactor1(IGF1),andtumornecrosisfactor(TNF).
ThemolecularsignalsmediatingtheproliferativeeffectsincludetheRAS/RAF/mitogenactivated
proteinkinase(MAPK)pathway,whereasthephosphoinositide3kinase(PI3K/AKT)pathway
providescellsurvivalanddrugresistancesignals.Improvedunderstandingoftheseinteractions
andthemolecularmechanismsmediatingthemhasallowedtheevaluationofnoveltherapiesthat
directlytargetmultiplemyelomacellsaswellasactonthebonemarrowmicroenvironmentand
othermilieus,includingcorticalbone.

Monoclonalgammopathyofunknownsignificance(MGUS)

PatientswithMGUSdevelopmyeloma,lymphoma,oramyloidosisatarateof1%peryear.Recent
studiesindicatethatthediagnosisofsymptomaticmultiplemyelomaistypicallyprecededby
monoclonalgammopathyfor2ormoreyears.

SignsandSymptoms

Theclinicalfeaturesofmultiplemyelomaarevariable.Findingsthatsuggestthediagnosisinclude
lyticbonelesions,anemia,azotemia,hypercalcemia,andrecurrentinfections.Approximately30%
ofpatientsarefreeofsymptomsandarediagnosedonroutinephysicalswithabnormallaboratory
studies,includingelevationofserumprotein.

Bonedisease

Bonepain,especiallyfromcompressionfracturesofthevertebraeorribs,isthemostcommon
symptom.Atdiagnosis,70%ofpatientshavelyticlesions,whichareduetoacceleratedbone
resorption.Thesechangesareduetopathologicalimbalancebetweenosteoblast(boneformation)
andosteoclast(boneresorption)activityinthebonemarrowmicroenvironment,inducedbythe
presenceofmyelomacells.Factorsinducingosteoclasticactivityincludeinterleukin(IL)1beta,
TNF,andIL6,aswellasnewlyidentifiedfactorssuchasosteoprotogerin,TNFrelatedactivation
inducedcytokine(TRANCE),macrophageinflammatoryprotein(MIP)1,andreceptoractivatorof
nuclearfactorkappaB(RANK)ligand.

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OsteoblasticactivityisinhibitedduetoproductionofasolublefactorDickkopfhomolog1(DKK1)
bymultiplemyelomacells,andoverexpressionofActivinAbybonemarrowstromalcells.

Anemia

Normocytic,normochromicanemiaispresentin60%ofpatientsatdiagnosis.Itisdueprimarilyto
thedecreasedproductionofredbloodcellsbymarrow,infiltrationwithplasmacells,andthe
suppressiveeffectofvariouscytokines.Patientswithrenalfailuremayalsohavedecreasedlevels
oferythropoietin,whichcanworsenthedegreeofanemia.

Hypercalcemia

Amongnewlydiagnosedpatients,upto20%havehypercalcemia(correctedserumcalciumlevel>
11.5mg/dL)secondarytoprogressivebonedestruction,whichmaybeexacerbatedbyprolonged
immobility,especiallyinthecontextoffracture.Hypercalcemiashouldbesuspectedinpatientswith
myelomawhohavenausea,fatigue,confusion,polyuria,orconstipation.Itmayalsosuggesthigh
tumorburden.Itshouldbeconsideredanoncologicemergencyandrequiresprompttreatmentwith
aggressivehydration,useofbisphosphonates,calcitonin,andantimyelomatherapy,including
steroids.

Renalfailure

Approximately20%ofpatientspresentwithrenalinsufficiencyandatleastanother20%to40%
developthiscomplicationinlaterphasesofthedisease.Lightchaincastnephropathyisthemost
commoncauseofrenalfailure.Additionalcausesincludehypercalcemia,dehydration,and
hyperuricemia.Lesscommonly,amyloidosis,lightchaindepositiondisease,nonsteroidalanti
inflammatoryagentstakenforpaincontrol,intravenousradiographiccontrastadministration,and
calciumstonesmaycontributetorenalfailure.Morerecently,bisphosphonatetherapyhasbeen
associatedwithazotemia,whichisusuallyreversiblewithtreatmentcessation.

Infections

Manypatientswithmyelomadevelopbacterialinfectionsthatmaybeserious,andinfectious
complicationsremainthemostcommoncauseofdeathinmyelomapatients.Inthepast,gram
positiveorganisms(eg,Streptococcuspneumoniae,Staphylococcusaureus)andHaemophilus
influenzaewerethemostcommonpathogens.Morerecently,however,infectionswithgram
negativeorganisms,anaerobes,andfungihavebecomefrequent.Theincreasedsusceptibilityof
patientswithmultiplemyelomatobacterialinfections,specificallywithencapsulatedorganisms,has
beenattributedtoimpairmentsofhostdefensemechanisms(suchashypogammaglobulinemia,
qualitativedeficiencyinimmunoglobulinfunction,granulocytopenia,decreasedcellmediated
immunity)andtheprolongeduseofsteroids.

ScreeningandDiagnosis

Noscreeningmeasuresformultiplemyelomahavedemonstratedanybenefittodate.

Thediagnosisusuallyrequiresthepresenceofbonemarrowplasmacytosisandamonoclonal
proteinintheurineand/orserum(Table2),alongwithendorgandamage.Oneimmunoglobulin
classisproducedinexcess,whereastheotherclassesareusuallydepressed,withallthreeheavy
chainstypicallyreducedinthepresenceoflightchaindisease.

Initialworkup

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Theinitialworkupforpatientssuspectedofhavingaplasmacelldyscrasia
shouldinclude:

CBCwithdifferentialcountandplateletcount

Routineserumchemistrypanel(toincludecalcium,bloodureanitrogen,
creatinine)

Bonemarrowaspirateandbiopsytoassessclonalplasmacytosis

Serumproteinelectrophoresisandimmunofixationtoquantitateanddefine TABLE2:Commonlaboratory
featuresofplasmacell
proteintype dyscrasias

Serumbeta2microglobulin,serumalbumin

Serumfreelightchain

24Hoururineprotein,electrophoresis,andimmunofixation

Quantitativeserumimmunoglobulinlevels

Skeletalsurvey(bonescanscontributelittlesinceisotopeuptakeisoftenlowinpurelylyticbone
disease)

Cytogenetics,includingFISH(fluorescenceinsituhybridization)onbonemarrowplasmacells.

Therecentlyavailableserumfreelightchainassayisusefulespeciallyinpatientswithlightchain
onlydisease,oligoornonsecretorymyeloma,renalfailure,andamyloidosis.

MRIisanexcellenttoolforevaluationofspinalcordcompression/impingement.Inaddition,MRI
identifiesgeneralizedmarrowsignalabnormalitiesandfocallesionsthatcanbemonitoredafter
therapy.Wholebody18Ffluorodeoxyglucose(FDG)positronemissiontomography(PET)/CTscan
providesdetailsofaxialandappendicularskeletalinvolvementbutalsoidentifiesextramedullary
softtissueplasmacytomaspresentingasmacrofocallesions.BothMRIandPET/CTareespecially
usefulinstagingoligoornonsecretorydisease.

Additionalusefuldatamaybeobtainedbyanalysisofsuchprognosticfactorsasplasmacell
labelingindex,ploidy,immunophenotyping,flowcytometry,Creactiveprotein(CRP),andlactate
dehydrogenase(LDH)levels.

LaboratoryandPathologicFeatures

Peripheralblood

Theperipheralbloodsmearmayrevealanormocytic,normochromicanemiawithrouleaux
formation.Lesscommonly,circulatingplasmacellsmayalsobeseen.

Bonemarrow

Bonemarrowexaminationusuallyrevealsanincreasednumberofplasmacells.Thesecellsare
stronglypositiveforCD38,CD138,MUM1,SLAMF7,andasingleclassofcytoplasmic
immunoglobulin(cIg).ThemajorityofmyelomacellsalsoexpressCD40andCD56.Myelomacells
arenegativeforCD5,CD19,andsurfaceIg(sIg)expression.CD20maybeexpressedinasubset
ofmyelomapatientspresentingwiththet(1114)translocation.CD10expressionisgenerally

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negativebuthassometimesbeennotedinadvanceddisease.Monoclonalityisfrequently
demonstratedbyimmunoperoxidasestainingwithandantibodies.

Thepatternofbonemarrowinvolvementinplasmacellmyelomamaybemacrofocal.Asaresult,
plasmacellcountmaybenormalwhenanaspiratemissesthefocalaggregatesofplasmacellsthat
arebettervisualizedradiographicallyorondirectneedlebiopsy,wherethedegreeofplasmacytosis
willbecommensurablyhigh.

Monoclonalproteins

ThetypesofmonoclonalproteinproducedareIgG(60%),IgA(20%),IgD(2%),IgE(<0.1%),or
lightchainoronly(18%).IgMmyelomaisrare,butdistinctfromitslymphoplasmacytic
counterpart,Waldenstrmsmacroglobulinemia.Biclonalelevationsofmyelomaproteinsoccurin<
1%ofpatients,and<5%ofpatientsareconsideredtohavenonsecretorydisease,becausetheir
plasmacellsdonotsecretedetectablelevelsofmonoclonalIg.

StagingandPrognosis

PatientswithsymptomaticmyelomashouldbestagedusingeithertheDurieSalmonsystemat
diagnosisortheInternationalStagingSystem(ISS),whichisdeterminedatthetimesystemic
therapyisbegun.ThesetwosystemsarecomparedinTable3.TheDurieSalmonstagingsystem
betterprovidesinformationontumorburden,whereastheISSbetterservesasaprognostic
indicator.TheISSiseasiertouse,anditclassifiespatientscorrectlyregardlessoftheirgeographic
origin(ie,NorthAmerica,Europe,orAsia),age(ie,65yearsvsyoungerage),ortypeoftreatment
(ie,conventionalchemotherapyvshighdosetherapyfollowedbyautologousstemcell
transplantation).MorerecentstudieshaveprovidedevidencethattheISSisalsoreliableinpatients
treatedwiththalidomide(Thalomid),bortezomib,orlenalidomide,andhasprognosticvalueat
relapse.

