多發(fā)性骨髓瘤研究進(jìn)展和治療選擇演示文稿

多發(fā)性骨髓瘤研究進(jìn)展和治療選擇演示文稿目前一頁\總數(shù)一百三十九頁\編于六點(diǎn)優(yōu)選多發(fā)性骨髓瘤研究進(jìn)展和治療選擇目前二頁\總數(shù)一百三十九頁\編于六點(diǎn)OutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithms目前三頁\總數(shù)一百三十九頁\編于六點(diǎn)內(nèi)容大綱診斷，分期，及風(fēng)險(xiǎn)評估初治骨髓瘤病人的初始治療復(fù)發(fā)和/或難治性病人的新選擇當(dāng)前骨髓瘤治療法則的代表性病例分析目前四頁\總數(shù)一百三十九頁\編于六點(diǎn)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目前五頁\總數(shù)一百三十九頁\編于六點(diǎn)診斷標(biāo)準(zhǔn)主要標(biāo)準(zhǔn)1.組織活檢證實(shí)有漿細(xì)胞瘤2.骨髓漿細(xì)胞增多>30%3.過量血清M蛋白>3.5g/dLIgG2.0g/dLIgA尿中k

或l輕鏈1.0g/24小時(shí)次要標(biāo)準(zhǔn)A.骨髓漿細(xì)胞增多10-30%B.M蛋白未達(dá)主要標(biāo)準(zhǔn)的第3項(xiàng)C.溶骨性病變D.正常Igs降低IgM<500mg/dLIgA<1g/dLIgG<6g/dL目前六頁\總數(shù)一百三十九頁\編于六點(diǎn)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目前七頁\總數(shù)一百三十九頁\編于六點(diǎn)確診條件2個(gè)主要標(biāo)準(zhǔn)1個(gè)主要+1個(gè)次要標(biāo)準(zhǔn)1+B,1+C,1+D2+B,2+C,2+D3+A,3+C,3+D包含A及B的三個(gè)次要標(biāo)準(zhǔn)A+B+C,A+B+D1Clusterofplasmacellsinthebonemarrow.Bataille,RandHarousseau,JL.N.Engl.J.Med.336:1657,1997.1目前八頁\總數(shù)一百三十九頁\編于六點(diǎn)ProblemswithThisMethodCriteriaarecumbersomeDifficulttouseforpatientsandphysiciansTheboundariesarearbitrary31%marrowplasmacytosisisamajorcriterionwhile29%isn’t,butarethesereallydifferent?Somepatientsmay“fallthroughthecracks”Apatientwithmultiplepainfullyticlesionsmaynotmeetcriteria,butneedssystemictherapy40%ofsymptomaticpatientshaveanM-proteinof<30g/L,and5%have<10%marrowinvolvement目前九頁\總數(shù)一百三十九頁\編于六點(diǎn)這項(xiàng)標(biāo)準(zhǔn)存在的問題判定標(biāo)準(zhǔn)煩瑣不方便病人及醫(yī)生使用界線設(shè)定獨(dú)斷31%骨髓漿細(xì)胞增多為主要標(biāo)準(zhǔn)而29%則不是,但兩者是否存在差異?部分病人可能處于“夾縫狀態(tài)”某些有多發(fā)性痛性溶骨病變的病人可能沒有達(dá)到判定標(biāo)準(zhǔn)，但需要系統(tǒng)性治療40%有癥狀的病人表現(xiàn)為M蛋白<30g/L,并且5%表現(xiàn)為<10%骨髓侵潤目前十頁\總數(shù)一百三十九頁\編于六點(diǎn)MGUSInternationalMyelomaWorkingGroupcriteriaM-proteininserum<3.0g/dLClonalbonemarrowplasmacytosisof<10%,andalowlevelofplasmacellinfiltrationinamarrowbiopsy,ifthiswasdoneNootherB-cellproliferativedisorderNoendorgandamage,includingbonelesionsKyle,RAetal.Br.J.Haematol.121:749,2003.目前十一頁\總數(shù)一百三十九頁\編于六點(diǎn)MGUS國際骨髓瘤工作組判定標(biāo)準(zhǔn)血清M蛋白<3.0g/dL骨髓漿細(xì)胞增多<10%；并且如進(jìn)行骨髓活檢，可見漿細(xì)胞侵潤程度低無其它B細(xì)胞增殖異常無終末器官損傷（包括骨病變）Kyle,RAetal.Br.J.Haematol.121:749,2003.