Plasma Cell Diseases (…and some Bonus
Content!) SethPolitanoDOFACPAssociateProgramDirector
ClinicalAssistantProfessorofMedicineKeckSchoolofMedicineofUSC
Plasma Cell Dyscrasias • Clonalplasmaorlymphoplasmacyticdiseases• DetectablemonoclonalAb(M-Protein)intheserumorurine• Canbeheavychain(IgG,IgA,IgD,IgM)withaκorλlightchainORκorλdiseasealonewithoutaheavychainorheavychainalone
α1α2β1β2γ
Alpha1Region:A1AntitrypsinAFP
HDLVLDLAlpha2Region:Haptoglobin CeruloplasminAntithrombin3BetaRegion:TransferrinHemoglobinCRPC3BetalipoproteinGammaRegion:Immunoglobulins
Intro to Protein Electrophoresis
Plasma Cell Dyscrasias – The Tests • SPEPanUPEP:CantellifthereisanM-protein,andhowmuch,butnottheactualchainsubtype
• Freelightchainanalysistellsusamountofthesecomponentsnotcomplexedtoheavychains-reportedasratioofκ/λ(normalisapprox.3-1.7)
• Immunofixationtestingtellsustheactualchainsubtypes
Plasma Cell Dyscrasias – The Tests
• Inadditiontovariousfindingsonlabsandimaging(morelater)–thinkofthisspectrumofdiseaseswith:
• “M-spike”onelectrophoresismapping(above)• ElevatedTotalGammaGlobulinConcentrationonlabs• QuantitativeImmunoglobulinLevelswithoneelevated(ieIgG)andtherest
suppressed• κ/λofusually>2(muchhigherinactualcases)
Multiple Myeloma • Malignantclonaldisorderofplasmacells• 2ndmostcommonhematologicmalignancy• Peakincidencein60s• Riskfactorsincluderace(AfricanAmerican),andmodestincreasewithradiation/chemicalexposure
Multiple Myeloma – Clinical Presentation/clues • 20%areasymptomatic• Fatigueanddyspnea• Hypercalcemia• RenalFailure• BonePain• PathologicFractures• NeurologicComplications• RecurrentInfections• BleedingTendency• Cryoglobulinema• AMS/BlurredVision/Headache/HeartFailure/Dyspnea• Canprogresstoamyloidosis
Multiple Myeloma – Clinical Presentation/clues Workupevaluation–tellmeaboutthe:
CBC
BloodSmear
Ua
BMP
LiverPanel
Multiple Myeloma – Clinical Presentation/clues Whatotherworkupshouldbedone?
• SPEPandIF• UPEPandIF• Serumlightfreechainanalysistogetkappa/lambda
• QuantitativeImmunoglobulinLevels
Multiple Myeloma – Clinical Presentation/clues
MonoclonalSpike/LightchainsinUrine
RaisedIgGorIgA(IgM,IgD,andIgEmyelomascanbeseenbutrarely).
Multiple Myeloma
Bone Survey (not a Bone Scan). If negative – MRI or PET
Check Spine, Skill, Pelvis, Humeri and Femurs
Multiple Myeloma
Multiple Myeloma DiagnosticCriteria:ThediagnosisofSymptomaticmultiplemyelomarequires???
