多發(fā)性骨髓瘤研究進展和治療選擇課件

NewDevelopmentsandTreatmentOptionsforMultipleMyelomaRobertZ.Orlowski,MD,PhDMaryElizabethThomasAssociateProfessorofMedicine,DivisionofHematology/OncologyAssociateProfessor,DepartmentofPharmacology多發(fā)性骨髓瘤

研究進展和治療選擇RobertZ.Orlowski,MD,PhDMaryElizabethThomasAssociateProfessorofMedicine,DivisionofHematology/OncologyAssociateProfessor,DepartmentofPharmacologyOutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithmsDiagnosticCriteriaMajorCriteria1.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診斷標準主要標準1.組織活檢證實有漿細胞瘤2.骨髓漿細胞增多>30%3.過量血清M蛋白>3.5g/dLIgG2.0g/dLIgA尿中k

或l輕鏈1.0g/24小時次要標準A.骨髓漿細胞增多10-30%B.M蛋白未達主要標準的第3項C.溶骨性病變D.正常Igs降低IgM<500mg/dLIgA<1g/dLIgG<6g/dLArrivingattheDiagnosisTwomajorcriteriaOnemajor+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確診條件2個主要標準1個主要+1個次要標準1+B,1+C,1+D2+B,2+C,2+D3+A,3+C,3+D包含A及B的三個次要標準A+B+C,A+B+D1Clusterofplasmacellsinthebonemarrow.Bataille,RandHarousseau,JL.N.Engl.J.Med.336:1657,1997.1這項標準存在的問題判定標準煩瑣不方便病人及醫(yī)生使用界線設(shè)定獨斷31%骨髓漿細胞增多為主要標準而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到判定標準，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MGUS國際骨髓瘤工作組判定標準血清M蛋白<3.0g/dL骨髓漿細胞增多<10%；并且如進行骨髓活檢，可見漿細胞侵潤程度低無其它B細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.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.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.有癥狀多發(fā)性骨髓瘤血清和/或尿中有M蛋白骨髓漿細胞增多或漿細胞瘤通常以10%為標準相關(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,反復細菌感染[>2次/12個月])Kyle,RAetal.Br.J.Haematol.121:749,2003.Durie-SalmonStagingSystemSeveralfactorsareincludedinthestaging1HemoglobinRenalfunctionSerumcalciumM-proteinproductionBonylesionsand/orpresenceofaplasmacytomaDrawbacksManyfactorsmakeitcumbersometoapplyDoesnotusenew,powerfulprognostictoolsInternationalMyelomaWorkingGroupstudied11,171patients2Multivariateanalysisfoundonlyb2-microglobulinandalbuminasprognosticfactors1Durie,BGMandSalmon,SE.Cancer36:842,1975.2Greipp,PRetal.Blood102:190a,Abstract664,2003.Durie-Salmon分期系統(tǒng)本分期系統(tǒng)中包括下列指標1血紅蛋白腎功能血清鈣M蛋白骨病變和/或有漿細胞瘤缺點指標太多不方便使用沒有包括新的、有力的預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后因子1Durie,BGMandSalmon,SE.Cancer36:842,1975.2Greipp,PRetal.Blood102:190a,Abstract664,2003.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≥5.52770291Greipp,PRetal.J.Clin.Oncol.23:3412,2005.ISSandPrognosisSignificantsurvivaldifferencesforthreestages(P<0.0001)BetteroutcomepredictorthanthepriorDurie-SalmonmethodStilldoesnotincorporatecytogeneticsCytogeneticFactors:Del13Deletionofchromosome13wasthesinglemostpowerfuladverseprognosticfactorforalltimestoeventsinpatientsreferredforhigh-dosetherapyOS65.1±9.8vs26.7±4.1monthsFacon,Tetal.Blood97:1566,2001.細胞遺傳學指標: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面預后因子，影響所有的“至事件發(fā)生時間”指標總生存65.1±9.8vs26.7±4.1個月Facon,Tetal.Blood97:1566,2001.萬珂與13號染色體缺失APEX將病人隨機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.ConclusionsStagingandprognosisismostaccuratelydeterminedusingtheISSNewprognosticfactorsareemergingthatmayhelprefinethisfurtherCytogeneticandFISHstudiescanprovideadditionalprognosticinformation,andintheverynearfuturemayguidetherapeuticdecisions結(jié)論用ISS能更好地確定分期及預后新的預后因子正在顯現(xiàn)，未來可對分期預后系統(tǒng)有進一步的改進細胞遺傳學及FISH研究能提供更多的預后信息，在不久的將來可能會為治療方法的確定提供指導內(nèi)容大綱診斷，分期，及風險評估初治骨髓瘤病人的初始治療能進行移植的病人復發(fā)和/或難治性病人的新選擇當前骨髓瘤治療法則的代表性病例分析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.沙立度胺+地塞米松Thal/dex

