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Published by the IC
nternational M I
yeloma FT
oundation
INGSpecialEdiStion:2008
Serum Free Light Chain Assays Issue
The International Myeloma Foundation (IMF) presents this edition of Citings, our premiere
publication featuring the most up-to-date information on myeloma treatment and supportive care. This edition
is focused solely on Serum Free Light Chain Assays, a trademarked procedure known commonly as the FreeliteTM
test. The Binding Site is the company responsible for this incredibly useful tool that provides necessary diagnostic
information for multiple myeloma, amyloidosis, and other hematologic malignancies.
It is our hope that CITINGS will help keep you abreast of the latest developments in myeloma treatment.
As always, we welcome your feedback; you may contact the IMF at (800) 452-CURE (2873) or at our website
www.myeloma.org.
Susie Novis, President, IMF
Serum Free Light Chain Assays Publications 2008
NIsolation and biochemical characterization of plasma monoclonal free light chains in amyloidosis and
multiple myeloma: a pilot study of intact and truncated forms of light chains and their charge properties.
Kaplan B, Ramirez-Alvarado M, Dispenzieri A, Zeldenrust SR, Leung N, Livneh A, Gallo G.
Clin Chem Lab Med. 2008;46(3):335-41.
:
http://www.ncbi.nlm.nih.gov/pubmed/18254719?ordinalpos=40&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors develop a procedure that may be applied to reveal distinguishing chemical features of free light chains in serum, which could
be important in predicting the pathologic form of disease and in yielding information to better understand the mechanism(s) involved in
the deposition of light chains in tissues.
BACKGROUND: The presence of monoclonal immunoglobulin free light chains (FLC) in the serum is commonly associated with the
gammopathies, including multiple myeloma, systemic light chain amyloidosis and non-amyloid light chain deposition disease. Although
a sensitive nephelometry-based assay is used for quantification of serum FLC and patient follow-up, this method does not provide infor-
mation regarding the biochemical properties of these proteins. The present study focused on the development of the procedure for isola-
tion and biochemical characterization of monoclonal FLC in small plasma specimens from patients with these disorders. METHODS:
Methods used in this study were ultrafiltration, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), protein elution
from gel and support membranes, dialysis, lyophilization, isoelectric focusing (IEF) and Western blotting. RESULTS: The isolation,
concentration and partial purification of FLC was based on micro-preparative SDS-PAGE employing analytical scale gels. For the deter-
mination of the isoelectric point of FLC, the developed protocol included consecutive IEF, electrotransfer of IEF-separated proteins onto
and elution from support membranes, and their analysis by SDS-PAGE-based Western blotting. The procedures, which require only
20-50 microL of starting plasma, allow biochemical characterization of the monomeric, dimeric and truncated forms of FLC, including
their charge properties. CONCLUSIONS: The developed procedure may be applied to reveal distinguishing chemical features of FLC
in serum, which could be important in predicting the pathologic form of disease, and in yielding information to better understand the
mechanism(s) involved in the deposition of light chains in tissues.
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Funded by an unrestricted educational grant from The Binding Site.

NLong-term follow-up of plasma cells in bone marrow and serum free light chains in primary systemic
AL amyloidosis.
Yoshida T, Matsuda M, Katoh N, Tazawa K, Shimojima Y, Gono T, Ishii W, Nakazawa Y, Sakashita K, Koike K, Yamada T, Ikeda S.
Intern Med. 2008;47(20):1783-90. [Epub 2008 Oct 15.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18854629?ordinalpos=91&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
To prospectively investigate the production of M-protein and plasma cells in bone marrow before and after chemotherapy, the authors
perform flow cytometry and analysis of serum free light chains. They find that abnormal plasma cells in the bone marrow, particularly
the MPC-1(+)CD45(-)CD49e(-) subset, may be important as a follow-up marker before and after chemotherapy in primary systemic
AL amyloidosis.
