多发性骨髓瘤研究进展和治疗选择演示文稿

多发性骨髓瘤研究进展和治疗选择演示文稿第一页，共一百三十九页。优选多发性骨髓瘤研究进展和治疗选择第二页，共一百三十九页。OutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithms第三页，共一百三十九页。内容大纲诊断，分期，及风险评估初治骨髓瘤病人的初始治疗复发和/或难治性病人的新选择当前骨髓瘤治疗法则的代表性病例分析第四页，共一百三十九页。DiagnosticCriteriaMajorCriteria1.Plasmacytomaontissuebiopsy2.Bonemarrowplasmacytosis>30%3.Monoclonalserumprotein>3.5g/dLIgG2.0g/dLIgA1.0g/24hrskorllightchaininurineMinorCriteriaA.Bonemarrowplasmacytosis10-30%B.Smallermonoclonalspikethaninmajorcriterion#2C.LyticbonylesionsD.DepressednormalIgsIgM<500mg/dLIgA<1g/dLIgG<6g/dL第五页，共一百三十九页。诊断标准主要标准1.组织活检证实有浆细胞瘤2.骨髓浆细胞增多>30%3.过量血清M蛋白>3.5g/dLIgG2.0g/dLIgA尿中k

或l轻链1.0g/24小时次要标准A.骨髓浆细胞增多10-30%B.M蛋白未达主要标准的第3项C.溶骨性病变D.正常Igs降低IgM<500mg/dLIgA<1g/dLIgG<6g/dL第六页，共一百三十九页。ArrivingattheDiagnosisTwomajorcriteriaOnemajor+oneminorcriterion1+B,1+C,1+D2+B,2+C,2+D3+A,3+C,3+DThreeminorcriteriathatincludeAandBA+B+C,A+B+D1Clusterofplasmacellsinthebonemarrow.Bataille,RandHarousseau,JL.N.Engl.J.Med.336:1657,1997.1第七页，共一百三十九页。确诊条件2个主要标准1个主要+1个次要标准1+B,1+C,1+D2+B,2+C,2+D3+A,3+C,3+D包含A及B的三个次要标准A+B+C,A+B+D1Clusterofplasmacellsinthebonemarrow.Bataille,RandHarousseau,JL.N.Engl.J.Med.336:1657,1997.1第八页，共一百三十九页。ProblemswithThisMethodCriteriaarecumbersomeDifficulttouseforpatientsandphysiciansTheboundariesarearbitrary31%marrowplasmacytosisisamajorcriterionwhile29%isn’t,butarethesereallydifferent?Somepatientsmay“fallthroughthecracks”Apatientwithmultiplepainfullyticlesionsmaynotmeetcriteria,butneedssystemictherapy40%ofsymptomaticpatientshaveanM-proteinof<30g/L,and5%have<10%marrowinvolvement第九页，共一百三十九页。这项标准存在的问题判定标准烦琐不方便病人及医生使用界线设定独断31%骨髓浆细胞增多为主要标准而29%则不是,但两者是否存在差异?部分病人可能处于“夹缝状态”某些有多发性痛性溶骨病变的病人可能没有达到判定标准，但需要系统性治疗40%有症状的病人表现为M蛋白<30g/L,并且5%表现为<10%骨髓侵润第十页，共一百三十九页。MGUSInternationalMyelomaWorkingGroupcriteriaM-proteininserum<3.0g/dLClonalbonemarrowplasmacytosisof<10%,andalowlevelofplasmacellinfiltrationinamarrowbiopsy,ifthiswasdoneNootherB-cellproliferativedisorderNoendorgandamage,includingbonelesionsKyle,RAetal.Br.J.Haematol.121:749,2003.第十一页，共一百三十九页。MGUS国际骨髓瘤工作组判定标准血清M蛋白<3.0g/dL骨髓浆细胞增多<10%；并且如进行骨髓活检，可见浆细胞侵润程度低无其它B细胞增殖异常无终末器官损伤（包括骨病变）Kyle,RAetal.Br.J.Haematol.121:749,2003.第十二页，共一百三十九页。AsymptomaticMultipleMyelomaPreviously“smo(u)lderingmyeloma”SerumM-protein≥3.0g/dLand/orClonalmarrowplasmacytosis≥10%Norelatedorganortissueimpairment(noendorgandamage,includingbonelesions)orsymptomsKyle,RAetal.Br.J.Haematol.121:749,2003.第十三页，共一百三十九页。无症状多发性骨髓瘤以前的“冒烟型骨髓瘤”血清M蛋白≥3.0g/dL和/或骨髓浆细胞增多≥10%无相关器官或组织损伤（无终末器官损伤，包括骨病变)或症状Kyle,RAetal.Br.J.Haematol.121:749,2003.第十四页，共一百三十九页。SymptomaticMultipleMyelomaPresenceofaserumand/orurineM-proteinClonalmarrowplasmacytosisorplasmacytoma10%isgenerallyacceptedRelatedorganortissueimpairmentAnemia(<10g/dL,or2g/dLbelowlowerlimitofnormal)Bonylesions(lyticlesion,orosteoporosiswithcompressionfracture)Hypercalcemia(>2.75mmol/L,or>0.25mmol/Laboveupperlimitofnormal)Renalinsufficiency(creatinine>173mmol/L)Other(hyperviscosity,amyloidosis,recurrentbacterialinfections[>2episodesin12months])Kyle,RAetal.Br.J.Haematol.121:749,2003.第十五页，共一百三十九页。