漿細(xì)胞病演示文稿

漿細(xì)胞病演示文稿1當(dāng)前1頁(yè)，總共96頁(yè)。2（優(yōu)選）漿細(xì)胞病當(dāng)前2頁(yè)，總共96頁(yè)。漿細(xì)胞?。≒lasmacelldyscrasias）定義：漿細(xì)胞或產(chǎn)生免疫球蛋白的B淋巴細(xì)胞過(guò)度增殖所引起的一組疾病。本疾病可分為兩型骨髓瘤（孤立性、多發(fā)性、髓外漿細(xì)胞病、漿細(xì)胞白血?。辉l(fā)性巨球蛋白血癥；重鏈??；原發(fā)淀粉樣變性。當(dāng)前3頁(yè)，總共96頁(yè)。隱性漿細(xì)胞病良性單克隆免疫球蛋白血癥；繼發(fā)性單克隆免疫球蛋白血癥。病因：尚未完全明了可能與遺傳有關(guān)，有染色體異常病毒感染繼發(fā)于其他疾?。怨撬柩?、結(jié)核、慢性肝炎）當(dāng)前4頁(yè)，總共96頁(yè)。M蛋白免疫球蛋白兩條相似的重鏈和兩條輕鏈組成，重鏈γαμδε，輕鏈κλ。免疫球蛋白IgGIgAIgMIgDIgE當(dāng)前5頁(yè)，總共96頁(yè)。血清中M蛋白的特點(diǎn)和測(cè)定可能完整的單克隆免疫球蛋白或?yàn)橐粭l重鏈和一條輕鏈的免疫球蛋白采用血清蛋白電泳定量測(cè)量法（M蛋白至少＞2g/L或0.2g/dL，才出現(xiàn)單峰）確定免疫球蛋白的類型（定性）當(dāng)前6頁(yè)，總共96頁(yè)。尿中M蛋白特點(diǎn)和測(cè)定通常是一條游離的輕鏈在某些重鏈疾病中，由某些特定區(qū)域的游離重鏈片段組成免疫球蛋白電泳：定量測(cè)定24小時(shí)的輕鏈蛋白（κλ

）當(dāng)前7頁(yè)，總共96頁(yè)。本周氏蛋白多條輕鏈。分子量小，通過(guò)腎小球，從尿排出。加溫45-60℃凝固→沸點(diǎn)重新溶解→冷至60℃以下出現(xiàn)沉淀又稱凝溶蛋白初期時(shí)間間歇出現(xiàn)，本周氏蛋白陰性不能排除本病。當(dāng)前8頁(yè)，總共96頁(yè)。多發(fā)性骨髓瘤（multiplemyeloma）定義：漿細(xì)胞異常增生的惡性腫瘤，異常漿細(xì)胞（骨髓瘤細(xì)胞）浸潤(rùn)骨骼和軟組織，產(chǎn)生M蛋白，引起骨骼破壞，出現(xiàn)貧血、腎功能損害和免疫功能異常。發(fā)病率：4/100，000，多發(fā)性骨髓瘤占惡性腫瘤的1%，血液惡性疾病的10%，通常無(wú)法治愈，接受標(biāo)準(zhǔn)治療病人中位生存時(shí)間為4年。發(fā)病高峰年齡：60-70歲，男女比2：1當(dāng)前9頁(yè)，總共96頁(yè)。MultipleMyeloma:EpidemiologySecondmostcommonhematologicalmalignancy.Incidenceandrates:1%ofallcancersUSincidence:19,900newcasesperyearUSprevalence:100,000patientsDeaths:estimated10,790peryearMorethan80%ofaffectedpatients>age60.Affectsslightlymorementhanwomen(1.6:1).MerckManualProfessional.2005;GeorgeED,etal.AmFamPhys.1999;59(7):1401-1405.當(dāng)前10頁(yè)，總共96頁(yè)。ClinicalManifestations

ofMultipleMyelomaOverproliferationofplasmacellscancause:RiskofinfectionOsteolyticbonelesionsHypercalcemiaBonemarrowsuppression(pancytopenia)RenalcomplicationriskProductionofmonoclonalMproteinscauses:DecreasedlevelsofnormalimmunoglobulinsHyperviscosity/pdfs/ph07-eng_f2.pdf當(dāng)前11頁(yè)，總共96頁(yè)。溶骨性損害病理性骨折高鈣血癥貧血骨髓浸潤(rùn)骨破壞單克隆免疫球蛋白尿：腎功能衰竭血：高粘滯性冷凝球蛋白神經(jīng)病變組織：淀粉樣變性正常免疫球蛋白減少感染多發(fā)性骨髓瘤病史和體檢血細(xì)胞計(jì)數(shù)，分類及血小板尿素氮/肌酐，電解質(zhì)，血鈣/白蛋白血免疫球蛋白定量血清蛋白電泳及免疫沉淀24小時(shí)尿蛋白電泳及免疫沉淀骨骼掃描骨髓穿刺+活檢?2-微球蛋白C反應(yīng)蛋白LDH細(xì)胞遺傳學(xué)檢查±FISH通常有用的檢查（對(duì)一些患者的預(yù)后判斷有幫助）漿細(xì)胞標(biāo)記指數(shù)PCLI—反映漿細(xì)胞惡性克隆增生能力骨髓流式細(xì)胞儀檢測(cè)