OBJECTIVE: Primary systemic AL amyloidosis arises from immunoglobulin light chains produced by plasma cell dyscrasia. To pro-
spectively investigate the production of M-protein and plasma cells in bone marrow before and after chemotherapy, we performed flow
cytometry and analysis of serum free light chains (FLCs). PATIENTS AND METHODS: Fifty-nine patients with primary systemic AL
amyloidosis (mean age, 59.9+/-8.8 years) were enrolled in this study, and of these 31 were serially studied before and after chemotherapy.
Complete hematological remission was defined as normalization of the FLC kappa/lambda ratio. RESULTS: MPC-1(-)CD45(-) (p<0.05)
and MPC-1(+)CD45(-)CD49e(-) (p<0.005) were significantly higher, and MPC-1(-)-CD45(+) (p<0.05), MPC-1(+)CD45(+)CD49e(-)
(p<0.0001) and MPC-1(+)CD45(+)CD49e(+) (p<0.0005) were significantly lower in the patients with AL amyloidosis than in con-
trols. There was a significantly positive correlation between the serum predominant FLC/serum creatinine ratio and MPC-1(+)CD45(-)
CD49e(-) (p<0.05). After chemotherapies, such as high-dose melphalan with autologous stem cell support, 20 of 31 patients with AL
amyloidosis achieved complete hematological remission. There were no significant differences in any subtype of plasma cells before treat-
ment between the remission and non-remission groups, but in the former group MPC-1(+)CD45(-)CD49e(-) and MPC-1(-)CD45(+)
were significantly decreased and increased after chemotherapy compared with before, respectively. CONCLUSION: Abnormal plasma
cells in the bone marrow, particularly the MPC-1(+)CD45(-)CD49e(-) subset, may be important as a follow-up marker before and after
chemotherapy in primary systemic AL amyloidosis. These cells maintain low levels as long as no relapse occurs.
NImmunoglobulin free light chain ratio is an independent risk factor for progression of smoldering
(asymptomatic) multiple myeloma.
Dispenzieri A, Kyle RA, Katzmann JA, Therneau TM, Larson D, Benson J, Clark RJ, Melton LJ 3rd, Gertz MA, Kumar SK, Fonseca R,
Jelinek DF, Rajkumar SV.
Blood. 2008 Jan 15;111(2):785-9. [Epub 2007 Oct 17.]
:
http://www.ncbi.nlm.nih.gov/pubmed/17942755?ordinalpos=38&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors find that the serum immunoglobulin free light chain ratio is an important additional determinant of clinical outcome in
patients with smoldering multiple myeloma.
We hypothesized that increased monoclonal free kappa or lambda immunoglobulin light chains in smoldering multiple myeloma (SMM),
as detected by the serum free light chain (FLC) assay, indicates an increased risk of progression to active myeloma. Baseline serum samples
obtained within 30 days of diagnosis were available in 273 patients with SMM seen from 1970 to 1995. At a median follow-up of surviv-
ing patients of 12.4 years, transformation to active disease has occurred in 59%. The best breakpoint for predicting risk of progression was
an FLC ratio of 0.125 or less, or 8 or more (hazard ratio, 2.3; 95% CI, 1.6-3.2). The extent of abnormality of FLC ratio was indepen-
dent of SMM risk categories defined by number of bone marrow plasma cells (BMPCs) and size of serum M proteins (BMPC>or=10%
and serum M protein>or=3 g/dL; BMPC>or=10% but serum M protein<3 g/dL; and serum M protein>or=3 g/dL but BMPC<10%).
Incorporating the FLC ratio into the risk model, the 5-year progression rates in high-, intermediate-, and low-risk groups were 76%, 51%,
and 25%, respectively. The serum immunoglobulin FLC ratio is an important additional determinant of clinical outcome in patients
with SMM.
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NDetection of serum free light chain and its clinical significance in nonsecretory multiple myeloma.