有症状多发性骨髓瘤血清和/或尿中有M蛋白骨髓浆细胞增多或浆细胞瘤通常以10%为标准相关器官或组织损伤贫血(<10g/dL,或低于正常值下限2g/dL)骨病变(溶骨性病变,或骨质疏松伴压缩骨折)高钙血症(>2.75mmol/L,或高于正常值上限>0.25mmol/L)肾功能不全(肌酐>173mmol/L)其他(高粘血症,淀粉样变,反复细菌感染[>2次/12个月])Kyle,RAetal.Br.J.Haematol.121:749,2003.第十六页，共一百三十九页。Durie-SalmonStagingSystemSeveralfactorsareincludedinthestaging1HemoglobinRenalfunctionSerumcalciumM-proteinproductionBonylesionsand/orpresenceofaplasmacytomaDrawbacksManyfactorsmakeitcumbersometoapplyDoesnotusenew,powerfulprognostictoolsInternationalMyelomaWorkingGroupstudied11,171patients2Multivariateanalysisfoundonlyb2-microglobulinandalbuminasprognosticfactors1Durie,BGMandSalmon,SE.Cancer36:842,1975.2Greipp,PRetal.Blood102:190a,Abstract664,2003.第十七页，共一百三十九页。Durie-Salmon分期系统本分期系统中包括下列指标1血红蛋白肾功能血清钙M蛋白骨病变和/或有浆细胞瘤缺点指标太多不方便使用没有包括新的、有力的预后工具国际骨髓瘤工作组研究了11,171例病人2多变量分析发现，只有b2微球蛋白及白蛋白是预后因子1Durie,BGMandSalmon,SE.Cancer36:842,1975.2Greipp,PRetal.Blood102:190a,Abstract664,2003.第十八页，共一百三十九页。InternationalStagingSystemGreipp,PRetal.J.Clin.Oncol.23:3412,2005.Stageb2MAlbuminNOSI<3.5≥3.5240162mos.II<3.5≥3.5-<5.5<3.5OR327844III≥5.5277029第十九页，共一百三十九页。国际分期系统（ISS）Greipp,PRetal.J.Clin.Oncol.23:3412,2005.分期b2M白蛋白N总生存期I<3.5≥3.5240162mos.II<3.5≥3.5-<5.5<3.5或327844III≥5.5277029第二十页，共一百三十九页。1Greipp,PRetal.J.Clin.Oncol.23:3412,2005.ISSandPrognosisSignificantsurvivaldifferencesforthreestages(P<0.0001)BetteroutcomepredictorthanthepriorDurie-SalmonmethodStilldoesnotincorporatecytogenetics第二十一页，共一百三十九页。1Greipp,PRetal.J.Clin.Oncol.23:3412,2005.ISS与预后的关系三期间有显著的生存差异(P<0.0001)与Durie-Salmon分期相比，有更好的预测结果但仍未包括细胞遗传学指标第二十二页，共一百三十九页。CytogeneticFactors:Del13Deletionofchromosome13wasthesinglemostpowerfuladverseprognosticfactorforalltimestoeventsinpatientsreferredforhigh-dosetherapyOS65.1±9.8vs26.7±4.1monthsFacon,Tetal.Blood97:1566,2001.第二十三页，共一百三十九页。细胞遗传学指标:13号染色体缺失在接受高剂量化疗的病人中，13号染色体缺失是单一最有效的负面预后因子，影响所有的“至事件发生时间”指标总生存65.1±9.8vs26.7±4.1个月Facon,Tetal.Blood97:1566,2001.第二十四页，共一百三十九页。BortezomibandDel13APEXrandomizedpatientstobortezomibordexamethasone11/74(15%)onthebortezomibarmand13/94(14%)onthedexarmhadmetaphasedel13Del13wasassociatedwithpoorsurvivalondexarmcomparedwithcontrolsDel13wasnotassociatedwithaninferiorsurvivalonthebortezomibarmJagannath,Setal.ASCOAbstract6501,2005.第二十五页，共一百三十九页。万珂与13号染色体缺失APEX将病人随机分入万珂组或地塞米松组万珂组11/74(15%)、地塞米松组13/94(14%)有分裂中期13号染色体缺失地塞米松组，13号染色体缺失与更差的生存期相关（与对照相比）万珂组，13号染色体缺失与更差的生存期无关Jagannath,Setal.ASCOAbstract6501,2005.第二十六页，共一百三十九页。ConclusionsStagingandprognosisismostaccuratelydeterminedusingtheISSNewprognosticfactorsareemergingthatmayhelprefinethisfurtherCytogeneticandFISHstudiescanprovideadditionalprognosticinformation,andintheverynearfuturemayguidetherapeuticdecisions第二十七页，共一百三十九页。结论用ISS能更好地确定分期及预后新的预后因子正在显现，未来可对分期预后系统有进一步的改进细胞遗传学及FISH研究能提供更多的预后信息，在不久的将来可能会为治疗方法的确定提供指导第二十八页，共一百三十九页。OutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsPatientswithtransplantasanoptionNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithms第二十九页，共一百三十九页。内容大纲诊断，分期，及风险评估初治骨髓瘤病人的初始治疗能进行移植的病人复发和/或难治性病人的新选择当前骨髓瘤治疗法则的代表性病例分析第三十页，共一百三十九页。Thalidomide+DexamethasoneThal/dexsuperiortodex(p=0.002)1Mediantimetoresponseforbothwas1.1mosProgression3%vs.5%

