1、杜鹃杜鹃上海长征医院血液科上海长征医院血液科全军骨髓瘤与淋巴瘤疾病中心全军骨髓瘤与淋巴瘤疾病中心多发性骨髓瘤的精确诊断12MGUS SMM MMl 10%BMPC ANDl10%BMPC ORl 3gm/dL M protein ANDlNo CRABlClonal PCPDlCRABCRAB:C=Calcium(elevated),R=Renal failure,A=Anemia,B=Bone lesionsRajkumar SV.Cell Textbook of Medicine,24th Edition 20123MGUS SMM MMl 10%BMPC ANDl10%-60%BMPC
2、ORl 3gm/dL S.M protein ORl 500mg/24h Ur.M protein AND lNo MDElPCPDl1 or more MDElCRABl 60%BMPCl100 FLC ratiol 1 MRI focal lesions 2014年修改的IMWG诊断标准Rajkumar V et al Lancet Oncol 2014,15:e538-48MDE,myeloma defining events 60%BMPC 鉴定其克隆性，骨髓活检、涂片、流式中国多发性骨髓瘤诊治指南中国多发性骨髓瘤诊治指南(2015(2015版版)4SMM VS MGUS 进展比例5P
3、erez-Persona E,et al.Blood.2007;110:2586-92.95%aPC/BMPC or paresisn=22(10 progr.)95%aPC/BMPC+paresisn=39(28 progr.)No adverse factorsn=28(1 progr.)1209672482401.00.80.60.40.20.0MonthsTTP(%)Median not reached Median 73 monthsp=0.003Median 23 months8%42%82%High Risk Low Risk 冒烟型骨髓瘤向症状性骨髓瘤演变风险based on
4、the%of aberrant PCs by immunophenotype plus immunoparesis1.05 yrs6MM的诊断标准(IMWG)的更新的缘由不必治不必治疗疗!“冒烟型”骨髓瘤(MC 3 g/dl&/or PC 10%.No CRAB)pEarly MP vs.deferred MP1,2,3.No benefitpThalidomide4,5 only 30%PR&No benefit in TTP/OSpBisphosphonates6,7.No benefit in OR/TTP/OS1.Hjorth M,et al.Eur J Haematol.1993;5
5、0:95-102.2.Grignani G,et al.Br J Cancer.1996;73:1101-07.3.Riccardi A,et al.Br J Cancer.2000;824.Rajkumar SV,et al.Am J Hematol 2010;85(10):737-40 5.Barlogie B,et al.Blood.2008;112:3122-25.6.Musto P,et al.Leuk Lymphoma.2011;52(5):771-7757.Musto P,et al.Cancer.2008;113:1588-95.7Lenalidomide+dexLenalid
6、omide+dex（Rd)Rd)对高危对高危冒烟型冒烟型MMMM患者的临床试验研究患者的临床试验研究median TTP 21(P0.001)median TTP not reached13 Progressions(22%)47 Progressions(76%)Mateos et al NEJM 2013,ASH 2014(Abs3465)To meet SMM diagnosis criteriaat least 95%phenotypically aberrant plasma cells in the BMPCreductions in one or two uninvolved i
7、mmunoglobulins of more than 25%9 cycle Rd induction therapy followedby maintenance therapy with lenalidomide8Lenalidomide+dexLenalidomide+dex（Rd)Rd)对高危对高危冒烟型冒烟型MMMM患者的临床试验研究患者的临床试验研究TTPOS TTPMateos et al NEJM 2013,ASH 2014(Abs3465)OS from the date of inclusion in the studyOS from the date of diagnos
8、is of SMM94%80%94%78%3 years5 yearsThis randomized,phase 3 trial showed that early treatment with Rd,followed by maintenance therapy with lenalidomide,in patients with high-risk SMM significantly delayed the time to progression to symptomatic disease and resulted in an OS benefit.9Progression to mye
9、loma occurred within 2 years of the diagnosis in 95%of the patients with 60%or more bone marrow plasma cells,with a median time to progression of 7 months(95%CI,1.0 to 12.9)1.Time to progression of disease patients with SMMTime to progression of disease patients with SMM1.Rajkumar SV,et al.N Engl J