—表達(dá)漿細(xì)胞抗原（PCA-1),CD20、CD40、CD28、CD31、CD54、CD44當(dāng)前12頁(yè)，總共96頁(yè)。MajorSymptomsatDiagnosis骨痛（Bonepain）-58%乏力（Fatigue）-32%體重減輕（Weightloss）-24%感覺(jué)異常（Paresthesias）-5%無(wú)癥狀（Asymptomatic）-11%KyleRA.MayoClinProc2003;78:21當(dāng)前13頁(yè)，總共96頁(yè)。浸潤(rùn)性表現(xiàn)1.骨痛早期和主要癥狀，發(fā)生率75%，腰骶痛（70%），胸痛（20%），肢體其他部位（10%）。2.骨骼變形和病理性骨折骨骼變形：主要在胸骨和脊椎，胸骨柄及胸部凹陷，胸肋鎖骨連接外呈串珠樣結(jié)節(jié)。病理性骨折：多發(fā)生在肋骨，多在第五肋以下可引起胸腔積液及胸部疼痛。當(dāng)前14頁(yè)，總共96頁(yè)。3.造血器官的損害：貧血，多為中度。4、髓外浸潤(rùn)：脾、肝、淋巴結(jié)，腎常見(jiàn)。神經(jīng)系統(tǒng)病變以胸腰椎脊髓壓迫癥狀為主（10.5%）當(dāng)前15頁(yè)，總共96頁(yè)。1.易感染性：與異常M蛋白大量產(chǎn)生，正常免疫球蛋白減少或γ-球蛋白分解增加有關(guān)。細(xì)菌感染尤以革蘭氏陰性桿菌感染為主（72%）病毒感染有所增加感染常是本病致死的主要原因。大量M蛋白的及其多肽鏈引起的臨床表現(xiàn)當(dāng)前16頁(yè)，總共96頁(yè)。2.高粘滯血癥IgA分子易形成多聚體，IgA型更易發(fā)生此癥。3.出血傾向M蛋白被血小板吸附，導(dǎo)致血小板聚集和血小板第3因子釋放失常有關(guān)。4.腎功能損害40-60%蛋白尿慢性腎功能衰竭（尿中本周氏蛋白陽(yáng)性發(fā)生率是無(wú)本周氏蛋白的2倍）當(dāng)前17頁(yè)，總共96頁(yè)。5.淀粉樣變10-20%，IgD型常見(jiàn)，有淀粉樣變者生存＜1年，多死于心臟病。舌、心、胃腸道、骨骼、平滑肌、神經(jīng)、皮膚是發(fā)生淀粉樣變常見(jiàn)部位當(dāng)前18頁(yè)，總共96頁(yè)。1.主要標(biāo)準(zhǔn)：①組織活檢為漿細(xì)胞瘤；②骨髓漿細(xì)胞增多，＞30%③M蛋白IgG＞3.5/dL或IgA＞2.0/dL，輕鏈每日排出＞1g2.次要標(biāo)準(zhǔn)①骨髓漿細(xì)胞增多，10-30%；②M蛋白IgG＜3.5/dL或IgA＜2.0/dL；③溶骨性改變；④正常免疫球蛋白降低，IgM＜50mg/dL，IgA＜100mg/dL，IgG＜600mg/dL。SWOG有關(guān)多發(fā)性骨髓瘤的診斷標(biāo)準(zhǔn)當(dāng)前19頁(yè)，總共96頁(yè)。對(duì)于一個(gè)有癥狀的病人，凡符合以下條件者可以診斷⑴主要診斷標(biāo)準(zhǔn)①或②+次要標(biāo)準(zhǔn)①、②或③；⑵主要診斷標(biāo)準(zhǔn)③；⑶次要診斷標(biāo)準(zhǔn)①+②+③或①+②+④當(dāng)前20頁(yè)，總共96頁(yè)。骨髓中漿細(xì)胞15％并有異常漿細(xì)胞或有病理證實(shí)的漿細(xì)胞瘤血清中出現(xiàn)單克隆蛋白(M蛋白):IgG＞35g/L,IgA＞20g/L,IgM＞15g/L,

IgD＞2.0g/L,IgE＞

2.0g/L,少數(shù)出現(xiàn)雙克隆或三克隆性無(wú)其它原因的溶骨病變或廣泛骨質(zhì)疏松

國(guó)內(nèi)

診斷標(biāo)準(zhǔn)*注釋:診斷IgM型,除符合1、2項(xiàng)外，須具備MM臨床表現(xiàn)和多部位溶骨病變。只有1、3項(xiàng)屬不分泌MM；對(duì)僅有1、2項(xiàng)者，尤其無(wú)原、幼漿者，除外意義未明的單克隆丙種球蛋白血癥和反應(yīng)性漿細(xì)胞增多癥當(dāng)前21頁(yè)，總共96頁(yè)。CriteriaforDiagnosisofMultipleMyelomaMonoclonalplasmacellspresentinthebonemarrow≥10%,and/orpresenceofadocumentedplasmacytoma.

+

PresenceofMcomponentinserumand/orurine.*

+Oneormoreofthefollowing(CRABcriteria):Calciumelevation(serumcalcium>11.5mg/dL)Renalinsufficiency(serumcreatinine>2mg/dL)Anemia(hemoglobin<10g/dLor2g/dL<normal)Bonedisease(lyticlesionsorosteopenia)DurieetalfortheInternationalMyelomaWorkingGroup.Leukemia.2006:1-7.*MonoclonalMspikeonelectrophoresisIgG>3.5g/dL,IgA>2g/dL,lightchain>1g/dLin24-hoururinesample.

當(dāng)前22頁(yè)，總共96頁(yè)。DiagnosticEvaluationofMultipleMyelomaTestFinding(s)WithMyelomaCBCwithdifferentialcounts↓Hgb,↓WBC,↓plateletsElectrolytes↑Creat,↑Ca+,↑Uricacid,↓AlbSerumelectrophoresiswithquantitativeimmunoglobulins↑Mproteininserum,mayhave↓levelsofnormalantibodiesImmunofixationIdentifieslight/heavychaintypesMproteinβ2-microglobulin↑Levels(measureoftumorburden)24-hoururineproteinelectrophoresis↑Monoclonalprotein(BenceJones)Bonemarrowbiopsy≥10%plasmacellsSkeletalimagingOsteolyticlesions,osteoporosisSerumfreelightchain↑FreelightchainsMRIEvaluationofinvolvementofdiseaseAlb=albumin;CBC=completebloodcount;Creat=creatinine;Hgb=hemoglobin;MRI=magneticresonanceimaging;WBC=whitebloodcell.Abella.OncologyNewsInternational.2007;16:27;