Progressionfreesurvival25.3vs.17.3monthsStemcellharvestsweresuccessful1Bestresponsewasevaluatedwithin4cycles.200mgpoqd.PRwas≥50%serum&urineM-proteinreduction,or≥90%urineM-reductionifonlyurinewasinvolved.RajkumarSVetal.J.Clin.Oncol.24:431,2006.第三十一页，共一百三十九页。沙立度胺+地塞米松Thal/dex

优于dex(p=0.002)1中位至缓解时间均为1.1个月进展3%vs.5%

无进展生存25.3

vs.17.3

个月可成功采集干细胞1Bestresponsewasevaluatedwithin4cycles.200mgpoqd.PRwas≥50%serum&urineM-proteinreduction,or≥90%urineM-reductionifonlyurinewasinvolved.RajkumarSVetal.J.Clin.Oncol.24:431,2006.第三十二页，共一百三十九页。DVdvs.VAdasInitialTherapyResponseDVd(n=97)VAd(n=95)CR3(3.1%)0Remission15(15.5%)15(15.8%)PR25(25.8%)24(25.3%)SD38(39.2%)46(48.4%)PD2(2.1%)0DVd:D@40mg/m2d1,V@1.4mg/m2withmax.of2mgd1,d@40mgd1-4.Rifkin,RMetal.ASCOAbstract6509,2004.DVdalsohadlessneutropenia,alopecia,andchangesintheLVEF,butatthecostofHFS/PPE第三十三页，共一百三十九页。DVdvs.VAd作为初始治疗疗效情况DVd(n=97)VAd(n=95)CR3(3.1%)0Remission15(15.5%)15(15.8%)PR25(25.8%)24(25.3%)SD38(39.2%)46(48.4%)PD2(2.1%)0DVd:D@40mg/m2d1,V@1.4mg/m2withmax.of2mgd1,d@40mgd1-4.Rifkin,RMetal.ASCOAbstract6509,2004.DVd组中性粒细胞减少、脱发、LVEF改变发生少,但HFS/PPE较多第三十四页，共一百三十九页。ShouldWePushHarderforaCR?668ptsundergoingTotalTherapy2StringentCRassociatedwithanimproved4-yearOSandEFSHowever,nodifferenceinoutcomebetweenPRand<PRpatients,whohadvirtuallysuperimposablesurvivalcurvesTricot,Getal.ASHAbstract936,2004.第三十五页，共一百三十九页。我们是否应更努力去取得CR?668例病人接受TotalTherapy2方案治疗以严格的CR判定标准，取得了更好的4年总生存率及无事件生存率但是，PR与<PR间结果无差异，其生存曲线令人意外Tricot,Getal.ASHAbstract936,2004.第三十六页，共一百三十九页。

CombinationTherapywithLenalidomidePlusDexamethasone(Rev/Dex)forNewlyDiagnosedMyelomaS.VincentRajkumar,SuzanneHayman,MarthaQ.Lacy,AngelaDispenzieri,SusanM.Geyer,BrianKabat,StevenR.Zeldenrust,ShajiKumar,PhilipR.Greipp,RafaelFonseca,JohnA.Lust,StephenJ.Russell,RobertA.Kyle,ThomasE.Witzig,MorieA.Gertz

DivisionofHematology,MayoClinic,Rochester,MN,USA;DivisionofBiostatistics,MayoClinic,Rochester,MN,USA;DivisionofHematology/Oncology,MayoClinic,Scottsdale,AZ,USAAbstract781