優(yōu)于dex(p=0.002)1中位至緩解時間均為1.1個月進展3%vs.5%

無進展生存25.3vs.17.3

個月可成功采集干細胞1Bestresponsewasevaluatedwithin4cycles.200mgpoqd.PRwas≥50%serum&urineM-proteinreduction,or≥90%urineM-reductionifonlyurinewasinvolved.RajkumarSVetal.J.Clin.Oncol.24:431,2006.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/PPEDVdvs.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組中性粒細胞減少、脫發(fā)、LVEF改變發(fā)生少,但HFS/PPE較多ShouldWePushHarderforaCR?668ptsundergoingTotalTherapy2StringentCRassociatedwithanimproved4-yearOSandEFSHowever,nodifferenceinoutcomebetweenPRand<PRpatients,whohadvirtuallysuperimposablesurvivalcurvesTricot,Getal.ASHAbstract936,2004.我們是否應更努力去取得CR?668例病人接受TotalTherapy2方案治療以嚴格的CR判定標準，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.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

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

StudyDesignStudyof“Rev/dex”regimenin34previouslyuntreatedpatientsPhaseII,prospectivetrialdesignLenalidomide:25mgpodays1-21q28Dexamethasone40mgpodays1-4,9-12,and17-20Aspirin(80or325mg)dailyforDVTprophylaxisRajkumar,SVetal.Blood106:4050,2005.研究設(shè)計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Lenalidomide:25mgpodays1-21q28

地塞米松40mgpodays1-4,9-12,17-20阿司匹林(每日80or325mg)，預防深部靜脈血栓形成(DVT)Rajkumar,SVetal.Blood106:4050,2005.ResponsesResponseratewas91%(31/34),definedaspatientswith≥50%serumM-proteinreductionand≥90%urineM-proteinCRratewas6%(2/34)Another32%(11/34)achievedvgPR/nCR53%(18/34)hadaPRAmongpatientswhodidnotachievearesponse,2hadMRand1hadSDStemcellscouldbecollectedsuccessfully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可成功采集干細胞ToxicitiesHematologictoxicity,%G1/2G3/4Thrombocytopenia270Neutropenia3212Lymphopenia156Non-hematologictoxicity,%G1/2G3Fatigue4115Muscleweakness296Neuropathy210Pneumonitis36Rash66Anxiety156毒性反應血液學毒性,%G1/2G3/4血小板減少270中性粒細胞減少3212淋巴細胞減少156非血液學毒性,%G1/2G3疲乏4115肌無力296神經(jīng)病變210肺炎36皮疹66焦慮156PADRegimenDayBortezomib1.3mg/m2

