多發(fā)性骨髓瘤的精確診斷

1、多發(fā)性骨髓瘤的精確診斷多發(fā)性骨髓瘤的精確診斷第1頁(yè)多發(fā)性骨髓瘤的精確診斷第2頁(yè)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 多發(fā)性骨髓瘤的精確診斷第3頁(yè)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診療標(biāo)準(zhǔn)Rajkumar V et al Lancet Oncol , 15: e538-48MDE, myeloma defining events 60% BMPC 判定其克隆性，骨髓活檢、涂片、流式中國(guó)多發(fā)性骨髓瘤診治指南(版)多發(fā)性骨髓瘤的精確診斷第4頁(yè)SMM VS MGUS 進(jìn)展百分比多發(fā)性骨髓瘤的精確診斷第5頁(yè)P(yáng)erez-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 冒煙型骨髓瘤向癥狀性骨髓瘤演變風(fēng)險(xiǎn)b

4、ased on the % of aberrant PCs by immunophenotype plus immunoparesis1.05 yrs多發(fā)性骨髓瘤的精確診斷第6頁(yè)MM診療標(biāo)準(zhǔn)(IMWG)更新緣由無(wú)須治療!“冒煙型” 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.多發(fā)性骨髓瘤的精確診斷第7頁(yè)Lenalidomide+dex（Rd)對(duì)高危冒煙型MM患者臨床試驗(yàn)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多發(fā)性骨髓瘤的精確診斷第8頁(yè)Lenalidomide+dex（Rd)對(duì)高危冒煙型MM患者臨床試驗(yàn)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.多發(fā)性骨髓瘤的精確診斷第9頁(yè)P(yáng)rogression 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.多發(fā)性骨髓瘤的精確診斷第10頁(yè)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.多發(fā)性骨髓瘤的精確診斷第11頁(yè)完整單克隆免疫球蛋白單克隆游離輕鏈血清蛋白電泳血清免疫固定電泳尿免疫固定電泳血清游離輕鏈類 IgG IgA IgD IgM IgE型、血清游離輕鏈（sFLC）多發(fā)性骨髓

12、瘤的精確診斷第12頁(yè)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多發(fā)性骨髓瘤的精確診斷第13頁(yè)，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”檢測(cè)多發(fā)性

14、骨髓瘤的精確診斷第14頁(yè)“早期”“及時(shí)”檢測(cè)IgG20-25 daysIgA6-7 daysIgM6-8 daysFree Kappa2-4hFree Lambda3-6h多發(fā)性骨髓瘤的精確診斷第15頁(yè)Dispenzieri A. et al. Blood sFLC ratio 8 or 0.1258sFLC ratio 0.12540% (2years)TTP to symptomatic MM from sFLC ratio多發(fā)性骨髓瘤的精確診斷第16頁(yè)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處骨質(zhì)破壞多發(fā)性骨髓瘤的精確診斷第21頁(yè)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.多發(fā)性骨髓瘤的精確診斷第22頁(yè)P(yáng)ET/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, 中位隨訪2.2年16% 出現(xiàn) Fls, 未出現(xiàn)溶骨性改變2年P(guān)ET/CT進(jìn)展百分比：58%（陽(yáng)性） VS 33% （陰性）多發(fā)性骨髓瘤的精確診斷第23頁(yè)高危冒煙型骨髓瘤疾病進(jìn)展情況多發(fā)性骨髓瘤的精確診斷第24頁(yè)Revised International Myeloma Working Group Diagnostic Criteria for Multiple MyelomaRajkumar et

18、 al, Lancet Oncology, ; 15:e538-548多發(fā)性骨髓瘤的精確診斷第25頁(yè)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多發(fā)性骨髓瘤的精確診斷第26頁(yè)極高危SMM = 活動(dòng)性骨髓瘤MGUS、SMM和MM界定標(biāo)準(zhǔn)(IMWG)特征CRAB癥狀西班牙標(biāo)準(zhǔn)梅奧標(biāo)準(zhǔn)極高危骨髓瘤高危骨髓瘤低危骨髓瘤意義未明免疫球蛋白血癥（MGUS)Slim-CRAB癥狀S (60% 漿細(xì)胞增多)Li (sFLC ratio