10、Med.20112.Kastritis E.et al.Leukemia 20133.Waxman AJ.et al.J Clin Oncol 201495%N=655 SMM(1996.01-2010.06 at Mayo Clinic)N=21 pts(3.2%)Greek Myeloma Group2the University of Pennsylvania3.10TTP of disease patients with SMMMayo 2007TTP of disease patients with SMMMayo 2007In 2007 N Engl J MedDuring pas
11、t 26 years,276 SMM at Mayo Clinic p6 of 276 patients(2%)60%PC in BMl4 patients progressed to symptomatic MM from 3 to 9 monthsl1 of these patients died 13.5 months(no specific reason)l1 SMM progressed to MM 50 months,death within 2 years of that date.Kyle RA,et al.N Engl J Med.2007 Jun 21;356(25):25
12、82-90.11完整的单克隆免疫球蛋白单克隆游离轻链血清蛋白电泳血清免疫固定电泳尿免疫固定电泳尿免疫固定电泳血清游离轻链血清游离轻链类 IgG IgA IgD IgM IgE型、血清游离轻链（sFLC）12IgGIgAIgM FLCTotal light chain assay versus sFLC assay Total assaySerum FLC assay FLC8g/L2g/L1g/L10mg/L10mg/LIn healthy individual:Total =11.01 g/L In healthy individual:Free =10 mg/L In light chai
13、n myeloma Total =11.05 g/L 50mg/LIn light chain myeloma:Free =50 mg/L 50mg/L8g/L2g/L1g/Lg/L polyclonal immunoglobulin background13，mg/Lmg/L，mg/Lmg/LSPEPSPEP1 12,000500Serum IFESerum IFE1 1150100UPEPUPEP2 23030Urine IFEUrine IFE2 22020sFLCsFLC assay assay3 31.21.71.Katzmann et al.Clin Chem.2002;1437-
14、1444.2.Beetham et al.Ann Clin Biochem.2000,37:581-587.3.Bradwell et al.Serum Free Light Chains Analysis.4thed.“高度敏感”的“定量”检测14“早期”“及时”的检测IgGIgG20-25 daysIgAIgA6-7 daysIgMIgM6-8 daysFree KappaFree Kappa2-4hFree LambdaFree Lambda3-6h15Dispenzieri A.et al.Blood 2008sFLC ratio 8 or 0.1258sFLC ratio 0.125
15、40%(2years)TTP to symptomatic MM from sFLC ratio16sFLC ratio as a biomarker for high-risk SMMMedian TTP was 15 mosFLC ratio 100Median TTP was 55 mosFLC ratio 10072%28%Larsen JT,et al.Leukemia.2013586 patients with SMM diagnosed between 1970 to 2010VariablessFLC 1 focal lesion on spinal MRI in 9 of 6
16、5 patients(14%)with SMM.高危SMM的MRI 1处骨质破坏21MRI value in patients with SMMRegarding smoldering or asymptomatic myeloma,all patients should undergo whole-body MRI(WB-MRI;or spine and pelvic MRI if WB-MRI is not available),and if they have one focal lesion of a diameter 5 mm,they should be considered to
17、 have symptomatic disease that requires therapy.22PET/CT focal,but not osteolytic,lesions predict the progression of SMM to active diseaseZamagni E et al.Leukemia.2016 Feb;30(2):417-22120 pts,中位随访2.2年16%出现 Fls,未出现溶骨性改变2年PET/CT进展比例：58%（阳性）VS 33%（阴性）23高危冒烟型骨髓瘤疾病进展情况24Revised International Myeloma Work