第三十七页，共一百三十九页。Lenalidomide联合地塞米松(Rev/Dex)治疗新诊断的骨髓瘤S.VincentRajkumar,SuzanneHayman,MarthaQ.Lacy,AngelaDispenzieri,SusanM.Geyer,BrianKabat,StevenR.Zeldenrust,ShajiKumar,PhilipR.Greipp,RafaelFonseca,JohnA.Lust,StephenJ.Russell,RobertA.Kyle,ThomasE.Witzig,MorieA.Gertz

DivisionofHematology,MayoClinic,Rochester,MN,USA;DivisionofBiostatistics,MayoClinic,Rochester,MN,USA;DivisionofHematology/Oncology,MayoClinic,Scottsdale,AZ,USA摘要781

第三十八页，共一百三十九页。StudyDesignStudyof“Rev/dex”regimenin34previouslyuntreatedpatientsPhaseII,prospectivetrialdesignLenalidomide:25mgpodays1-21q28Dexamethasone40mgpodays1-4,9-12,and17-20Aspirin(80or325mg)dailyforDVTprophylaxisRajkumar,SVetal.Blood106:4050,2005.第三十九页，共一百三十九页。研究设计34例初治患者接受“Rev/dex”

方案治疗临床II期、前瞻性研究设计Lenalidomide:25mgpodays1-21q28

地塞米松40mgpodays1-4,9-12,17-20阿司匹林(每日80or325mg)，预防深部静脉血栓形成(DVT)Rajkumar,SVetal.Blood106:4050,2005.第四十页，共一百三十九页。ResponsesResponseratewas91%(31/34),definedaspatientswith≥50%serumM-proteinreductionand≥90%urineM-proteinCRratewas6%(2/34)Another32%(11/34)achievedvgPR/nCR53%(18/34)hadaPRAmongpatientswhodidnotachievearesponse,2hadMRand1hadSDStemcellscouldbecollectedsuccessfully第四十一页，共一百三十九页。疗效缓解率91%(31/34)，定义为患者血浆M-蛋白减少≥50%，及尿M-蛋白减少≥90%完全缓解率-CR

6%(2/34)另外32%(11/34)获得vgPR/nCR53%(18/34)部分缓解未缓解者中，2例MR，1例SD可成功采集干细胞第四十二页，共一百三十九页。ToxicitiesHematologictoxicity,%G1/2G3/4Thrombocytopenia270Neutropenia3212Lymphopenia156Non-hematologictoxicity,%G1/2G3Fatigue4115Muscleweakness296Neuropathy210Pneumonitis36Rash66Anxiety156第四十三页，共一百三十九页。毒性反应血液学毒性,%G1/2G3/4血小板减少270中性粒细胞减少3212淋巴细胞减少156非血液学毒性,%G1/2G3疲乏4115肌无力296神经病变210肺炎36皮疹66焦虑156第四十四页，共一百三十九页。PADRegimenDayBortezomib1.3mg/m2

14815

18Cycle11121Dex40mgDox0,4.5,or9mg/m2

Bortezomib1.3mg/m2

14815

18Cycles2–4

1121Dex40mgDox0,4.5,or9mg/m2NewlydiagnosedptsbeforestemcelltransplantEvaluateresponserates,toxicity,andstemcellharvestandsubsequenttransplantationOakervee,HEetal.Br.J.Haematol.129:755,2005.第四十五页，共一百三十九页。PAD方案天万珂1.3mg/m2

14815

18第1周期1121地塞米松40mg阿霉素0,4.5,or9mg/m2

万珂1.3mg/m2

14815

18第2–4周期

1121地塞米松40mg阿霉素0,4.5,or9mg/m2干细胞移植前的初治患者评价疗效、毒性反应，干细胞采集、及后续移植治疗Oakervee,HEetal.Br.J.Haematol.129:755,2005.第四十六页，共一百三十九页。OutcomesData95%CR+PRrateafterPADinductiontherapyalone(20/21)CR+near-CRrate24%20/21patientsweremobilizedsuccessfully18/20transplantedCR+near-CRroseto57%

MyelomaProtein(g/L)0102030405060708090Pre-Rx#1#2#3#4TreatmentCycleOakervee,HEetal.Br.J.Haematol.129:755,2005.第四十七页，共一百三十九页。疗效结果单用PAD诱导治疗后,CR+PR95%(20/21)CR+nCR24%20/21例干细胞动员成功18/20进行了移植CR+nCR提高到57%