目前十二頁\總數(shù)一百三十九頁\編于六點(diǎn)AsymptomaticMultipleMyelomaPreviously“smo(u)lderingmyeloma”SerumM-protein≥3.0g/dLand/orClonalmarrowplasmacytosis≥10%Norelatedorganortissueimpairment(noendorgandamage,includingbonelesions)orsymptomsKyle,RAetal.Br.J.Haematol.121:749,2003.目前十三頁\總數(shù)一百三十九頁\編于六點(diǎn)無癥狀多發(fā)性骨髓瘤以前的“冒煙型骨髓瘤”血清M蛋白≥3.0g/dL和/或骨髓漿細(xì)胞增多≥10%無相關(guān)器官或組織損傷（無終末器官損傷，包括骨病變)或癥狀Kyle,RAetal.Br.J.Haematol.121:749,2003.目前十四頁\總數(shù)一百三十九頁\編于六點(diǎn)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.目前十五頁\總數(shù)一百三十九頁\編于六點(diǎn)有癥狀多發(fā)性骨髓瘤血清和/或尿中有M蛋白骨髓漿細(xì)胞增多或漿細(xì)胞瘤通常以10%為標(biāo)準(zhǔn)相關(guān)器官或組織損傷貧血(<10g/dL,或低于正常值下限2g/dL)骨病變(溶骨性病變,或骨質(zhì)疏松伴壓縮骨折)高鈣血癥(>2.75mmol/L,或高于正常值上限>0.25mmol/L)腎功能不全(肌酐>173mmol/L)其他(高粘血癥,淀粉樣變,反復(fù)細(xì)菌感染[>2次/12個(gè)月])Kyle,RAetal.Br.J.Haematol.121:749,2003.目前十六頁\總數(shù)一百三十九頁\編于六點(diǎn)Durie-SalmonStagingSystemSeveralfactorsareincludedinthestaging1HemoglobinRenalfunctionSerumcalciumM-proteinproductionBonylesionsand/orpresenceofaplasmacytomaDrawbacksManyfactorsmakeitcumbersometoapplyDoesnotusenew,powerfulprognostictoolsInternationalMyelomaWorkingGroupstudied11,171patients2Multivariateanalysisfoundonlyb2-microglobulinandalbuminasprognosticfactors1Durie,BGMandSalmon,SE.Cancer36:842,1975.2Greipp,PRetal.Blood102:190a,Abstract664,2003.目前十七頁\總數(shù)一百三十九頁\編于六點(diǎn)Durie-Salmon分期系統(tǒng)本分期系統(tǒng)中包括下列指標(biāo)1血紅蛋白腎功能血清鈣M蛋白骨病變和/或有漿細(xì)胞瘤缺點(diǎn)指標(biāo)太多不方便使用沒有包括新的、有力的預(yù)后工具國際骨髓瘤工作組研究了11,171例病人2多變量分析發(fā)現(xiàn)，只有b2微球蛋白及白蛋白是預(yù)后因子1Durie,BGMandSalmon,SE.Cancer36:842,1975.2Greipp,PRetal.Blood102:190a,Abstract664,2003.目前十八頁\總數(shù)一百三十九頁\編于六點(diǎn)InternationalStagingSystemGreipp,PRetal.J.Clin.Oncol.23:3412,2005.Stageb2MAlbuminNOSI<3.5≥3.5240162mos.II<3.5≥3.5-<5.5<3.5OR327844III≥5.5277029目前十九頁\總數(shù)一百三十九頁\編于六點(diǎn)國際分期系統(tǒng)（ISS）Greipp,PRetal.J.Clin.Oncol.23:3412,2005.