免疫グロブリン遊離L鎖κ/λ比
• 免疫グロブリンはリンパ, 形質細胞で合成
– 1つの形質細胞より1種類のH鎖, L鎖が産生され,
H鎖はγ(IgG), α(IgA), µ(IgM), δ(IgD), ε(IgE)の5種あり,
L鎖はκとλ鎖の2種類ある.
– 多発性骨髄腫のような形質細胞が単クローン性に増殖している場合,
κ鎖 or λ鎖どちらかが優位に増加するため, κ/λ比は偏る.
– また, L鎖はH鎖より40%ほど過剰に産生されるため,
H鎖と結合できないL鎖が増加する(free light chain; FLC).
モダンメディア 2012;58:278-283
• 従って, κ/γ比やFLCの評価がMMの早期診断や
フォローに使用できる可能性がある.
– 単クローン性のFLCはBence Jones蛋白のこと.
– 健常人におけるκ型FLC 7.3[3.3-19.4], λ型FLC 12.7[5.7-26.3]mg/Lであり,
κ/λ比は0.58[0.26-1.65]が正常範囲とされる.
Am. J. Hematol. 85:787–790, 2010.

• また, 従来のM蛋白測定法の検出感度は,
– 血清蛋白電気泳動法(SPE)で500-2000mg/L,
IFE法(Immunofixation; 免疫電気泳動)で150-500mg/Lであるのに対し,
• FREELITETMを用いたFLCの測定では5mg/Lとかなり優秀.
– 従ってMGUSや多発性骨髄腫の早期診断が可能となる.
(ただし, 多クローン性のものの鑑別が必要となる)
– 多クローン性のFLCが上昇する疾患は,
腎不全(排出低下), 慢性炎症, 膠原病等.
– 末期腎不全でのκ/λ比は1.19[0.37-3.1]となる
Am. J. Hematol. 85:787–790, 2010.
– ただし, H鎖とL鎖の産生バランスが1:1のMMではFLCは正常
• 単クローン性と多クローン性FLCの鑑別に有用なのがκ/λ比
– κ/λ比が0.26-1.65ならば多クローン性の可能性が高く,
<0.26ではλ型の単クローン性, >1.65ならばκ型の単クローン性となる.
モダンメディア 2012;58:278-283

100 000
血清λ型FLC濃度（mg/L）
10 000
＋ 健常者（n=282）
● BJP-κ型多発性骨髄腫（n=120）
1000
□ 腎機能障害（n=31）
▲ BJP-λ型多発性骨髄腫（n=104）
100
○ 非分泌型多発性骨髄腫（n=28）
10
1
0.1
0.
1
1
10
0
10
0
00
1
10
00
血清κ型FLC濃度（mg/L）
0
0
10
0
00
図 3 健常者と多発性骨髄腫患者における血清 FLC 値の分布 （文献 7 から引用）
健常者と腎機能障害患者においてはκ/λ比が基準範囲内に分布しているが、
多発性骨髄腫患者におけるκ/λ比は異常値を示す。

• 尿中のκ/λ比の尿中BJP陽性に対する感度, 特異度は,
– Cutoffは <0.1, >5.5とした場合,
感度 86.4%[75.0-94.0], 特異度 94.0%[88.6-97.0]
Clin Chem Lab Med 2004;42(4):429–434
• Monoclonal gammopahtyの精査をされた833例では,
– 最終的に28例がMM, 25例がB-cell NHL, 156例がMGUS
– 血清蛋白電気泳動(PE), 血清FLC κ/λ比, 血清, 尿中IFEの
上記疾患群(monoclonal
P. Vermeersch et al
B-cell disorders)に対する感度, 特異度は,
Table I. Comparison of different strategies for the diagnosis of malignant monoclonal B-cell disorders and MGUS.
Strategy
Sensitivity (%)
Specificity (%)
Missed monoclonal B-cell disorders and MGUS
FLC j/k ratio
SPE
SPE ± IFE
SPE ± IFE + UIFE
SPE ± IFE + FLC j/k ratio
SIFE
SIFE + FLC j/k ratio
SIFE + UIFE
36Æ8
80Æ4
78Æ5
81Æ8
82Æ3
91Æ9
93Æ8
92Æ3
96Æ8
77Æ9
100
100
96Æ8
100
96Æ8
100
3 MM, 1 PC, 112 MGUS, 16 B-NHL
1 MM, 1 AL-A, 1 PC, 25 MGUS, 13 B-NHL
1 MM, 1 AL-A, 1 PC, 26 MGUS, 16 B-NHL
24 MGUS, 14 B-NHL
1 PC, 23 MGUS, 13 B-NHL
15 B-NH L, 2MGUS
12 B-NHL, 1 MGUS
14 B-NHL 2 MGUS
AL-A, AL amyloidosis; PC, plasmacytoma; MM, multiple myeloma; SIFE, serum immunofixation electrophoresis; UIFE, urine immunofixation
British Journal of Haematology 2008;143:496–502
electrophoresis; SPE ± IFE, serum IFE on positive serum PE (SPE) samples.