21、 100)M (MRI 1處或多處骨質(zhì)破壞)SMM中國(guó)多發(fā)性骨髓瘤診治指南(版)從 CRAB 到 SLiM CRAB多發(fā)性骨髓瘤的精確診斷第27頁(yè)多發(fā)性骨髓瘤的精確診斷第28頁(yè)診療標(biāo)準(zhǔn)其它更新腎功效損害 (肌酐去除率40ml/min，肌酐177mmol/L)M蛋白不做診療必須指標(biāo)（3%不分泌型，30%sFLC指標(biāo)正常）孤立漿細(xì)胞瘤兩種類型孤立漿細(xì)胞瘤：骨髓無(wú)克隆漿細(xì)胞 （PD: 10%/3年）孤立孤立漿細(xì)胞瘤:克隆漿細(xì)胞10%PD: 60%/3年 (骨漿細(xì)胞瘤）PD: 20%/3年 (軟組織漿細(xì)胞瘤）多發(fā)性骨髓瘤的精確診斷第29頁(yè)25% /year risk of MM多發(fā)性骨髓瘤的精確診斷第

22、30頁(yè)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 多發(fā)性骨髓瘤的精確診斷第31頁(yè)思索與啟示推薦MRI，PET-CT或者CT對(duì)全部SMM或者漿細(xì)胞瘤患者進(jìn)行影像學(xué)檢測(cè)方法 （X線）疑似骨質(zhì)改變 3-6月復(fù)檢高危SMM在出現(xiàn)CRAB前，需親密觀察sFLC肌酐去除率影像學(xué)多發(fā)性骨髓瘤的精確診斷第32頁(yè)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評(píng)定腫瘤負(fù)荷和預(yù)后分期Durie-Salmon stage (DS)多發(fā)性骨髓瘤的精確診斷第33頁(yè)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, .多發(fā)性骨髓瘤的精確診斷第34頁(yè)FISH Del 17p t(14;16) t(14;20) GEP 高危特征全部其它類型包含: 超二倍體 t(11;14) t(6;14)FISH t(4;14)*細(xì)胞遺傳學(xué)13號(hào)染色體缺失 或 低二倍體PCLI 3%高危 20%中危 20%標(biāo)危 60% 3 年 4-5 年 8-10 年 mSMART 2.0: 多發(fā)性骨髓瘤預(yù)后分層體系染色體異常 Chromosomal abnormalities (CA)使用iFISH方法檢測(cè)多發(fā)性骨髓瘤的精確診斷第35頁(yè)乳酸脫氫酶(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多發(fā)性骨髓瘤的精確診斷第36頁(yè)乳酸脫氫酶(LDH)Chim CS, et al. Eur J Haematol. Apr;94(4):330-5多發(fā)性骨髓瘤的精確診斷第37頁(yè)P(yáng)revious Studies Assessing Combinations of Prognostic Tools

28、以上數(shù)據(jù)是對(duì)年輕、適合移植患者分析整理，不過(guò)對(duì)于老年患者及不適合移植患者數(shù)據(jù)尚無(wú)！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, 多發(fā)性骨髓瘤的精確診斷第38頁(yè)Revised International Myeloma Working Group ISS stage for Multiple Myeloma多發(fā)

29、性骨髓瘤的精確診斷第39頁(yè)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多發(fā)性骨髓瘤的精確診斷第40頁(yè)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)多發(fā)性骨髓瘤的精確診斷第41頁(yè)Overall survival (OS) in patients with multiple myeloma stratified by R-ISS algorithmUnivariable analysis of OSA med