分期b2M白蛋白N總生存期I<3.5≥3.5240162mos.II<3.5≥3.5-<5.5<3.5或327844III≥5.5277029目前二十頁\總數(shù)一百三十九頁\編于六點(diǎn)1Greipp,PRetal.J.Clin.Oncol.23:3412,2005.ISSandPrognosisSignificantsurvivaldifferencesforthreestages(P<0.0001)BetteroutcomepredictorthanthepriorDurie-SalmonmethodStilldoesnotincorporatecytogenetics目前二十一頁\總數(shù)一百三十九頁\編于六點(diǎn)1Greipp,PRetal.J.Clin.Oncol.23:3412,2005.ISS與預(yù)后的關(guān)系三期間有顯著的生存差異(P<0.0001)與Durie-Salmon分期相比，有更好的預(yù)測結(jié)果但仍未包括細(xì)胞遺傳學(xué)指標(biāo)目前二十二頁\總數(shù)一百三十九頁\編于六點(diǎn)CytogeneticFactors:Del13Deletionofchromosome13wasthesinglemostpowerfuladverseprognosticfactorforalltimestoeventsinpatientsreferredforhigh-dosetherapyOS65.1±9.8vs26.7±4.1monthsFacon,Tetal.Blood97:1566,2001.目前二十三頁\總數(shù)一百三十九頁\編于六點(diǎn)細(xì)胞遺傳學(xué)指標(biāo):13號染色體缺失在接受高劑量化療的病人中，13號染色體缺失是單一最有效的負(fù)面預(yù)后因子，影響所有的“至事件發(fā)生時(shí)間”指標(biāo)總生存65.1±9.8vs26.7±4.1個(gè)月Facon,Tetal.Blood97:1566,2001.目前二十四頁\總數(shù)一百三十九頁\編于六點(diǎn)BortezomibandDel13APEXrandomizedpatientstobortezomibordexamethasone11/74(15%)onthebortezomibarmand13/94(14%)onthedexarmhadmetaphasedel13Del13wasassociatedwithpoorsurvivalondexarmcomparedwithcontrolsDel13wasnotassociatedwithaninferiorsurvivalonthebortezomibarmJagannath,Setal.ASCOAbstract6501,2005.目前二十五頁\總數(shù)一百三十九頁\編于六點(diǎn)萬珂與13號染色體缺失APEX將病人隨機(jī)分入萬珂組或地塞米松組萬珂組11/74(15%)、地塞米松組13/94(14%)有分裂中期13號染色體缺失地塞米松組，13號染色體缺失與更差的生存期相關(guān)（與對照相比）萬珂組，13號染色體缺失與更差的生存期無關(guān)Jagannath,Setal.ASCOAbstract6501,2005.目前二十六頁\總數(shù)一百三十九頁\編于六點(diǎn)ConclusionsStagingandprognosisismostaccuratelydeterminedusingtheISSNewprognosticfactorsareemergingthatmayhelprefinethisfurtherCytogeneticandFISHstudiescanprovideadditionalprognosticinformation,andintheverynearfuturemayguidetherapeuticdecisions目前二十七頁\總數(shù)一百三十九頁\編于六點(diǎn)結(jié)論用ISS能更好地確定分期及預(yù)后新的預(yù)后因子正在顯現(xiàn)，未來可對分期預(yù)后系統(tǒng)有進(jìn)一步的改進(jìn)細(xì)胞遺傳學(xué)及FISH研究能提供更多的預(yù)后信息，在不久的將來可能會為治療方法的確定提供指導(dǎo)目前二十八頁\總數(shù)一百三十九頁\編于六點(diǎn)OutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsPatientswithtransplantasanoptionNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithms目前二十九頁\總數(shù)一百三十九頁\編于六點(diǎn)內(nèi)容大綱診斷，分期，及風(fēng)險(xiǎn)評估初治骨髓瘤病人的初始治療能進(jìn)行移植的病人復(fù)發(fā)和/或難治性病人的新選擇當(dāng)前骨髓瘤治療法則的代表性病例分析目前三十頁\總數(shù)一百三十九頁\編于六點(diǎn)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.目前三十一頁\總數(shù)一百三十九頁\編于六點(diǎn)沙立度胺+地塞米松Thal/dex