1) MProteinPresent(aka“TheSpike”)–THEAMOUNTDOESNOTMATTERFORDX)2) PlasmaCells>10%orPlasmocytoma3) SignofOrganDysfunction(atleast1)
§ Ca>11.5§ Cr>2§ Hgb<10§ LyticLesions§ Amyloidosis§ Hyperviscosity§ BacterialInfections(>2inprevious12months)
What if a hospitalized patient with pneumonia has a globulin gap on admit labs? There is normal Cr, no symptoms of lytic disease, normal calcium and normal hemoglobin. You send an SPEP which reveals a 2.8 g/dL monoclonal spike…
MGUS: • No Evidence of Symptomatic Disease • <10% Plasma Cells • There is an M-Spike of IgG or IgA, but it is Less than 3 g/dL
• MGUS is seen in 1% of individuals at age 50, 7% in those older than 85
• Osteoporosis is common in MGUS
• 1-2% Annual Transformation into Multiple Myeloma, overall risk 20%
• ThepresenceofanIgAorIgMgammopathy,anMproteinlevelof1.5g/dLormore,andanabnormalserumFLCratioarepredictiveofprogressiontomultiplemyelomaorotherPCDinnon–light-chainMGUS
• Oninitialeval,quantifyMproteinlevelandFLClevel• Ifnoriskfactorsforprogression:Canfollow-upwithyearlyhistoryandphysicalexam.Considerlabevaluationq2-3years
• Ifatleastoneriskfactor:Yearlyhistory,examandlabs• FollowupconsistsofCBC,Calcium,CrandMproteinLevels.Others(ieimaging)guidedbyexam/symptoms
• IfpatienthasincreasedMprotein,clinicallyevidentdisease(symptoms/exam/labs),orabnormalFLCratio,furtherw/upforMMisneededwithaBMbiopsy.
• ConsiderbaselineDEXAinallpatientswithMGUS
MGUS Follow up/Approach
SmolderingMM:• NoEvidenceofSymptomaticDisease• ≥10%PlasmaCells• ThereisanM-SpikeofIgGorIgA,butitisAtLeast3g/dL• Thesepatientshaveahigherrateofconversationtomultiple
myeloma,soveryclosefollow-upisneeded• Oninitialevaluation,MRIisusuallydonetoassessforbonelesions• Indicationstotreat:
• Bonelesions• AbnormalFLCRatio• PlasmaCells>60%onBiopsy
Stagingandrisk:
Ifpresent,theseshouldbeaddressedimmediately• SevereAnemia
• RenalFailure
• Hypercalcemia
• LyticLesions
• CompressionFractures
• Hyperviscosity
Treatment
Treatment Whydoweneedtoaddressallofthesementioned?
• AllPatients<70withGoodPerformanceStatusshouldbeconsideredforPBSCT
• Initialinductionregimendependsonifpatientisacandidateforhigh-dosechemotherapywithautologousperipheralbloodstemcelltransplantation(PBSCT).
• ZoledronicAcidimprovespainandsurvival
• InductionConsistsofanycombinationofThalidomide/LenalidomideBortezomibSteroidsMelphalanCyclophosphamide
• PBSCTtypicallyundergoinitialtherapywithregimensthatavoidalkylatingagentsbecausethesedrugsdamagestemcellsandimpairtheircollectioninadequatenumbers.
• Afterinductiontherapy,multipleregimens,usuallyincludinglenalidomide,areusedformaintenancetherapy
Treatment
Mostpatientswillrelapse,evenwithPBSCT• Ifpriorlong-responseduration,repeatedinductiontherapyused• Ifnot,usuallyissingleorcombochemowithnewagent• Relapsedpatientsreceivedifferentclassesofmedication,includecarfilzomib,andotherimmunomodulatoryagents(suchaspomalidomide)
Treatment
Quiz SideeffectofThalidomide?Thrombosis(especiallyifgettingsteroidsandpatientsimmobilized)PeripheralNeuropathyFatigueConstipationWhatelseisitusedfor?ErythemaNodosumLeprosumSideeffectofBortezomib?ThrombocytopeniaPeripheralNeuropathy
Prevention of Infections • AnnualInfluenza• Pneumococcalvaccination• IVIGisgiventosomepatientswithlowIGlevelsandrecurrentinfections
• IndolentB-cellnon-Hodgkinlymphoma• IgMκorλMprotein• Classifiedsimilartomyeloma(i.esmolering/symptomatic)
Waldenström Macroglobulinemia
• Commonlypatientshavefatigueandanemia• Beingalymphoma,“Bsymptoms”arealsoprominent• Bleedingcanbeseenuponpresentation(hyperviscosity,plateletdysfunctionetc)• Hyperviscosity–headache,hearingloss,tinittus,blurryvision,AMS• Abdominalpainfromliver/spleeninfiltration• Neuropathy• Canpresentwithcryoglobulinemiaandcoldagglutinindisease.