Barlogieetal.In:WilliamsHematology.7thed.2006:1501;Durieetal.HematolJ.2003;4:379;MMRF.MultipleMyeloma:DiseaseOverview.2006.;Rajkumaretal.Blood.2005;106(3):812.當(dāng)前23頁(yè)，總共96頁(yè)。Durie-SalmonStagingSystemforMultipleMyelomaDurieandSalmon,Cancer1975;36(9):842-854Subclassificationcriteria:ANormalrenalfunction(serumcreatininelevel<2.0mg/dL)BAbnormalrenalfunction(serumcreatininelevel2.0mg/dL)

StageCriteriaMyelomacellmass

(1012cells/m2)IAllofthefollowing:

Hemoglobin>10g/dL

Serumcalciumlevel12mg/dL(normal)

Normalboneorsolitaryplasmacytomaon

x-ray

LowMcomponentproductionrate:

IgG<5g/dLIgA<3g/dL

BenceJonesprotein<4g/24hr<0.6(low)IINotfittingstageIorIII0.6-1.2(intermediate)IIIOneormoreofthefollowing:

Hemoglobin<8.5g/dL

Serumcalciumlevel>12mg/dL

Multiplelyticbonelesionsonx-ray

HighM-componentproductionrate:

IgG>7g/dLIgA>5g/dL

BenceJonesprotein>12g/24hr>1.2(high)當(dāng)前24頁(yè)，總共96頁(yè)。臨床分期分期骨髓瘤細(xì)胞（cell/m2）I1.血紅蛋白＞10g/dL2.血鈣正常（≤12mg/dl）＜0.6×10123.影像學(xué)顯示正常骨結(jié)構(gòu)或孤立骨髓瘤4、降低的M蛋白產(chǎn)量a.IgG＜5g/dLb.IgA＜3g/dLc.尿輕鏈蛋白＜4g/24hII介入I或III之間0.6–1.2×1012III以下一項(xiàng)或多項(xiàng)1.血紅蛋白＜8.5g/dL2.血鈣＞12mg/dL3.晚期溶骨性損害4.高的M蛋白產(chǎn)量＞1.2×1012a.IgG＞

7g/dLb.IgA＞5

g/dLc.尿輕鏈蛋白＞

12g/24h任何期別的亞期A血肌酐＜2mg/dlB血肌酐≥2mg/dl當(dāng)前25頁(yè)，總共96頁(yè)。2M=serum2microglobulininmg/dL;ALB=serumalbumining/dLInternationalStagingSystem

forSymptomaticMultipleMyelomaGreippPR,etal.Blood2005;102:190aSTAGEVALUESStage1?2M<3.5mg/dLALB3.5g/dLStage2NotStage1or3Stage3?2M>5.5mg/dL當(dāng)前26頁(yè)，總共96頁(yè)。多發(fā)性骨髓瘤預(yù)后因素新的多發(fā)性骨髓瘤國(guó)際分期系統(tǒng)(ISS)使用了兩項(xiàng)實(shí)驗(yàn)室參數(shù):β2-微球蛋白(β2M)水平和血清白蛋白水平.I期:β2M水平<3.5mg/L且白蛋白水平≥3.5g/dL(中位生存62月);II期：(介于I期和III期)(中位生存44月);III期:β2M≥5.5mg/L(中位生存29月).當(dāng)前27頁(yè)，總共96頁(yè)。類型特征處理MGUS血清單克隆蛋白<3g/dL骨髓中漿細(xì)胞<10%無(wú)貧血、腎衰、高鈣血和溶骨性損害無(wú)正常免疫球蛋白減少觀察至病情進(jìn)展SmolderingMM（頓挫型/冒煙型）血清單克隆蛋白>3g/dL和（或）骨髓中漿細(xì)胞>10%無(wú)貧血、腎衰、高鈣血和溶骨性損害觀察至病情進(jìn)展MultipleMyelomaResearchFoundation.Availableat:MM的分類

當(dāng)前28頁(yè)，總共96頁(yè)。類型特征處理IndolentMM（惰性MM）血清/尿中有M蛋白成分骨髓中漿細(xì)胞增多輕度貧血或有少數(shù)小的溶骨性破壞無(wú)明顯癥狀每3個(gè)月復(fù)查一次，病情進(jìn)展時(shí)開(kāi)始治療SymptomaticMM（癥狀性MM）血清/尿中有M蛋白成分骨髓中漿細(xì)胞增多貧血、腎衰、高鈣血或溶骨損害既有原發(fā)淀粉樣變性，又伴有骨髓中漿細(xì)胞數(shù)目≥30%的患者診斷為MM和淀粉樣變性立即開(kāi)始治療 MM的分類

MultipleMyelomaResearchFoundation.Availableat:當(dāng)前29頁(yè)，總共96頁(yè)。⑴IgG型骨髓病50-60%，血清M蛋白可很高，常因正常免疫球蛋白明顯減少→感染腫瘤生長(zhǎng)緩慢，腫瘤細(xì)胞倍增時(shí)間10.1月。⑵IgA型占25%，高鈣血癥明顯，合并感染較少。出現(xiàn)淀粉樣變，出凝血異常發(fā)生率較高，易出現(xiàn)高粘滯血癥。腫瘤細(xì)胞倍增時(shí)間6.3月，預(yù)后較差。臨床分型當(dāng)前30頁(yè)，總共96頁(yè)。⑶IgD型僅占1.5%，60%病人＜60歲，骨外播散，高鈣血癥、淀粉樣變、嚴(yán)重貧血、氮質(zhì)血癥多見(jiàn)血漿總蛋白通常不高本周蛋白尿幾乎每例都有，90%為λ型骨髓瘤細(xì)胞分化較差，形態(tài)較惡，較易并發(fā)漿細(xì)胞白血?。òl(fā)生率5%），生存期較短，平均僅9個(gè)月。當(dāng)前31頁(yè)，總共96頁(yè)。⑷輕鏈骨髓瘤占20%，生長(zhǎng)較快，瘤細(xì)胞倍增時(shí)間為3.4個(gè)月80-100%有本周氏蛋白60%有溶骨性損害和高鈣血癥；更易合并腎功能衰竭和淀粉樣變，預(yù)后很差。⑸IgE型骨髓瘤很罕見(jiàn)，起特點(diǎn)有明顯貧血，血沉快，易并發(fā)漿細(xì)胞性白血病。當(dāng)前32頁(yè)，總共96頁(yè)。⑹非分泌性骨髓瘤＜1%，血中無(wú)M蛋白尿中無(wú)本周氏M蛋白；腎功能衰竭較少見(jiàn)，其他臨床表現(xiàn)與分泌型相同。⑺冒煙性骨髓瘤（Smolderingmyeloma）1.5-2%。診斷上符合骨髓瘤標(biāo)準(zhǔn)，但無(wú)貧血，溶骨性損害及腎功能衰竭，病程趨向良性，病情發(fā)展緩慢。當(dāng)前33頁(yè)，總共96頁(yè)。⑻孤立性骨髓瘤（Solitarymyeloma）發(fā)病年齡較輕，溶骨僅發(fā)生在一處骨髓中漿細(xì)胞不增加，無(wú)貧血、高血鈣及氮質(zhì)血癥，半數(shù)病人出現(xiàn)M蛋白，但I(xiàn)gG或IgA＜1.6g/dL，尿本周蛋白＜500mg/dL。⑼兩種以上M蛋白的骨髓瘤，相對(duì)良性⑽半分子IgA多發(fā)性骨髓瘤