優(yōu)于dex(p=0.002)1中位至緩解時(shí)間均為1.1個(gè)月進(jìn)展3%vs.5%

無進(jìn)展生存25.3

vs.17.3

個(gè)月可成功采集干細(xì)胞1Bestresponsewasevaluatedwithin4cycles.200mgpoqd.PRwas≥50%serum&urineM-proteinreduction,or≥90%urineM-reductionifonlyurinewasinvolved.RajkumarSVetal.J.Clin.Oncol.24:431,2006.目前三十二頁\總數(shù)一百三十九頁\編于六點(diǎn)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目前三十三頁\總數(shù)一百三十九頁\編于六點(diǎn)DVdvs.VAd作為初始治療療效情況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組中性粒細(xì)胞減少、脫發(fā)、LVEF改變發(fā)生少,但HFS/PPE較多目前三十四頁\總數(shù)一百三十九頁\編于六點(diǎn)ShouldWePushHarderforaCR?668ptsundergoingTotalTherapy2StringentCRassociatedwithanimproved4-yearOSandEFSHowever,nodifferenceinoutcomebetweenPRand<PRpatients,whohadvirtuallysuperimposablesurvivalcurvesTricot,Getal.ASHAbstract936,2004.目前三十五頁\總數(shù)一百三十九頁\編于六點(diǎn)我們是否應(yīng)更努力去取得CR?668例病人接受TotalTherapy2方案治療以嚴(yán)格的CR判定標(biāo)準(zhǔn)，取得了更好的4年總生存率及無事件生存率但是，PR與<PR間結(jié)果無差異，其生存曲線令人意外Tricot,Getal.ASHAbstract936,2004.目前三十六頁\總數(shù)一百三十九頁\編于六點(diǎn)

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

目前三十七頁\總數(shù)一百三十九頁\編于六點(diǎn)Lenalidomide聯(lián)合地塞米松(Rev/Dex)治療新診斷的骨髓瘤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

目前三十八頁\總數(shù)一百三十九頁\編于六點(diǎn)StudyDesignStudyof“Rev/dex”regimenin34previouslyuntreatedpatientsPhaseII,prospectivetrialdesignLenalidomide:25mgpodays1-21q28Dexamethasone40mgpodays1-4,9-12,and17-20Aspirin(80or325mg)dailyforDVTprophylaxisRajkumar,SVetal.Blood106:4050,2005.目前三十九頁\總數(shù)一百三十九頁\編于六點(diǎn)研究設(shè)計(jì)34例初治患者接受“Rev/dex”

方案治療臨床II期、前瞻性研究設(shè)計(jì)Lenalidomide:25mgpodays1-21q28

地塞米松40mgpodays1-4,9-12,17-20阿司匹林(每日80or325mg)，預(yù)防深部靜脈血栓形成(DVT)Rajkumar,SVetal.Blood106:4050,2005.目前四十頁\總數(shù)一百三十九頁\編于六點(diǎn)ResponsesResponseratewas91%(31/34),definedaspatientswith≥50%serumM-proteinreductionand≥90%urineM-proteinCRratewas6%(2/34)Another32%(11/34)achievedvgPR/nCR53%(18/34)hadaPRAmongpatientswhodidnotachievearesponse,2hadMRand1hadSDStemcellscouldbecollectedsuccessfully目前四十一頁\總數(shù)一百三十九頁\編于六點(diǎn)療效緩解率91%(31/34)，定義為患者血漿M-蛋白減少≥50%，及尿M-蛋白減少≥90%完全緩解率-CR