1481518Cycle11121Dex40mgDox0,4.5,or9mg/m2

Bortezomib1.3mg/m2

1481518Cycles2–4

1121Dex40mgDox0,4.5,or9mg/m2NewlydiagnosedptsbeforestemcelltransplantEvaluateresponserates,toxicity,andstemcellharvestandsubsequenttransplantationOakervee,HEetal.Br.J.Haematol.129:755,2005.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干細胞移植前的初治患者評價療效、毒性反應，干細胞采集、及后續(xù)移植治療Oakervee,HEetal.Br.J.Haematol.129:755,2005.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.療效結(jié)果單用PAD誘導治療后,CR+PR95%(20/21)CR+nCR24%20/21例干細胞動員成功18/20進行了移植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.ToxicitiesDiscontinuationsoccurredduetoposturalhypotensionandneuropathyDrug-relatedSAEsincludedposturalhypotension,shingles,nausea/vomiting,andperipheralneuropathySensoryneuropathyin48%(5%grade3)Painfulneuropathyin48%(grade3in5%)AllimprovedafterthecompletionoftherapyOakervee,HEetal.Br.J.Haematol.129:755,2005.毒性反應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.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

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

Toxicities9%sensoryand9%painfulneuropathy;allgrade1-21discon-tinuationMRSA毒性反應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）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%療效出色的緩解率PAD不影響干細胞動員與高劑量PAD方案相比，毒性反應降低療效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%ConclusionsNewinductionregimensareemergingthathavetheabilitytoinduceoverallresponseratesof90%ormore,withmoreCRsPatientsareabletohavestemcellscollectedandmoveontotransplantationsafelyAdditionalstudieswillbeneededtoidentifytheoptimalregimen(s)結(jié)論新的誘導方案正在出現(xiàn)，能達到90％以上的總緩解率，其中有更多的CRs能進行干細胞采集，并安全地進行移植需要進行更多的研究以發(fā)現(xiàn)最佳方案OutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsPatientswithouttransplantasanoptionNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithms內(nèi)容大綱診斷，分期，及風險評估初治骨髓瘤病人的初始治療不能進行移植的病人復發(fā)和/或難治性病人的新選擇當前骨髓瘤治療法則的代表性病例分析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

萬珂聯(lián)合美法蘭、強的松(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,BelgiumAbstract786StudyDesignPhaseI/IIstudyPatientswithmyeloma≥65yearsofageFourcyclesof6weekseachMPdays1-4Bortezomibdays1,4,8,11,22,25,29,32Fivecyclesof5weekseachMPdays1-4Bortezomibdays1,8,15,22研究設(shè)計臨床I/II期研究≥65歲骨髓瘤病人

每周期6周，共4個周期MP 第1-4天萬珂 第1,4,8,11,22,25,29,32天每周期5周，共5個周期MP 第1-4天萬珂 第1,8,15,22天ToxicitiesGrade3/4EventsIncidence(N=60)Thrombocytopenia52%Neutropenia43%Infection17%Diarrhea17%Anemia10%EventscomparabletoothermyelomaregimensEvent-freesurvival85%6deathsBortezomibdosereductionsin35%Neuropathy毒性反應3/4級發(fā)生率(N=60)血小板減少52%中性粒細胞減少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Responses86%ofpatientsrespondedHighproportionofCR/IFX-Responsenotinfluencedbydel13orIgHPhaseIIItrialplanned療效緩解率86%CR/IFX-比例高療效不受del13或IgH的影響計劃進行臨床III期研究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

美法蘭-強的松(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-強的松(MP)和自體干細胞移植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