18、ing Group Diagnostic Criteria for Multiple MyelomaRajkumar et al,Lancet Oncology,2014;15:e538-54825 Clonal BM PC10%or biopsy proven bony or extramedullary plasmacytoma and ANY ONE OR MORE OF THE FOLLOWING MYELOMA DEFINING EVENTS(MDE)End organ damage(CRAB)that attributed to the PC disorder,Hypercalce
19、mia:11 mg/dLRenal insufficiency:Cr Cl 2 mg/dLAnemia:Hb value 2 g/dL below the lower limit of normal Bone lesions:one or more osteolytic lesions on skeletal radiography,CT,or PET-CT,Any one or more of the following New biomarkers of malignancy(Early MM)60%PC in BM Involved/uninvolved serum free light
20、 chain ratio 100 1 focal lesions on magnetic resonance imaging studies Rajkumar V et al Lancet Oncol 2014,15:e538-48Revised International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma26极高危极高危SMM=SMM=活动性骨髓瘤活动性骨髓瘤MGUS、SMM和MM的界定标准(IMWG)特征CRAB症状西班牙标准梅奥标准极高危骨髓瘤高危骨髓瘤低危骨髓瘤意义未明的免疫球蛋白血症（MGUS
21、)Slim-CRAB症状S (60%浆细胞增多)Li(sFLC ratio 100)M (MRI 1处或多处骨质破坏)SMM中国多发性骨髓中国多发性骨髓瘤诊治指南瘤诊治指南(2015(2015版版)从 CRAB 到 SLiM CRAB2728诊断标准其它更新l肾功能损害(肌酐清除率40ml/min，肌酐177mmol/L)lM蛋白不做诊断必须指标（3%不分泌型，30%sFLC指标正常）l孤立浆细胞瘤的两种类型p孤立浆细胞瘤：骨髓无克隆浆细胞（PD:10%/3年）p孤立孤立浆细胞瘤:克隆浆细胞10%PD:60%/3年(骨的浆细胞瘤）PD:20%/3年(软组织的浆细胞瘤）2925%/year ri
22、sk of MM302-year TTP 6High levels of circulating plasma cells80%1Abnormal plasma cell immunophenotype 95%plus immunoparesis50%2Evolution of smouldering multiple myeloma*65%3Cytogenetic subtypes:t(4;14),1q amp,or del 17p50%4High bone marrow plasma cell proliferative rate80%5Unexplained decrease in cr
23、eatinine clearance by 25%accompanied by a rise in urinary monoclonal protein or serum free light-chain concentrationsNot known*Increase in serum monoclonal protein by 10%on each of two successive evaluations within a 6-month period.高危SMM：中位TTP2年1、Bianchi et al.Leukemia 2013.2、Perez-Persona E et al.B
24、r J Haematol 20103、Rosinol et al.Br J Haematol 2003 4、Rajkumar et al.Leukemia 20135、Madan et all.Mayo Clin Proc 2010.6、Rajkumar et al.Lancet Oncol 201431思考与启示l推荐MRI，PET-CT或者CT的对所有SMM或者浆细胞瘤患者进行的影像学检测方法（X线）p疑似骨质改变 3-6月复检l高危SMM在出现CRAB前，需密切观察psFLCp肌酐清除率p影像学32ISSP 1.0p=0.0025P53 deletionPerez-Simon Blood
25、 1996,Gutierrez,Leukemia 2007Tumor Burden-Circulating PC（FCM）-Extramedullary Disease Gonzalves Leukemia 2014;Usmani Leukemia,2012 Zamagni E.et al,Blood 2011FISH评估肿瘤负荷和预后的分期Durie-Salmon stage(DS)33ISS分期分期分期ISSISS分期分期中位生存中位生存2-MG3.5mg/L，白蛋白 35/L；62月不符合和期的所有患者45月2-MG5.5mg/L。29月Greipp,PR et al.J.Clin.On
26、col.23:3412,2005.34FISH Del 17p t(14;16)t(14;20)GEP 高危特征所有其他类型包含:超二倍体 t(11;14)t(6;14)FISH t(4;14)*细胞遗传学13号染色体缺失 或 低二倍体PCLI 3%高危高危 20%20%中危中危 20%20%标危标危 60%60%3 3 年年 4-5 4-5 年年 8-10 8-10 年年 mSMART 2.0:多发性骨髓瘤的预后分层体系染色体异常 Chromosomal abnormalities(CA)使用iFISH方法检测35乳酸脱氢酶(LDH)中位OS（月）LDH高于正常正常LDHBarlogie B