6%(2/34)另外32%(11/34)獲得vgPR/nCR53%(18/34)部分緩解未緩解者中，2例MR，1例SD可成功采集干細(xì)胞目前四十二頁\總數(shù)一百三十九頁\編于六點(diǎn)ToxicitiesHematologictoxicity,%G1/2G3/4Thrombocytopenia270Neutropenia3212Lymphopenia156Non-hematologictoxicity,%G1/2G3Fatigue4115Muscleweakness296Neuropathy210Pneumonitis36Rash66Anxiety156目前四十三頁\總數(shù)一百三十九頁\編于六點(diǎn)毒性反應(yīng)血液學(xué)毒性,%G1/2G3/4血小板減少270中性粒細(xì)胞減少3212淋巴細(xì)胞減少156非血液學(xué)毒性,%G1/2G3疲乏4115肌無力296神經(jīng)病變210肺炎36皮疹66焦慮156目前四十四頁\總數(shù)一百三十九頁\編于六點(diǎn)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.目前四十五頁\總數(shù)一百三十九頁\編于六點(diǎn)PAD方案天萬珂1.3mg/m2

14815

18第1周期1121地塞米松40mg阿霉素0,4.5,or9mg/m2

萬珂1.3mg/m2

14815

18第2–4周期

1121地塞米松40mg阿霉素0,4.5,or9mg/m2干細(xì)胞移植前的初治患者評價(jià)療效、毒性反應(yīng)，干細(xì)胞采集、及后續(xù)移植治療Oakervee,HEetal.Br.J.Haematol.129:755,2005.目前四十六頁\總數(shù)一百三十九頁\編于六點(diǎn)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.目前四十七頁\總數(shù)一百三十九頁\編于六點(diǎn)療效結(jié)果單用PAD誘導(dǎo)治療后,CR+PR95%(20/21)CR+nCR24%20/21例干細(xì)胞動員成功18/20進(jìn)行了移植CR+nCR提高到57%

M蛋白(g/L)0102030405060708090Pre-Rx#1#2#3#4治療周期Oakervee,HEetal.Br.J.Haematol.129:755,2005.目前四十八頁\總數(shù)一百三十九頁\編于六點(diǎn)ToxicitiesDiscontinuationsoccurredduetoposturalhypotensionandneuropathyDrug-relatedSAEsincludedposturalhypotension,shingles,nausea/vomiting,andperipheralneuropathySensoryneuropathyin48%(5%grade3)Painfulneuropathyin48%(grade3in5%)AllimprovedafterthecompletionoftherapyOakervee,HEetal.Br.J.Haematol.129:755,2005.目前四十九頁\總數(shù)一百三十九頁\編于六點(diǎn)毒性反應(yīng)因體位性低血壓及神經(jīng)毒性出現(xiàn)停藥藥物相關(guān)的SAEs包括體位性低血壓，帶狀皰疹，惡心/嘔吐，及周圍神經(jīng)病變感覺神經(jīng)病變48%(5%為3級)神經(jīng)病變伴疼痛48%(3級為5%)所以病例在治療結(jié)束后有改善Oakervee,HEetal.Br.J.Haematol.129:755,2005.目前五十頁\總數(shù)一百三十九頁\編于六點(diǎn)

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

目前五十一頁\總數(shù)一百三十九頁\編于六點(diǎn)減量PAD聯(lián)合方案（PS-341/硼替佐米,阿霉素和地塞米松）治療初治的多發(fā)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

目前五十二頁\總數(shù)一百三十九頁\編于六點(diǎn)Toxicities9%sensoryand9%painfulneuropathy;allgrade1-21discon-tinuationMRSA目前五十三頁\總數(shù)一百三十九頁\編于六點(diǎn)毒性反應(yīng)9%感覺性、9%痛性周圍神經(jīng)病變;所有均為1-2級1退出治療MRSA（甲氧西林耐藥金黃色葡萄球菌）目前五十四頁\總數(shù)一百三十九頁\編于六點(diǎn)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%目前五十五頁\總數(shù)一百三十九頁\編于六點(diǎn)療效出色的緩解率PAD不影響干細(xì)胞動員與高劑量PAD方案相比，毒性反應(yīng)降低療效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%目前五十六頁\總數(shù)一百三十九頁\編于六點(diǎn)ConclusionsNewinductionregimensareemergingthathavetheabilitytoinduceoverallresponseratesof90%ormore,withmoreCRsPatientsareabletohavestemcellscollectedandmoveontotransplantationsafelyAdditionalstudieswillbeneededtoidentifytheoptimalregimen(s)目前五十七頁\總數(shù)一百三十九頁\編于六點(diǎn)結(jié)論新的誘導(dǎo)方案正在出現(xiàn)，能達(dá)到90％以上的總緩解率，其中有更多的CRs能進(jìn)行干細(xì)胞采集，并安全地進(jìn)行移植需要進(jìn)行更多的研究以發(fā)現(xiàn)最佳方案目前五十八頁\總數(shù)一百三十九頁\編于六點(diǎn)OutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsPatientswithouttransplantasanoptionNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithms目前五十九頁\總數(shù)一百三十九頁\編于六點(diǎn)內(nèi)容大綱診斷，分期，及風(fēng)險(xiǎn)評估初治骨髓瘤病人的初始治療不能進(jìn)行移植的病人復(fù)發(fā)和/或難治性病人的新選擇當(dāng)前骨髓瘤治療法則的代表性病例分析目前六十頁\總數(shù)一百三十九頁\編于六點(diǎn)