StudyDesign1Clodronatewasgiventoallpatients.StandardMP1

12coursesat6-weekintervalsn=191MP+T1MPasabove+Thalupto400mgqdn=124Mel100mg/m2x21VADx2;Cy3g/m2+G-CSFn=121Untreated,stageI-IIIpatientsage65-75(N=436)研究設(shè)計1Clodronatewasgiventoallpatients.標準的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)AResponseEdgeforMPTMPn=124MPTn=191Mel100n=1211CR(%)21517≥vgPR(%)74941≥PR(%)408172DVT13%inMPT(vs.5and6.5%)36%onMPThadPN1Only63%ofpatientsunderwentthesecondtransplant.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.±1.3OS、PFS的臨床獲益MPT總體生存時間更長MPTvs.MP:NR@56vs.30.3月±5.8P=0.0008MPTvs.Mel100:NR@56vs38.6±3.0P=0.014無進展生存時間更長MPTvs.MP:29.5±3.6vs.17.2月±1.5MPTvs.Mel100:29.5±3.6vs.19.0月±1.3Toxicities30%onMPTalsohadneuropathyDeathduetoinfectionssimilar(2%,2%,4%)MPn=124MPTn=191Mel100n=121Severeinfection111739Neutropenia3241100DVT5126.5毒性反應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嚴重的感染111739中性粒細胞減少癥3241100DVT5126.5ConclusionsMPmaynolongerbethestandardofcareforallolderpatientswithmultiplemyelomaMPVandMPThavehigheroverallandcompleteresponseratesOtherregimens(ThaDD)arealsoeffectiveMPThasasurvivaladvantageoverMPMPRmaybebettertoleratedthanMPTAdditionalstudiesareneeded結(jié)論MP方案可能不再是高齡骨髓瘤病人的標準治療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)勢需要進行進一步的臨床研究OutlineDiagnosis,stagingandriskidentificationInitialtherapyinnewlydiagnosedmyelomapatientsNoveloptionsforpatientsintherelapsedand/orrefractorysettingRepresentativecasepresentationsofcurrentmyelomatreatmentalgorithms內(nèi)容大綱診斷，分期，及風險評估初治骨髓瘤病人的初始治療復發(fā)和/或難治性病人的新選擇當前骨髓瘤治療法則的代表性病例分析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

復發(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

PhaseIIIStudyDesignRANDOMIZATIONPlacebo4+Dexamethasone2Lenalidomide1+Dexamethasone2orPlacebo31Len:25mgpoqdondays1-21every28days.2Dex40mgpoqdondays1-4,9-12,and17-20every28days.3Placeboqdondays21-28ofeach28daycycle.4Placeboqdondays1-28every28days.x4cycles,laterDexonlydays1-4臨床III期研究的設(shè)計隨機化安慰劑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EuropeanResults351ptsrandomized176forlen/dex175fordex/placeboRelapsedorrefractorywith>1priortreatmentLen/dexhadabetteroverallRR&CRrate歐洲結(jié)果351名患者隨機入組len/dex176例dex/安慰劑175例復發(fā)或難治、之前的治療>1次Len/dex總RR&CR率更高TimetoProgressionTimetoProgression(months)ProportionofPatients2.557.51012.51517.52022.500.81.0Len/Dex13.3mos.Dexalone5.1mos.P<0.000001009009010010進展時間疾病進展時間(月)患者百分數(shù)2.557.51012.51517.52022.500.81.0Len/Dex13.3月Dex單藥5.1月P<0.000001009009010010ToxicitiesLen/dexdgrade3/4neutropenia16.5%vs.1.2%fordexMosteventsgrade1or2Grade3/4infectionsweresimilarGrade3/4thrombocytopeniad27%vs.2%DVT/PEriskdProphylactica-coagulationNorthAmericanstudyDVT/PEriskhigher:15.3%vs.3.5%毒性反應Len/dexd，3-4級中性粒細胞減少癥16.5%vs.1.2%地塞米松多數(shù)不良反應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風險

d預防血液凝集北美研究DVT/PE風險增加:15.3%vs.3.5%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,IncAbstract2547APEX的最新進展：復發(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,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,IncAbstract2547PhaseIIIStudyDesign273treatmentdays280treatmentdays1.3mg/m2IVpushD1,4,8,11q3-wkcycle8cycles1.3mg/m2IVpushD1,8,15,22q5-wkcycle4cycles3cycles5cycles40mgPOD1–4,9–12,17–20q5-wkcycle40mgPOD1–4q4-wkcycleInductionMaintenanceRandomizationBortezomibDexamethasoneRichardson,PGetal.N.Engl.J.Med.352:2487,2005.III期臨床研究設(shè)計273天治療280天治療1.3mg/m2