[Article in Chinese]
Chen HF, Hou J, Yuan ZG, Wang DX, Fu WJ, Chen YB.
Zhonghua Xue Ye Xue Za Zhi. 2008 Feb;29(2):113-6.
:
http://www.ncbi.nlm.nih.gov/pubmed/18681313?ordinalpos=37&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors explore the clinical significance of serum free light chain (sFLC) levels in nonsecretory multiple myeloma (NSMM) and con-
clude that quantification of sFLC by immuno-nephelometry is more sensitive than that of serum total light chain measurement and is
helpful in estimating the clonality of the light chain in patients with NSMM.
OBJECTIVE: To explore the clinical significance of serum free light chain (sFLC) levels in nonsecretory multiple myeloma (NSMM).
METHODS: Nine NSMM patients were hospitalized in our department from Feb 2002 to Sep 2006 and no M-components was
found in their serum and urine by immunofixation electrophoresis (IFE). sFLC was assayed by immuno-nephelometry. The clonality
of sFLC was estimated by serum kappa:lambda sFLC ratio. Meanwhile, serum immunoglobulin, total kappa and lambda light chain
level were also determined in these patients. RESULTS: Increased serum concentrations of either kappa or lambda sFLC (and abnormal
kappa/lambda ratios) were detected in 6 of 9 patients with NSMM although their serum immunoglobulin levels were not elevated and
total kappa:lambda light chain ratios (1.32 - 2.20) were in the reference range. All the 9 patients had clonal IgH gene rearrangements.
CONCLUSION: Quantification of sFLC by immuno-nephelometry is more sensitive than that of serum total light chain measurement
and is helpful in estimating the clonality of the light chain in patients with NSMM.
NEvaluation of the serum-free light chain test in untreated patients with AL amyloidosis.
Bochtler T, Hegenbart U, Heiss C, Benner A, Cremer F, Volkmann M, Ludwig J, Perz JB, Ho AD, Goldschmidt H, Schonland SO.
Haematologica. 2008 Mar;93(3):459-62. [Epub 2008 Feb 20.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18287137?ordinalpos=33&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors evaluate the serum free light chain test in a series of 133 untreated patients with systemic AL amyloidosis.
We evaluated the Serum Free Light Chain (FLC) test in a series of 133 untreated patients with systemic AL amyloidosis. The FLC test
detected the monoclonal gammopathy in 87% compared with 92% for immunofixation of serum and urine in combination. However,
both tests proved complementary. The FLC test was also a valuable tool in patients with advanced renal failure in spite of uninvolved light
chain retention. Higher FLC levels were associated with higher bone marrow plasmocytosis, poorer Karnofsky index and heart involve-
ment, and therefore reflected disease severity.
NThe evolving use of serum free light chain assays in haematology.
Pratt G.
Br J Haematol. 2008 May;141(4):413-22. [Epub 2008 Mar 3.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18318757?ordinalpos=27&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The author discusses the new immunoassays that have emerged over the last few years, allowing the measurement of free immunoglobulin
light chains in serum to a level of 2-4 mg/l and provide a much greater sensitivity than older methods.
Over the last few years new immunoassays have emerged that allow the measurement of free immunoglobulin light chains (FLCs) in
serum to a level of 2-4 mg/l and provide a much greater sensitivity than older methods, such as immunofixation, which is able to detect
FLCs at a minimum concentration of 100-150 mg/l. The new FLC assay has enabled the detection of monoclonal protein in some
patients with non-secretory myeloma and amyloidosis that were previously undetectable. FLC measurements are quantitative, correlating
with disease activity, and are an advance in monitoring light chain only multiple myeloma, AL amyloidosis, non-secretory and oligo-
secretory multiple myeloma. Serum FLC concentrations also reflect the disease course in the majority of myeloma patients producing
intact monoclonal immunoglobulin proteins and have been incorporated into the new response criteria. The rapid half life of lambda and
kappa free light chains means that FLC assays may provide a more rapid indication of the response to treatment but their clinical utility
in this setting needs further study. An abnormal FLC ratio has been shown to be a risk factor for progression of monoclonal gammopathy
of undetermined significance, smouldering myeloma and solitary plasmacytoma of bone and is prognostic in multiple myeloma.