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-Lara?a,J.M.Ribera,D.Carrera,J.Bladé,F.Prósper,D.L.Esseltine,H.vandeVelde,D.Schenkein,J.F.SanMiguel

GrupoEspa?oldeMM,GEM/PETHEMA,Spain;MilenniumPharmaceuticals,INC,Cambridge,MA,USA;JohnsonandJohnsonPharmaceuticalResearchandDevelopment,Beerse,BelgiumAbstract786目前六十一頁\總數(shù)一百三十九頁\編于六點(diǎn)

萬珂聯(lián)合美法蘭、強(qiáng)的松(V-MP)

用于老年初治的多發(fā)性骨髓瘤患者(MM)的I/II期全國、多中心、開放性的研究

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-Lara?a,J.M.Ribera,D.Carrera,J.Bladé,F.Prósper,D.L.Esseltine,H.vandeVelde,D.Schenkein,J.F.SanMiguel

GrupoEspa?oldeMM,GEM/PETHEMA,Spain;MilenniumPharmaceuticals,INC,Cambridge,MA,USA;JohnsonandJohnsonPharmaceuticalResearchandDevelopment,Beerse,BelgiumAbstract786目前六十二頁\總數(shù)一百三十九頁\編于六點(diǎn)StudyDesignPhaseI/IIstudyPatientswithmyeloma≥65yearsofageFourcyclesof6weekseachMPdays1-4Bortezomibdays1,4,8,11,22,25,29,32Fivecyclesof5weekseachMPdays1-4Bortezomibdays1,8,15,22目前六十三頁\總數(shù)一百三十九頁\編于六點(diǎn)研究設(shè)計(jì)臨床I/II期研究≥65歲骨髓瘤病人

每周期6周，共4個(gè)周期MP 第1-4天萬珂 第1,4,8,11,22,25,29,32天每周期5周，共5個(gè)周期MP 第1-4天萬珂 第1,8,15,22天目前六十四頁\總數(shù)一百三十九頁\編于六點(diǎn)ToxicitiesGrade3/4EventsIncidence(N=60)Thrombocytopenia52%Neutropenia43%Infection17%Diarrhea17%Anemia10%EventscomparabletoothermyelomaregimensEvent-freesurvival85%6deathsBortezomibdosereductionsin35%Neuropathy目前六十五頁\總數(shù)一百三十九頁\編于六點(diǎn)毒性反應(yīng)3/4級發(fā)生率(N=60)血小板減少52%中性粒細(xì)胞減少43%感染17%腹瀉17%貧血10%與其他骨髓瘤方案相似無事件生存率85%6例死亡35%的患者降低了萬珂的劑量神經(jīng)病變目前六十六頁\總數(shù)一百三十九頁\編于六點(diǎn)Responses86%ofpatientsrespondedHighproportionofCR/IFX-Responsenotinfluencedbydel13orIgHPhaseIIItrialplanned目前六十七頁\總數(shù)一百三十九頁\編于六點(diǎn)療效緩解率86%CR/IFX-比例高療效不受del13或IgH的影響計(jì)劃進(jìn)行臨床III期研究目前六十八頁\總數(shù)一百三十九頁\編于六點(diǎn)