Waldenström Macroglobulinemia
UNLIKEMULTIPLEMYELOMA:1) Amyloidisrare2) Lyticlesionsarerare3) Renalinsufficiencyisrare
Waldenström Macroglobulinemia
Physicalexamwiththesepatients:• Lymphadenopathyandhepatosplenomegalyarecommon• Funduscopicexammayrevealdilatedretinalveins,papilledema,andflamehemorrhages
Waldenström Macroglobulinemia
• Workupissimilartomyeloma(SPEPandIFwithmonoclonalGammaGlobulinoftheIgMclass)
• Evaluateforbleedingdisorderswithcoagulationpanel
• Watchforhemolysis/skinfindingsofcryoandworkupasneeded
• PrognosisdeterminedbyLDH,β2-microglobulinandalbumin
• DiagnosismadeviaBoneMarrowBiopsy
Waldenström Macroglobulinemia
• Ifthereisaconcernforhyperviscosity,treatmentincludesplasmapheresis
• AutologousHSCThasbeenusedinsomepatients
• Otherwise,treatmentisrituximab+alkylatingagent(chlorambucil,cyclophosphamide,bendamustine)orapurineanalog(fludarabine,cladribine)orbortezomibwithorwithoutaglucocorticoid.Ibrutinibrecentlyapproved
Waldenström Macroglobulinemia
A52-year-oldmanisevaluatedforlowbackpainof3months'durationthatisnonradiating,progressive,andworsewithambulation.Hereportsnoprecedinginjury.Medicalhistoryisnotableforsmolderingmultiplemyelomadiagnosed1yearago;hehasbeenstablesincethattime.Hisonlymedicationisas-neededacetaminophen.Onphysicalexamination,temperatureis36.8,bloodpressureis132/82,pulserateis70,andrespirationrateis14.Nofocalneurologicfindingsarenoted.Hehaspaintopalpationofthelowerlumbarspine.Theremainderoftheexaminationisunremarkable.Laboratorystudiesshowahemoglobinlevelof13,serumcreatininelevelof1.0andserumcalciumlevelof9.8.Plainradiographsofthelumbosacralspinedemonstratenolyticlesionsorfractures.
Whatisthemostappropriatenextstep?1) Observationwithcontinuedlabevaluation2) ZoledronicAcid3) MRIoftheLumbarSpine4) ReferralforChemotherapy5) Lidocainepatchwithhydrocodoneforbreakthroughpain
A56-year-oldwomanisevaluatedforanelevatedserumproteinleveldiscoveredduringaroutineexaminationforalifeinsurancepolicy.Sheisasymptomatic.Medicalandfamilyhistoriesareunremarkable,andshetakesnomedications.Onphysicalexamination,vitalsignsarenormal,andtheremainderoftheexaminationisunremarkable.
Hgb 13.4
LeukocyteCount 6400
Platelets 224,000
Calcium 9.6
Cr 0.7
Albumin 3.9
IgG 2080(Elevated)
SerumproteinelectrophoresisandimmunofixationrevealamonoclonalIgGbandmeasuring0.8g/dL.A24-hoururineproteinelectrophoresisreveals80mgoftotalproteinandtracemonoclonalfreeκlightchainsthataretoolowtoquantify.Abonemarrowaspirateandbiopsyrevealsclonalplasmacellsrepresenting8%oftheoverallmarrowcellularity.Askeletalsurveydemonstratesnolyticlesions,osteopenia,orfractures.Whatisthemostappropriatenexttest?1) MRIofthecervical,thoracicandlumbarspine2) SerumFreeLightChainTesting3) SerumLDH4) RepeatBoneMarrowBiopsy5) SerumB2-microglobumin
A72-year-oldmanisevaluatedfora6-monthhistoryofprogressivefatigue,dyspneawithexertion,intermittentdrenchingnightsweats,anda6.8-kg(15-lb)weightloss.Medicalhistoryisunremarkable,andhetakesnomedications.Onphysicalexamination,thepatientappearsfatigued.Temperatureis37.0°C(98.6°F),bloodpressureis148/86mmHg,pulserateis88/min,andrespirationrateis16/min.BMIis24.Neurologicandfunduscopicexaminationsarenormal.Lungsarecleartoauscultation.Rubbery,1.5-to2.5-cmlymphnodesarepalpableinthebilateralanteriorcervicallymphnodechains,rightaxilla,andbilateralinguinalregions.Thespleenispalpable2cmbelowthemidleftcostalmargin.