-極為罕見(jiàn)

-臨床癥狀與典型骨髓瘤相似

-尿本周氏蛋白陽(yáng)性

-病情進(jìn)展迅速，預(yù)后較差。當(dāng)前34頁(yè)，總共96頁(yè)。Bichel等人報(bào)告，2%發(fā)生漿細(xì)胞白血病。IgD型和IgE型相對(duì)較易發(fā)生。診斷標(biāo)準(zhǔn)①外周血漿細(xì)胞＞2×109/L（2000/mm2

）②漿細(xì)胞符合惡性細(xì)胞學(xué)診斷，肝脾腫大以及白細(xì)胞＞15×109/L（15000/mm3

）漿細(xì)胞白血病當(dāng)前35頁(yè)，總共96頁(yè)。ChallengesinMMManagement

Currentlyincurableinmostpatients.Long-termcompleteresponsesarerare.Mediansurvivalwithstandardtherapyisabout3years.Autologousstemcelltransplantmayprolongprogressionfreesurvival,butit’snotcurative.Treatmentofrelapse:Nostandardtherapy.Existingoptionsinadequate.

Newtreatmentoptionsneeded.NCCNPracticeGuidelines;Rajkumaretal.MayoClinProc.2002;77:813-822.當(dāng)前36頁(yè)，總共96頁(yè)。NCCNReviewCategoriesTransplantNCCNCategoryNonTransplantNCCNCategoryDexamethasone2ABortezomib/Melphalan/Prednisone(VMP)*1L-Doxorubicin/Vincristine/Dexamethasone(DVD)2AMelphalan/Prednisone/Thalidomide(MPT)1Thalidomide/Dexamethasone2AVincristine/Doxorubicin/Dexamethasone(VAD)2ABortezomib/Dexamethasone2BDexamethasone2ABortezomib/Thalidomide/Dexamethasone(VTD)2BMelphalan/Prednisone(MP)2ALenalidomide/Dexamethasone2BThalidomide/Dexamethasone2ABortezomib/Doxorubicin/Dexamethasone2BLenalidomide/lowDexamethasone*2BBortezomib/Lenalidomide/Dexamethasone(VRD)*2BL-Doxorubicin/Vincristine/Dexamethasone(DVD)2BNCCNClinicalPracticeGuidelinesinOncology,v22009NCCNCategoriesofEvidenceandConsensus:1 High-levelevidence,uniformconsensus2A Lower-levelevidence,uniformconsensus2B Lower-levelevidence,non-uniformconsensusGenericName TradeNameBortezomib VelcadeLenalidomide RevlimidThalidomide Thalomid當(dāng)前37頁(yè)，總共96頁(yè)。多發(fā)性骨髓瘤治療的演進(jìn)馬法蘭＋強(qiáng)的松（MP方案）

(AlexanianetalJAMA1969;208:1680-5)VAD方案(AlexanianR,BarlogieB,etalAmJHematol1990,33;86-89)間斷大劑量DXM方案(AlexanianetalBlood1992,80(4):887-890)大劑量化療聯(lián)合干細(xì)胞移植(McElwainetal,Lancet.1983;2:822;tomutiplestudiestill1999)

反應(yīng)停

(SinghaletalNEnglJMed1999,341:1565-1571)反應(yīng)停＋DXM

(WeberetalJCO2003,21(1):16-19)Bortezomib(PS341,Velcade,蛋白酶體抑制劑)

(RichardsonetalNEnglJMed2003;348: 2609-2617)CC-5013(Revlimid,Lenalidomide,反應(yīng)停類似物)當(dāng)前38頁(yè)，總共96頁(yè)。*已經(jīng)提請(qǐng)F(tuán)DA批準(zhǔn)MM的治療

單藥治療烷化劑(馬法蘭,環(huán)磷酰胺)類固醇激素(地塞米松,強(qiáng)的松)反應(yīng)停*Bortezomib（蛋白酶體抑制劑）聯(lián)合化療MPVBAPVADVBMCPTDDT-PACEABCM當(dāng)前39頁(yè)，總共96頁(yè)。MM是否需要治療的干預(yù)1.單克隆球蛋白白血癥＜3g/dL，骨髓中漿細(xì)胞＜10%無(wú)高鈣血癥、腎衰、骨損害：無(wú)限期隨訪。但有20-25%最終發(fā)展為MM，淀粉樣變性或NHL。2.血清中單克隆蛋白≥3g/dL。骨髓中漿細(xì)胞≥10%，無(wú)貧血、骨損害、高鈣血癥、腎功能不全：

SmolderingMM（SMM）數(shù)月數(shù)年觀察，許多SMM生存多年，而無(wú)病情進(jìn)展。治療原則當(dāng)前40頁(yè)，總共96頁(yè)。Hjorth：延遲性治療未改善病人的生存。Witzig和Kyle：SMM中位疾病進(jìn)展時(shí)間為2年。3.孤立性漿細(xì)胞病，無(wú)其他骨髓受侵或髓外受侵受侵部位，接受RT，密切觀察。如RT后，仍有殘留單克隆蛋白，有進(jìn)展或顯性MM的危險(xiǎn)。當(dāng)前41頁(yè)，總共96頁(yè)。4.一旦診斷MM首先確定是否可進(jìn)行自體干細(xì)胞的移植。如不符合，如年齡較大、腎功能不全、體力較差。選擇標(biāo)準(zhǔn)的MP方案化療，