M蛋白(g/L)0102030405060708090Pre-Rx#1#2#3#4治疗周期Oakervee,HEetal.Br.J.Haematol.129:755,2005.第四十八页，共一百三十九页。ToxicitiesDiscontinuationsoccurredduetoposturalhypotensionandneuropathyDrug-relatedSAEsincludedposturalhypotension,shingles,nausea/vomiting,andperipheralneuropathySensoryneuropathyin48%(5%grade3)Painfulneuropathyin48%(grade3in5%)AllimprovedafterthecompletionoftherapyOakervee,HEetal.Br.J.Haematol.129:755,2005.第四十九页，共一百三十九页。毒性反应因体位性低血压及神经毒性出现停药药物相关的SAEs包括体位性低血压，带状疱疹，恶心/呕吐，及周围神经病变感觉神经病变48%(5%为3级)神经病变伴疼痛48%(3级为5%)所以病例在治疗结束后有改善Oakervee,HEetal.Br.J.Haematol.129:755,2005.第五十页，共一百三十九页。

ReducedDosePADCombinationTherapy(PS-341/Bortezomib,AdriamycinandDexamethasone)forPreviouslyUntreatedPatientswithMultipleMyeloma

RakeshPopat,HeatherE.Oakervee,NicolaCurry,NicolaFoot,CurlyMorris,MaryDrake,SamirAgrawal,PatriciaSmith,DavidSchenkein,Dixie-LeeEsseltine,JamieD.Cavenagh

Haematology,St.Bartholomew'sHospital,London,UnitedKingdom;Haematology,BelfastCityHospital,Belfast,UnitedKingdom;MillenniumPharmaceuticals,Cambridge,MA,USAAbstract2554

第五十一页，共一百三十九页。减量PAD联合方案（PS-341/硼替佐米,阿霉素和地塞米松）治疗初治的多发性骨髓瘤

RakeshPopat,HeatherE.Oakervee,NicolaCurry,NicolaFoot,CurlyMorris,MaryDrake,SamirAgrawal,PatriciaSmith,DavidSchenkein,Dixie-LeeEsseltine,JamieD.Cavenagh

Haematology,St.Bartholomew'sHospital,London,UnitedKingdom;Haematology,BelfastCityHospital,Belfast,UnitedKingdom;MillenniumPharmaceuticals,Cambridge,MA,USAAbstract2554

第五十二页，共一百三十九页。Toxicities9%sensoryand9%painfulneuropathy;allgrade1-21discon-tinuationMRSA第五十三页，共一百三十九页。毒性反应9%感觉性、9%痛性周围神经病变;所有均为1-2级1退出治疗MRSA（甲氧西林耐药金黄色葡萄球菌）第五十四页，共一百三十九页。ResponsesExcellentresponserateStemcellsmobilizationnotimpactedbyPADImprovedtoxicityprofilecomparedwithhigherdosePADResponseFollowingPADn=19FollowingPBSCTn=13CR2(11)6(46)nCR1(5)1(8)CR+nCR3(16%)7(54%)VGPR5(26)1(8)PR9(47)5(38)CR+PR89%100%第五十五页，共一百三十九页。疗效出色的缓解率PAD不影响干细胞动员与高剂量PAD方案相比，毒性反应降低疗效PAD后n=19PBSCT后n=13CR2(11)6(46)nCR1(5)1(8)CR+nCR3(16%)7(54%)VGPR5(26)1(8)PR9(47)5(38)CR+PR89%100%第五十六页，共一百三十九页。ConclusionsNewinductionregimensareemergingthathavetheabilitytoinduceoverallresponseratesof90%ormore,withmoreCRsPatientsareabletohavestemcellscollectedandmoveontotransplantationsafelyAdditionalstudieswillbeneededtoidentifytheoptimalregimen(s)第五十七页，共一百三十九页。结论新的诱导方案正在出现，能达到90％以上的总缓解率，其中有更多的CRs能进行干细胞采集，并安全地进行移植需要进行更多的研究以发现最佳方案第五十八页，共一百三十九页。OutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsPatientswithouttransplantasanoptionNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithms第五十九页，共一百三十九页。内容大纲诊断，分期，及风险评估初治骨髓瘤病人的初始治疗不能进行移植的病人复发和/或难治性病人的新选择当前骨髓瘤治疗法则的代表性病例分析第六十页，共一百三十九页。

APhaseI/IINational,Multi-Center,Open-LabelStudyofBortezomibPlusMelphalanandPrednisone(V-MP)inElderlyUntreatedMultipleMyeloma(MM)PatientsM.V.Mateos,M.Hernández,J.DíazMediavilla,L.Palomera,M.J.Moro,J.Hernández,J.J.Lahuerta,J.DelaRubia,M.J.Terol,A.Sureda,J.Bargay,F.Arriba,A.Alegre,P.Rivas,J.García-Laraña,J.M.Ribera,D.Carrera,J.Bladé,F.Prósper,D.L.Esseltine,H.vandeVelde,D.Schenkein,J.F.SanMiguel