Hgb 9.4
Leukocytes 5400
Platelets 184000
ReticCount 1.5%
BUN 20
Cr 1.1
IgG,IgA,IGM 540,80,3880
LDH 120
TotalProtein 9.3
BloodsmearisunremarkablewiththeexceptionofreducedRBCs.Coombsisnegative.SPEP/IFrevealsmonoclonalIgMbandof3.2g/dL.BMBiopsyrevealsclonalplasmacells,plasmacytoidlymphocytes,andmatureBcells,representing50%oftheoverallmarrowcellularitywithouterythroidhyperplasia.CToftheneck,chest,abdomen,andpelvisdemonstratessplenomegalyandcervical,axillary,mesenteric,andinguinallymphadenopathywithlymphnodesmeasuringupto3cm.Thelungfieldsareclear.
Whichofthefollowingisthemostappropriatemanagement?1) ColdAgglutinTitier2) PlasmaExchange3) RituximabplusChemotherapy4) JAK2Testing5) ThalidomideplusDexamethasone
Bonus Topics… YAY!
A68-year-oldmanisevaluatedfora6-monthhistoryofprogressivedyspneaonexertion,dizzinessonstanding,lowerextremityedema,andburningpainwithnumbnessinhisextremities.Healsonotesintermittentloosestoolsupto6timesdaily.Medicalhistoryisotherwiseunremarkable,andhetakesnomedications.Heiscurrentwithscheduledhealthmaintenancescreeninginterventions,andlaboratorystudiesobtained3yearsagoforaninsurancephysicalexaminationwerenormal.Onphysicalexamination,temperatureisnormal,pulserateis90,andrespirationrateis20.Bloodpressureis140/70mmHgsitting;uponstanding,bloodpressuredropsto90/60mmHgwithdizziness.BMIis27.Estimatedcentralvenouspressureis7cmH2O.Decreasedbreathsoundsareheardatthelungbasesbilaterally.Heartexaminationdoesnotrevealaruborgallop.Abdominalexaminationrevealsmildhepatosplenomegaly.Onneurologicexamination,thereisimpairedtouchandvibrationsenseinagloveandstockingdistribution.Bilaterallowerextremityedemaisnotedtotheleveloftheankles.
EKGrevealsLowvoltageinthelimbleads.Echocardiogramrevealsamildpericardialeffusion,restrictivefillingpatternwithandEFof65%,andincreasedechogenicityofthemyocardiumDiagnosis?Thoughts?
Albumin 2.8
Electrolytes Normal
FastingPlasmaGlucose 90
Ua 3+protein,noblood/casts
UrineP/Cr 4.8
• ExtracellulardepositionofLMWProteins• Manyformsoccurincluding:
• Otherformsincludehereditary,senile,dialysisandorgan-specificrelatedamyloid
Amyloidosis
Type Diseases Amyloid
ALAmyloidosis Plasmacelldyscrasia Monoclonalfreeλorκlightchains
AAamyloidosis
Rheumatoidarthritis,inflammatoryboweldisease,familialMediterraneanfever,chronicinfection
SerumamyloidAprotein
Amyloid - Clinical Ofnote,apatientmaypresentwiththeclinicalpresentationof:
• RenalDisease–CKD,NephroticSyndrome
• Cardiacinvolvement–HeartFailure,arrhythmia,CAD
• GI/Liver–Hepatomegaly,Dysmotility
• Heme:BleedingRisk
• Musculoskeletal–Macroglossia,Muscleinfiltration,Arthritis
• Neuro:CarpalTunnelSyndrome,AutonomicNeuropathy,Stroke
• Other:Bruising,Periorbitalpurpura,Edema,JawClaudication,Hoarseness/voicechange
Amyloid - Workup • FatpadaspirateandBoneMarrowmostrevealingofDxwithlowestrisk
• Ifabovenegative,biopsyaffectedsite(or“random”biopsies)
• Oncefound,performamyloidtyping
• Workupforcause(althoughusuallyevident)
