多发性骨髓瘤的精确诊断

1、多发性骨髓瘤的精确诊断多发性骨髓瘤的精确诊断第1页多发性骨髓瘤的精确诊断第2页MGUS SMM MM 10% BMPC AND10% BMPC OR 3gm/dL M protein ANDNo CRABClonal PCPDCRABCRAB: C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesionsRajkumar SV. Cell Textbook of Medicine, 24th Edition 多发性骨髓瘤的精确诊断第3页MGUS SMM MM 10% BMPC AND10%-60% BMPC OR

2、 3gm/dL S. M protein OR 500mg/24h Ur. M protein AND No MDEPCPD1 or more MDECRAB 60% BMPC100 FLC ratio 1 MRI focal lesions 年修改IMWG诊疗标准Rajkumar V et al Lancet Oncol , 15: e538-48MDE, myeloma defining events 60% BMPC 判定其克隆性，骨髓活检、涂片、流式中国多发性骨髓瘤诊治指南(版)多发性骨髓瘤的精确诊断第4页SMM VS MGUS 进展百分比多发性骨髓瘤的精确诊断第5页Perez-Per

3、sona E, et al. Blood. ;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b

4、ased on the % of aberrant PCs by immunophenotype plus immunoparesis1.05 yrs多发性骨髓瘤的精确诊断第6页MM诊疗标准(IMWG)更新缘由无须治疗!“冒烟型” 骨髓瘤 (MC 3 g/dl &/or PC 10%.No CRAB)Early MP vs. deferred MP1,2,3.No benefitThalidomide4,5 only 30% PR & No benefit in TTP/OSBisphosphonates6,7.No benefit in OR/TTP/OS1.Hjorth M, et al.

5、 Eur J Haematol. 1993;50:95-102. 2.Grignani G, et al. Br J Cancer. 1996;73:1101-07. 3.Riccardi A, et al. Br J Cancer. ;824. Rajkumar SV, et al. Am J Hematol ; 85(10):737-40 5. Barlogie B, et al. Blood. ;112:3122-25. 6. Musto P, et al. Leuk Lymphoma. ;52(5):771-7757. Musto P, et al. Cancer. ;113:1588

6、-95.多发性骨髓瘤的精确诊断第7页Lenalidomide+dex（Rd)对高危冒烟型MM患者临床试验研究median TTP 21 (P0.001)median TTP not reached13 Progressions (22%)47 Progressions (76%)Mateos et al NEJM , ASH (Abs3465) To meet SMM diagnosis criteriaat least 95% phenotypically aberrant plasma cells in the BMPCreductions in one or two uninvolved

7、 immunoglobulins of more than 25%9 cycle Rd induction therapy followedby maintenance therapy with lenalidomide多发性骨髓瘤的精确诊断第8页Lenalidomide+dex（Rd)对高危冒烟型MM患者临床试验研究TTPOS TTPMateos et al NEJM , ASH (Abs3465) OS from the date of inclusion in the studyOS from the date of diagnosis of SMM94%80%94%78%3 years

8、5 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.多发性骨髓瘤的精确诊断第9页Progression to myeloma occurre

9、d 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 SMMRajkumar SV, et al. N Engl J Med. Kastritis E. et al. Leukemia Waxman AJ. et al. J

10、Clin Oncol 95%N=655 SMM (1996.01-.06 at Mayo Clinic)N=21 pts (3.2%)Greek Myeloma Group2the University of Pennsylvania3.多发性骨髓瘤的精确诊断第10页TTP of disease patients with SMMMayo In N Engl J MedDuring past 26 years, 276 SMM at Mayo Clinic 6 of 276 patients (2%) 60% PC in BM4 patients progressed to symptomat

11、ic MM from 3 to 9 months1 of these patients died 13.5 months(no specific reason)1 SMM progressed to MM 50 months, death within 2 years of that date.Kyle RA, et al. N Engl J Med. Jun 21;356(25):2582-90.多发性骨髓瘤的精确诊断第11页完整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血清游离轻链类 IgG IgA IgD IgM IgE型、血清游离轻链（sFLC）多发性骨髓

12、瘤的精确诊断第12页IgGIgAIgM 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 chain myeloma Total = 11.05 g/L 50mg/LIn light chain myeloma:Free = 50 mg/L 50mg/L8g/L2g/L1g/L

13、g/L polyclonal immunoglobulin background多发性骨髓瘤的精确诊断第13页，mg/L，mg/LSPEP12,000500Serum IFE1150100UPEP23030Urine IFE22020sFLC assay31.21.71. Katzmann et al. Clin Chem. ; 1437-1444.2. Beetham et al. Ann Clin Biochem. , 37: 581-587.3. Bradwell et al. Serum Free Light Chains Analysis. 4thed.“高度敏感”“定量”检测多发性

14、骨髓瘤的精确诊断第14页“早期”“及时”检测IgG20-25 daysIgA6-7 daysIgM6-8 daysFree Kappa2-4hFree Lambda3-6h多发性骨髓瘤的精确诊断第15页Dispenzieri A. et al. Blood sFLC ratio 8 or 0.1258sFLC ratio 0.12540% (2years)TTP to symptomatic MM from sFLC ratio多发性骨髓瘤的精确诊断第16页sFLC ratio as a biomarker for high-risk SMMMedian TTP was 15 mosFLC r