GrupoEspañoldeMM,GEM/PETHEMA,Spain;MilenniumPharmaceuticals,INC,Cambridge,MA,USA;JohnsonandJohnsonPharmaceuticalResearchandDevelopment,Beerse,BelgiumAbstract786第六十一页，共一百三十九页。

万珂联合美法兰、强的松(V-MP)

用于老年初治的多发性骨髓瘤患者(MM)的I/II期全国、多中心、开放性的研究

M.V.Mateos,M.Hernández,J.DíazMediavilla,L.Palomera,M.J.Moro,J.Hernández,J.J.Lahuerta,J.DelaRubia,M.J.Terol,A.Sureda,J.Bargay,F.Arriba,A.Alegre,P.Rivas,J.García-Laraña,J.M.Ribera,D.Carrera,J.Bladé,F.Prósper,D.L.Esseltine,H.vandeVelde,D.Schenkein,J.F.SanMiguel

GrupoEspañoldeMM,GEM/PETHEMA,Spain;MilenniumPharmaceuticals,INC,Cambridge,MA,USA;JohnsonandJohnsonPharmaceuticalResearchandDevelopment,Beerse,BelgiumAbstract786第六十二页，共一百三十九页。StudyDesignPhaseI/IIstudyPatientswithmyeloma≥65yearsofageFourcyclesof6weekseachMPdays1-4Bortezomibdays1,4,8,11,22,25,29,32Fivecyclesof5weekseachMPdays1-4Bortezomibdays1,8,15,22第六十三页，共一百三十九页。研究设计临床I/II期研究≥65岁骨髓瘤病人

每周期6周，共4个周期MP 第1-4天万珂 第1,4,8,11,22,25,29,32天每周期5周，共5个周期MP 第1-4天万珂 第1,8,15,22天第六十四页，共一百三十九页。ToxicitiesGrade3/4EventsIncidence(N=60)Thrombocytopenia52%Neutropenia43%Infection17%Diarrhea17%Anemia10%EventscomparabletoothermyelomaregimensEvent-freesurvival85%6deathsBortezomibdosereductionsin35%Neuropathy第六十五页，共一百三十九页。毒性反应3/4级发生率(N=60)血小板减少52%中性粒细胞减少43%感染17%腹泻17%贫血10%与其他骨髓瘤方案相似无事件生存率85%6例死亡35%的患者降低了万珂的剂量神经病变第六十六页，共一百三十九页。Responses86%ofpatientsrespondedHighproportionofCR/IFX-Responsenotinfluencedbydel13orIgHPhaseIIItrialplanned第六十七页，共一百三十九页。疗效缓解率86%CR/IFX-比例高疗效不受del13或IgH的影响计划进行临床III期研究第六十八页，共一百三十九页。

MajorSuperiorityofMelphalan–Prednisone(MP)+Thalidomide(THAL)overMPandAutologousStemCellTransplantationintheTreatmentofNewlyDiagnosedElderlyPatientswithMultipleMyelomaThierryFacon,J.Y.Mary,C.Hulin,L.Benboubker,M.Attal,M.Renaud,J.L.Harousseau,B.Pegourie,G.Guillerm,C.Chaleteix,M.Dib,L.Voillat,H.Maisonneuve,J.Troncy,V.Dorvaux,M.Monconduit,C.Martin,P.Casassus,J.Jaubert,H.Jardel,B.Kolb,F.BautersCHU,LILLE,OnBehalfoftheIntergroupeFrancophoneduMyelome,FranceAbstract780

第六十九页，共一百三十九页。美法兰-强的松(MP)+沙利度胺(THAL)

治疗初治的高年多发性骨髓瘤患者

优于美法兰-强的松(MP)和自体干细胞移植ThierryFacon,J.Y.Mary,C.Hulin,L.Benboubker,M.Attal,M.Renaud,J.L.Harousseau,B.Pegourie,G.Guillerm,C.Chaleteix,M.Dib,L.Voillat,H.Maisonneuve,J.Troncy,V.Dorvaux,M.Monconduit,C.Martin,P.Casassus,J.Jaubert,H.Jardel,B.Kolb,F.BautersCHU,LILLE,OnBehalfoftheIntergroupeFrancophoneduMyelome,FranceAbstract780

第七十页，共一百三十九页。StudyDesign1Clodronatewasgiventoallpatients.StandardMP1

12coursesat6-weekintervalsn=191MP+T1MPasabove+Thalupto400mgqdn=124Mel100mg/m2x21VADx2;Cy3g/m2+G-CSFn=121Untreated,stageI-IIIpatientsage65-75(N=436)第七十一页，共一百三十九页。研究设计1Clodronatewasgiventoallpatients.标准的MP1