was 36Æ8% (Table I). Serum FLC j/k ratio was abnormal
(i) in 24 of the 28 patients (86%) diagnosed with a malignant
plasma cell disorder (including 18 patients with an intact
MM, two with a light chain MM, and three with AL
amyloidosis), (ii) in nine of the 25 patients with a B-NHL
(36%), and (iii) in 44 of the 156 patients (28%) diagnosed
with MGUS (Table II).
Twenty-three patients had an abnormal j/k ratio but no
monoclonal band on serum or urine IFE. Of these 23 patients,
three were diagnosed with a B-NHL (Table III, patients 1–3).
The results and clinical data of the other 20 patients that were
considered false-positive are summarized in Table III (Patients
4–23). The specificity of serum FLC j/k ratio in our study was
96Æ8%. Six of the 20 (30%) false-positive patients had a
polyclonal increase of immunoglobulins compared to 99 of the
604 (16%) true-negative patients. Nine of the 20 (45%) falsepositive patients had a glomerular filtration rate (GFR) of
<60 ml/min/1Æ73 m2 compared to 243 of the 604 (40%) truenegative patients. Five (20%) false-positive patients had a GFR
of <30 ml/min/1Æ73 m2 compared to 97 (16%) true-negative
patients. The percentage of false-positive results in patients
with a GFR of GFR of ‡60, <60 and <30 ml/min/1Æ73 m2 was
2Æ9%, 3Æ6% and 4Æ9% respectively.
• FLC κ/λ比は MM, リンパ腫,
AL-Amyloidosisに保険適応があるが,
– リンパ腫に対する感度はイマイチ.
– MGUSも正常例が多い.
Serum FLC j/k ratio in patients with a malignant
plasma cell disorder or MGUS
British
Serum FLC j/k ratio was abnormal in 77 of the 209 patients
(36Æ8%) with a malignant plasma cell disorder, B-NHL or
MGUS (Tables I and II). Of these 77 patients, 74 had a
monoclonal band on serum and/or urine IFE. The change in
serum FLC j/k ratio was concordant with serum and/or urine
IFE in 73 of the 74 patients. One patient who was diagnosed
with a IgGk MGUS (reconfirmed 6 months later) had an
increased serum FLC j/k ratio with individual concentrations
of j and k within the normal reference range. The sensitivity of
serum FLC j/k ratio in patients with a monoclonal
gammopathy on serum and/or urine IFE was 38Æ3%.
Journal of Haematology 2008;143:496–502
Three patients diagnosed with a B-NHL had an abnormal
j/k ratio but no monoclonal band on serum or urine IFE. The
Table II. Results of different strategies using serum FLC, serum PE,
serum IFE and/or urine IFE.
Number of positive patients
n
j/k
ratio SPE*
SPE ± IFE* SIFE UIFE
Malignant plasma cell disorders
Intact MM
18 15
17 (1) 17 (1)
18
Light chain MMà
2 2
2
2
2
Plasmacytoma
1 0
0
0
1
Osteosclerotic myeloma 1 1
1
1
1
Plasma cell leukaemia
1 1
1
1
1
WM
2 2
2
2
2
Primary amyloidosis
3 3
2
2
3
All
28 24
25
25
28
B non-Hodgkin lymphoma (B-NHL)
B-CLL
8 3
4 (1)
3 (1)
3
B-NHL (other)
17 6
8 (2)
6 (1)
7
All
25 9
12 (3)
9 (2)
10
Monoclonal gammopathy of unknown significance (MGUS)
All§
156 44 131 (3) 130 (3)
154
Other patients
All
624 20 138 (47) 0
0
17
2
1
1
1
2
2
26
2
7
9
71
0
WM, Waldenstrom macroglobulinaemia; B-CLL, B-cell chronic lymphocytic leukaemia; SIFE, serum immunofixation electrophoresis;
UIFE, urine immunofixation electrophoresis; SPE ± IFE, serum IFE on
positive serum PE (SPE) samples.
*Values within parentheses indicate the number of patients in which
hypogammaglobulinaemia on CZE was the only abnormality.
Monoclonal component in patients with intact MM on SIFE: 9 IgGj,
3 IgGk, 4 IgAj, 1 IgAk, 1 IgDk.
àMonoclonal component in patients with light chain MM on SIFE:
1 j, 1 k.
§Monoclonal component in MGUS patients with SIFE: 59 IgGj, 40
IgGk, 1 IgG(k?), 29 IgMj, 8 IgMk, 2 IgM(?), 4 IgAj, 9 IgAk, 2
IgMj+k, 1 IgMj+IgGk, and 1 j (also in urine). Two patients with
IgMk were negative with normal SIFE but positive when serum was
kept at 37°C.
5
change in serum FLC j/k ratio in these three patients was
concordant with the clonality of the malignant B-cell disorder
(Table III, patients 1–3).