Prognosis

Prognosticindicatorsmayhelpguidetreatmentstrategy,butthepresenceof
poorprognosticfeaturesalsoshouldnotresultininitiationoftherapyin
patientswithasymptomaticmyeloma,althoughtheyshouldengendercaution.
Prognosticfactorsforriskstratificationarewellestablishedforconventional
chemotherapy.Useofbortezomiband,tosomeextent,lenalidomidemaybe
abletoovercomesomefeaturesofpoorrisk,includingadversecytogenetics.

Cytogeneticabnormalities.Cytogeneticabnormalitiesdetectedby TABLE3:TheDurieSalmon
conventionalkaryotyping,suchashyperdiploidy,hypodiploidyor systemandtheInternational
StagingSystemformultiple
translocations,anddeletionsandpresenceofmarkerchromosomesare myeloma
associatedwithadverseoutcome.Primarytranslocationsinvolving14q32and
4p16(fibroblastgrowthfactorreceptor3[FGFR3]),16q23(cmafprotooncogene),anddel17p13
(TP53)oramplificationof1q21detectedbyFISHinmultivariateanalysishavebeenshowntobe
importantpredictorsofpoorsurvival.ThesecryptictranslocationsarebestdetectedusingFISH,
whichhasbeenshowntobeprognosticallyusefultoevaluatepatientsbothatdiagnosisandat
relapse.

Beta2microglobulin.Serumbeta2microglobulinlevelisanimportantprognosticindicator,is
integraltotheISS,andincombinationwithcytogenetics(includingFISH)hasstrongpredictive
value.Asbeta2microglobulinisexcretedbythekidneys,highlevelsareobservedinpatientswith
renalfailureeveninthissetting,elevatedserumbeta2microglobulinisassociatedwithpoor
outcome.

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LDH.HighLDHlevelsalsohavebeenassociatedwithplasmablasticdisease,extramedullarytumor,
plasmacellleukemia,plasmacellhypodiploidy,drugresistance,andshortenedsurvival.

Otherindicators.OtherindicatorsofshortenedsurvivalincludeelevatedCRP,DNAhypodiploidy,
highplasmacelllabelingindices,andplasmablastichistology.PatientswithDNAhypodiploidyare
alsolesslikelytorespondtoconventionalchemotherapy.Finally,extramedullarydiseaseis
associatedwithworseoutcome,especiallyinthecontextofalargetumorburdensuchasbone
involvementandbulkdisease.

TreatmentResponseCriteria

Becausethecriteriafortreatmentresponseinpatientswithmultiplemyelomahavevariedamong
institutionsandevolvedovertime,responserateshavebeendifficulttocompareinthepast.In
responders,theBenceJonesproteinlevelisreducedmorerapidlythanisserummyelomaprotein,
becauseoftherapidrenalclearanceoflightchains.

TheCenterforInternationalBoneMarrowTransplantRegistry/EuropeanBoneMarrowTransplant
Registry(CIBMTR/EBMTR)responsecriteriahavebeenprospectivelyvalidatedinnumerous
studiesandareasfollows:

Completeresponse(CR)requiresallofthefollowing:

Noserum/urineMproteinbyimmunofixationelectrophoresisfor6weeks

<5%plasmacellsinbonemarrowaspirate

Noincreaseinthesizeornumberoflyticbonelesions

Disappearanceofsofttissueplasmacytomas.

Partialresponserequiresallofthefollowing:

50%reductioninserumMprotein>6weeks

90%reductionin24hoururinarylightchainexcretion

50%reductioninsofttissueplasmacytomas.

Minimalresponse(but49%)requires:

25%reductioninserumMproteinfor>6weeks

50%89%reductionin24hoururinarylightchainexcretion

Noincreaseinthesizeornumberoflyticbonelesions.

ThemorerecentUniformCriteriaforresponseproposedbytheInternationalMyelomaWorking
Group(IMWG)havesoughttofurtherrefinethesecriteriabydescribingastringentCRandavery
goodpartialresponse(VGPR>90%reductionintheserumparaproteinlevel),aswellasdefining
progressivediseaseintermsofminimumrequirementsofparaproteinincrease,asopposedto
changesinimmunofixationalone.Nearcompleteresponseisanothermodificationofthecriteria
andhasbeenappliedtotheEBMTRaspartofanumberofprospectivestudies.

Treatment

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Excitingadvancesintheunderstandingoftumorbiologyandmicroenvironmentandtheirpotential
interactionhavehelpedtoidentifyuniquetargetsforrationaltherapeuticinterventiontoenhance
outcome,whichhasnotimprovedwithconventionalchemotherapyoverthepast3decades.Until
recently,only5%to10%ofpatientswithmultiplemyelomalivedlongerthan10years.While
survivalhasimproveddramaticallywiththeintroductionofnoveltherapies,cureremainselusive
andtheoutcomeforrelapsedandrefractorypatientsisdismal.

Newlydiagnosedpatients

Thegoaloffirstlinetherapyformyelomaistoobtainthemaximumtumorcytoreductionand
maintaintheremissionaslongaspossible.Thisisaccomplishedbycombinationchemotherapy
overaperiodof9to12monthstoobtainmaximumtumorcytoreduction.Inyounger,willing,andfit
patients,chemotherapyisfollowedbyhighdosemelphalanandautologousstemcellrescueasa
consolidationtreatment,toinducelonger,deeperremissionandprolonglifeexpectancy.After
maximumtumorcytoreductionwithinitialtherapyand/orstemcelltransplantation,thepatientmay
beofferedmaintenancetherapy.

Chemotherapy.

Dexamethasone/thalidomideThalidomide(definedasanimmunomodulatorydrug[IMiD]andthe
firstinitsclasstobetestedclinically)hasbeenemployedaloneandincombinationwith
dexamethasoneasinitialtherapyinnewlydiagnosedpatients.Whenemployedalone,response
(50%reductioninparaprotein)wasobservedin36%ofpatientswhenitwasusedalongwith
dexamethasone,theresponseratewashigher(72%and64%intwostudies),includinga16%CR
rateinonestudy.

Thalidomideanddexamethasoneincombinationisnowalesspopularinductiontherapyfornewly
diagnosedsymptomaticmyelomapatients.However,thisregimenisclearlysuperiortovincristine,
doxorubicin,anddexamethasone(VAD)chemotherapyasapretransplantregimenandtheuseof
melphalan(Alkeran)andprednisone(MP)fortransplantineligiblepatients,withthelattertwo
regimensconsideredobsolete.Currentpreferreduseofthalidomidewouldbeasathirdagentin
combinationwithbortezomibanddexamethasone(VTD)orcyclophosphamide,andwith
dexamethasone(CTD)ormelphalanandprednisone(MPT).Adequateattentionandpreventive
measuresarerequiredforconstipation,deepveinthrombosis(DVT),bradycardia,andperipheral
neuropathy.

PulsedexamethasonealonePulsedexamethasoneadministeredaloneas
initialtherapyisnolongerrecommended.However,brieftherapywithpulse
dexamethasonemaybewarrantedunderspecialclinicalcircumstances(eg,
renalfailure,hypercalcemia,cordcompromiserequiringradiationtherapy,
cytopenia)(Table4).

MPThecombinationofmelphalanandprednisonehasbeenusedoverthe
past40years,andothercombinationsofmultiplealkylatingagentshavenot
beenfoundtobesuperiortoMP.Approximately40%ofpatientsrespondto
theMPregimen,withamedianremissiondurationof18monthsandan
overallmediansurvivalof3years.TheMPregimenshouldbeavoidedin
patientsconsideredtobetransplantcandidates.Currently,MPshouldbe
combinedwithanovelagent,suchasthalidomide,bortezomib,or TABLE4:Proposedinitial
treatmentsformultiple
lenalidomide,asdescribedbelow. myeloma

MPandthalidomide(MPT)Intwolarge,prospective,randomizedtrialsinpatientsolderthan65,
andathirdrandomizedtrialinpatientsover75yearsofage,MPThasbeenshowntobesuperiorto
MPforresponserateaswellasprogressionfreesurvivalandoverallsurvival.Sideeffects
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(includingconstipation,DVT,andperipheralneuropathy)weremorecommonlyencounteredwith
thalidomidebutwerefoundtobemanageable.MPToffersapossiblealternativeforolderpeople
whogenerallyarenotcandidatesforhighdosetherapy.

MPandVelcade(bortezomibMPV)Bortezomibisafirstinclass,potent,selective,and
reversiblesmallmoleculeinhibitoroftheproteasome.Inalarge,international,randomizedclinical
trial,MPVwasshowntobesuperiortoMPforresponseaswellassurvivalendpoints.MPVinduced
completeremissionsinonethirdofthepatients,withanORRof71%anda2yearoverallsurvival
of>80%.SuchhighCRspreviouslywereneverseeninthispopulationofpatients,whereonethird
ofthepatientswereoverage75years.Adversesideeffects(eg,peripheralneuropathy,asthenia,
fatigue,diarrhea,andconstipation)weremorefrequentlyencounteredonthebortezomibarm.
However,thetreatmentwaswelltoleratedbymostpatients,withtreatmentdiscontinuationdueto
toxicitynotedinonly14%ofpatientsinbotharms,andatreatmentrelatedmortalityof1%with
MPV(vs2%intheMPgroup).

Twolargerandomizedtrialssupporttheuseofweeklybortezomibtoreducetheadverseside
effects,especiallyneuropathy,withoutcompromisingefficacy.Furthermore,subcutaneous
administrationofbortezomibhasimprovedthetoleranceofthisagentandreduceditstoxicity,
especiallyneuropathy,althoughthisapproachincombinationrequiresfurtherstudy.