ORR50%。CR＜10%MST3yrs，5yrs24%。積極的治療方案-M2方案

VCR+BCNU+Melphalan+CTX+PDNORR60-70%，與MP相比無(wú)生存優(yōu)勢(shì)。當(dāng)前42頁(yè)，總共96頁(yè)。1.冒煙或惰性骨髓瘤瘤細(xì)胞常＜20%，無(wú)癥狀→觀察→如有進(jìn)展治療。2.孤立性骨髓瘤對(duì)病變局部采用根治劑量放療4000-5000cGy

復(fù)發(fā)率10-30%，30%骨骼受侵和70%髓外受侵，經(jīng)過(guò)RT治療可長(zhǎng)期生存當(dāng)前43頁(yè)，總共96頁(yè)。3.標(biāo)準(zhǔn)的誘導(dǎo)化療對(duì)癥狀性多發(fā)型骨髓瘤的ECOG前瞻性隨機(jī)臨床試驗(yàn)。比較溫和MP和較強(qiáng)烈的VBMCP方案

ORRMST5-1yrsurvivalMP51%28-30mos19%VBMCP72%28-30mos26%當(dāng)前44頁(yè)，總共96頁(yè)。Melphalan8mg/m2D1-4PDN60mg/m2D1-4■Repeatcycleevery28daysforatleast1year.■由于Melphalan口服吸收較差，推薦謹(jǐn)慎提高劑量，直到隨后周期中白細(xì)胞數(shù)量出現(xiàn)2000-3000/dL。當(dāng)前45頁(yè)，總共96頁(yè)。VBCMP方案（M2方案）VCR1.2mg/m2iv，d1BCNU20mg/m2iv，d1-4Melphalan8mg/m2，d1-4CTX400mg/m2，d1PDN40mg/m2，d1-7

（allcycle）

20mg/m2，d8-14

（cycle1-3only）當(dāng)前46頁(yè)，總共96頁(yè)。RepeatcycleofVBMCPevery35daysforatleast1year.體力狀態(tài)較差（部分或完全臥床，ECOG評(píng)分2-4分）≥70歲無(wú)法耐受VBMCP方案者，接受MP方案治療當(dāng)前47頁(yè)，總共96頁(yè)。4.其他誘導(dǎo)方案①VBMCP+IFN-α2IFN對(duì)20%復(fù)發(fā)病人有效。治療時(shí)間2年優(yōu)點(diǎn)：VBMCP+IFN-α2完全緩解率高于VBMCP，緩解時(shí)間較長(zhǎng)，生存延長(zhǎng)。一組meta分析，ORR分別為54.4%和45.9%

總生存延長(zhǎng)5個(gè)月，延長(zhǎng)無(wú)復(fù)發(fā)生存時(shí)間長(zhǎng)達(dá)7個(gè)月。缺點(diǎn)：費(fèi)用較高和IFN毒性反應(yīng)。當(dāng)前48頁(yè)，總共96頁(yè)。②VCR+Melphlam+CTX+PDN/VCR+BCNU+ADM+PDN

（VMCP/VBAP方案交替）③解救治療VAD當(dāng)前49頁(yè)，總共96頁(yè)。VAD方案VCR+ADM+DXM劑量VCR:0.4mg/天IV×4天ADM:9mg/m2/天IV×4天DXM:40mgpod1–4,d9–12,d17–20每28天重復(fù)4周期療效:70%的病人可以取得腫瘤負(fù)荷減少>75%的療效中位起效時(shí)間:0.9個(gè)月VAD方案可使50％的患者達(dá)部分緩解（PR),5-10%的患者達(dá)完全緩解(CR)(蛋白電泳及免疫固定電泳無(wú)單克隆球蛋白且骨髓漿細(xì)胞＜5％)。BarlogieBetal.NEnglJMed.1984;310:1353InternationalMyelomaFoundation.Basicmyelomastatistics.Availableat:當(dāng)前50頁(yè)，總共96頁(yè)。VAD方案

優(yōu)點(diǎn)在于在伴有高鈣血癥或腎功能損害的病人中，可獲早期緩解。藥物不經(jīng)腎臟排泄，在腎功衰竭的病人中應(yīng)用較安全。突出優(yōu)點(diǎn)是對(duì)造血干細(xì)胞影響較小。當(dāng)前51頁(yè)，總共96頁(yè)。DVD方案患者：33位新診斷的MM患者方案：DVD方案楷萊：40mg/m2,第1天長(zhǎng)春新堿：2.0mg,第1天地塞米松40mg/d（口服或靜脈），連用4天每4周一個(gè)周期連續(xù)應(yīng)用6個(gè)或更多周期，和/或達(dá)最佳治療反應(yīng)后再繼續(xù)應(yīng)用2個(gè)周期HusseinMA,etal.Cancer2002;95:2160-2168.當(dāng)前52頁(yè)，總共96頁(yè)。HusseinMA,etal.Cancer2002;95:2160-2168.總有效率達(dá)88％當(dāng)前53頁(yè)，總共96頁(yè)。3年的總生存率為67％HusseinMA,etal.Cancer2002;95:2160-2168.當(dāng)前54頁(yè)，總共96頁(yè)。DVDT

多中心II期臨床39例初治多發(fā)性骨髓瘤患者治療方案

楷萊

40mg/m2IVd1

VCR2mgIVd1DXM40mgd1～4，第1個(gè)化療周期d15～18Thalidomide（沙利度胺）200mg，睡前口服每28天重復(fù)1次，共4療程AnnOncol.2004Jan;15(1):134-138當(dāng)前55頁(yè)，總共96頁(yè)。療效總有效率74％，CR4人（10％）；PR25人（64％）微小反應(yīng)3人（8％）