Table IV. Results of 25 patients newly diagnosed with a B non-Hodgkin lymphoma (including Ann Arbor stage at diagnosis).
No Age (years) Sex SPE
SIFE
j (mg/l) k (mg/l) j/k ratio GFR UIFE Diagnosis/other details
1
2
3
4
5
6
7
8
9
10
11
74
66
66
71
58
58
58
64
64
80
56
F
F
M
M
M
F
M
M
F
F
F
MP
HypoG
pMP
0
pMP
0
0
0
MP
pMP
0
IgG-j
IgG-j
IgM-k
0
0
0
0
0
IgM-j
IgM-k
0
52Æ7 ›
12Æ9
12Æ8
13Æ0
18Æ1
9Æ4
12Æ9
17Æ9
68Æ0 ›
28Æ0 ›
3Æ57
11Æ3
4Æ6 fl
42Æ5 ›
5Æ7 fl
18Æ2
10Æ0
14Æ3
32Æ4 ›
39Æ4 ›
110 ›
21Æ3
4Æ66
2Æ82
0Æ30
2Æ30
0Æ99
0Æ94
0Æ90
0Æ55
1Æ73
0Æ29
0Æ17
12
13
14
15
16
17
18
57
61
59
81
67
47
46
F
M
M
F
F
M
F
0
0
0
GM
0
0
HypoG
0
0
IgM-j
0
0
0
0
12Æ4
30Æ7 ›
14Æ2
14Æ3
41Æ5 ›
12Æ3
10Æ0
19
20
21
22
23
24
25
77
80
51
59
76
61
65
F
F
M
F
M
F
M
0
MP
pMP
0
MP
HypoG
RP
0
IgG-j
IgG-j
0
IgM-j
IgM-j
0
17Æ9
144 ›
24Æ3 ›
8Æ9
34Æ4 ›
3Æ6
34Æ4 ›
›
›
›
fl
fl
‡60
‡60
52
‡60
‡60
‡60
‡60
‡60
46
51
51
j
0
k
0
0
0
0
0
j
k
0
41Æ8 ›
22Æ7
8Æ8
19Æ4
38Æ0 ›
15Æ2
5Æ0 fl
0Æ30
1Æ35
1Æ61
0Æ74
1Æ09
0Æ81
2Æ02 ›
‡60
‡60
‡60
‡60
‡60
‡60
30
k
0
j
0
0
0
0
15Æ8
12Æ3
20Æ7
11Æ2
11Æ7
4Æ5 fl
62Æ8 ›
1Æ13
11Æ71 ›
1Æ17
0Æ80
2Æ94 ›
0Æ79
0Æ55
48
‡60
‡60
‡60
46
‡60
‡60
0
j
0
0
j
0
0
›
B-CLL (BM: s-j)
B-CLL (BM: s-j)
B-CLL (BM: cy-k)
B-CLL (BM: s-j) (Table III, patient 1)
B-CLL (BM: s-k)
B-CLL (BM: s-j)
B-CLL (BM: s-j)
B-CLL (BM: s-j)
B-NHL: marginal zone lymphoma? (stage IVa)
Mantle cell lymphoma (stage IVb) (BM: s-k)
Mantle cell lymphoma (stage IVb) (BM: s-k)
(Table III, Patient 2)
Mantle cell lymphoma (stage IVb) (BM: s-k)
Mantle cell lymphoma (stage IVb)
Mantle cell lymphoma (stage IVa) (BM: s-j)
MALT-lymphoma (stage IVa)
MALT-lymphoma (stage Ia)
Follicular lymphoma (stage IIIa)
Follicular lymphoma (stage IIa) (lymph node: k)
(Table III, patient 3)
Follicular lymphoma (stage IIa)
Diffuse large B-cell lymphoma (stage IVb)
Diffuse large B-cell lymphoma (stage IIIsb)
Diffuse large B-cell lymphoma (stage IIea)
Diffuse large B-cell lymphoma (stage IIea)
Diffuse large B-cell lymphoma (stage Ib)
Post-transplant lymphoproliferative disorder (stage IVa)
British Journal of Haematology 2008;143:496–502
Results of immunophenotyping are given within parentheses.
+, abnormal (cfr. methods); 0, no abnormality detected; s-j, surface IgKappa; cy-k, cytoplasmatic IgLambda; DD, differential diagnosis; SPE, serum
protein electrophoresis; SIFE, serum immunofixation electrophoresis; UIFE, urine immunofixation electrophoresis; B-CLL, B-cell chronic lymphocytic leukaemia; MALT-lymphoma, mucosa-associated lymphoid tissue lymphoma.

Immunochemotherapy
Median FLC
Kappa
J
Range
Lambda
Range
Total FLC
Range
Abnormal FLC ratio
Elevated FLC
Elevated kappa
Elevated lambda
76
1.53
Clin Oncol 2011;29:1620-1626.
0.73-5.57
1.69
0.43-15.2
3.27
1.48-19.1
• リンパ腫におけるFLC ratioの異常は0-36%と様々.
– リンパ腫のタイプにより異なり,
100
9
26
23
11
DLBCLでは8%程度, Mantle-cell lymphomaでは36%. CLL/SLLでは24%.
11.8
34.2
30.3
14.5
• DLBCLにおけるFLC ratioの予後予測能
Abbreviations: NCCTG, North Central Cancer Treatment Group; SPORE, Specialized
LDH, lactate dehydrogenase; ULN, upper limit of normal; IPI, International Prognosti
– North Central Cancer Treatment Group trialよりDLBCL 76例,
University of lowa/Mayo Clinic Specialized age, worse performance status, advancedExcellence creatProgram of Research stage, and elevated
Molecular Epidemiology
inine, although association with the IPI was modest (Table 2).
An increase in serum
Resource(MER)より219例を解析 FLC was univariately associated with EFS
and OS in both cohorts for ␭ (all P Ͻ .05), ␬ (all P Ͻ .02), and total FLC
(all P Ͻ .002) measurements (Appendix Table A1, Appendix Figs
– FLC ratioの異常は全体の14%で認められた.
Lambda mg/dL
100
MER
N0489
10
i
T
F
␬
1
1
0.1
A
i
a
E
O
s
.
(
w
(
1
10
100
Kappa mg/dL
Fig 1. Pretreatment serum free light chain values (mg/dL) from North Central Cancer
Treatment Group N0489 and Specialized Program of Research Excellence Molecular
Epidemiology Resource (MER) cohorts. Dashed box indicates normal range.
n
e
h
e
2
a