Rd(lenalidomideanddexamethasone)Lenalidomideandweeklydexamethasonealoneorin
combinationwithclarithromycinhavebeenshowntobeanactiveinductionregimenregardlessof
whetherthepatientisconsideredeligibleforhighdosetherapyandstemcelltransplantation.
Threeyearoverallsurvivalestimatesareapproximately80%instudiestodate.Generally,stemcell
harvestisrecommendedafterexposureto46cyclesoftreatmenttoavoidcompromisingstemcell
yield.Chemotherapybasedmobilization(suchaswithhighdosecyclophosphamide)oruseof
plerixafor(Mozobil)isrecommended.

TheFIRSTtrialwasapivotalstudythatestablishedlenaliomideandweeklydexamethasone(Rd)
administeredcontinuouslyuntilprogressionasthestandardofcareforpatientsnotundergoing
highdosetherapyconsolidation.TheFIRSTtrial,amulticentricopenlabeledrandomizedphaseIII
trialhascomparedRdcontinuouslyuntilprogression(Rdc)to72weeksofRd(Rd18)or
melphalanprednisonethalidomide(MPT).ItshowedthatRdcwaswelltoleratedeveninpatients
over75yearsofage,andwasassociatedwithsignificantlybetteroutcomebasedonprogression
freesurvivalandoverallsurvival,respectively42%at3yearsand59.4%at4years.TheORRwas
75%andtheCRratewasabout15%.RdinductionwasalsonotedtobeasgoodasMPRorCRP
inductiontherapyhowever,theuseofmelphalanwasassociatedwithmorecytpenia.

AdverseeventswithRdincludelowbloodcounts,skinrash,infection,andDVT.DVTprophylaxisis
mandatoryandaspirin,warfarin,orenoxaparinisemployed,dependingonadditionalriskand
comorbidities.Peripheralneuropathyislesscommon.Lenalidomideusedincombinationwitha
onceweeklydoseofdexamethasone(Rd)shouldbepreferredtoitsusewithmoreintensive
dexamethasone(RD)asthelatterwasassociatedwithincreasedriskofthrombocyticevents,
infections,andearlydeath.

Lenalidomideandweeklydexamethasoneisalsoanacceptableinductiontherapyforyounger
patientsconsideringhighdosetherapyandstemcelltransplant.However,transplanteligible
patientsshouldnotbeexposedtomorethan3to6monthsoflenalidomidepriortostemcell
harvest.Lenalidomide,likemelphalan,doesimpedestemcellmobilizationwithmoreextensive
exposure.

Pretransplantinduction.Pretransplantinductionchemotherapyisgenerallybrief,consistingof3
to6cyclesofcombinationchemotherapy.Manydifferentcombinationshavebeenusedsuccessfully
asnotedbelow.Inalargerandomizedtrial,bortezomibcontainingcombinationshaveshown
greaterantitumorresponsecomparedtoconventionalchemotherapy.
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MPRLenalidomidecanbeaddedtomelphalanandprednisone,butadosereductionof
melphalanandlenalidomideisrequired.Aninternationalrandomizedclinicaltrialhasshownthat
melphalanandprednisoneisequivalenttomelphalan,prednisone,andlenalidomidegivenfor9
months,butifthemelphalanprednisonecombinationwasfollowedbylenalidomidemaintenance,
theprogressionfreesurvivalimprovedbyalmostayearandahalfcomparedwithprogressionfree
survivalinpopulationswhowereunmaintained.

Bortezomibanddexamethasone(VD)Additionofbortezomibtothe
inductionregimenhassubstantiallyimprovedpatientoutcomes,especiallyfor
patientswithadversegeneticriskfactors.RandomizedphaseIIItrialshave
shownbortezomibcombinations(bortezomibanddexamethasone[VD]
bortezomib,adriamycin,anddexamethasone[PAD]bortezomib,thalidomide,
anddexamethasone[VTD])tobesuperiortotheVADinductionregimen
bortezomibdexamethasonesignificantlyimprovedpostinductionandpost
transplantationcompleteresponse,yieldedverygoodpartialresponserates
comparedwithVAD,andresultedinatrendtowardlongerprogressionfree
survivalandoverallsurvival.Thecombinationofbortezomib,lenalidomide,
TABLE5:Othertreatment
anddexamethasone(VRD)iswelltoleratedandyieldsthehighestoverallCR optionsformultiplemyeloma
rateandaVGPRratecomparabletothatofanyregimenusedtodatewithout
transplantationinthenewlydiagnosedsetting.Otherpromisingregimensinclude
cyclophosphamide,bortezomib,anddexamethasone(CyBorD)aswellasthecombinationof
carfilzomib(arecentlyapprovedsecondgenerationproteasomeinhibitorindicatedforuseinthe
relapsedsetting)withlenalidomideanddexamethasone(CRd).

Bortezomib/lenalidomide/dexamethasone(VRD)TwophaseIIstudieshaveshownagreater
depthofresponsetoinductiontherapywithVRD,withanORRaround75%andaVGPR+CRrate
from11%to32%after4cycles.Sideeffectsincludeperipheralneuropathy(17%grade3inthe
EVOLUTIONstudy).DVTandherpeszostervirus(HZV)prophylaxisaremandated.PhaseIIItrials
usingbortezomib,lenalidomide,anddexamethasoneareongoingandwillhelptodefinetheroleof
lenalidomideinassociationwithbortezomibanddexamethasonecomparedwith
bortezomib/dexamethasonealoneorlenalidomide/dexamethasonealone.Additionofafourthagent
(liposomaldoxorubicin,cyclophosphamide)hasnotimprovedtheresponseratebuthasaddedto
treatmenttoxicity.

Bortezomib/cyclophosphamide/dexamethasone(CyBorDorVCD)TwophaseIItrialshave
showntheefficacyofthecombinationofbortezomib,cyclophosphamide,anddexamethasoneto
comparabletothatofVRD.TheORRwasover80%to90%,withVGPRorbetterseenin50%to
60%ofpatients.Themajortoxicitywashematologic.Thiscombinationisparticularlywellsuitedfor
patientswithrenalimpairment.

Bortezomib/thalidomide/dexamethasone(VTD)ThreephaseIIItrialshaveshownthe
combinationofVTDtoinduceahighresponserate,superiortothatassociatedwiththalidomide
dexamethasoneorbortezomibpluscombinationchemotherapy(VBMCP/VBAP).Inductiontherapy
of3to6monthsinducesaVGPRorbetterinover50%to60%ofpatientsandanORRof85%or
better.Grade3orgreaterneuropathyoccursin10%to15%ofpatientstreatedwithfulldose
bortezomib.Cyclophosphamidecanbeaddedtotheregimen.Thiscombinationiswellsuitedfor
patientswithrenalimpairment.

Bortezomib/doxorubicin/dexamethasone(PAD)PADsuperiorityoverVADinductionwas
demonstratedinaphaseIIItrial.TheORRreportedwas78%withaVGPRorbetterrateexceeding
40%.PADinductionwasassociatedwithmoregastrointestinalsymptoms,peripheralneuropathy,
HZV,orthrombocytopenia.However,patientswithrenalimpairmentbenefitedfromthisregimen.

CarfilzomibcontainingtripletregimenPhaseIItrialshavedemonstratedthesafetyandefficacy
ofcarfilzomibcontainingregimensforinduction.Incombinationwithimmunomodulatorydrugs
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(thalidomideorlenalidomide)orcyclophophamide,anORRover90%to95%hasbeenreported
withaVGPRorbetterseenin64%withCarTD,65%withCarCD,and85%withCarRD.Good
resultswerealsoseenwithCarMP.Allcombinationsarewelltolerated,andsuitableforelderly
patients.Sideeffectsincludecardiacsymptoms,dyspnea,andconstitutionalsymptoms.

Cyclophophamide/thalidomide/dexamethasone(CTD)AphaseIIIstudyofnoninferioritybetween
CVADandCTDhasshownan82.8%ORRand43%ofpatientswithCR+VGPRresponseatthe
endofinductionintheCTDarm.Sideeffectsincludedinfection,cytopenia,somnolence,and
constipation.CTDwithdoseadjustmentforelderlypatientsintheMRCMyelomaIXtrialhasbeen
associatedwithbetterdepthofresponse,showinganORRof64%,whichisalmosttwicetheORR
obtainedwithMP,andaCRrateof13%.Despitethoseresults,itwasnotcorrelatedwithan
improvementinprogressionfreesurvivaloroverallsurvival.Contrarytoresultswithother
thalidomidebasedregimens,overallsurvivalwaslow,withamedianoverallsurvivalof33.2
months.Sideeffectsencounteredincludedperipheralneuropathyandmotorneutropathy,
thromboembolicevents,andinfections.

Cyclophosphamide/lenalidomide/dexamethasone(CRD)Cyclophosphamideaddedto
bortezomibanddexamethasonehasshownpromisingresults.OnephaseIItrialshowedagood
responsetoadministrationofCRD.Oneadvantageofthisregimenwasthelowrateofneuropathy,
similartowhathasbeendescribedwithVCD.However,ahighrateofcytopenia,especially
neutropenia(seenin60%ofpatients),anda25%rateofharvestfailureonGCSF(granulocyte
colonystimulatingfactor)aloneoffsetthepositiveresponsetothisregimen.TheORRwas79%
after4cycles,withaVGPR+CRrateof30%.

Melphalan/prednisone/thalidomide(MPT)Melphalanprednisone(MP)hasbeenusedasa
standardofcareforelderlypeopleformanyyears.Theadditionofthalidomidehasdemonstrated
animprovementintheoutcome.AmetaanalysisofthesixtrialsfoundMPTincreasedtheORR
improvedprogressionfreesurvival,withabenefitof5.6monthsandimprovedoverallsurvival,with
a6.6monthbenefit.Duringthefirstyearoftreatment,however,ahighermortalitywasseenwith
thisregimen.Sideeffectsfromthalidomideincludeperipheralneuropathy,DVT,constipation,
asthenia,bradycardia,andinfection.DVTprophylaxisisrecommended.