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

目前六十九頁\總數(shù)一百三十九頁\編于六點(diǎn)美法蘭-強(qiáng)的松(MP)+沙利度胺(THAL)

治療初治的高年多發(fā)性骨髓瘤患者

優(yōu)于美法蘭-強(qiáng)的松(MP)和自體干細(xì)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

目前七十頁\總數(shù)一百三十九頁\編于六點(diǎn)StudyDesign1Clodronatewasgiventoallpatients.StandardMP1

12coursesat6-weekintervalsn=191MP+T1MPasabove+Thalupto400mgqdn=124Mel100mg/m2x21VADx2;Cy3g/m2+G-CSFn=121Untreated,stageI-IIIpatientsage65-75(N=436)目前七十一頁\總數(shù)一百三十九頁\編于六點(diǎn)研究設(shè)計(jì)1Clodronatewasgiventoallpatients.標(biāo)準(zhǔn)的MP1

12療程，6周間隔n=191MP+T1MP同上+沙利度胺，至400mgqdn=124

Mel100mg/m2x21VADx2;Cy3g/m2+G-CSFn=121初治,臨床I-III期研究、年齡65-75歲(N=436)目前七十二頁\總數(shù)一百三十九頁\編于六點(diǎn)AResponseEdgeforMPTMPn=124MPTn=191Mel100n=1211CR(%)21517≥vgPR(%)74941≥PR(%)408172DVT13%inMPT(vs.5and6.5%)36%onMPThadPN1Only63%ofpatientsunderwentthesecondtransplant.目前七十三頁\總數(shù)一百三十九頁\編于六點(diǎn)MPT的療效MPn=124MPTn=191Mel100n=1211CR(%)21517≥vgPR(%)74941≥PR(%)408172MPT組DVT發(fā)生率13%(5、6.5%)36%MPT出現(xiàn)PN1僅63%的患者接受第2次移植目前七十四頁\總數(shù)一百三十九頁\編于六點(diǎn)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目前七十五頁\總數(shù)一百三十九頁\編于六點(diǎn)OS、PFS的臨床獲益MPT總體生存時(shí)間更長MPTvs.MP:NR@56vs.30.3月±5.8P=0.0008MPTvs.Mel100:NR@56vs38.6±3.0P=0.014無進(jìn)展生存時(shí)間更長MPTvs.MP:29.5±3.6vs.17.2月±1.5MPTvs.Mel100:29.5±3.6vs.19.0月±1.3目前七十六頁\總數(shù)一百三十九頁\編于六點(diǎn)Toxicities30%onMPTalsohadneuropathyDeathduetoinfectionssimilar(2%,2%,4%)MPn=124MPTn=191Mel100n=121Severeinfection111739Neutropenia3241100DVT5126.5目前七十七頁\總數(shù)一百三十九頁\編于六點(diǎn)毒性反應(yīng)MPT組30%出現(xiàn)神經(jīng)病變由于感染引起的死亡相似(2%,2%,4%)MPn=124MPTn=191Mel100n=121嚴(yán)重的感染111739中性粒細(xì)胞減少癥3241100DVT5126.5目前七十八頁\總數(shù)一百三十九頁\編于六點(diǎn)ConclusionsMPmaynolongerbethestandardofcareforallolderpatientswithmultiplemyelomaMPVand

MPThavehigheroverallandcompleteresponseratesOtherregimens(ThaDD)arealsoeffectiveMPThasasurvivaladvantageoverMPMPRmaybebettertoleratedthanMPTAdditionalstudiesareneeded目前七十九頁\總數(shù)一百三十九頁\編于六點(diǎn)結(jié)論MP方案可能不再是高齡骨髓瘤病人的標(biāo)準(zhǔn)治療MPV,MPT可取得更高的總緩解率和完全緩解率其他方案(ThaDD)也顯示療效MPT與MP相比顯示了生存優(yōu)勢需要進(jìn)行進(jìn)一步的臨床研究目前八十頁\總數(shù)一百三十九頁\編于六點(diǎn)OutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithms目前八十一頁\總數(shù)一百三十九頁\編于六點(diǎn)內(nèi)容大綱診斷，分期，及風(fēng)險(xiǎn)評估初治骨髓瘤病人的初始治療復(fù)發(fā)和/或難治性病人的新選擇當(dāng)前骨髓瘤治療法則的代表性病例分析目前八十二頁\總數(shù)一百三十九頁\編于六點(diǎn)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