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NSerum free light chains: Clinical utility. [Article in Spanish]
Encinas Madrazo A, González García ME, Cepeda Piorno J, González Huerta AJ, Fernández Rodríguez E.
An Med Interna. 2008 May;25(5):249-50.
:
http://www.ncbi.nlm.nih.gov/pubmed/18769754?ordinalpos=53&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
NSerum-free light chain elevation is associated with a shorter time to treatment in Waldenstrom's
macroglobulinemia.
Itzykson R, Le Garff-Tavernier M, Katsahian S, Diemert MC, Musset L, Leblond V.
Haematologica. 2008 May;93(5):793-4.
:
http://www.ncbi.nlm.nih.gov/pubmed/18450739?ordinalpos=29&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
NAppraisal of immunoglobulin free light chain as a marker of response.
Dispenzieri A, Zhang L, Katzmann JA, Snyder M, Blood E, Degoey R, Henderson K, Kyle RA, Oken MM, Bradwell AR, Greipp PR.
Blood. 2008 May 15;111(10):4908-15. [Epub 2008 Mar 25.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18364469?ordinalpos=26&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors explore the role immunoglobulin free light chain (FLC) assay should play in following myeloma patients with disease
that is measurable using serum and urine electrophoresis. They find that although baseline values of FLC are prognostic in newly
diagnosed myeloma patients, serial measurements do not appear to have added value in patients who have M-proteins measurable by
electrophoresis.
The immunoglobulin free light chain (FLC) assay is an invaluable tool for following patients with oligosecretory plasma cell dyscrasia.
Baseline values have also been shown to be prognostic in all plasma cell disorders tested. A looming question, however, is the role it should
play in following myeloma patients with disease that is measurable using serum and urine electrophoresis. We used the data and stored
samples from a mature Eastern Cooperative Oncology Group clinical trial (E9486) to assess serum levels of FLC at baseline and after 2
months of alkylator-based therapy. For serial determinations, the absolute level of involved serum FLC or the difference of the involved
and uninvolved FLC is preferred over the ratio of involved to uninvolved FLC. FLC response after 2 months of therapy was superior
to early M-protein measurement to predict overall response. The ideal cut-point for FLC change appears to be between 40% and 50%
reduction. The correlation between serial measurements of serum FLC and urine M-protein is inadequate to abolish the serial 24-hour
urine protein. Although baseline values of FLC are prognostic in newly diagnosed myeloma patients, serial measurements do not appear
to have added value in patients who have M-proteins measurable by electrophoresis.
NThe correlation of serum immunoglobulin free light chain levels and selected biological markers in multiple
myeloma.
Pika T, Minarik J, Schneiderka P, Budikova M, Langova K, Lochman P, Bacovsky J, Farbiakova V, Scudla V.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2008 Jun;152(1):61-4.
:
http://www.ncbi.nlm.nih.gov/pubmed/18795076?ordinalpos=22&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors examine the of correlation of free light chains (FLC) serum levels - kappa, lambda and their relation (K/L ratio) and serum
levels of selected biological markers in a group of myeloma patients examined at the time of the diagnosis. Their study confirms mutual
correlation of FLC serum levels and the levels of several selected biological markers.