Melphalan/prednisone/Velcade(bortezomibMPV)TheVISTAtrialestablishedMPVtobe
superiortoMPforpatientsineligibleforhighdosetherapy.TheORRwastwicetheORRobserved
withMP,andonethirdofthepatientsachievedacompleteremission.Therewasabenefitshownin
thetimetoprogression(withamedianof2yearsforVMPgroup)andintheoverallsurvival(46%of
thepatientswerealiveat5years).Useofvelcadewasassociatedwithmoreadversesideeffects,
suchasperipheralneuropathy,asthenia,diarrhea,constipation,andHZV.However,therateof
treatmentdiscontinuationduetotoxicitywasthesameinbothgroups.Sideeffects,especially
neuropathy,canbemitigatedwithoutlossofefficacybyadministeringbortezomibsubcutaneously
onceweekly.

Melphalan/lenalidomide/prednisone(MPR)TwophaseIIItrialshavedocumentedtheoutcomeof
thisregimenusingreduceddosesoflenalidomide.MPRshowedanORRofabout70%,witharate
ofVGPRorbetteraround30%.IntheMM015trial,itwascomparedagainstbothMPandMPR
withlenalidomidemaintenance(MPRR).MPRwassignificantlybetterthanMPintermsofORR,
howeveritdidnotyieldabetteroutcomeintermsofprogressionfreesurvivaloroverallsurvival,
contrarytoMPRR.PalumboetaldemonstratedthattheoutcomeoftreatmentwithRdMPRor
CRPwasstatisticallynodifferent,witha2yearprogressionfreesurvivalofabout50%anda2year
overallsurvivalof80%.However,theuseofmelphalanwassignificantlyassociatedwithmore
cytopenia,dosereduction,ordiscontinuationofthedrug.

Highdosetherapyfollowinginductiontherapy.Consolidationwithhighdosetherapyafter
inductiontherapyimprovestheresponserateaswellaseventfreesurvivalandoverallsurvival,
especiallyingoodriskpatients.RandomizedtrialsfromFranceandtheUnitedKingdomshowed
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improvementineventfreesurvivalandoverallsurvivalfollowinghighdosetherapy,comparedwith
conventionalchemotherapyalone.Inductionwithnovelagentscontainingbortezomiband
lenalidomidefollowedbyhighdosetherapyfurtherimprovedtheoutcome,withanexpected3year
survivalofabout80%.InarandomizedtrialreportedfromItaly,inductionwithVTD,followedby
tandemtransplantationandthenconsolidationwithVTDfollowedbysteroidmaintenance,resulted
inaveryhighCRof58%,3yearprogressionfreesurvivalof68%,andoverallsurvivalof86%,with
clearsuperioritytothalidomideanddexamethasone(TD)asacomparator.Anovelagentinduction
regimenfollowedbysingletransplantationhasthusbecomeanewstandardofcare,withthree
drugsnowgenerallypreferred(eg,thecombinationsRVDorVTD),especiallyinhighriskpatients.

Ahighdosealkylatingagent,mostcommonlymelphalanat200mg/m2withperipheralbloodstem
cellsupport,isastandardconditioningregimen.Additionoftotalbodyirradiation(TBI)doesnot
improvetheoutcomebutincreasesmorbidityandresultsinhighermortality.Interestingly,ina
randomizedstudy,Fermandetalhaveconfirmedanequivalentsurvivalbenefitbetweenupfront
highdosetherapyvshighdosetherapyasasalvageregimenatrelapsefollowinginitialinduction
therapy.Thisconceptisbeingfurtherevaluatedintheeraofnoveltherapies,particularlyinaseries
ofimportantongoingrandomizedtrials.

Highdosetherapysupportedbyautologousstemcelltransplant(HDC/ASCT)

Stemcellharvest.

SingletransplantInthe1990s,tworandomizedtrialgroupshavedemonstratedanimprovement
ineventfreesurvivalandoverallsurvival(withabenefitof1yearintheMRC[MedicalResearch
Council]MyelomaVIItrial)withtheuseofHDT/ASCTcomparedwithconventionalchemotherapy.
Newertherapiesincludingproteasomeinhibitors(bortezomib)andtheimmunomodulatorydrugs
(thalidomide)havesubsequentlyfoundaplaceintheinductionregimensandhaveincreasedthe
pretransplantresponse(seeinductiontreatment).TheoverallsurvivalreportedwithVTDfollowed
byasingleHDT/ASCTisabout80%at3years.

Mostrandomizedclinicaltrialstodateshowimprovementinthedepthofresponseandprogression
freesurvival.Onemetaanalysisconfirmedtheprogressionfreesurvivalbenefit,whereasnooverall
survivalbenefitwasshown.Moreover,thesurvivalbenefitisunclearintheeraofnovelagentsand
maintenancetherapy.Randomizedclinicaltrialsarecurrentlyunderwaytoaddresstheroleofhigh
dosetherapyandstemcelltransplant.Ahighdosealkylatingagent,mostcommonlymelphalanat
200mg/m2withperipheralbloodstemcellsupport,isastandardconditioningregimen.Additionof
totalbodyirradiation(TBI)doesnotimprovetheoutcomebutincreasesmorbidityandresultsin
highermortality.

TandemtransplantsTheimprovedoutcomereportedaftertandemtransplantsinlargecohortsof
patientsinsingleinstitutionstudieshasnotbeenconfirmed.Metaanalysispointedoutincreased
treatmentrelatedmortalityandalackofsufficientinformationinthosetrialstodrawfirm
conclusions.IntheIntergroupeFrancophoneduMylome(IFM)IFM94randomizedstudy,11years
afterinitiationoftherapy,therewasonlyatrendineventfreesurvivalandoverallsurvivalinfavorof
tandemtransplants.Moreover,theaddedbenefitofthesecondtransplantwasnotseeninasubset
ofpatientswithaCRoraVGPRafterthefirsttransplantineitherstudy.Withtheadventofnovel
therapies,theuseoftandemtransplanthasundergonereevaluation,andtheneedforasecond
transplantinpatientsrespondingtonovelagentbasedtherapyandsingletransplantappearsto
havediminished,makingthisapproachlessattractivethan,forexample,adelayedtransplantafter
subsequentrelapse.

Recently,trialscomparingtheuseofconsolidationchemotherapy(melphalanprednisone
lenalidomideorcyclophosphamidelenalidomidedexamethasoneafterlenalidomide

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dexamethasoneinduction)versustandemtransplantdemonstratedabenefitinprogressionfree
survivalfromtheuseoftandemHDC/ASCT,althoughnooverallsurvivalimprovementwasseen.

Radiotherapy.Higherdosesofradiotherapy(4050Gy)areemployedforlocalcontrolandcureof
solitaryplasmacytomainvolvingboneandextramedullarysites.Lowerdoses(2030Gy)maybe
employedforpalliationoflocalbonepainfromtumorinfiltration,pathologicfractures,andspinal
cordcompression.Itshouldbeemphasizedthatexcellentpainreliefmaybeobtainedbyprompt
institutionofhighdosecorticosteroidtherapy,especiallyinnewlydiagnosedpatients.

Radiotherapyshouldbeemployedsparingly,asirradiationofmultiplesitesmayimpairstemcell
mobilizationinpatientswhoarecandidatesforhighdosetherapy.Employmentofhighdosesof
radiationtothespinemayprecludethesubsequentuseofTBIasaconditioningregimenforhigh
dosetherapy,althoughthelatterisnowrarelyused.

Remissionmaintenance

Maintenancetherapybeenshowntoprolongremissiondurationafterinitialtreatmentwithor
withouthighdosetherapyandimprovesurvival,withtheuseofspecificnovelagents,namely
lenalidomideandbortezomib.Itcontinuestobeanareaofintenseclinicalresearch.

Lenalidomide.TheFIRSTtrialdemonstratesthatRdcoffereda5monthprogressionfreesurvival
benefitcomparedwithRd18.Similarly,intheMM015trial,MPRfollowedbylenalidomide
maintenancewasassociatedwitha17monthprogressionfreesurvivalbenefitcomparedwith
MPR.Thosetrialssupporttheuseoflenalidomideformaintenanceafterinduction,howeverno
differenceinoverallsurvivalwasreported.

Intheposttransplantationsetting,IFM2005002andalandmarkCancerandLeukemiaGroupB
(CALGB)studyhaveevaluatedtheuseoflenalidomideasmaintenance.Thesestudieshaveshown
improvementinprogressionfreesurvivalbyatleast18monthsforlenalidomidemaintenance
comparedwithplacebo.TheCALGBtrialalsodemonstratedanoverallsurvivalbenefit.IntheIFM
study,recentdataafteramedianfollowupof77monthsstillshowednosurvivalbenefitthisis
becauseofbettersecondprogressionfreesurvivalintheplacebogroup.Therewasanincreased
incidenceofsecondprimarymalignancyinthelenalidomidemaintenancearmsinthesestudies
(8%and13%),withasmalleffectontheoccurrenceofvarioussolidtumorsandhematologic
malignancies,includingmyelodysplasticsyndromeandacutemyeloidleukemiapostHDC/SCT
apparentwithcurrentfollowup.Currentlyitappearsthattheriskofrelapseanddeathfrom
myelomafaroutweighstheriskofdyingfromasecondprimarymalignancy.Whenlenalidomide
maintenanceisrecommendedfollowingamelphalanbasedregimen,carefulobservationis
recommendedandthepatientshouldbecounseledappropriatelyregardingthesepotentialrisks,
withamaintenancedurationof2yearsrecommended.Thedurationofmaintenancetherapy
remainsaquestion(limiteddurationvsuntilprogression).IntheIFMstudy,lenalinomidewas
discontinuedafter24monthshowever,therewasstillaprogressionfreesurvivalbenefitfor
patientswhohadreceivedlenalidomide.