12疗程，6周间隔n=191MP+T1MP同上+沙利度胺，至400mgqdn=124

Mel100mg/m2x21VADx2;Cy3g/m2+G-CSFn=121初治,临床I-III期研究、年龄65-75岁(N=436)第七十二页，共一百三十九页。AResponseEdgeforMPTMPn=124MPTn=191Mel100n=1211CR(%)21517≥vgPR(%)74941≥PR(%)408172DVT13%inMPT(vs.5and6.5%)36%onMPThadPN1Only63%ofpatientsunderwentthesecondtransplant.第七十三页，共一百三十九页。MPT的疗效MPn=124MPTn=191Mel100n=1211CR(%)21517≥vgPR(%)74941≥PR(%)408172MPT组DVT发生率13%(5、6.5%)36%MPT出现PN1仅63%的患者接受第2次移植第七十四页，共一百三十九页。MajorBenefitsinOSandPFSLongermedianoverallsurvivalwithMPTMPTvs.MP:NR@56vs.30.3mos.±5.8P=0.0008MPTvs.Mel100:NR@56vs38.6±3.0P=0.014LongermedianprogressionfreesurvivalMPTvs.MP:29.5±3.6vs.17.2mos.±1.5MPTvs.Mel100:29.5±3.6vs.19.0mos.±1.3第七十五页，共一百三十九页。OS、PFS的临床获益MPT总体生存时间更长MPTvs.MP:NR@56vs.30.3月±5.8P=0.0008MPTvs.Mel100:NR@56vs38.6±3.0P=0.014无进展生存时间更长MPTvs.MP:29.5±3.6vs.17.2月±1.5MPTvs.Mel100:29.5±3.6vs.19.0月±1.3第七十六页，共一百三十九页。Toxicities30%onMPTalsohadneuropathyDeathduetoinfectionssimilar(2%,2%,4%)MPn=124MPTn=191Mel100n=121Severeinfection111739Neutropenia3241100DVT5126.5第七十七页，共一百三十九页。毒性反应MPT组30%出现神经病变由于感染引起的死亡相似(2%,2%,4%)MPn=124MPTn=191Mel100n=121严重的感染111739中性粒细胞减少症3241100DVT5126.5第七十八页，共一百三十九页。ConclusionsMPmaynolongerbethestandardofcareforallolderpatientswithmultiplemyelomaMPVand

MPThavehigheroverallandcompleteresponseratesOtherregimens(ThaDD)arealsoeffectiveMPThasasurvivaladvantageoverMPMPRmaybebettertoleratedthanMPTAdditionalstudiesareneeded第七十九页，共一百三十九页。结论MP方案可能不再是高龄骨髓瘤病人的标准治疗MPV,MPT可取得更高的总缓解率和完全缓解率其他方案(ThaDD)也显示疗效MPT与MP相比显示了生存优势需要进行进一步的临床研究第八十页，共一百三十九页。OutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithms第八十一页，共一百三十九页。内容大纲诊断，分期，及风险评估初治骨髓瘤病人的初始治疗复发和/或难治性病人的新选择当前骨髓瘤治疗法则的代表性病例分析第八十二页，共一百三十九页。StudyofLenalidomidePlusDexamethasoneVersusDexamethasoneAloneinRelapsedorRefractoryMultipleMyeloma(MM):ResultsofaPhase3Study(MM-010)MeletiosA.Dimopoulos,AndrewSpencer,MichaelAttal,MilesPrince,Jean-LucHarousseau,AnnaDmoszynska,ZhinuanYu,MartaOlesnyckyj,JeromeZeldisRobertKnightUniversityGeneralAlexandrasHospital,Athens,Greece;TheAlfredHospital,Prahran,Victoria,Australia;HopitalPurpan,Toulouse,France;DepartmentofHematology&MedicalOncology,PeterMacCallumCancerInstitute,EastMelbourne,Victoria,Australia;CentreHospitalierHotel-Dieu,Nantes,France;HematologyDepartment,UniversitySchoolofMedicine,Lublin,Poland;CelgeneCorporation,Summit,NJ,USAAbstract6

第八十三页，共一百三十九页。复发性或难治性多发性骨髓瘤

Lenalidomide联合地塞米松与地塞米松单药

治疗的对比研究:临床III期研究结果(MM-010)MeletiosA.Dimopoulos,AndrewSpencer,MichaelAttal,MilesPrince,Jean-LucHarousseau,AnnaDmoszynska,ZhinuanYu,MartaOlesnyckyj,JeromeZeldisRobertKnightUniversityGeneralAlexandrasHospital,Athens,Greece;TheAlfredHospital,Prahran,Victoria,Australia;HopitalPurpan,Toulouse,France;DepartmentofHematology&MedicalOncology,PeterMacCallumCancerInstitute,EastMelbourne,Victoria,Australia;CentreHospitalierHotel-Dieu,Nantes,France;HematologyDepartment,UniversitySchoolofMedicine,Lublin,Poland;CelgeneCorporation,Summit,NJ,USAAbstract6