?級(jí)毒副反應(yīng)中性粒細(xì)胞減少：15％血小板減少15％深靜脈血栓10%便秘10％，皮疹5％，外周神經(jīng)病5％AnnOncol.2004Jan;15(1):134-138當(dāng)前56頁(yè)，總共96頁(yè)。NONHOOO反應(yīng)停(Thalomid?)口服免疫調(diào)節(jié)劑谷氨酸衍生物具有抗血管生成和誘導(dǎo)凋亡的作用當(dāng)前57頁(yè)，總共96頁(yè)。IL-6TNFIL-1IGFVEGFbFGF漿細(xì)胞間質(zhì)細(xì)胞ICAM,VCAMXXXXX反應(yīng)停的抑制作用反應(yīng)停的作用機(jī)制X血管NFΚ-B,CIAP-2,FLIPCaspace-8,TRAILIL-2Γ-IFNPBMCCD8NKcells當(dāng)前58頁(yè)，總共96頁(yè)。Thalidomide25mg–300mg/d

中位有效劑量200mg/d低劑量Thalidomide的作用機(jī)制抗炎免疫調(diào)節(jié)作用抑制巨噬細(xì)胞分化分泌INF-α和IL-2當(dāng)前59頁(yè)，總共96頁(yè)。ThalidomideRelapseFrontlineThalidomide25%-35%35%-45%MonoThalidomide/DexCedar59%76%Mayo-64%MDA65%78%當(dāng)前60頁(yè)，總共96頁(yè)。24685102050100200治療時(shí)間（月）腫瘤負(fù)荷DXM對(duì)反應(yīng)停的增效作用HCVAD反應(yīng)停200,400600600+Dexa當(dāng)前61頁(yè)，總共96頁(yè)。反應(yīng)停聯(lián)合DXM在初治患者的療效病例數(shù)PR/CR%深靜脈血栓Mayo5064％MDACC69％13024ECOG*69％51％103107183TD聯(lián)合D單藥*Rajkumaretal,ASH2004,Abst#205華法令1.0mg抗凝n5無(wú)抗凝治療np<.05當(dāng)前62頁(yè)，總共96頁(yè)。NNHOOOO反應(yīng)停

(Thalomid?)口服免疫調(diào)節(jié)劑,谷氨酸衍生物具有抗血管生成和誘導(dǎo)凋亡的作用Lenalidomide

(CC-5013;Revlimid?)ONNHOONH2當(dāng)前63頁(yè)，總共96頁(yè)。RandomizedmulticenterPhaseIIIECOGE4A03studyRDarm(223patients)Lenalidomide25mg(days1-21)Dexamethasone40mg(days1-4,9-12,17-20)Rdarm(222patients)Lenalidomide25mg(days1-21)Dexamethasone40mg(days1,8,15,22)Primaryendpoint:responserateat4monthsLenalidomide/Dexamethasone(RD)vsLenalidomide/Low-DoseDexamethasone(Rd)inTransplant-IneligiblePatientsRajkumaretal,Blood2007110:Abstract74當(dāng)前64頁(yè)，總共96頁(yè)。ResultsFromLenalidomide/Dexamethasone(RD)vsLenalidomide/Low-DoseDexamethasone(Rd)EfficacyRDRd1-yearSurvival88%96%2-yearSurvival75%87%OSinPts<65(1year)92%97%OSinPts>65(1year)83%94%Deaths4216Rajkumaretal,Blood2007110:Abstract74;Jacobusetal.,Blood2008112:Abstract1740Toxicity(Grade>3)RD(N=223)Rd(N=222)Neutropenia2.7%3.2%Thrombocytopenia1.8%1.4%DVT/PE25.6%11.4%AtrialFibrillation/Flutter3.1%0.0%Infection/Pneumonia16.1%9.0%Fatigue11.7%4.1%Hyperglycemia5.8%2.3%Neuropathy0.4%1.4%當(dāng)前65頁(yè)，總共96頁(yè)。Velcade?(bortezomib):prescribinginformation,2004Bortezomib(PS341;Velcade?)作用機(jī)制可逆性抑制26S蛋白酶體的糜蛋白酶樣活性通過(guò)抑制蛋白酶體阻止泛素化蛋白的裂解破壞細(xì)胞的自穩(wěn)狀態(tài),引起凋亡當(dāng)前66頁(yè)，總共96頁(yè)。XXX硼替佐米當(dāng)前67頁(yè)，總共96頁(yè)。Bortezomib(PS-341,Velcade?)療效%n100193Total612CRIF+47CR1733PRBortezomib1.3mg/m2IVd1,4,8,11 x最多8周期,或達(dá)到CR的再給2周期27%Richardson,etal.NEJM2003;348:2609-2617當(dāng)前68頁(yè)，總共96頁(yè)。Bortezomibvs大劑量DXM治療復(fù)發(fā)的MM*DXM治療進(jìn)展的患者給予bortezomib治療

APEX研究,III期臨床DXM40mgPO*

Days1–4,9–12,17–20

5周一療程×4周期

(n=336)Bortezomib13mg/m2,IV

Days1,4,8,11

3周為一療程×8周期

(n=333)DXM40mgPO

Days1–4

28天一周期×

5周期Bortezomib13mg/m2,IV

Days1,8,15,22

5周為一療程×3周期接受過(guò)1~3個(gè)療程治療的復(fù)發(fā)MM患者,對(duì)DXM治療無(wú)抗拒的(n=569)誘導(dǎo)化療維持治療治療280天治療278天RichardsonPetal.OralPresentation.46thAnnualMeetingoftheAmericanSocietyofHematology;

December4–7,2004;SanDiego,California[abstract336.5]當(dāng)前69頁(yè)，總共96頁(yè)。有效率BortezomibDexPValue病例數(shù),n333336中位TTP,月6.23.5<0.00011年生存,%80660.0005有效率,%3818中位TTR,天4343緩解時(shí)間,月8.05.6RichardsonPetal.OralPresentation.46thAnnualMeetingoftheAmericanSocietyofHematology;

December4–7,2004;SanDiego,California[abstract336.5]Bortezomibvs大劑量DXM治療復(fù)發(fā)的MM