Aims: the presented study is aimed at the evaluation of correlation of free light chains serum levels - kappa, lambda and their relation
(K/L ratio) and serum levels of selected biological markers in a group of patients with multiple myeloma examined at the time of the
diagnosis. Methods: 102 patients with multiple myeloma were included in this prospective study. Free light chains serum levels were
determined by Freelite Binding Site system, for determination of serum levels of selected parameters the following methods were used:
REA thymidinekinase (TK), RIA (beta(2)microglobulin (beta(2)m), ICTP, PINP), enzymoimmunoassay (sIL-6R, sVCAM-1, sICAM-1,
sOPG) and quantitative enzymatic immunoassay (sHGF, sVEGF, sSyndecan-1 (sSyn-1) a sFas). Results: There was found a correlation in
the kappa-group of the dominant kappa chain and serum readings of beta(2)m (r = 0.344, p = 0.005), TK (r = 0.263, p = 0.035), ICTP
(r = 0.402, p = 0.001), PINP (r = 0.264, p = 0.039), sOPG (r = 0.328, p = 0.028), sSyn-1 (r = 0.255, p = 0.046) and sFas (r = 0.418,
p = 0.001). In case of K/L ratio there was found a statistically significant association of levels of beta(2)m (r = 0.316, p = 0.01), TK (r
= 0.274, p = 0.027), ICTP (r = 0.346, p = 0.006), PINP (r = 0.261, p = 0.042), sSyn-1 (r = 0.283, p = 0.026) and sFas (r = 0.377, p =
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0.002). In the lambda-group the analysis confirmed mutual dependence of the dominant lambda chain levels on beta(2)m (r = 0.476, p
= 0.003), ICTP (r = 0.375, p = 0.022), sVCAM-1 (r = 0.383, p = 0.019), sHGF (r = 0.441, p = 0.006) and sFas (r = 0.334, p = 0.040).
In addition we ascertained a correlation of L/K ratio and levels of beta(2)m (r = -0.473, p = 0.003), TK (r = -0.412, p = 0.011), ICTP (r
= -0.331, p = 0.045), PINP (r = -0.409, p = 0.012), sHGF (r = -0.357, p = 0.028), sSyn-1 (r = -0.449, p = 0.005) a sFas (r = - 0.371, p =
0.022). Conclusions: The study confirmed mutual correlation of FLC serum levels and the levels of several selected biological markers, in
particular beta(2)m, TK, ICTP, PINP, sSyn-1 a sFas at time of the diagnosis. It referred to the mutual relation of bone marrow microenvi-
ronment, biological qualities of clonal plasmocytes and the intensity of the free light chains production by the tumour cell population.
NImprovement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum
free light chains.
Leung N, Gertz MA, Zeldenrust SR, Rajkumar SV, Dispenzieri A, Fervenza FC, Kumar S, Lacy MQ, Lust JA, Greipp PR, Witzig TE,
Hayman SR, Russell SJ, Kyle RA, Winters JL.
Kidney Int. 2008 Jun;73(11):1282-8. [Epub 2008 Apr 2.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18385667?ordinalpos=23&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This study finds that the relationship between renal recovery and free light chain reduction is present only in myeloma patients with biopsy
proven cast nephropathy, showing the importance of extracorporeal light chain removal in this disease.
Cast nephropathy is the most common cause of renal disease in multiple myeloma, however, treatment with plasma exchange remains
controversial even after 3 randomized controlled studies. We sought to determine the importance of diagnostic confirmation and goal
directed therapy in the treatment of cast nephropathy in forty patients with confirmed multiple myeloma and renal failure who underwent
plasma exchange. A positive renal response was defined as a decrease by half in the presenting serum creatinine and dialysis independence.
No baseline differences were noted between eventual renal responders and non-responders. Three quarters of the patients with biopsy
proven cast nephropathy resolved their renal disease when the free light chains present in the serum were reduced by half or more but
there was no significant response when the reduction was less. The median time to a response was about 2 months. In patients without
cast nephropathy, renal recovery occurred despite reductions in free light chain levels of the serum. No association was found between free
light chains in the serum, urinary monoclonal proteins, overall proteinuria and cast nephropathy. We found that the relationship between
renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance
of extracorporeal light chain removal in this disease.