15、atio 100Median TTP was 55 mosFLC ratio 10072%28%Larsen JT, et al. Leukemia. 586 patients with SMM diagnosed between 1970 to VariablessFLC 1 focal lesion on spinal MRI in 9 of 65 patients (14%) with SMM.高危SMMMRI 1处骨质破坏多发性骨髓瘤的精确诊断第21页MRI value in patients with SMMRegarding smoldering or asymptomatic m

16、yeloma, 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 have symptomatic disease that requires therapy.多发性骨髓瘤的精确诊断第22页PET/CT focal, but not osteolytic, lesions

17、predict the progression of SMM to active diseaseZamagni E et al. Leukemia. 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进展百分比：58%（阳性） VS 33% （阴性）多发性骨髓瘤的精确诊断第23页高危冒烟型骨髓瘤疾病进展情况多发性骨髓瘤的精确诊断第24页Revised International Myeloma Working Group Diagnostic Criteria for Multiple MyelomaRajkumar et

18、 al, Lancet Oncology, ; 15:e538-548多发性骨髓瘤的精确诊断第25页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, Hypercalcemia: 11 mg/dLRenal insufficiency: Cr Cl 2 mg/

19、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 BMInvolved/uninvolved serum free light chain ratio 1001 focal lesions on m

20、agnetic resonance imaging studies Rajkumar V et al Lancet Oncol , 15: e538-48Revised International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma多发性骨髓瘤的精确诊断第26页极高危SMM = 活动性骨髓瘤MGUS、SMM和MM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免疫球蛋白血症（MGUS)Slim-CRAB症状S (60% 浆细胞增多)Li (sFLC ratio

21、 100)M (MRI 1处或多处骨质破坏)SMM中国多发性骨髓瘤诊治指南(版)从 CRAB 到 SLiM CRAB多发性骨髓瘤的精确诊断第27页多发性骨髓瘤的精确诊断第28页诊疗标准其它更新肾功效损害 (肌酐去除率40ml/min，肌酐177mmol/L)M蛋白不做诊疗必须指标（3%不分泌型，30%sFLC指标正常）孤立浆细胞瘤两种类型孤立浆细胞瘤：骨髓无克隆浆细胞 （PD: 10%/3年）孤立孤立浆细胞瘤:克隆浆细胞10%PD: 60%/3年 (骨浆细胞瘤）PD: 20%/3年 (软组织浆细胞瘤）多发性骨髓瘤的精确诊断第29页25% /year risk of MM多发性骨髓瘤的精确诊断第

22、30页2-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

23、creatinine 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 .2、Perez-Persona E et al.

24、 Br J Haematol 3、Rosinol et al. Br J Haematol 4、Rajkumar et al. Leukemia 5、Madan et all. Mayo Clin Proc . 6、Rajkumar et al. Lancet Oncol 多发性骨髓瘤的精确诊断第31页思索与启示推荐MRI，PET-CT或者CT对全部SMM或者浆细胞瘤患者进行影像学检测方法 （X线）疑似骨质改变 3-6月复检高危SMM在出现CRAB前，需亲密观察sFLC肌酐去除率影像学多发性骨髓瘤的精确诊断第32页ISSP 1.0p=0.0025P53 deletionPerez-Simon

25、Blood 1996, Gutierrez , Leukemia Tumor Burden -Circulating PC （FCM）- Extramedullary Disease Gonzalves Leukemia ; Usmani Leukemia, Zamagni E. et al, Blood FISH评定肿瘤负荷和预后分期Durie-Salmon stage (DS)多发性骨髓瘤的精确诊断第33页ISS分期分期ISS分期中位生存2-MG3.5mg/L，白蛋白 35/L；62月不符合和期全部患者45月2-MG5.5mg/L。29月Greipp, PR et al. J. Clin.

26、 Oncol. 23:3412, .多发性骨髓瘤的精确诊断第34页FISH Del 17p t(14;16) t(14;20) GEP 高危特征全部其它类型包含: 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 20%中危 20%标危 60% 3 年 4-5 年 8-10 年 mSMART 2.0: 多发性骨髓瘤预后分层体系染色体异常 Chromosomal abnormalities (CA)使用iFISH方法检测多发性骨髓瘤的精确诊断第35页乳酸脱氢酶(LDH)中位OS（月）LDH高于正常正常LDHBarlog

27、ie B, 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, 2151多发性骨髓瘤的精确诊断第36页乳酸脱氢酶(LDH)Chim CS, et al. Eur J Haematol. Apr;94(4):330-5多发性骨髓瘤的精确诊断第37页Previous Studies Assessing Combinations of Prognostic Tools

28、以上数据是对年轻、适合移植患者分析整理，不过对于老年患者及不适合移植患者数据尚无！10-13: Neben K, et al. Haematologica 95:1150-1157, ; Boyd KD, et al. Leukemia 26:349-355, ; Avet-Loiseau H, Leukemia 27:711-717, ; Moreau P, J Clin Oncol 32:2173-2180, 多发性骨髓瘤的精确诊断第38页Revised International Myeloma Working Group ISS stage for Multiple Myeloma多发

29、性骨髓瘤的精确诊断第39页修改ISS分期（R-ISS）4,445 patients with NDMM11 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 2005-01ISS stage, CA by FISH (CD138+)serum LDHThe primary end poin

30、t was OSThe secondary end point was PFS4,445 patients 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,mul

31、ticenter 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 2005-01多发性骨髓瘤的精确诊断第40页R-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ISS分期（R-ISS）high-risk CA: del(17p) and/or t(4;14) and/or t(14;16)多发性骨髓瘤的精确诊断第41页Overall survival (OS) in patients with multiple myeloma stratified by R-ISS algorithmUnivariable analysis of OSA med