多发性骨髓瘤的精确诊断

κ，mg/L 2,000 150 30 20 1.2
λ，mg/L 500 100 30 20 1.7
1. Katzmann et al. Clin Chem. 2002; 1437-1444. 2. Beetham et al. Ann Clin Biochem. 2000, 37: 581-587. 3. Bradwell et al. Serum Free Light Chains Analysis. 4thed.
8<sFLC ratio ≥0.125
Dispenzieri A. et al. Blood 2008
sFLC ratio as a biomarker for high-risk SMM
586 patients with SMM diagnosed between 1970 to 2010
72%
1 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. 2007 Jun 21;356(25):2582-90.
中国多发性骨髓瘤诊治指南(2015版)
• MDE, myeloma defining events • ≥ 60% BMPC 鉴定其克隆性，骨髓活检、涂片、流式
Rajkumar V et al Lancet Oncol 2014, 15: e538-48
SMM VS MGUS 进展比例
冒烟型骨髓瘤向症状性骨髓瘤演变风险
Mateos et al NEJM 2013, ASH 2014 (Abs3465)
Time to progression of disease patients with SMM
N=655 SMM (1996.01-2010.06 at Mayo Clinic)
95%
N=21 pts (3.2%)
IgAκ
2g/L
2g/L
IgMκ
1g/L
1g/L
κ FLC
10mg/L 50mg/L
g/L polyclonal immunoglobulin background
In healthy individual: Total κ = 11.01 g/L In κ light chain myeloma Total κ = 11.05 g/L
Greek Myeloma Group2 the University of Pennsylvania3.
1. Rajkumar SV, et al. N Engl J Med. 2011 2. Kastritis E. et al. Leukemia 2013 3. Waxman AJ. et al. J Clin Oncol 2014
plasma cells in the BMPC reductions in one or two uninvolved
immunoglobulins of more than 25%
median TTP not reached 13 Progressions (22%)
median TTP 21 (P<0.001) 47 Progressions (76%)
Serum FLC κ assay
κ FLC
10mg/L
50mg/L
In healthy individual: Free κ = 10 mg/L
In κ light chain myeloma: Free κ = 50 mg/L
“高度敏感”的“定量”检测
SPEP1 Serum IFE1 UPEP2 Urine IFE2 sFLC assay3
>95% aPC/BMPC + paresis n = 39 (28 progr.)
> 95% aPC/BMPC or paresis n = 22 (10 progr.)
No adverse factors n = 28 (1 progr.)
Median not reached
8%
Low Risk
based on the % of aberrant PCs by immunophenotype plus immunoparesis
TTP (%)
1.0 1.0 p = 0.003
0.8
0.6
0.4
0.2
0.0
0
24
5 yrs 82%
High Risk
Median 23 months
Median 73 months 42%
1.Hjorth M, et al. 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. 2000;82
4. 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):771-775 7. Musto P, et al. Cancer. 2008;113:1588-95.
CRAB: C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions Rajkumar SV. Cell Textbook of Medicine, 24th Edition 2012
2014年修改的IMWG诊断标准
Lenalidomide+dex（Rd)对高危冒烟型MM患者的临床试验研究
9 cycle Rd induction therapy followed by maintenance therapy with lenalidomide
To meet SMM diagnosis criteria at least 95% phenotypically aberrant
MGUS
SMM
< 10% BMPC AND < 3gm/dL M protein AND No MDE
>10%-60% BMPC OR > 3gm/dL S. M protein
OR > 500mg/24h Ur. M
protein AND No MDE
MM
PCPD 1 or more MDE CRAB ≥ 60% BMPC ≥100 FLC ratio > 1 MRI focal lesions
sFLC ratio ≥100
Median TTP was 15 mo
28%
Median TTP was 55 mo sFLC ratio <100
Variables sFLC <100 sFLC ≥100
PD to MM, %
48%
98%
Within 1 year
15%
43%
Within 2 years 28%
Mateos et al NEJM 2013, ASH 2014 (Abs3465)
Lenalidomide+dex（Rd)对高危冒烟型MM患者的临床试验研究
TTP
OS from the date of inclusion in the study
94%
80%
OS from theOdaSte of
作为治疗的开始 判断髓外病变情况 鉴定孤立的浆细胞瘤还是全身系统的累及 正确评估骨骼改变程度（骨质破坏，骨折…） 疗效评估及后续随访
diagnosis of SMM 94%
78%
3 years
5 years
This 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.
72%
Within 3 years 40%
87%
Larsen JT, et al. Leukemia. 2013
sFLC ratio as a biomarker for high-risk SMM
2014 Penn Risk Stratification Model
High risk SMM: Serum free light chain ratio of 100 or greater and a minimal involved FLC level of at least 100 mg/L
血清游离轻链（sFLC）
型
Κ、λ
类 IgG IgA IgD IgM IgE
完整的单克隆免疫球蛋白
血游离轻链
Total light chain assay versus sFLC assay
Total κ assay
IgGκ
8g/L
8g/L
“早期”“及时”的检测
IgG IgA IgM Free Kappa Free Lambda
20-25 days 6-7 days 6-8 days 2-4h 3-6h
TTP to symptomatic MM from sFLC ratio
sFLC ratio ≥8 or <0.125
40% (2years)
Waxman AJ, Mick R, Garfall AL, et al. Modeling the risk of progression in smoldering multiple myeloma. J Clin Oncol 2014;32:A8607
高级成像技术的应用
影像学检查的作用
骨髓瘤患者发生骨相关事件—— 70% 精确的鉴定骨事件的发生，出现骨质的破坏，
TTP of disease patients with SMM——Mayo 2007
In 2007 N Engl J Med During past 26 years, 276 SMM at Mayo Clinic
6 of 276 patients (2%) ≥ 60% PC in BM
4 patients progressed to symptomatic MM from 3 to 9 months
48
72
Months
96
120
Perez-Persona E, et al. Blood. 2007;110:2586-92.
MM的诊断标准(IMWG)的更新的缘由
“冒烟型” 骨髓瘤 (MC >3 g/dl &/or PC > 10%....No CRAB)
不必治疗!!!
Early MP vs. deferred MP1,2,3…….No benefit Thalidomide4,5 …………only 30% PR & No benefit in TTP/OS Bisphosphonates6,7……………….No benefit in OR/TTP/OS
Progression to myeloma 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.
多发性骨髓瘤的精确诊断
杜鹃 上海长征医院血液科 全军骨髓瘤与淋巴瘤疾病中心
MGUS
< 10% BMPC AND < 3gm/dL M protein AND No CRAB
SMM
>10% BMPC OR > 3gm/dL M protein AND No CRAB
MM
Clonal PCPD CRAB