• Assesscardiac(Tp,BNP,CXR,Echo,EKG)andLiverfunction• AssesspresenceofacoagulopathywithPT/PTT/INR
Amyloid - Treatment • Guidedsymptomaticmanagement
• ForAL–Similartomyeloma(Transplant/Chemo)
• ForAA–Treat/Controlthedisease
A39-year-oldmanisevaluatedforalowerextremityrashandnumbnessofthearmsfor3weeks'duration.Hehasnorecenthistoryofacold,flu,orotherinfection.Hetakesnomedications.Onphysicalexamination,temperatureis99.2°F,bloodpressureis136/86mmHg,pulserateis66/min,andrespirationrateis12/min.BMIis24.Smallvascularinfarctionsareobservedontheearsandfingertips.Therearescatteredpalpablepurpuriclesionsonthebilaterallowerextremities,whicharelessprominentonthesoles.Strengthisreducedintherightwrist.Labsreveal:
ESR 66
C3 Normal
C4 Decreased
Cr 2.3
RF Positive
HCVAb Positive
Ua RBCCasts
Whatismostlikelytoestablishthediagnosis?1) Anti-CCP2) SPEP/UPEP3) ANA4) p-ANCA5) SerumCryoLevels
Cryoglobulinemia
• Cryoglobulinsareproteinsthatprecipitatefromserumandplasmaattemperaturelessthanbodytemperature.Theydissolvewithwarming.
• Proteinsinvolvedareimmunoglobulinsalone,orinconjunctionwithcomplement.
• Thepresenceoftheseproteinscanbeasymptomaticorcausevariableamountsofvasculitis,thrombosisorhyperviscosity
Cryoglobulinemia TypeI:PlasmaCellDiseasesandLymphoproliferativedisorder(BcellNHL,CLL)Monoclonalimmunoglobulin(IgG,IgM,orIgA)withnoRFactivityTypeII:HCV,SLE,Sjogren’s,lymphoproliferativedisordersPolyclonalimmunoglobulins+monoclonalimmunoglobulin(IgM,IgA)withRFactivityTypeIII:HCV,Chronicinflammatoryconditions(i.eendocarditis),RheumaticDisease(especiallySLE,Sjogren’s,vasculitis)&lymphoproliferativedisordersPolyclonalimmunoglobulinswithRFactivity
Cryoglobulinemia - Causes A32yearoldwithIVDruguseandcryoConsiderationsincludeHCVandEndocarditisA25yearoldmalewithhistoryofceliacdiseasethathascryo+palpablepurpura,arthritis,hematuriaandabdominalpainHSPA42yearoldfemalewithcryo,fevers,anacardiacexaminationwitha“flop”soundonauscultationAtrialMyxoma
Cryoglobulinemia Symptomsvaryonthetypebutbeonthelookoutfor:• Arthralgias• Neuropathy• Nephropathy• Digitalischemia• Acrocyanosis• Palpablepurpura• Livedoreticularis• Skinulcers/necrosis• Hyperviscosity• MPGNandsystemicvasculitis(CNS,Pulmonary,GI)
Cryoglobulinemia - Testing • Testingneedstobedoneonwarmedsyringes• SendRFandcomplementlevels• ConsiderESRandCRP• Workupforsuspectedunderlyingcondition
Cryoglobulinemia - Testing Workupforsuspectedunderlyingcondition• HepatitisC• PlasmaCellDisorders• Leukemia(espCLL)• DruginducedVasculitis• AutoimmuneVasculitis(HSP,GPA,EPGA,mPA,SLE,RA,Sjogrens)• InfectiousVasculitis(endocarditis,poststrep,Rickettsial,Malaria)• AntiphospholipidSyndrome• TTP/HUS• AtrialMyxoma
Cryoglobulinemia - Treatment • Addresstheunderlyingcause
• TypeI:Treatmalignancy+Hyperviscositytreatment(plasmapheresis)
• TypeII/III:Treatdiseaseandvasculitissymptomswithrituximaborcyclophosphamide+glucocorticoids
Thank You
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