27、,et al.Ann InternMed 110:521-525,19891544Dimopoulos MA,et al.Ann Intern Med 115:931-935,19912276Terpos E,et al.Eur J Haematol 85:114-119,2010215136乳酸脱氢酶(LDH)Chim CS,et al.Eur J Haematol.2015 Apr;94(4):330-537Previous Studies Assessing Combinations of Prognostic Tools以上数据是对年轻、适合移植的患者的分析整理，但是对于老年患者及不适
28、合移植患者的数据尚无！10-13:Neben K,et al.Haematologica 95:1150-1157,2010;Boyd KD,et al.Leukemia 26:349-355,2012;Avet-Loiseau H,Leukemia 27:711-717,2013;Moreau P,J Clin Oncol 32:2173-2180,201438Revised International Myeloma Working Group ISS stage for Multiple Myeloma39修改的ISS分期（R-ISS）4,445 patients with NDMM11
29、 international,multicenter clinical trials,from 2005 to 2012IST-CAR-506EMN 01RV-MM-EMN-441MM-RV-PI-209GIMEMA-MM-05-05GIMEMA-MM-03-05MMY2069HOVON-65/GMMG-HD4VTD v TDGEM05MENOS65IFM 2005-01pISS stage,pCA by FISH(CD138+)pserum LDHpThe primary end point was OSpThe secondary end point was PFS4,445 patien
30、ts with NDMM 11 international,multicenter clinical trials,from 2005 to 2012IST-CAR-506EMN 011RV-MM-EMN-441MM-RV-PI-209GIMEMA-MM-05-05GIMEMA-MM-03-05MMY2069HOVON-65/GMMG-HD4VTD v TDGEM05MENOS65IFM 2005-014,445 patients with NDMM11 international,multicenter clinical trials,from 2005 to 2012IST-CAR-506
31、EMN 01RV-MM-EMN-441MM-RV-PI-209GIMEMA-MM-05-05GIMEMA-MM-03-05MMY2069HOVON-65/GMMG-HD4VTD v TDGEM05MENOS65IFM 2005-0140R-ISS stageCriteriaISS stage I and standard-risk CA by iFISH and normal LDHNot R-ISS stage I or IIIISS stage III and either high-risk CA by iFISH or high LDH修改的ISS分期（R-ISS）high-risk
32、CA:del(17p)and/or t(4;14)and/or t(14;16)41Overall survival(OS)in patients with multiple myeloma stratified by R-ISS algorithmUnivariable analysis of OSA median follow-up of 46 months82%62%40%5 yrs42PFS in patients with multiple myeloma stratified by R-ISS algorithm55%36%24%43R-ISS and OS by type of
33、treatment nontransplantation-based regimenstransplantation-based regimens44R-ISS and OS by type of treatmentimmunomodulatory-based regimensproteasome inhibitorbased 45R-ISS and OS by ageYounger than 65 yearsolder than 65 years46pIn this study,the most common prognostic tools(ISS stage,CA,and serum L
34、DH level)were combined to define a simple,reliable,and pragmatic risk stratification of patients with NDMM.pIn the univariable Cox analyses,we found that ISS stage III,high-risk CA,and elevated serum LDH were associated with a significantly poorer OS(HR from 2.03 to 4.68).Their combination in the R-ISS improved the stratification and the impact on OS(HR from 3.68 to 9.95).pThe prognostic impact of R-ISS on OS was confirmed independently of age and therapy.R-ISS significant 47总结与思考l治疗模式的转变l提高QOLl提高疗效和预后l潜在的治愈可能性.4849