Table 1. Clinical Characteristics of the Patients With New, Untreated Diffuse Large B-Cell Lymphoma Enrolled Onto This Study
NCCTG N0489 (n ϭ 76)
Characteristic
Median age, years
Range
Male sex
Age Ͼ 60 years
Performance status 2ϩ
Ann Arbor stage III/IV
Two or more extranodal sites
LDH Ͼ ULN
IPI
0-1
2
3
4-5
B symptoms
Bulky disease
Bone marrow involvement
Creatinine Ͼ ULN
Immunochemotherapy
Median FLC
Kappa
Range
Lambda
Range
Total FLC
Range
Abnormal FLC ratio
Elevated FLC
Elevated kappa
Elevated lambda
No.
%
SPORE MER (n ϭ 219)
No.
62
21-82
%
All Patients (N ϭ 295)
No.
64
21-93
%
62
21-93
43
43
11
61
25
52
56.6
56.6
14.5
80.3
32.9
68.4
117
131
42
126
46
103
53.4
59.8
19.2
58.1
21.4
48.4
160
174
53
187
71
155
54.2
59.0
18.0
63.8
24.4
53.6
18
17
28
13
29
13
9
12
76
23.7
22.4
36.8
17.1
38.2
17.1
11.8
15.8
100
79
59
49
32
46
26
29
28
186
36.1
26.9
22.4
14.6
21.0
11.9
14.3
13.4
85.3
97
76
77
45
75
39
38
40
262
23.9
25.8
26.1
15.3
25.4
13.3
13.6
14.0
89.1
1.53
0.73-5.57
1.69
0.43-15.2
3.27
1.48-19.1
9
26
23
11
1.48
0.02-45.7
1.44
0.20-11.8
2.93
0.37-51.1
11.8
34.2
30.3
14.5
32
68
63
29
1.50
0.02-45.7
1.51
0.20-15.2
3.08
0.37-51.1
14.8
31.1
28.8
13.2
41
94
86
40
14.0
31.9
29.2
13.6
Abbreviations: NCCTG, North Central Cancer Treatment Group; SPORE, Specialized Program of Research Excellence; MER, Molecular Epidemiology Resource;
LDH, lactate dehydrogenase; ULN, upper limit of normal; IPI, International Prognostic Index; FLC, free light chain.
J Clin Oncol 2011;29:1620-1626.

Table 2. Association of Clinical Characteristics With FLC Abnormalities
Characteristic
No.
% Elevated FLC
OR
All patients
Sex
Female
Male
Age, years
Ͻ 60
60ϩ
Performance status
0-1
2ϩ
Ann Arbor stage
I-II
III-IV
Extranodal sites, No.
0-1
2ϩ
LDH
Ͻ ULN
Ͼ ULN
B symptoms
Absent
Present
Bulky disease
Absent
Present
Bone marrow involvement
No
Yes
Creatinine
Ͻ ULN
Ͼ ULN
Treatment
Immunochemotherapy
Other
IPI
0-1
2
3
4-5
0-2
3-5
295
31.9
135
160
28.2
35.0
1.00
1.37
121
174
20.7
39.7
1.00
2.52
242
53
26.9
54.7
1.00
3.29
106
187
24.5
35.8
1.00
1.72
220
71
32.3
28.2
1.00
0.82
134
155
33.6
31.0
1.00
0.89
220
75
30.0
37.3
1.00
1.39
255
39
31.0
38.5
1.00
1.39
241
38
29.5
36.8
1.00
1.40
245
40
28.6
57.5
1.00
3.38
262
32
30.5
40.6
0.62
1.00
97
76
77
45
173
122
22.7
34.2
37.7
37.8
27.8
37.7
1.00
1.77
2.06
2.07
1.00
1.58
95% CI
P
% Abnormal ␬:␭ Ratio
OR
95% CI
P
.21
11.9
15.7
1.00
1.39
0.71 to 2.72
.34
Ͻ .001
11.7
15.6
1.00
1.40
0.70 to 2.80
.34
Ͻ .001
13.3
17.3
1.00
1.37
0.61 to 3.07
.45
.05
10.4
16.2
1.00
1.67
0.80 to 3.49
.17
.52
16.5
7.0
1.00
0.38
0.14 to 1.02
.05
.64
15.7
13.1
1.00
0.81
0.42 to 1.57
.53
.24
12.3
18.9
1.00
1.66
0.82 to 3.67
.16
.35
14.6
10.3
1.00
0.67
0.22 to 1.99
.47
.36
12.5
24.3
1.00
2.25
0.67 to 5.23
.06
1.70 to 6.71
.005
12.4
25.0
1.00
2.37
1.05 to 5.33
.04
0.30 to 1.36
.25
13.9
15.6
0.87
1.00
0.31 to 2.40
.78
10.3
19.7
16.0
8.9
14.5
13.3
1.00
2.14
1.66
0.85
1.00
0.91
0.90 to 5.08
0.67 to 4.08
0.25 to 2.87
.08
.27
.79
0.46 to 1.79
.79
14.0
0.83 to 2.25
1.48 to 4.37
1.79 to 6.06
1.01 to 2.93
0.46 to 1.48
0.54 to 1.46
0.80 to 2.41
0.69 to 2.80
0.68 to 2.86
0.91 to 3.47
1.06 to 3.99
0.96 to 4.46
.09
.03
.06
0.96 to 2.59
.07
Abbreviations: FLC, free light chain; OR, odds ratio; LDH, lactate dehydrogenase; ULN, upper limit of normal; IPI, International Prognostic Index.