療效總結(jié)當(dāng)前70頁(yè)，總共96頁(yè)。VTDvs.TDinPatients

WhoAreTransplantEligibleStudyobjectiveVTDvsTDinpreparationforautologousstemcelltransplantation(ASCT)StudydesignRandomizedtrialThreecyclesofinductiontherapyMethodsPts.randomizedtoeitherVDT(n=199)orTD(n=200).Stemcellswerecollected.Consolidationtherapywithsametreatmenttopts.Resultsdrawnfromafinalanalysisof399patients.PhaseIIIBortezomib-Thalidomide-Dexamethasone(VTD)vsThalidomide-Dexamethasone(TD)PriortoStemCellTransplantation(SCT))Cavoetal.Blood2008112:Abstract158當(dāng)前71頁(yè)，總共96頁(yè)。ProphylaxisAcyclovirprophylaxisagainstreactivationofVZV.TEEprophylaxiswithlowmolecularweightheparin,aspirin,orwarfarin;fixedlow-dosewarfariniseffective.Conclusions:IncomparisonwithTD,321-dcyclesofVTDasprimarytherapysignificantlyincreasedCR+nCRrates.TheseresponseratestranslatedintosignificantlyhigherCR+nCRafterfirstASCTintheVTDarm.Combinationsofnovelinductionagents,suchasVTD,canhavearemarkableimpactonbothpre-andpost-ASCTclinicaloutcome.ConclusionsFromVTDvs.TDCavoetal.Blood2008112:Abstract158當(dāng)前72頁(yè)，總共96頁(yè)。BortezomibandDexamethasonePrior

toASCTinTransplant-EligiblePatientsPhaseIII,activecontrol,multicenter,openlabel,randomizedObjective:comparetheCRratewithvincristine/adriamycin/dexamethasone(VAD)andbortezomib/dexamethasonecombinationsasinductiontherapy.NumberofsevereAEwassimilarbetweenthearms:Harousseauetal,Blood2007110:Abstract450.PostInductionPostASCTCR/nCR≥VGPR≥PRCR/nCR≥VGPR≥PRVAD9%24%71%28%50%88%Bortezomib/Dexamethasone22%50%89%38%66%87%P-value0.00850.0001NS0.1270.021NS當(dāng)前73頁(yè)，總共96頁(yè)。Post-inductioncompleteremission(CR)wasincreasedbyVDcomparedtoVAD.One-yearPFSandOSrateswere93%and97%withVDand90%and95%withVAD,respectively.ConclusionsFromBortezomibandDexamethasonePriortoASCTHarousseauetal,Blood2007110:Abstract450.當(dāng)前74頁(yè)，總共96頁(yè)。VISTATrial:VMPvsMP

inTransplant-IneligiblePatientsStudyobjective:DefinethedifferencesinefficacyandoutcomebetweenVMPvsMPStudydesignandmethod:VMParm(IVBortezomibincombinationwithoralprednisoneandoralmelphalan)vsMParm(oralmelphalanandprednisone)Primaryendpoint:Timetoprogression(TTP)Secondaryendpoints:Progression-freesurvival(PFS),overallsurvival(OS),overallresponserate(ORR),timetoprogression(TTP)anddurationofresponse(DOR),and

safetyAPhase3StudyComparingBortezomib/Melphalan/Prednisone(VMP)WithMelphalan/Prednisone(MP)SanMigueletalBlood2007110:Abstract76;SanMigueletalBlood2008112:Abstract650;HarousseauetalBlood2008112:Abstract650Mateousetal.Haematologica2008;93(4),560-565當(dāng)前75頁(yè)，總共96頁(yè)。Mateos,etal.Haematologica2008;93(4)560-565VISTATrial:VMPvs.MP

MostCommonAdverseEvents(in≥30%Patients)receivingVMP(n=60)AdverseEvent%ToxicitiesAllGrades%ToxicitiesGrades3/4Anemia8610Thrombocytopenia9351Infection7516Neutropenia8543Asthenia635Nausea552Diarrhea5516PeripheralNeuropathy5517Constipation528Anorexia382Vomiting302當(dāng)前76頁(yè)，總共96頁(yè)。VISTA:UpdatedResults

SanMiguelJF,etal.Blood2008112:Abstract650.VMPassociatedwith~36%reducedriskofdeath.43%ofptsintheMParmwhohadsubsequenttherapyreceivedBortezomibupondiseaseprogression.Ptswhoreceived>4cyclesofBortezomib:1-and2-yrOS:98.5%and89%,respectivelyMonthsPtsw/oEvent(%)01020304050607080901000246810121416182022242628303234363840Medianfollow-up:25.9mos

VMP:medianOSnotreached(75deaths);3-yrOSrate:72%

MP:medianOSnotreached(111deaths);3-yrOSrate:59%HR=0.644;P=.0032VMPMPOS當(dāng)前77頁(yè)，總共96頁(yè)。Conclusions