ArecentEuropeanMyelomaNetworktrialhasalsocomparedthebenefitofintroducingprednisone
alongwithlenalidomide(RP).Althoughdiscontinuationofthesteroidiscurrentlypreferredwith
longtermtreatment,thistrialshowedaprogressionfreesurvivalbenefittotreatmentwithRP.
Moreover,thetoxicitywasequivalentandrashwasobservedlessoftenintheRParm.

Thalidomide.SixlargephaseIIItrialshavereportedabenefitinprogressionfreesurvivalwith
thalidomide,whileonlytworeportedanoverallsurvivalbenefitfromthalidomidemaintenance
followinghighdosemelphalantherapywithautologousstemcelltransplant(HDM/ASCT).Similar
resultswereseeninpatientswhowerenotundergoingtransplant.Overall,metaanalysisconfirmed
animprovementinsurvival(progressionfreesurvivalandoverallsurvival).However,tolerabilityof

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thedrugremainsachallengebasedonthehighrateoftherapydiscontinuation,relatedmainlyto
neuropathy.Ofnote,theMRCMyelomaIXTrialshowedthatthalidomidemaintenancewas
associatedwithworsesurvivalforpatientswithhighriskgeneticsasdeterminedbyFISH.

Bortezomib.TwophaseIIItrialshavecomparedintransplanteligiblepatientsthecontributionof
bortezomibmaintenance.TheHOVONstudycomparedbortezomibreceivedininductionand
maintenancetherapytoaconventionalinductiontherapywiththalidomidemaintenance.Bortezomib
wasassociatedwithasignificantimprovementintermsofprogressionfreesurvivalandoverall
survival.Notably,patientswithrenalimpairmentandinthehighriskgroup(basedonISSand
cytogenetics)seemedtobenefitfrombortezomib.AnotherPETHEMAtrialreportedasignificant
improvementinprogressionfreesurvivalwithbortezomibthalidomidemaintenancecomparedwith
thalidomidealoneafterASCT.InanotherstudybytheSpanishmyelomagroupfollowinga
bortezomibbasedinductionregimenforpatientsineligiblefortransplantation,maintenancewith
bortezomibthalidomidewasshowntobesuperiortobortezomibprednisone,andastudyfromthe
Italianmyelomagroupshowedasurvivalbenefitwithbortezomibandthalidomidecomparedwith
observationalone,howevertheinductiontherapiesweredifferent.

Bortezomibasmaintenancetherapyis,however,associatedwithneuropathy,whichisoften
responsiblefortreatmentdiscontinuation.Theuseofsubcutaneousandoralformsisbeing
evaluated.

Interferon.Twentyfourrandomizedtrialshaveinvestigatedinterferonasmaintenancetherapy,
andneitherconsistentnorsignificantbenefitshavebeenseen.AlargeIntergrouptrialalsoreported
nobenefitofinterferonmaintenancetherapyafterconventionaltherapyandautotransplantation.
Sideeffects,includingfatigueanddepression,haveseriouslylimitedtheutilityofthisapproach.

Alkylatingagents.Maintenancetherapywithalkylatingagentshasnotprolongedsurvivalwhen
comparedwithnotherapy,andthisapproachisnolongerrecommended.

Steroidsformaintenance.Twolarge,randomizedtrialshaveshownthatglucocorticoid
maintenanceprolongsthedurationofremissionandimproveslifeexpectancy,althoughsideeffects
areaconcern,particularlywithlongtermuse.TheSouthwestOncologyGroup(SWOG)studyused
prednisone(50mg)everyotherday,whereasthemaintenanceregimenintheNationalCancer
InstituteofCanada(NCIC)trialincludeddexamethasone(40mg)dailyfor4daysevery4weeks.
Morerecentdatasuggestthattheuseoflenalidomidewithpredinosemaybesuperiorto
lenalidomidealoneinthiscontext.

Relapsed,andrelapsedandrefractorydisease

Themajorityofpatientsprogressafterinitialrelapse,whichusuallylastsbetween18monthsand5
years.Rapidprogressisbeingmadeinthemanagementofrelapseddiseaseandmanynewdrugs
arebeingintroducedinasuccessionofpromisingclinicaltrials,althoughtheentityofrelapsedand
refractorydiseaseremainsamajorchallenge.

Conventionalchemotherapy.Alkylatingagents,aloneorincombination,havebeeneffectivein
approximatelyonethirdofpatientswithVADrefractorydisease.Patientsrelapsingaftertreatment
withnovelagentsoftenhaverespondedtoalkylatingagenttherapy,especiallyincombinationwith
novelagents.PatientspresentingwithhighLDHlevelsandsofttissueplasmacytomamayrespond
tocombinationchemotherapywithcyclophosphamide,etoposide,cisplatin,anddexamethasone
(DCEP)withorwithoutdoxorubicin,bortezomib,orthalidomide(VDTPACE).Althoughthisregimen
isactive,prolongeduseislimitedbysideeffects,andtheuseofnoveltherapyaspartofthese
regimensappearsimportantinimprovingefficacy.

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Highdosechemotherapy.HDMandstemcellrescueshouldbeofferedtopatientswhohave
deferredthetransplantinitially.Arandomizedtrialperformedintheprenoveltherapyeraonearly
vslatetransplantationhasshownthatanequivalentsurvivalbenefitisconferredonpatients
undergoingsalvage,comparedwithearlytransplantation,withongoingstudiesfurtherevaluating
theoptimaltimingofSCTinthecurrenteraofnewtreatments.

Novelagents

Thalidomide.Thalidomidehasalongestablishedroleintherapyforrelapsedandrefractory
multiplemyeloma,with30%ofpatientsachievingatleasta50%reductioninparaproteinlevels.
Remissionsobtainedinrespondingpatientsareusuallydurable.Inalargecohortofpatientswith
multiplemyelomareceivingthalidomide,2yeareventfreesurvivalratesofabout25%havebeen
observed.Initially,thalidomidewasemployedinadoseescalatingschedule,startingat200mgand
achievingamaximaldoseof800mg.Recently,lowerdoseshavebeenemployedincombination
withsteroidsaswellaswithotheragentsandhaveprovedmoreeffectiveandbettertolerated
(Table4).

Lenalidomide.Lenalidomidehasgreaterpotencythanthalidomideinpreclinicalstudies.Inclinical
trialsithasgreaterefficacyandisbettertolerated,withlessneurotoxicity,somnolence,and
constipation.

Twolarge,multicenter,phaseIIItrialshavebeenperformedoflenalidomide(givenatadoseof25
mgdailyfor3weeks,with1weekoff)combinedwithdexamethasonecomparedwith
dexamethasoneandplaceboinpatientswithrelapsedmultiplemyeloma.IntheUSstudy,therewas
significantimprovementintheresponserate(PR,59%vs21%,respectively)andtimetodisease
progression(11.1vs4.7months,respectively)inthecohortreceivingthelenalidomidecombination
theresultsofthesecondstudy,fromEurope,werealmostidentical.Similarresponseswereseenin
patientsrelapsingafterpriorbortezomiborthalidomideexposure.ProphylaxisagainstDVTand
monitoringformyelosuppressionarerecommendedbasedonthesideeffectsseen,but
lenalidomideisgenerallywelltolerated.

Proteasomeinhibitors.Alarge,multiinstitution,phaseIItrialoftheproteasomeinhibitor
bortezomib(givenIVatadoseof1.3mg/m2ondays1,4,8,and11every21days)demonstrated
remarkableactivityofbortezomibinaheavilytreatedpopulationofpatientswithrelapsedand
refractorymultiplemyeloma,includingpatientsrelapsingaftertransplantationornotrespondingto
thalidomide,withdurableresponsesnotedinabout35%(with10%CR).Sideeffectsrelatedtothe
drugwerepredominantlygastrointestinalinnature,withneuropathy,fatigue,andreversible
cytopeniasalsonoted.Toxicitiesweregenerallymanageablewithsupportivecareanddose
reduction.Patientswhodidnotrespondtobortezomibmonotherapy(thosewithprogressive
diseaseafter2cyclesorstablediseaseafterthefirst4cycles)werepermittedtoreceive
combinationbortezomibanddexamethasone.Combinationtherapyinducedadditionalresponsesin
18%ofpatients.

Thelarge,randomized,phaseIIIAPEXtrialofbortezomibmonotherapycomparedwithhighdose
dexamethasoneenrolled669patientswithrelapsedmultiplemyeloma.Thistrialshowedsignificant
improvementinthemediantimetodiseaseprogression(6.5vs3.6months,respectivelyP<.0001)
andmedianoverallsurvival(29.8vs23.7months,respectivelyP=.027).Therateofresponseto
bortezomibasasingleagentwasimpressiveat43%.Themostcommonlyreportedadverseevents
forbortezomibwereneuropathy,gastrointestinalevents,fatigue,pyrexia,andthrombocytopeniafor
highdosedexamethasone,theyincludedfatigue,insomnia,andanemia.Neuropathywasthemost
importantissuewithbortezomib,butitprovedgenerallymanageablewithdosereductionand
schedulechange.DVTwasveryrare,andefficacyinpatientswithsignificantrenaldysfunctionwas
noted.Finally,encouragingresponseswerenotedinpatientswithadversecytogeneticsaswellas
inpatientswithadvancedbonedisease.
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Bortezomibhassynergisticactivitywhencombinedwithpegylatedliposomaldoxorubicin,
thalidomide,melphalan,andlenalidomide,withimpressivediseasecontrolshowninrefractory
myeloma.Inarandomized,phaseIII,multicenter,internationalstudyinpatientswith
relapsed/refractorymyeloma,thecombinationofbortezomib(1.3mg/m2ondays1,4,8,and11)
andpegylatedliposomaldoxorubicin(30mg/m2onday4)wasreportedtobesuperiorto
bortezomibaloneintermsofbothoverallresponse(50%vs42%,respectivelyP=.05)andtimeto
diseaseprogression(9.3monthsvs6.5months,respectivelyP<.0001).Whenbortezomib(ata
doseof1mg/m2or1.3mg/m2)wasadministeredwiththalidomide(indosesrangingfrom50to200
mgstartingatcycle2),86%ofpatientswithrelapsedorrefractorydiseaseachievedacompleteor
partialresponseandrandomizeddatahaverecentlydemonstratedthesuperiorityofthisapproach
tothalidomide/dexamethasoneinrelapsedmultiplemyeloma.AphaseIIstudycombining
bortezomibwithlenalidomideanddexamethasone(RVD)hasalsoshownpromisingactivitywith
relativelylimitedtoxicity.