Event-Free Survival (%)
FLC ratioの異常は予後不良因子の1つとなる.
A
100
80
60
40
20
0
Nonelevated FLC - N0489
Nonelevated FLC - MER
Elevated FLC - N0489
Elevated FLC - MER
12
24
36
48
60
48
60
Time (months)
B
Overall Survival (%)
J Clin Oncol 2011;29:1620-1626.
100
80
60
40
20
0
Nonelevated FLC - N0489
Nonelevated FLC - MER
Elevated FLC - N0489
Elevated FLC - MER
12
24
36
Time (months)
Fig 2. (A) Event-free survival and (B) overall survival Kaplan-Meier survival
curves by serum free light chain (FLC) in two cohorts (North Central Cancer
Treatment Group trial N0489 and the Specialized Program of Research Excellence Molecular Epidemiology Resource [MER]) of patients with untreated
diffuse large B-cell lymphoma.

• 1020例でFLC κ/λ比を評価
879
Clinical Chemistry 51, No. 5, 2005
– 899名のPlasma cell disorderを含む
Clinical Chemistry 51:5 878 – 881 (2005)
routine clinical laboratory practice, we reviewed the diagnoses and FLC results for these 1020 patients.
Materials and Methods
We queried the Laboratory Information System for the
FLC results of all Mayo Clinic patients who were tested
for serum ␬ and ␭ FLCs from January 1, 2003, to December
31, 2003. The list of 1020 patients was merged with data
from the Dysproteinemia database, which contained each
patient’s diagnosis, date of diagnosis, and serum and
urine IFE results. Individual patient histories were reviewed for any patients not contained in the database. If a
patient had more than one sample tested, only the initial
2003 sample was included in this study. The samples were
obtained at the patient’s initial presentation, during disease monitoring, or depending on the diagnosis, post
treatment. The treatment status of the AL and NSMM
patients was determined from the patient history. All
queries to the Laboratory Information System, Dysproteinemia database, or patient histories followed a protocol
approved by the Mayo Institutional Review Board.
The serum FLC assay was performed on the same day
as the venipuncture and was reported to the patient’s
medical record. The FLC assay (FREELITETM; The Binding Site Ltd.) (6 ) was performed on a Dade Behring BNII
automated nephelometer. This assay consists of two sep-
Table 1. Distribution of PCDs (n ‫.)998 ؍‬
Diagnosis
No. of cases
Multiple myeloma
NSMM
Osteosclerotic myeloma
SMM
Indolent/evolving myeloma
Plasmacytoma (solitary)
Extramedullary myeloma
Multiple solitary plasmacytoma
Macroglobulinemia
IgM lymphoproliferative disease
IgM lymphoma
Smoldering macroglobulinemia
Primary systemic amyloidosis
LCDD
MGUS
Idiopathic Bence Jones proteinuria
Heavy chain disease
Cryoglobulinemia
Acquired Fanconi syndrome
Scleromyxedema
Plasma cell leukemia
330
20
15
72
8
22
5
3
9
2
5
2
269
7
114
4
2
4
3
2
1
abnormal FLC ␬/␭ ratio. The 6 NSMM patients with
normal FLC ␬/␭ ratios had all received a stem cell

