多发性骨髓瘤的精确诊断.ppt

杜鹃上海长征医院血液科全军骨髓瘤与淋巴瘤疾病中心,多发性骨髓瘤的精确诊断,MGUSSMMMM,3gm/dLMproteinANDNoCRAB,ClonalPCPDCRAB,CRAB:C=Calcium(elevated),R=Renalfailure,A=Anemia,B=BonelesionsRajkumarSV.CellTextbookofMedicine,24thEdition2012,MGUSSMMMM,3gm/dLS.MproteinOR500mg/24hUr.MproteinANDNoMDE,PCPD1ormoreMDECRAB60%BMPC100FLCratio1MRIfocallesions,2014年修改的IMWG诊断标准,RajkumarVetalLancetOncol2014,15:e538-48,MDE,myelomadefiningevents60%BMPC鉴定其克隆性，骨髓活检、涂片、流式,中国多发性骨髓瘤诊治指南(2015版),SMMVSMGUS进展比例,Perez-PersonaE,etal.Blood.2007;110:2586-92.,95%aPC/BMPCorparesisn=22(10progr.),95%aPC/BMPC+paresisn=39(28progr.),Noadversefactorsn=28(1progr.),120,96,72,48,24,0,1.0,0.8,0.6,0.4,0.2,0.0,Months,TTP(%),Mediannotreached,Median73months,p=0.003,Median23months,8%,42%,82%,HighRisk,LowRisk,冒烟型骨髓瘤向症状性骨髓瘤演变风险,basedonthe%ofaberrantPCsbyimmunophenotypeplusimmunoparesis,1.0,5yrs,MM的诊断标准(IMWG)的更新的缘由,不必治疗!,“冒烟型”骨髓瘤,(MC3g/dl50:95-102.2.GrignaniG,etal.BrJCancer.1996;73:1101-07.3.RiccardiA,etal.BrJCancer.2000;82,4.RajkumarSV,etal.AmJHematol2010;85(10):737-405.BarlogieB,etal.Blood.2008;112:3122-25.6.MustoP,etal.LeukLymphoma.2011;52(5):771-7757.MustoP,etal.Cancer.2008;113:1588-95.,Lenalidomide+dex（Rd)对高危冒烟型MM患者的临床试验研究,medianTTP21(P0.001),medianTTPnotreached,13Progressions(22%),47Progressions(76%),MateosetalNEJM2013,ASH2014(Abs3465),TomeetSMMdiagnosiscriteriaatleast95%phenotypicallyaberrantplasmacellsintheBMPCreductionsinoneortwouninvolvedimmunoglobulinsofmorethan25%,9cycleRdinductiontherapyfollowedbymaintenancetherapywithlenalidomide,Lenalidomide+dex（Rd)对高危冒烟型MM患者的临床试验研究,TTP,OS,TTP,MateosetalNEJM2013,ASH2014(Abs3465),OSfromthedateofinclusioninthestudy,OSfromthedateofdiagnosisofSMM,94%,80%,94%,78%,3years,5years,Thisrandomized,phase3trialshowedthatearlytreatmentwithRd,followedbymaintenancetherapywithlenalidomide,inpatientswithhigh-riskSMMsignificantlydelayedthetimetoprogressiontosymptomaticdiseaseandresultedinanOSbenefit.,Progressiontomyelomaoccurredwithin2yearsofthediagnosisin95%ofthepatientswith60%ormorebonemarrowplasmacells,withamediantimetoprogressionof7months(95%CI,1.0to12.9)1.,TimetoprogressionofdiseasepatientswithSMM,RajkumarSV,etal.NEnglJMed.2011KastritisE.etal.Leukemia2013WaxmanAJ.etal.JClinOncol2014,95%,N=655SMM(1996.01-2010.06atMayoClinic),N=21pts(3.2%),GreekMyelomaGroup2theUniversityofPennsylvania3.,TTPofdiseasepatientswithSMMMayo2007,In2007NEnglJMedDuringpast26years,276SMMatMayoClinic6of276patients(2%)60%PCinBM4patientsprogressedtosymptomaticMMfrom3to9months1ofthesepatientsdied13.5months(nospecificreason)1SMMprogressedtoMM50months,deathwithin2yearsofthatdate.,KyleRA,etal.NEnglJMed.2007Jun21;356(25):2582-90.,完整的单克隆免疫球蛋白,单克隆游离轻链,血清蛋白电泳血清免疫固定电泳,尿免疫固定电泳血清游离轻链,类IgGIgAIgDIgMIgE,型、,血清游离轻链（sFLC）,TotallightchainassayversussFLCassay,Totalassay,SerumFLCassay,FLC,10mg/L,Inhealthyindividual:Total=11.01g/L,Inhealthyindividual:Free=10mg/L,InlightchainmyelomaTotal=11.05g/L,50mg/L,Inlightchainmyeloma:Free=50mg/L,1.Katzmannetal.ClinChem.2002;1437-1444.2.Beethametal.AnnClinBiochem.2000,37:581-587.3.Bradwelletal.SerumFreeLightChainsAnalysis.4thed.,“高度敏感”的“定量”检测,“早期”“及时”的检测,DispenzieriA.etal.Blood2008,sFLCratio8or0.125,81处骨质破坏,MRIvalueinpatientswithSMM,Regardingsmolderingorasymptomaticmyeloma,allpatientsshouldundergowhole-bodyMRI(WB-MRI;orspineandpelvicMRIifWB-MRIisnotavailable),andiftheyhaveonefocallesionofadiameter5mm,theyshouldbeconsideredtohavesymptomaticdiseasethatrequirestherapy.,PET/CTfocal,butnotosteolytic,lesionspredicttheprogressionofSMMtoactivedisease,ZamagniEetal.Leukemia.2016Feb;30(2):417-22,120pts,中位随访2.2年16%出现Fls,未出现溶骨性改变2年PET/CT进展比例：58%（阳性）VS33%（阴性）,高危冒烟型骨髓瘤疾病进展情况,RevisedInternationalMyelomaWorkingGroupDiagnosticCriteriaforMultipleMyeloma,Rajkumaretal,LancetOncology,2014;15:e538-548,ClonalBMPC10%orbiopsyprovenbonyorextramedullaryplasmacytomaandANYONEORMOREOFTHEFOLLOWINGMYELOMADEFININGEVENTS(MDE)Endorgandamage(CRAB)thatattributedtothePCdisorder,Hypercalcemia:11mg/dLRenalinsufficiency:CrCl2mg/dLAnemia:Hbvalue2g/dLbelowthelowerlimitofnormalBonelesions:oneormoreosteolyticlesionsonskeletalradiography,CT,orPET-CT,AnyoneormoreofthefollowingNewbiomarkersofmalignancy(EarlyMM)60%PCinBMInvolved/uninvolvedserumfreelightchainratio1001focallesionsonmagneticresonanceimagingstudies,RajkumarVetalLancetOncol2014,15:e538-48,RevisedInternationalMyelomaWorkingGroupDiagnosticCriteriaforMultipleMyeloma,极高危SMM=活动性骨髓瘤,MGUS、SMM和MM的界定标准(IMWG),特征,CRAB症状,西班牙标准梅奥标准,极高危骨髓瘤,高危骨髓瘤,低危骨髓瘤,意义未明的免疫球蛋白血症（MGUS),Slim-CRAB症状S(60%浆细胞增多)Li(sFLCratio100)M(MRI1处或多处骨质破坏),SMM,中国多发性骨髓瘤诊治指南(2015版),从CRAB到SLiMCRAB,诊断标准其它更新,肾功能损害(肌酐清除率40ml/min，肌酐177mmol/L)M蛋白不做诊断必须指标（3%不分泌型，30%sFLC指标正常）孤立浆细胞瘤的两种类型孤立浆细胞瘤：骨髓无克隆浆细胞（PD:10%/3年）孤立孤立浆细胞瘤:克隆浆细胞10%PD:60%/3年(骨的浆细胞瘤）PD:20%/3年(软组织的浆细胞瘤）,25%/yearriskofMM,*Increaseinserummonoclonalproteinby10%oneachoftwosuccessiveevaluationswithina6-monthperiod.,高危SMM：中位TTP2年,1、Bianchietal.Leukemia2013.2、Perez-PersonaEetal.BrJHaematol20103、Rosinoletal.BrJHaematol20034、Rajkumaretal.Leukemia20135、Madanetall.MayoClinProc2010.6、Rajkumaretal.LancetOncol2014,思考与启示,推荐MRI，PET-CT或者CT的对所有SMM或者浆细胞瘤患者进行的影像学检测方法（X线）疑似骨质改变3-6月复检高危SMM在出现CRAB前，需密切观察sFLC肌酐清除率影像学,ISS,P3%,高危20%,中危20%,标危60%,3年4-5年8-10年,mSMART2.0:多发性骨髓瘤的预后分层体系,染色体异常Chromosomalabnormalities(CA)使用iFISH方法检测,乳酸脱氢酶(LDH),乳酸脱氢酶(LDH),ChimCS,etal.EurJHaematol.2015Apr;94(4):330-5,PreviousStudiesAssessingCombinationsofPrognosticTools,以上数据是对年轻、适合移植的患者的分析整理，但是对于老年患者及不适合移植患者的数据尚无！,10-13:NebenK,etal.Haematologica95:1150-1157,2010;BoydKD,etal.Leukemia26:349-355,2012;Avet-LoiseauH,Leukemia27:711-717,2013;MoreauP,JClinOncol32:2173-2180,2014,RevisedInternationalMyelomaWorkingGroupISSstageforMultipleMyeloma,修改的ISS分期（R-ISS）,ISSstage,CAbyFISH(CD138+)serumLDH,TheprimaryendpointwasOSThesecondaryendpointwasPFS,修改的ISS分期（R-ISS）,high-riskCA:del(17p)and/ort(4;14)and/ort(14;16),Overallsurvival(OS)inpatientswithmultiplemyelomastratifiedbyR-ISSalgorithm,UnivariableanalysisofOS,Amedianfollow-upof46months,82%,62%,40%,5yrs,PFSinpatientswithmultiplemyelomastratifiedbyR-ISSalgorithm,55%,36%,24%,R-ISSandOSbytypeoftreatment,nontransplantation-basedregimens,transplantation-ba