第八十四页，共一百三十九页。PhaseIIIStudyDesignRANDOMIZATIONPlacebo4+Dexamethasone2Lenalidomide1+Dexamethasone2orPlacebo31Len:25mgpoqdondays1-21every28days.2Dex40mgpoqdondays1-4,9-12,and17-20every28days.3Placeboqdondays21-28ofeach28daycycle.4Placeboqdondays1-28every28days.x4cycles,laterDexonlydays1-4第八十五页，共一百三十九页。临床III期研究的设计随机化安慰剂4+地塞米松2Lenalidomide1+地塞米松2或安慰剂31Len:25mgpoqdondays1-21every28days.2Dex40mgpoqdondays1-4,9-12,and17-20every28days.3Placeboqdondays21-28ofeach28daycycle.4Placeboqdondays1-28every28days.x4周期，随后接受Dex，第1-4天第八十六页，共一百三十九页。EuropeanResults351ptsrandomized176forlen/dex175fordex/placeboRelapsedorrefractorywith>1priortreatmentLen/dexhadabetteroverallRR&CRrate第八十七页，共一百三十九页。欧洲结果351名患者随机入组len/dex176例dex/安慰剂175例复发或难治、之前的治疗>1次Len/dex总RR&CR率更高第八十八页，共一百三十九页。TimetoProgressionTimetoProgression(months)ProportionofPatients2.557.51012.51517.52022.500.20.40.60.81.0Len/Dex13.3mos.Dexalone5.1mos.P<0.000001009009010010第八十九页，共一百三十九页。进展时间疾病进展时间(月)患者百分数2.557.51012.51517.52022.500.20.40.60.81.0Len/Dex13.3月Dex单药5.1月P<0.000001009009010010第九十页，共一百三十九页。ToxicitiesLen/dexdgrade3/4neutropenia16.5%vs.1.2%fordexMosteventsgrade1or2Grade3/4infectionsweresimilarGrade3/4thrombocytopeniad27%vs.2%DVT/PEriskdProphylactica-coagulationNorthAmericanstudyDVT/PEriskhigher:15.3%vs.3.5%第九十一页，共一百三十九页。毒性反应Len/dexd，3-4级中性粒细胞减少症16.5%vs.1.2%地塞米松多数不良反应1–2级3-4级感染2组类似3-4级血小板减少症

d27%vs.2%DVT/PE风险

d预防血液凝集北美研究DVT/PE风险增加:15.3%vs.3.5%第九十二页，共一百三十九页。BortezomibContinuestoDemonstrateSuperiorEfficacyComparedwithHigh-DoseDexamethasoneinRelapsedMultipleMyeloma:UpdatedResultsoftheAPEXTrial

PaulRichardson,P.Sonneveld,M.Schuster,D.Irwin,E.Stadtmauer,T.Facon,J.Harousseau,D.Ben-Yehuda,S.Lonial,H.Goldschmidt,D.Reece,J.SanMiguel,J.Blade,M.Boccadoro,J.Cavenagh,W.Dalton,A.Boral,D.Schenkein,K.Anderson

Dana-FarberCancerInst;UnivHospRotterdam,Netherlands;NY-PresbyterianHosp;AltaBatesCancerCtr;UnivPACancerCtr;HospClaudeHuriez,France;HotelDieuHosp,France;HadassahUnivHosp,Israel;EmoryUniv;UnivHeidelberg,Germany;PrincessMargaretHosp,Canada;HospUnivSalamanca,Spain;UnivBarcelona,Spain;UnivTorino,Italy;St.Bartholomew'sHosp,UnitedKingdom;H.LeeMoffittCancerCtr;MillenniumPharmaceuticals,IncAbstract2547第九十三页，共一百三十九页。APEX的最新进展：复发性骨髓瘤患者

与高剂量地塞米松相比，

硼替佐米持续表现卓越的疗效

PaulRichardson,P.Sonneveld,M.Schuster,D.Irwin,E.Stadtmauer,T.Facon,J.Harousseau,D.Ben-Yehuda,S.Lonial,H.Goldschmidt,D.Reece,J.SanMiguel,J.Blade,M.Boccadoro,J.Cavenagh,W.Dalton,A.Boral,D.Schenkein,K.Anderson

Dana-FarberCancerInst;UnivHospRotterdam,Netherlands;NY-PresbyterianHosp;AltaBatesCancerCtr;UnivPACancerCtr;HospClaudeHuriez,France;HotelDieuHosp,France;HadassahUnivHosp,Israel;EmoryUniv;UnivHeidelberg,Germany;PrincessMargaretHosp,Canada;HospUnivSalamanca,Spain;UnivBarcelona,Spain;