FLC results. (It should be remembered, however, that in
ALTable 2. FLC results. requires histopathologically confirmed
the diagnosis
CurrentAL amyloid.) With these Retrospective published data
study
2 caveats in mind, we are
Diagnosis
n
Abnormal FLC ratio, %regarding the diagnostic use of the FLC assay as
n
Abnormal FLC ratio, %
Reference
reassured
Normal
282
0
Katzmann et al. (1
a tool that is complementary to other laboratory tests. )
Polyclonal
25
0
Katzmann et al. (1 )
The current gold standard for detection of a monocloNonmonoclonal gammopathy
121
0
NSMM, untreated
5
28
68
nal100
FLC is IFE. IFE assays are qualitative, Drayson although
and et al. (2 )
NSMM, treated
15
60
their sensitivities may vary98among laboratoriesal. and
AL, untreated
110
91
262
Lachmann et
(3 )
among antiserum lots, nonlaboratorians tend to et al. (4 ) of
34
88
Abraham think
LCDD
7
100
89
them as black or 19
white with no ambiguity Katzmann et al. (1 )
in results. The
MGUS
114
44
97
43
Rajkumar et al. (7 )
use 88 a quantitative assay with defined normal cutoffs
of
SMM
72
relies on low assay variability and long-term reagent
stability
standard. Although we are reassured as new reagents
formed by the clinical laboratory as samples were re-that will yield consistent results by the performance
• ALとLCDD(light chain deposition disease)ではthis 1-year produced by a
ceived, and during this 1-year time frame, are used 2
we prepared. TheFLC assay during currently study period, a
of the FLC assay is
different reagent lots. Earlier, we chose to single the
define manufacturer, and there is no developed.international
verifiable standard needs to be defined
FLC ratioの感度は良好.
reference interval for the FLC ␬/␭ ratio as the interval that
In addition to the absence of false-positive results, this
included all of the reference population to ensure high
study has also Clinical Chemistry the FLC – 881 ratio as a
validated use of 51:5 878 ␬/␭ (2005)
specificity (1 ). The absence of abnormal results in the 121
diagnostic tool in the light chain diseases. The identificaTable tion of abnormal results in various AL (n ‫)011 ؍‬
patients with no monoclonal gammopathy in this study, 3. Diagnostic performance indisease groups closely
however, was unexpected. We assume that 2 factors may Assay
% diagnostic
matches the published retrospective data. The Positive (CI)a
have contributed to the absence of false-positive results.
FLC ␬/␭ ratio results in AL are similar to those in 2 published studies
91 (84–96)
The first is that most of the requests were from the
(3, 4 ). In this study and in our previous retrospective
Serum IFE
69 (60–78)
Division of Hematology and not from general medical
study (4 ), the sensitivity of the FLC assay in AL was lower
Urine IFE
83 (74–89)
practice. As the assay becomes more widely requested, we
than the sensitivity of 98% reported by Lachmann et al.
expect to see false-positive FLC results. The second, and ϩ urineThat study used a 95% reference interval95 (90–99)
Serum IFE
(3 ). IFE
for the FLC
perhaps more important, factor is that in this study some
␬ ␭ ratio (0.3–1.2) vs our use of a range that encompassed
FLC ␬/␭ ratio ϩ/urine IFE
91 (84–96)
of the clinical diagnoses may have been influenced by the
100% of the reference population (0.26 –1.65). None of the
ratio ϩ serum IFE
99 (95–100)
FLC ␬/␭ in
FLC results. (It should be remembered, however, that
110 AL patients, however, had borderline FLC ␬/␭ ratios
AL the diagnosis requires histopathologically confirmed
All 3 assays that would have been categorized differently by the 2
99 (95–100)
AL amyloid.) With these 2 caveats in mind, we are
a
criteria. determined by the exact diagnostic sensitivity
CI, confidence intervalAny differences in thebinomial distribution.
reassured regarding the diagnostic use of the FLC assay as
therefore cannot be explained by the different criteria
a tool that is complementary to other laboratory tests.

Log lambda FLC (mg/ L )
Log kappa/la
FLC concentrations, but had an abnormal κ/λ FLC ratio.
0
The other case had elevated κ and λ FLC concentrations
and, consequently, had Ann Hematol (2005) 84: 588–593
a normal κ/λ FLC ratio.
There were 12 cases where M protein was not detected in
-1 61例のMM, 45例の非MM例*, 120例のContorl群において,
•
serum PEP, although they were MM patients (Table 2). M
protein was detected in three of these cases (37.5%, 3/8) by
蛋白電気泳動(PEP), 免疫固定電気泳動(IFE),12 cases had abnormal concentrations of
IFE. However, all FLCを評価.
-2
κ or λ FLC or abnormal κ/λ FLC ratios. Case 1 had normal
Kappa type Lambda type Other disease Control
concentrations of both
– MM
非MM症例は腎疾患, DM, 悪性リンパ腫, CTD, 悪性腫瘍, FLC types and case 2 showed a
group
group
MM
normal κ/λ FLC ratio due to increases in both κ and λ FLC
高血圧, 慢性B型肝炎, BPH, and 塞, IDA, クローン病, 骨髄炎.
Fig. 1 Distribution of κ and λ FLC concentrations (a)脳 κ/λ FLC concentrations. Table 2 shows that they were mostly light
ratios (b) in the multiple myeloma group, other diseases group, and 590
chain type MM, and the detected M protein at the time of
control group
– FLC κ/λ比は,
Adiagnosis was mainly in the β region. Cases 6 and 7 had
6
high κ FLC concentrations (>4,000 mg/l), but they were
nine λ light chain types. Control群と
MMと非MM, In urine, the monoclonal im- not detected by PEP.
5
FLC concentrations in the MM urine samples were
munoglobulin and light chains were composed of five
明らかに異なる.
IgG-κ types, one IgA-κ type, two IgA-λ types, three κ light similar to those in the serum samples. Twelve of 14 cases
4
had abnormal FLC concentrations according to their
chain types, and three λ light chain types.
– PEPとFLCのMMに対する
abnormal κ/λ
Fifty-nine out of 61 MM patients (97%) had elevated κ specific light chain type and all cases hadKappa type MM
3
Lambda type MM
or λ FLC concentrations according to their specific light FLC ratios. Although the FLC concentrations in the urine
感度, 特異度は
Otherdis, group
chain type and simultaneously showed abnormal κ/λ FLC samples were all abnormal, M protein was not detected by
2
Control group
ratios. One of the other two patients had normal κ and λ PEP in six of these samples (Table 3).
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
PEP
76.3
100
100
71.4
Cutoff values of upper limit in diagnostic ranges of κ/λ FLC ratioa
>1.2
96.1
84.2
73.7
97.9
>1.5
93.4
95.8
91.0
96.9
>2.0
89.5
100
100
95.3
PPV positive predictive value, NPV negative predictive value
The lower limit in each diagnostic range is 0.3
a
0
Other diseases group
-1
The other diseases group was divided into three subgroups
3
5
by -1
serum PEP1 results: A, no abnormal findings (n=19,
42%); B, polyclonal FLC (mg/ L )
Log kappa gammopathy with an increased γ
globulin fraction (n=17, 38%); and C, minor abnormalities
Bother than polyclonal gammopathy such as increased α
and/or β globulin fractions (n=9, 20%) (Table 4). The
subgroup with no abnormal findings 13 14 cases with
had
2
normal κ/λ FLC ratios (11 normal and three elevated FLC
concentrations) and five cases with abnormal κ/λ FLC
C ratio
Table 1 Comparison of diagnostic characteristics for the PEP and
cutoff values of κ/λ FLC ratio
1
1
Ta
PE
Ca
1
2
3
4
5
6
7
8
9
10
11
12
IF
n
a
T
[4
m
κ