Carfilzomib.Carfilzomibisanirreversibleproteasomeinhibitorwhichselectivelytargetsthe
chemotrypsinelikeactivityoftheproteasome.Itsactivityasasingleagenthasbeendemonstrated
inrelapsed/refractorymultiplemyelomapatientswhoarebortezomibnaiveorrefractory.AnORRof
about50%wasachievedinacohortof129bortezomibnaivepatients,whiletheORRwas
approximately20%inbortezomibtreatedpatients.Sideeffectsaremanageableandinclude
hematologictoxicity,fatigue,dyspnea,andgastrointestinalproblems.Interestingly,therateof
neuropathyseenhasbeenlow.However,useofcarfilzomibisassociatedwithariskofcardiologic
events(congestiveheartfailure)andpatientsshouldbecarefullymonitored.

ResultsofthephaseIIIrandomizedASPIREtrialfirmlyestablishedthatathreedrugcombinationis
superiortoatwodrugcombination.Aregimencomprisingcarfilzomib,lenalidomide,and
dexamethasonewassuperiortoonewithlenalidomideanddexamethasoneintermsofORR(87%
vs67%),CRrate(32%vs9.3%),andmedianprogressionfreesurvival(26.3mosvs17.6mos).In
theinterimanalysistherewasnodifferenceinsurvival,butthetrendfavoredtriplettherapy.

Pomalidomide.PomalidomideisathirdgenerationIMiDthathasrecentlybeenFDAapprovedfor
relapsedorrefractorymultiplemyeloma.Indeed,whenusedincombinationwithdexamethasone,
theORRrangesfrom20%to35%inheavilypretreatedpatientswhoarenotablylenalidomide
refractoryand/orbortezomibrefractory.ThemulticentricrandomizedMM003trialhas
demonstratedasignificantadvantageinbothprogressionfreesurvival(median,4months)and
overallsurvival(median,12.7months)byusingpomalidomidealongwithdexamethasone
comparedtohighdosedexamethasonealoneinrelapsed/refractorymultiplemyeloma.Moreover,
theadvantageinthesurvivalwasseeninthelenalidomide(progressionfreesurvivalandoverall
survivalimprovements)andbortezomibandlenalidomiderefractory(progressionfreesurvival
improvement)subgroups.Inthosesubgroups,anORRofabout30%wasachieved.

Thedrugiswelltoleratedandthemostcommonsideeffectsincludemyelosupression,infections,
fatigue,orbonepain.Treatmentwithpomalidomiderequiresathromboembolicprophylaxissimilar
tothatusedwiththeotherIMiDs.Pomalidomideisapromisingagentanditsuseincombination
therapyalongwithproteasomeinhibitororalkylatoragentsiscurrentlybeingevaluatedinrelapsed
and/orrefractorymultiplemyeloma.Moreover,basedoncytogeneticsorGEPfindings,highrisk
patientsmightbenefitfromitsuse.

Bendamustine.Bendamustine,althoughnotFDAapprovedformyeloma,canofferagood
responseforpatientswithrelapsedandrefractorymultiplemyeloma.AnORRof48%wasseenina
phaseI/IItrialcombiningbendamustinewithbortezomibinrelapsed/refractorymultiplemyeloma.
AnothertrialincombinationwithlenalidomidereportedanORRof52%,with24%achievingVGPR.
Itsassociationwithpredisonehasbeencomparedinthelate1990stomelphalanprednisoneinthe
newlydiagnosedmultiplemyeloma.TheORRwas75%,witha32%CRrate,andshoweda4

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monthbenefitinthetimetotreatmentfailure.Nausea/vomitingandhematologic(leukopenia,
thombocytopenia)sideeffectsaremainlydescribed.

Promisingnovelagents

Proteasomeinhibitors.Treatmentwithixazomibasasingleagentyieldsanapproximately15%
ORRinbortezomibnonrefractorypatients.Itachievesa34%ORRincombinationwith
dexamethasone.AphaseI/IItrialhasevaluatedatotallyoralinductionregimen(ixazomib
lenalidomideanddexamethasone).TheORRinthistrialwas94%,with76%achievingmorethan
VGPR.Rareperipheralneuropathyhasbeendescribednotably,thesideeffectsincludedrash.Its
useinmaintenancetherapyalongwithlenalidomideiscurrentlybeingevaluated.Theinterim
resultsofTOURMALINE2,arandomized,doubleblind,placebocontrolledtrial,showedthata
combinationofixazomib,lenalidomide,anddexamethasoneissuperiortoatwodrugregimenof
lenalidomideanddexamethasone.

Oprozomibisanoralavailableanalogofcarfilzomib.AphaseI/IIstudyincludingmultiplemyeloma
hasshownagoodsafetyprofile.Adverseeventsweremostlycytopeniaandgastrointestinal
symptoms.

Monoclonalantibodies.Theactivityofmonoclonalantibodiesisrelatedtodifferentpathways.
Besidesthedirectcytotoxicityfrominducingapoptosis,theantigendependentcellularcytotoxicity
andcomplementdependentcytotoxicityareinvolvedintheireffect.

Elotuzumabisahumanizedmonoclonalantibody(IgG1)directedagainsttheSLAMF7glycoprotein
expressedonmyelomacellsandinvolvedintheadhesiontobonemarrowstromacells.PhaseI
andIIstudieshaveshownasynergisticactivityofelotuzumabincombinationwithlenalidomide,
withanencouragingORRinrelapsedmultiplemyelomaofabout80%andprolongedprogression
freesurvival(upto33months).Toxicitiesaremanageableandincludeneutropenia,
thrompocytopenia,fatigue,gastrointestinalissues,andinfusionrelatedevents.CurrentphaseIII
trialsarecomparingtheoutcomeoftheassociationoflenalidomidedexamethasonewithorwithout
elotuzumabinrelapseorinnewlydiagnosedmyeloma.ItsuseinassociationwithVRDisalso
underinvestigation.

DaratumumabisanantiCD38monoclonalantibodythathassofarshowedimpressiveresultsin
monotherapyorincombinationwithlenalidomideanddexamethasone.InvestigatorsofaphaseI/II
trialhavereportedanORRof100%andarateofVGPRorbettergreaterthan50%on6patients
withrelapsedorrefractorymultiplemyelomatreatedwithlenalidomide,dexamethasone,and
daratumumab.Neutropeniaandinfusionreactionwerethemainsideeffects.AnotherantiCD38
antibody,SAR650984,hasalsodemonstrateditssafetyandefficacyasmonotherapyinhighly
pretreatedpatients,achievinganORRof26.5%.

OthermonoclonalantibodiesincludeantiCD138(BT032),antiCD56,orantiCD40.Aswiththe
othermonoclonalantibodies,BT062hasshowedsynergisticactivityalongwithlenalidomide,
achievinganORRof72%inrelapsedorrefractorypatients.

Histonedeacetylase(HDAC)inhibitors.PanobinostatisthefirstHDACinhibitortoreceive
acceleratedapprovalfortreatmentofpatientswithrelapsedmyelomainwhomatleasttwoprior
regimenshavefailed.ApprovalwasbasedontheresultsofPANORAMA1,aninternational,
randomized,placebocontrolled,doubleblindphaseIIItrial.Patientsreceivingpanobinostat,
bortezomib,anddexamethasonehadahigherCRornearCR(28%vs16%)andalonger
progressionfreesurvival(medianprogressionfreesurvival,12mosvs8mos)withnodifferencein
overallsurvivalatthetimeoftheinterimanalysis.PatientsinthephaseIIPANORAMA2study
demonstrateda35%ORR,a5.4monthmedianprogressionfreesurvival,anda17.5month
medianoverallsurvivalinabortezomibrefractorypopulation.Itsusewithlenalidomideisalsobeing

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evaluated.Theadverseeventsencounteredwerethrombocytopeniaandfrequentgastrointestinal
sideeffects,includingdiarrheaandfatigue.

VorinostatisaHDACinhibitor.Althougththefirstresultsseemedencouragingintermsofits
combinationwithproteasomeinhibitors,resultsofaphaseIIItrialinvestigatingthetriplet
bortezomibvorinostatdexamethasoneinpatientswithrelapsedmultiplemyelomahaveonly
showna0.8monthdifferenceinprogressionfreesurvivalincomparisontoresultswithbortezomib
dexamethasone.TheORRwasbetter(56.2%vs40.6%).Theseresultswereovercomebythe
adverseeventsencountered(thrombocytopenia,frequentgastrointestinalsideeffects,andfatigue).

ACY1215isaselectiveHDAC6inhibitorthatdemonstratedanactivitywhenadministeredin
combinationtherapy,similartothatobservedwiththeotherdeacetylaseinhibitors.TheORRs
reportedwere25%inassociationwithbortezomibin20heavilypretreatedpatients,and69%in
associationwithlenalidomidein12patients.Gastrointestinalsideeffectswererare.