靜脈推注D1,4,8,11q3-wkcycle8周期1.3mg/m2IVpushD1,8,15,22q5-wkcycle4周期3周期5周期40mgPOD1–4,9–12,17–20q5-wkcycle40mgPOD1–4q4-wkcycle誘導維持治療隨機化硼替佐米

地塞米松Richardson,PGetal.N.Engl.J.Med.352:2487,2005.UpdatedResponseRatesOverallresponserateimproved:38%to43%56%(76/135)improvedresponseafter2cyclesMedianTTP6.2mos.MedianTTR1.4mos.0.8forCR,1.4forPRMedianDOR7.8mos.9.9forCR,11.5fornCR,7.6forPRResponse,%0102030405060708090100Update9%CR34%PR43%(7%nCR)38%6%CR32%PR(7%nCR)Initialanalysis更新的有效率總有效率改善:38%to43%56%(76/135)2周期后療效改善中位TTP6.2月中位TTR1.4月CR0.8,PR1.4中位DOR7.8月CR9.9,nCR11.5,PR7.6Response,%0102030405060708090100Update9%CR34%PR43%(7%nCR)38%6%CR32%PR(7%nCR)InitialanalysisResponseTimetable~20%ofrespondersachievedmaximalM-proteinresponseaftercycle8療效的時間曲線~20%治療有效的患者8周期后M-蛋白獲得了最大的療效反應OverallSurvival29.8mos.(23.2-?)vs.23.7(18.7-29.1),P=0.0272Survivalsuperiordespitecrossoverof62%80%at1yearvs.67%(P=0.002)總生存率29.8月(23.2-?)vs.23.7(18.7-29.1),P=0.0272盡管62%病人換組，仍表現(xiàn)生存優(yōu)勢1年生存率80%vs.67%(P=0.002)Bortezomib+LiposomalDoxorubicinSeparatetracksforsolidandhematologicmalignancypatientsPLD@30mg/m2

Bortezomib0.90to1.50mg/m2

Three-weekcyclelengthBortezomib()days1,4,8,11PLD()onday4Toxicityassessedbasedoncycle1oftherapyActivityevaluatedq2cyclesWeek1Week2Week3Orlowski,RZetal.Blood105:3058,2005.硼替佐米+脂質(zhì)體阿霉素分別研究實體瘤和血液惡性疾病的情況PLD@30mg/m2

硼替佐米、0.90to1.50mg/m2

3周一療程硼替佐米()第1,4,8,11天脂質(zhì)體阿霉素()第4天根據(jù)1周期的治療評價療效每2周期評價活性

Week1Week2Week3Orlowski,RZetal.Blood105:3058,2005.ResponseRatesCRrate(CR+n-CR)36%(8/22)OverallRR(CR+PR)73%(16/22)AsofstudydiscontinuationTwopatientswentoffstudywhenVELCADE?wasapprovedtoreceivetherapylocallyCRsseenatfirstdoselevel(0.90mg/m2bortezomib)1/20ptswhocompleted2cyclesprogressed?TrueprogressionOrlowski,RZetal.Blood105:3058,2005.有效率CR率(CR+n-CR)36%(8/22)總緩解率(CR+PR)73%(16/22)中斷治療當萬珂在當?shù)乇慌鷾噬鲜泻螅?名患者退出研究第一個劑量水平即看到了CRs(萬珂0.90mg/m2)1/20例在完成2個周期治療后進展?是否為真的進展Orlowski,RZetal.Blood105:3058,2005.OverallSurvivalMedianoverallsurvivalnotreachedwithamedianof36monthsoffollow-upSUMMITshowedOSof16mos.Biehn,SBetal.2006ASCOAbstract