Adverseevents46%withVMP36%withMPPatientsremainedontherapylongerwithVMP:46weekswithVMP39weekswithMPPatientshadalongertimetonexttherapy.Patientsalsohadlongertreatment-freesurvival.SanMigueletalBlood2007110:Abstract76;SanMigueletal.Blood2008112:Abstract650.VISTATrial:VMPvs.MPTheseresultsestablishVMPasanotheroptionforpatientsnoteligibleforSCT.當(dāng)前78頁(yè)，總共96頁(yè)。Bortezomib/Lenalidomide/DexamethasoneinPatientsWhoAreTransplantEligibleFirst-linePhaseI/IIstudyassessessafetyandefficacy(66patients).Lenalidomide15to25mg(days1-14)Bortezomib1.0to1.3mg/m2(days1,4,8,11)Dexamethasone40/20-mg(cycles1-4/5-8)(days1,2,4,5,8,9,11,12)Upto821-daycyclesManageabletoxicitiesAllG3/4hematological(3-15%)G3hypophosphatemia(8%)DVT/pulmonaryembolism(5%withdailyaspirin)Notreatment-relatedmortalityOverallresponseratewas98%(atmaximumplanneddose–100%)VGPR71%CR/nCR36%VRDwasefficaciousandwell-toleratedinNDMMpatients.Richardsonetal,Blood2008112:Abstract92當(dāng)前79頁(yè)，總共96頁(yè)。Bortezomib/Lenalidomide/DexamethasonevsBortezomib/DexamethasoneStudyinTransplant-EligiblePatientsRandomized,multicenterPhaseIIIstudyECOGE1A05(initiatedinAugust2008)Consolidationtherapyforpatientsafterdexamethasone-basedinduction.VRDregimenBortezomib1.3mg/m2(days1,4,8,11)Lenalidomide15mg(days1-14)Dexamethasone40mg(days1,8,15)VDregimenBortezomib1.3mg/m2(days1,4,8,11)Dexamethasone40mg(days1,8,15)Primaryendpoint:PFSSCTisdeferreduntilrelapseThestrategywillfurtherprolongsurvival.FonsecaandRajkumar,ClinLymphomaandMyeloma20085:315-317當(dāng)前80頁(yè)，總共96頁(yè)。MPTvsMPRinPatientsWhoAreTransplantIneligibleRandomizedmulticenterPhaseIIIECOGE1A06studyMPTregimenMelphalan(days1-4)Prednisone(days1-4)Thalidomide(days1-28)MPRregimenMelphalan(days1-4)Prednisone(days1-4)Lenalidomide(days1-21)28daysforupto12cyclesPrimaryobjective:PFS,OS/ct2/show/NCT00602641?term=e1a06&rank=1當(dāng)前81頁(yè)，總共96頁(yè)。VMPvs.VTPMateosetal.Blood2008112:Abstract651ExploringAlkylating(Melphalan)andImmunomodulatory(Thalidomide)CombinationsWithBortezomibinPhaseIIIStudyinElderlyTransplant-IneligiblePatientsStudyDesignVMPArm(80patients):IVBortezomib2xweeklyfor16-weekcycleIVBortezomib1xweeklyfor55-weekcycles+oralMelphalan/Prednisone1xdondays1-4ofeachcycleVTPArm(87patients):IVBortezomib2xweeklyfor16-weekcycleIVBortezomib1xweeklyfor55-weekcycles+oralPrednisone1xdandcontinuousThalidomideondays1-4ofeachcyclePrimaryEndPointOverallresponserate(ORR)當(dāng)前82頁(yè)，總共96頁(yè)。ResultsVMPVTPPValue≥G3Neutropenia34%19%p=0.009≥G3Thrombocytopenia21%9%p=0.01Non-hematologicalAE(total)133157p<0.005≥G3Non-hematologicalAE25%32%p=0.04≥G3Cardiactoxicity0%7%N/A≥G3Thromboembolicevents<1%3.4%N/A≥G3Peripheralneuropathy9%15%N/ATreatmentdiscontinuationduetoAE(patients)816p=0.08ConclusionsFromVMPvs.VTP6cycles:31weeksoftreatment)Mateosetal.Blood2008112:Abstract651Incidenceofnon-hematologicalAE(especiallycardiac)washigherintheVTParm,resultinginmoreseriousAEsandtreatmentdiscontinuationsThalidomidemaynotbeapartnerofchoiceforBortezomib-Lenalidomideshouldbeexplored當(dāng)前83頁(yè)，總共96頁(yè)。BortezomibandVorinostatinEarlyClinicalStudiesVorinostat(Zolinza):asyntheticinhibitorofthehistonedeacetylases(HDACs)InhibitscellcycleandsurvivalofcancercellsFDA-approvedforsometypesoflymphomaStudydesign:Non-randomized,openlabel,parallelassignment,safetystudy,treatment,uncontrolled34patientswithrelapsed/refractoryMMObjectives:Primary:MTDSecondary:safetyandtolerabilityasmeasuredbydiseaseprogressionorunacceptabletoxicityduringeachtreatmentcycleWeberetal,Blood2008112:Abstract871當(dāng)前84頁(yè)，總共96頁(yè)。VorinostatPlusBortezomib:ConclusionsCombinationofVorinostatplusBortezomibisactivefortreatmentofmultiplemyelomaintheearlystudy.Weberetal,Blood2008112:Abstract871

ToxicityNausea61.8%Diarrhea58.8%Thrombocytopenia50%Vomiting50%EfficacyPartialresponse(PR)26%Minimalresponse(MR)21%Stabledisease(SD)53%DurationSD(days)160Range(days)9–369當(dāng)前85頁(yè)，總共96頁(yè)。不良事件：FiveMajorCategoriesofSideEffectsforNovelMMTreatmentsMyelosuppressionThromboemboliceventsPeripheralneuropathyGastrointestinalsideeffectsSteroid-associatedsideeffectsIMF-NLB‘ConsensusStatements’CJONJune2008當(dāng)前86頁(yè)，總共96頁(yè)。Myelosuppression:

DefinitionandSymptoms;NLBConsensusRecommendations.CJONJune2008MarrowRedBlood

CellsWhite

Blood

CellsPlateletsAnemiaFatigue,malaiseandSOBNeutropeniaIncreasedriskofbacterial,fungal,andviralinfectionsThrombocytopeniaBruisingandbleedingNeutrophilEosinophilLymphocyteMonocyteBasophil當(dāng)前87頁(yè)，總共96頁(yè)。ManagementofMyelosuppressionRiskofGrade3and4MyelosuppressionWithNovelTherapiesAnemiaNeutropeniaThrombocytopeniaThalidomide/Dexamethasone16%13%4%Lenalidomide/Dexamethasone8%21%10%Bortezomib12%14%32%AdaptedfromNLBConsensusRecommendations.CJONJune2008Thalomid?PrescribingInformation,Revlimid?PrescribingInformation,Velcade?Generalrecommendations:MonitorsignsandsymptomsMonitorCBCEducateonsignsandsymptomsMyelosuppressionmanagement:

GrowthfactortherapyDosereductionasappropriateTransfusionasindicated當(dāng)前88頁(yè)，總共96頁(yè)。OverviewofThromboembolicEventsCancerpatientshaveahigherriskofTEevents(bloodclots),whichmayleadto:Deepveinthrombosis(DVT)Pulmonaryembolism(PE)MMpatientsareatanincreasedriskfo