NSerum free light chains for diagnosis and follow-up of multiple myeloma. [Article in Korean]
Jung S, Kim M, Lim J, Kim Y, Han K, Min CK, Min WS.
Korean J Lab Med. 2008 Jun;28(3):169-73.
:
http://www.ncbi.nlm.nih.gov/pubmed/18594166?ordinalpos=24&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors assess the clinical usefulness of serum free light chain (FLC) in multiple myeloma and consider it a good diagnostic method
in complement with protein electrophoresis and immunofixation electrophoresis, as well as a useful monitoring tool.
BACKGROUND: Free light chain (FLC) is widely used to evaluate B-cell proliferative diseases. Herein, we estimated the clinical useful-
ness of serum FLC in multiple myeloma (MM). METHODS: Fifty-one patients were enrolled. We performed FLC analysis, protein
electrophoresis (PEP), and immunofixation electrophoresis (IFE). FLC was measured using Toshiba 200 FR Neo with FREELITE, and
kappa/lambda (kappa/lambda) ratio was calculated. We compared these parameters in 41 patients with increased FLC before and after
bortezomib treatment. Complete response (CR) was defined as the disappearance of monoclonal (M) protein in serum and/or urine as
measured by IFE. Partial response (PR) was defined as >or=50% reduction of serum M protein. Early objective response (EOR) included
both CR and PR. Minimal response (MR) was defined as 25-49% reduction of M protein and stable disease (SD) as <25% reduction.
RESULTS: Forty-one (80.4%) of the 51 patients studied revealed increment of FLC and the five patients with no increment revealed an
abnormal kappa/lambda ratio. Especially, all of the light chain myeloma and non-secretory myeloma showed increased FLC concentra-
tions. Among the patients with EOR, 72.4% (21/29) showed a normal or subnormal FLC concentration after the first cycle of treatment.
Otherwise, PEP and IFE normalized in 24.1% (7/29) and 24.1% (7/29), respectively. The ratio of decreased FLC after the first cycle of
treatment was significantly different between EOR and other response groups (MR, SD) (90.6% vs 51.8%, P=0.011). CONCLUSIONS:
FLC was considered as a good diagnostic method in complement with PEP and IFE in MM, especially in light chain myeloma or non-
secretory myeloma. Moreover, FLC is a useful monitoring tool because it reflects therapy results more rapidly owing to a short serum
half-life.
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NSerum immunoglobulin free light chain correlates with tumor burden markers in Waldenstrom
macroglobulinemia.
Leleu X, Moreau AS, Weller E, Roccaro AM, Coiteux V, Manning R, Nelson M, Leduc R, Robu D, Dupire S, Hatjiharissi E, Burwick N,
Darre S, Hennache B, Treon SP, Facon T, Gertz MA, Ghobrial IM.
Leuk Lymphoma. 2008 Jun;49(6):1104-7.
:
http://www.ncbi.nlm.nih.gov/pubmed/18452095?ordinalpos=25&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This study aims to evaluate the association of known tumor burden markers and prognostic factors with serum free light chain (sFLC) in
98 patients with Waldenstrom macroglobulinemia ( WM) and concludes that sFLC is a new marker in WM disease.
The serum IgM level has been utilised as a marker of tumor progression and to assess response to therapy in patients with Waldenstrom
macroglobulinemia (WM). However, there are many limitations to the IgM protein level. The objective of this study was to evaluate the
association of known tumor burden markers and prognostic factors with serum free light chain (sFLC) in 98 patients with WM. We dem-
onstrated that sFLC measurement accurately differentiated IgM-MGUS compared with WM reflecting a measurement of tumor burden.
In univariate and multivariate analysis, median sFLC at the cut-off at 60 mg/L was higher for WM patients with low hemoglobin and
high beta2M, when we applied the WM-IPSS cut-offs, but showed no association with IgM level. This study demonstrates that sFLC is
a new marker in WM disease. Further analysis is required to prospectively study the role of sFLC in monitoring response to therapy and
as a prognostic marker in WM patients.