目前八十三頁\總數(shù)一百三十九頁\編于六點(diǎn)復(fù)發(fā)性或難治性多發(fā)性骨髓瘤

Lenalidomide聯(lián)合地塞米松與地塞米松單藥

治療的對比研究:臨床III期研究結(jié)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

目前八十四頁\總數(shù)一百三十九頁\編于六點(diǎn)PhaseIIIStudyDesignRANDOMIZATIONPlacebo4+Dexamethasone2Lenalidomide1+Dexamethasone2orPlacebo31Len:25mgpoqdondays1-21every28days.2Dex40mgpoqdondays1-4,9-12,and17-20every28days.3Placeboqdondays21-28ofeach28daycycle.4Placeboqdondays1-28every28days.x4cycles,laterDexonlydays1-4目前八十五頁\總數(shù)一百三十九頁\編于六點(diǎn)臨床III期研究的設(shè)計(jì)隨機(jī)化安慰劑4+地塞米松2Lenalidomide1+地塞米松2或安慰劑31Len:25mgpoqdondays1-21every28days.2Dex40mgpoqdondays1-4,9-12,and17-20every28days.3Placeboqdondays21-28ofeach28daycycle.4Placeboqdondays1-28every28days.x4周期，隨后接受Dex，第1-4天目前八十六頁\總數(shù)一百三十九頁\編于六點(diǎn)EuropeanResults351ptsrandomized176forlen/dex175fordex/placeboRelapsedorrefractorywith>1priortreatmentLen/dexhadabetteroverallRR&CRrate目前八十七頁\總數(shù)一百三十九頁\編于六點(diǎn)歐洲結(jié)果351名患者隨機(jī)入組len/dex176例dex/安慰劑175例復(fù)發(fā)或難治、之前的治療>1次Len/dex總RR&CR率更高目前八十八頁\總數(shù)一百三十九頁\編于六點(diǎn)TimetoProgressionTimetoProgression(months)ProportionofPatients2.557.51012.51517.52022.500.20.40.60.81.0Len/Dex13.3mos.Dexalone5.1mos.P<0.000001009009010010目前八十九頁\總數(shù)一百三十九頁\編于六點(diǎn)進(jìn)展時(shí)間疾病進(jìn)展時(shí)間(月)患者百分?jǐn)?shù)2.557.51012.51517.52022.500.20.40.60.81.0Len/Dex13.3月Dex單藥5.1月P<0.000001009009010010目前九十頁\總數(shù)一百三十九頁\編于六點(diǎn)ToxicitiesLen/dexdgrade3/4neutropenia16.5%vs.1.2%fordexMosteventsgrade1or2Grade3/4infectionsweresimilarGrade3/4thrombocytopeniad27%vs.2%DVT/PEriskdProphylactica-coagulationNorthAmericanstudyDVT/PEriskhigher:15.3%vs.3.5%目前九十一頁\總數(shù)一百三十九頁\編于六點(diǎn)毒性反應(yīng)Len/dexd，3-4級中性粒細(xì)胞減少癥16.5%vs.1.2%地塞米松多數(shù)不良反應(yīng)1–2級3-4級感染2組類似3-4級血小板減少癥

d27%vs.2%DVT/PE風(fēng)險(xiǎn)

d預(yù)防血液凝集北美研究DVT/PE風(fēng)險(xiǎn)增加:15.3%vs.3.5%目前九十二頁\總數(shù)一百三十九頁\編于六點(diǎn)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目前九十三頁\總數(shù)一百三十九頁\編于六點(diǎn)APEX的最新進(jìn)展：復(fù)發(fā)性骨髓瘤患者

與高劑量地塞米松相比，

硼替佐米持續(xù)表現(xiàn)卓越的療效

PaulRichardson