Spindlekinaseproteininhibitor.ARRY520hasshownactivityasmonotherapyandin
combinationwithdexamethasone.TheORRreportedwasabout15%.Halfofthepatients
experiencedgrades3and4myelosuppression.Thus,theuseofARRY520requiresgrowthfactor
support.Itsassociationwithproteasomeinhibitorsiscurrentlybeingevaluated.

Othersmallmoleculesunderstudyincludetheorallybioavailableagent,perifosine,whichtargets
AKT,JNK,andNFKB.Combinationswithbortezomibandlenalidomidehaveshownencouraging
results,butunfortunatelyaphaseIIItrialofperifosinecombinedwithbortezomiband
dexamethasonewasdiscontinuedwhenasignificantdifferenceinprogressionfreesurvival,the
primaryendpoint,wasnotachievedatinterimanalysis.

Allogeneicstemcelltransplantation.Foryoungerpatientswithresistantrelapsedorpoor
prognosisdisease(eg,withdeletionofchromosome13),allogeneictransplantationmaybean
importantoption.Theroleofallogeneictransplantinmyelomashouldstillbeconsidered
investigational.Highdosemyeloablativetherapywithallogeneicstemcellrescuehasbeen
abandonedinlightofhightransplantrelatedmortality.Anonmyeloablativeregimenisineffectivein
tumorcytoreductionand,consequently,isrelatedtoahighrelapserate.Thus,uniquelyinmultiple
myeloma,highdosemelphalanandstemcelltransplantisfollowedbyanonmyeloablativeregimen
andallogeneicstemcelltransplantation.Twolarge,randomizedtrialsfromFranceandItalythat
comparedtandemautologoustransplantationwithautologoustransplantationfollowedby
allogeneictransplantationfrommatchedsiblingdonorshaddifferentoutcomes.Frenchinvestigators
notednoimprovementinprogressionfreesurvivaloroverallsurvivalwheninclusioncriteriawere
restrictedtoahighriskgroup,whereasItalianinvestigatorsnotedbettereventfreesurvivaland
overallsurvivalwhennosuchrestrictionforpatiententrytothestudywasinplace.Inaddition,
chronicgraftvshostdiseaseinflictsconsiderablemorbidity,inexcessof50%ofpatientspost
allograft.Currently,useofallogeneicstemcelltransplantationisonlyrecommendedinthecontext
ofaclinicaltrial.

Supportivetherapy

Varioussupportivetherapiesmaybebeneficialinpatientswithmultiplemyeloma(Table6).

Chronicanemia.Theuseoferythropoieticstimulatingagents(ESAs)in
myelomashouldgenerallyberestrictedtopatientswhoareanemicdueto
concomitantchemotherapyormoderatetosevererenalfailure.The
combineduseofESAsandimmunomodulatoryagentsisassociatedwithan
increasedincidenceofvenousthromboembolism,butthisisnotseenwith TABLE6:Supportive
therapiesformultiple
bortezomib.ForadditionalinformationabouttheuseofESAsinpatientswith myeloma
cancer,visittheFDAinformationpageonESAs.

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Infection.Seriousinfectionwithencapsulatedorganismsisencounteredbypatientswithmyeloma
duetotheirinabilitytomountsuccessfulantibodyproduction(andlackofopsonization).Prompt
institutionofantibioticsisthereforerecommendedinthefaceofsystemicinfection.Antibiotic
prophylaxisisalsorecommendedwheneverhighdoseglucocorticoidsareusedfortreatment.
Patientswithrecurrentseriousinfectionsmaybenefitfrommonthlyintravenousgammaglobulin.
Shinglesisnotuncommoninmyelomapatients,andprophylaxisfollowingtransplantationand
duringbortezomibtherapyisadvisedwithappropriateantiviraltherapy.

Bonepainorimminentfracture.Therapywithbisphosphonates,suchaspamidronateor
zoledronicacid,hasbeenshowntoreduceskeletalrelatedeventsandimprovequalityoflifefor
patientswithmultiplemyeloma.Bisphosphonatesreduceskeletalrelatedeventsincludingbone
pain,hypercalcemia,lyticbonedisease,andcompressionfractures.Thereisreductioninthe
incidenceofskeletalrelatedeventswithinthefirstyearofstartingtherapy,eveninpatients
presentingwithnolyticbonedisease.ArecentlargerandomizedtrialfromtheMRCintheUKof
newlydiagnosedsymptomaticmyelomapatientshasshowncontinuoustherapywithzoledronic
aciduntilprogressionimprovesprogressionfreesurvivalandoverallsurvival.Theriskof
osteonecrosisofthejawwas3%to5%inthisstudy,andtherewasnoincreasedincidenceofrenal
impairment.

Zoledronicacid,themorepotentaminobisphosphonate,hasefficacyandsafetycomparableto
pamidronateinpreventingskeletallesions.Theeaseofadministrationofa4mgdose,which
reducestheinfusiontimeto15to30minutescomparedwith2hoursforpamidronate,hasledto
FDAapprovalofzoledronicacidforpreventionofbonerelatedcomplicationsinmyeloma.Caution
shouldbeexercisedwithlongtermuseofbisphosphonates,sincerenalimpairmentand
osteonecrosisofthejawboneshavebeenreported,aspreviouslymentioned.

Percutaneousvertebroplastyprovidespainreliefthatisnotonlyrapidbutsustained,anditalso
strengthensthevertebralbodies.Kyphoplastyisasaferprocedurethatinvolvesinsertionofa
balloonfollowedbyinjectionofpolymethylmethacrylate,theprincipalcomponentofbonecement,
intotheballoon.Itisperformedwiththepatientunderlocalanesthesia.Transientworseningofpain
andfeverthatmayoccurisresponsivetononsteroidalantiinflammatoryagents.

SmolderingMyeloma

Smoldering,orasymptomatic,myelomaischaracterizedbythepresenceofmonoclonalIg>3g/dL
and/orbonemarrowplasmacytosisinexcessof10%.Thediagnosisisoftenmadebyachance
findingofanelevatedserumproteinlevelduringascreeningexamination.

Laboratoryfeatures

Featuresoflowtumormassareusuallypresent,withoutrenaldisease,hypercalcemia,orlyticbone
lesions(Table2).Marrowplasmacytosisoccursinlessthan30%ofpatients,andanemia,if
present,ismild(hemoglobinvalue>10.5g/dL).

Treatment

Systemictherapyshouldbewithhelduntilthepatientbecomessymptomatic,althoughstudiesare
nowevaluatingvariousnovelagentsinthissetting.Theroleofbisphosphonatesandlenalidomide
hasbeenevaluated,andaseriesofstudieshavesuggestedbenefitfromreducingtheincidenceof
bonecomplicationsandincreasingthetimetoprogressionwithbisphosphonateuse.Theuseof
lenalidomideanddexamethasoneinpopulationsatparticularlyhighriskhasbeenassociatedwith
anoverallsurvivalbenefit,andtrialsinthisareaareongoing.AnMRIfindingofmultifocal

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plasmacytomasorFDGPET/CTfindingsofmultifocalosseouslesionswouldbeconsideredtobe
evidenceofendorgandamage,andshouldwarrantinitiationofadditionaltherapy.

Prognosticfactors.Smolderingmyelomagenerallyprogressestomultiplemyelomaattherateof
10%peryearforthefirst5years,3%peryearforthenext5years,andthen1%forthelast10
years.Theinitialconcentrationofserummonoclonalprotein>3g/dL,bonemarrowplasmacytosis>
10%,andanabnormalserumfreelightchainratioaresignificantpredictorsofprogressionto
symptomaticmyeloma.

OtherPlasmaCellDyscrasias
OtherplasmacelldyscrasiasincludeMGUS,solitaryplasmacytomaofbone(SPB),solitary
extramedullaryplasmacytoma,Waldenstrmsmacroglobulinemia,amyloidosis,POEMS
(polyneuropathy,organomegaly,endocrinopathy,monoclonalgammopathy,andskinchanges)
syndrome,andheavychaindiseases.

MonoclonalGammopathyofUnknownSignificance

MGUSoccursin1%ofnormalindividuals>40yearsold,anditsfrequencyrisesprogressivelywith
age.Recentstudiesindicatethatthediagnosisofsymptomaticmultiplemyelomaisalways
precededbymonoclonalgammopathyfor2ormoreyears.

Laboratoryfeatures

CommonlaboratoryfeaturesofMGUSarelistedinTable2.

Treatment

Approximately25%ofpatientswiththisdisorderdevelopmultiplemyeloma,macroglobulinemia,or
nonHodgkinlymphomaoveraperiodof20yearspostdiagnosis.Theinitialconcentrationofserum
monoclonalprotein>1.5g/dL,nonIgGtypeparaprotein,andabnormalserumfreelightchainratio
aresignificantpredictorsofdiseaseprogressionat20years.Thelongperiodofstabilitysupports
annualmonitoringwithserumelectrophoresisandbloodcountsandsuggeststhatchemotherapy
maybewithhelduntilthereisevidenceofprogressiontomyeloma.

SolitaryPlasmacytomaofBone

Approximately3%ofpatientswithmyelomahavesolitaryplasmacytomaofbone(SPB).

Laboratoryfeatures

Allpatientshaveeithernomyelomaproteinorverylowlevelsinserumorurine(Table2).MRImay
revealabnormalitiesnotdetectedbybonesurveyandmayupstagepatientstomultiplemyeloma.
Persistenceofmonoclonalproteinformorethan1yearafterirradiationpredictsearlydisease
progressiontomultiplemyeloma.

Treatment

ManagementofSPBconsistsofradiationtherapy(atleast45Gy).Multiplemyelomabecomes
evidentinmostpatientsovertime,soonly20%ofpatientsremainfreeofdiseaseformorethan10
years.Themediantimetodiseaseprogressionisapproximately2to3years.