test of the month
Am. J. Hematol. 85:787–790, 2010.
Figure 1. A diagnostic algorithm for the evaluation of a patient with a suspected monoclonal gammopathy. The screening panel includes quantitative immunoglobulins/serum protein electrophoresis (Igs/SPEP) and immunofixation electrophoresis (IFE) if necessary, along with quantitative serum free light chains (sFLC) with Kappa/Lambda ratio
(j/k). Occasionally 24 hour urine for evidence of monoclonal FLC or Bence-Jones protein (BJP) by electrophoretic assays is required. The presence of a monoclonal band
warrants an IFE and sFLC with j/k ratio (if not already sent), so as to characterize the monoclonal gammopathy. A normal SPEP/IFE and/or unexplained hypogammaglobulinemia warrants the performance of sFLC with j/k ratio so as to exclude light chain myeloma (LCM), light chain deposition disease (LCDD), or primary AL amyloidosis.
*If the work up for monoclonal gammopathy (including sFLC with j/k ratio and urine BJP) is negative but the clinical suspicion of AL amyloid is high, appropriate tissue biopsy
14
with special staining for amyloid must be performed. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

• FLCはフォローにも有用.
– FLCの半減期はκで2-4h, λで3-6h,
一方, ImmunoglobulinはIgGで20-25d(IgG3で8d),
IgAで6d, IgDで3d, IgEで2dであり, 治療への反応はよりFLCで迅速.
– 治療の強度やレジメ変更への判断基準となる可能性が示唆される.
15

tudy cohort was derived from persons who resided in the 11 counties
outheastern Minnesota who met previously established diagnostic
Blood. 2005; 106:812-817
ia for MGUS at the Mayo Clinic from January 1, 1960, through
mber 31, 1994.5 Of 1384 patients with MGUS diagnosed during this
d, a cohort whose baseline characteristics, methods of detection,
w-up, and risk of progression have been well described by us earlier,5
– 1148例のMGUSのフォロー.
patients who had cryopreserved serum samples collected within 30
of the MGUS diagnosis were studied. Follow-up was through the
15年間フォローし, 悪性化したのは87例(7.6%)であった.
w of each patient’s complete medical records at the Mayo Clinic. The AUGUST 2005 ⅐ VOLUME 106, NUMBER 3
BLOOD, 1
was approved by the Mayo Institutional Review Board.
– FLC κ/λ比の異常(<0.26, >1.65)はMMへの移行HR 2.6[1.7-4.2]
he FLC level in serum collected at the time MGUS was first
nized was determined on all 1148 patient samples using the FLC assay
Table 3. Multivariate analysis of prognostic factors for progression
lite; The Binding Site, Birmingham, United Kingdom) performed on a
of monoclonal gammopathy of undetermined significance
-Behring Nephelometer (Deerfield, IL).12-14 It consists of 2 separate
Hazard ratio (95%
urements, one to detect free-kappa (normal range, 3.3-19.4 mg/L) and
Prognostic factor
confidence interval)*
other to detect free-lambda (normal range, 5.7-26.3 mg/L) light
s.16 In addition to measuring the absolute levels of FLC, the test also
Abnormal FLC ratio
2.6 (1.7-4.2)
s the assessment of clonality based on the ratio of kappa-lambda light
• FLC比はMGUS→MMのリスク因子となる
Serum M protein size
2.4 (1.7-3.5)
IgA, IgM, or biclonal IgA plus IgM
2.6 (1.7-4.0)
*P Ͻ .001 for each variable.
confidence interval [CI], 2.3-5.5; P Ͻ .001). The risk of progression to myeloma or related malignancy at 10 years was 17% with
an abnormal ratio compared with 5% with a normal ratio;
corresponding rates at 20 years were 35% and 13%, respectively
(Figure 1B).
There was a good correlation between increasingly abnormal
FLC ratio and the relative risk of progression (Figure 2A). The
16
absolute risk of progression at 5, 10, 15, and 20 years for varying
FLC ratios is given in Table 2.