NSerum free light chains.
Forsyth J, Hill P.
Ann Clin Biochem. 2008 Jul;45(Pt 4):444-5; author reply 445-6.
:
http://www.ncbi.nlm.nih.gov/pubmed/18583637?ordinalpos=36&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
Comment on: Ann Clin Biochem. 2007 Nov;44(Pt 6):503-5.
NClinical value of the blood measurement of the free light chains of immunoglobulins. [Article in French]
Bidet A, Marit G, Bérard AM.
Ann Biol Clin (Paris). 2008 Jul-Aug;66(4):427-31.
:
http://www.ncbi.nlm.nih.gov/pubmed/18725344?ordinalpos=35&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors analyze a large cohort of patients with multiple myeloma and monoclonal gammapathy of undetermined significance in order
to better understand the interest of free light chains.
Monoclonal free light chains are found in the serum and urine of patients with B-cell proliferative disorders, including multiple myeloma.
Measuring free light chains in serum is useful for the diagnosis and monitoring of free light chains diseases. Moreover it could be interest-
ing in the monitoring of treated multiple myeloma with complete immunoglobulin and of monoclonal gammapathy of undetermined
significance (MGUS). The goal of our work was to analyze a large cohort of patients with multiple myeloma or MGUS from January
2003 to August 2006 in order to better understand the interest of free light chains.
NLaboratory characterizations on 2007 cases of monoclonal gammopathies in East China.
Wang H, Gao C, Xu L, Yang Z, Zhao W, Kong X.
Cell Mol Immunol. 2008 Aug;5(4):293-8.
:
http://www.ncbi.nlm.nih.gov/pubmed/18761817?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors find that monoclonal gammopathies can be identified with the combination of immunofixation electrophoresis, serum pro-
tein electrophoresis, Igs quantitation and urine light chain determination.
Monoclonal gammopathies are characterized by the presence of monoclonal immunoglobulin in patients with or without evidence of
multiple myeloma (MM), macroglobulinemia, amyloidosis (AL), or a related plasma cell proliferative disorder. This study aims to evaluate
laboratory diagnostic characters of monoclonal gammopathies and investigates the correlation between monoclonal gammopathies and
transforming growth factor beta1 (TGFbeta1). Immunofixation electrophoresis (IFE), serum protein electrophoresis (SPE), nephelometry
and urine light chain ELISA were used for laboratory identification of monoclonal immunoglobulins. Plasma TGFbeta1 was detected
with double-antibodies ELISA. Lightcycler was used for single nucleotide polymorphism (SNP) analysis. Totally 2,007 cases of monoclo-
nal immunoglobulin (M protein) were identified in 10,682 samples. The isotypes of M protein were IgG type 47.1%, IgA 23.0%, IgM
8.7%, IgD 5.3%, free light chain kappa 6.1%, lambda 9.8%. In reference to IFE, the coherency of diagnosis was serum light chain ratio
(kappa/lambda ) 94.4%, quantitation of Igs 83%, light chain quantitation 80.9%, and urine light chain ratio (kappa/lambda) 58.0%.
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Plasma TGFbeta1 was elevated significantly compared to normal control. The allelic frequency of codon 10 (C>T) was neither associated
with the existence of the M protein nor with the M protein isotype. Monoclonal gammopathies can be identified with the combination
of IFE, SPE, Igs quantitation and urine light chain determination. Although TGFbeta1, an important cytokine in immune regulation,
was elevated in monoclonal gammopathies, the SNPs in coding region of TGFbeta1 gene did not confer susceptibility to the development
of monoclonal gammopathies in this study.
NMeasurement of serum free light chains and its clinical significance in 20 newly diagnosed patients of multiple
myeloma. [Article in Chinese]
Mao XB, Chen XQ, Zhai YP, Liang R, Gao GX, Ma GG, Yu YP, Li F.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008 Aug;16(4):829-32.