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SolitaryExtramedullaryPlasmacytoma

IncontrasttoSPB,solitaryextramedullaryplasmacytomaisoftentrulylocalizedandcanbecured
inupto50%ofpatientswithlocalizedradiationtherapy(4550Gy)and/orresection.Careful
observationaftertreatmentisnonethelesswarranted.

WaldenstrmsMacroglobulinemia

Thisuncommondiseaseischaracterizedbylymphoplasmacyticbonemarrowandtissueinfiltratein
additiontoelevatedIgMproduction.Themutationpatternanalysissuggeststhatfinal
transformationoccursinthepostgerminalcenterIgMmemoryBcell.Correspondingwithvariation
incellmorphology,thereisvariationintheimmunophenotype.MatureplasmacellsexhibitCD38
antigenhowever,lymphoidcellsaretypicallypositiveforCD19,CD20,andCD22.

Waldenstrmsmacroglobulinemiausuallyaffectspeopleinthefifthtoseventhdecadesoflifeand
cancausesymptomsduetotumorinfiltration(marrow,lymphnodes,and/orspleen),circulatingIgM
(hyperviscosity,cryoglobulinemia,and/orcoldagglutininhemolyticanemia),andtissuedepositionof
IgM(neuropathy,glomerulardisease,and/oramyloidosis).NeuropathymaybeduetotheIgM
antibodyreactingwithmyelinassociatedglycoprotein.

Hyperviscositysyndrome

Withhyperviscositysyndrome,patientsmayhavevisualsymptoms,dizziness,cardiopulmonary
symptoms,decreasedconsciousness,andableedingdiathesis.

Therapyforhyperviscosityconsistsofplasmapheresisfollowedbychemotherapytocontrolthe
malignantproliferation.Patientswithpoorperformancestatusandelderlypatientswhoareunable
totoleratechemotherapymaybemaintainedwithperiodicplasmapheresis.

Treatment

Alkylatingagentsusedincombinationwithsteroidsorpurineanalogsremainthemainstayof
therapy.Alkylatingagentsaloneorincombinationwithsteroidseffecta50%reductionin
paraproteininabouthalfofpatients,andthemediansurvivaltimeisaround5years.Thepurine
analogsfludarabine(Fludara)andcladribine(Leustatin)elicitamorerapidresponsethanother
agents,witharesponserateofmorethan75%observedinasmallseriesofpatients.Preliminary
resultsofalarge,Americanmultiinstitutionevaluationoffludarabinereportedpartialresponsesin
only33%ofpatients.

Purineanalogtherapymayresultinsignificantmyelosuppressioninlatercyclesoftherapyand
prolongedimmunosuppressionwithincreasedopportunisticinfections.Purineanalogsareeffective
salvageoptionsinpatientsrefractorytoorrelapsingfollowingalkylatortherapy.Patientsrefractory
toonepurineanalogarerarelysalvagedbyadifferentpurineanalog.Patientswithresistantrelapse
arelesslikelytobenefitfrompurineanalogs(responserate,18%)andshouldbeconsideredfor
moreintensiveintervention,includinghighdosetherapy.

Othertreatmentoptions

Rituximab(Rituxan),anantiCD20monoclonalantibody,iseffectiveinWaldenstrms
macroglobulinemia,becausetheCD20antigenisusuallypresentonthelymphoidcellcomponent
ofmacroglobulinemia.Preliminaryresultsindicatethatabout30%ofpreviouslytreatedpatients
(refractoryorrelapsingwhileofftherapy)maybenefitfromrituximab.

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StrikingactivityofthalidomideinmultiplemyelomahasprompteditsuseinWaldenstrms
macroglobulinemia.Inaseriesof20patientsreceivingthalidomide,25%achieveda50%reduction
inparaprotein.Higherdosesofthalidomidewerenotwelltoleratedinanelderlycohortofpatients.
Interestingly,preliminaryresultsofbortezomibbasedtherapyinrelapsedWaldenstrms
macroglobulinemiahavebeenverypromising.Incontrast,lenalidomidehasprovedlessuseful,
primarilybecauseofmyelosuppression.

Highdosetherapywithautologousbonemarroworbloodstemcellrescuehasbeeneffectivein
achieving50%reductioninparaproteininalmostallpatientsinsmallpilottrials.

Amyloidosis

Amyloidosisoccursin10%ofpatientswithmultiplemyeloma.Thisinfiltrativeprocessresultsfrom
organdepositionofamyloidfibrils,whichconsistoftheNH2terminalaminoacidresiduesofthe
variableportionofthelightchainIgmolecule.Theabnormalproteinisproducedbyclonalplasma
cells.

Clinicalfeatures

Theseincludethenephroticsyndrome,cardiomyopathy,hepatomegaly,neuropathy,macroglossia,
carpaltunnelsyndrome,andperiorbitalpurpura.

Laboratoryfeatures

Serumandurineimmunofixationstudiesshowamonoclonalimmunoglobulininapproximately80%
ofpatients.Measurementofserumfreelightchainmayprovideamarkertoevaluateresponseto
therapy.Thelightchainismorefrequentlyofthetypethanthetype.Diagnosiscanbemadeby
thepresenceofapplegreenbirefringenceonpolarizedlightexaminationofsubcutaneousfat
aspiratesstainedwithCongored.ElevatedserumBtypenatriureticpeptidelevelsmayindicate
cardiacinvolvement,which,inthemajorityofpatients,maybeconfirmedwithechocardiography.

Treatmentofprimaryamyloidosis(ALmonoclonalproteinassociated)

Survivalofpatientswithamyloidosisisvariable.Patientswithcongestiveheartfailurehavea
mediansurvivalofonly4months.OralMPextendsthemediansurvivalto17months,ascompared
with13monthsinuntreatedpatients.Completehematologicresponseisraresimilarly,reversalof
organdamageisuncommon.

Inalargecohortofpatientsreceivinghighdosemelphalanwithstemcellsupport,acomplete
hematologicresponsewasobservedin47%ofpatientswithatleast1yearoffollowup.However,
thetransplantrelatedmortalityishighwithhighdosetherapy(14%to37%).Completehematologic
responsewasassociatedwithimprovedclinicalresponse(improvedorganfunction)andsurvival.
Completehematologicresponseintheabsenceofcardiacinvolvementpredictedexcellentoutcome
(1yearsurvival,91%).PhaseIandIIstudieshavealsoshownencouragingresultswithbortezomib
aswellaslenalidomide,bothinnewlydiagnosedandmoreadvanceddisease.Mostrecently,the
combinationofcyclophosphamide,bortezomib,anddexamethasonehasemergedasanimportant
newoptionforpatients.

PatientswiththeoverlapsyndromeofmyelomaandALamyloidosisshouldbetreatedaggressively
formyelomaresponsecanbeseenintermsofbothmyelomaandresolutionofamyloidsymptoms.

POEMSSyndrome

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Clinicalfeaturesandcourse

ThePOEMSsyndromeisarareplasmacelldyscrasiathatpresentswithperipheral,usually
sensorimotor,neuropathymonoclonalgammopathy(IgAbeingmorecommon)scleroticbone
lesions,notedinnearlyallpatientsandorganomegaly,endocrinopathy,andskinchanges.

Otherfeaturesincludehyperpigmentation,hypertrichosis,thickenedskin,papilledema,
lymphadenopathy,peripheraledema,hepatomegaly,splenomegaly,andhypothyroidism.Diabetes
mellitusisnotpartofthissyndrome.

Comparedwithpatientswithsymptomaticmyeloma,individualswithPOEMSsyndromeare
younger(medianage,51years)andlivelonger(median,8years).Theclinicalcourseiscommonly
characterizedbyprogressiveneuropathy.

Treatment

PlasmapheresisdoesnotappeartobeofbenefitinPOEMSsyndrome,andpatientsareoften
treatedsimilarlytothosewithmyeloma.Patientspresentingwithisolatedscleroticlesionsmayhave
substantialresolutionofneuropathicsymptomsafterlocaltherapyforplasmacytomawithsurgery
and/orradiotherapy.Autologousstemcelltransplantationhasbeenpursuedinselectedpatients
andhasbeenassociatedwithprolongedprogressionfreesurvival.

HeavyChainDiseases

Heavychaindiseasesarerareplasmacelldyscrasiascharacterizedbytheproductionofheavy
chainIgmoleculesthatlacklightchains(IgG,IgA,IgM).

Heavychaindisease

Thisconditionresultsfromlymphocyteandplasmacellinfiltrationofthemesentericnodesand
smallbowelandhasfeaturesofmalabsorption,suchasdiarrhea,weightloss,abdominalpain,
edema,andnailclubbing.Theheavychainmoleculemaybedetectedinserum,jejunalsecretions,
andurine.ThereisanassociationwithinfectionwithCampylobacterjejuniandheavychain
disease.Largeproportionsofpatientscanbenefitfromantibiotictherapydirectedatthisinfection.

Heavychaindisease

Patientswithheavychaindiseasemaypresentwithfever,weakness,lymphadenopathy,
hepatosplenomegaly,andinvolvementofWaldeyersring.Eosinophilia,leukopenia,and
thrombocytopeniaarecommon.TreatmentwithregimenssimilartothoseusedfornonHodgkin
lymphomamaybeeffective.

Heavychaindisease

Thisconditionisseenexclusivelyinpatientswithchroniclymphocyticleukemia(CLL).Vacuolated
plasmacellsarecommoninthemarrow,andmanypatientshavelightchainsintheurine.
TherapyissimilartothatusedforCLL(seetheChronicLymphocyticLeukemiaandHairyCell
Leukemiachapter).

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SourceURL:http://www.cancernetwork.com/cancermanagement/multiplemyelomaandotherplasmacelldyscrasias

Links:
[1]http://www.cancernetwork.com/cancermanagement
[2]http://www.cancernetwork.com/authors/sundarjagannathmd
[3]http://www.cancernetwork.com/authors/paulgrichardsonmd
[4]http://www.cancernetwork.com/authors/nikhilcmunshimd

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