0
• IgG4-RSDではκ/λ比は上昇する傾向.
– 16例においてκ/λ比を評価;
Control IgG4 IgG4
RD RD NA
0
Control IgG4 IgG4
RD RD NA
Figure 1: Kappa/lambda serum FLC in patients with IgG4-RD.
Comparison of serum-free 𝜅 and 𝜆 light chains in controls, IgG4RD patients with active disease (IgG4-RD) and nonactive disease
(IgG4-RD NA). Median and interquartile ranges are shown.
κ/λ比は1.63[1.06-3.2]と健常人よりも上昇する傾向にある.
4
International Journal of Rheumatology
P = 0.0035
2700
1200
550
P = 0.02
P = 0.0003
P < 0.0001
550
450
500
350
450
No correlation was evidenced in our cohort between FLC
levels and demographicP = clinical features of patients. 𝜅 and
or 0.0049
7
𝜆 FLC levels were higher in patients with more than 3 organ
involvement than in those with 3 or less (𝜅 49.8 mg/L (29.0–
6
799.2) versus 20.9 mg/L (20.1–61.85), 𝑃 = 0.2; 𝑙 29.63 mg/L
(18.42–195.7) versus 18.4 mg/L (13.0–33.24), 𝑃 = 0.2) but the
5
difference was not statistically significant.
P = 0.029
𝜆 sFLC (mg/L)
𝜅 sFLC (mg/L)
350
P = 0.029
𝜅/𝜆 ratio
3.3. 𝜅 : 𝜆 Ratio Is Increased in a Significant Proportion of IgG44
RD Patients. Normal 𝜅 : 𝜆 ratio according to the manufac300
turer is comprised between 0.26 and 1.65. In patients with
3
250
renal insufficiency the ratio can be higher and comprised
between 0.37 and 3.01 [1].
200
2
IgG4-RD patients with active disease had a significantly
150
higher 𝜅 : 𝜆 FLC ratio than controls (Figure 2) with a median
100
1.63 (1.06–3.2) versus 1.00 (0.91–1.1) (𝑃 = 0.0049). The 𝜅 : 𝜆
1
FLC ratio was higher than the upper range of 3.01 in 2 out
50
of 4 IgG4-RD patients with renal insufficiency (range 1.25–
0
0
5.11). It was higher than the upper range of IgG4-RD (41.6%)
1.65 in 5/12
Control
IgG4-RD
Control IgG4 IgG4
Control IgG4 IgG4
IgG4-RD patients without renal AD
insufficiency (range 2.09–
NA
RD RD NA
RD RD NA
6.6). Thus 7 out of 16 (43.7%) IgG4-RD patient presented
Figure increased abnormal 𝜅 FLC ratio in patients with IgG4Figure 1: Kappa/lambda serum FLC in patients with IgG4-RD.
with an 2: Kappa/lambda serum: 𝜆 FLC ratio at diagnosis. The
RD. FLC ratio was serum free 𝜅 and 𝜆 light chains ratio in controls,
Comparison of serum-free 𝜅 and 𝜆 light chains in controls, IgG4𝜅 : 𝜆 Comparison of also statistically different when comparing
IgG4-RD patients with inactive disease and controls (𝑃 =
RD patients with active disease (IgG4-RD) and nonactive disease
IgG4-RD patients with active disease (IgG4-RD AD) and nonactive
disease (IgG4-RD NA). Median and active disease, 𝑃 = shown.
(IgG4-RD NA). Median and interquartile ranges are shown.
0.029) but not with patients with interquartile ranges are 0.39.
Serum Immunoglobulin Free Light Chain Assessment in IgG4-Related Disease.
In both controls and IgG4-RD patients with inactive disease,
International Journal of Rheumatology 2013; online
all 𝜅 : 𝜆 FLC ratios were in the normal range.
400
250
120
110
100
90
80
70
60
50
40
30
20
10
0
5
I
6
w
𝜅
I
0
I
a
7
b
d
s
3
a
p
3
t
4
A
i
r
p
l
t
a
s
o
a
𝜅

• FLC, κ/λ ratioの使用のまとめ
– FLCはLight-chain only MM, AL amyloidosis, non-secretory MM,
Oligo-secretory MMの早期発見に有用な検査と言える.
Ligh-chain only MMでは尿FLCが疾患モニタリングとしても有用.
– FLCはMMやAL amyloidosisの治療反応性評価に有用である.
– FLCはMGUS, smouldering MM, solitary plasmacytomaにおける
悪性化のリスク評価に使用できる
– MM診断時のFLCや治療による低下速度は予後評価に使用できる.
– FLCはMM治療効果の早期判断に使用できる.
臨床的な利点については調査が必要.
– FLCはリンパ増殖性疾患の診断にも有用.
特にWM, CLL, mantle cell lymphomaでの感度は良好
– スクリーニングとして, FLCは尿中Bence Jones protein評価に
代わる検査となる. ただし蛋白尿評価としては使用できない.
18
British Journal of Haematology 2008;141:413–422