:
http://www.ncbi.nlm.nih.gov/pubmed/18718070?ordinalpos=30&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This study explores the clinical significance of measuring serum free light chains (sFLC) and to compare them with serum total light chains
( free and binded) in multiple myeloma. It concludes that testing sFLC by immuno-nephelometric assay combined with kappa/lambda ratio
is valuable for myeloma diagnosis, and the measurement of sFLC can be used as one of indicators for myeloma diagnosis.
The objective of this study was to explore the clinical significance of measuring serum free light chains (sFLC) and to compare with serum
total light chains (free and binded) in multiple myeloma (MM). sFLC in 20 newly diagnosed MM patients and 20 cases of healthy people
as control were measured by immuno-nephelometric assays; the serum light chains and kappa/lambda ratio were measured in all patients,
while immunofixation electrophoresis (IFE) tests were carried out at the same time in 18 out of 20 patients. The results showed that the
abnormality of serum free light chains and kappa/lambda ratio were found in all of the 20 newly diagnosed MM patients (p < 0.01). The
measurement of sFLC showed higher sensitivity than the total serum chains (p < 0.01). It is concluded that the method testing sFLC by
immuno-nephelometric assay combined with kappa/lambda ratio is valuable for MM diagnosis, and the measurement of sFLC can be
used as one of indicators for MM diagnosis.
NDiagnostic performance of serum free light chain measurement in patients suspected of a monoclonal B-cell
disorder.
Vermeersch P, Van Hoovels L, Delforge M, Mariën G, Bossuyt X.
Br J Haematol. 2008 Aug 20. [Epub ahead of print.]
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http://www.ncbi.nlm.nih.gov/pubmed/18729849?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This study aims to determine the diagnostic performance of different testing strategies to diagnose malignant B-cell disorder or monoclo-
nal gammopathy of unknown significance (MGUS). It finds that serum protein electrophoresis plus serum kappa/lambda free light chain
(FLC) has a significantly lower sensitivity than and serum immunofixation electrophoresis (IFE) plus FLC or serum IFE plus urine IFE for
the diagnosis of MGUS.
The present study aimed to determine the diagnostic performance of different testing strategies to diagnose malignant B-cell disorder
or monoclonal gammopathy of unknown significance (MGUS). Sensitivity and specificity were determined in 833 consecutive patients
investigated for a monoclonal gammopathy. Serum protein electrophoresis (PE), serum kappa/lambda free light chain (FLC) ratio, and
serum and urine immunofixation electrophoresis (IFE) were performed in all patients. Twenty-eight patients were diagnosed with a malig-
nant plasma cell disorder, 25 with B-cell non-Hodgkin lymphoma and 156 with MGUS. Serum PE (with follow-up IFE) plus FLC had
a sensitivity of 82.3% and a specificity of 96.8% and missed one plasmacytoma and 23 patients with MGUS. Serum IFE plus urine IFE
had a sensitivity of 92.3% and a specificity of 100% and missed two MGUS patients. Serum IFE plus FLC had a sensitivity of 93.8%
and a specificity of 96.8% and missed one MGUS patient. Serum PE plus FLC had a significantly lower sensitivity than serum IFE plus
FLC or serum IFE plus urine IFE for the diagnosis of MGUS. The sensitivity of serum IFE plus FLC was comparable to the sensitivity of
serum IFE plus urine IFE. The specificity of serum IFE plus FLC, however, was lower than the specificity of serum IFE plus urine IFE.
NMore studies are needed to assess the performance of serum free light chain measurement for the diagnosis of
B-cell disorders in routine clinical practice.
Vermeersch P, Mariën G, Bossuyt X.
Br J Haematol. 2008 Sep;143(1):143-5; author reply 145-6. [Epub 2008 Jul 30.]
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http://www.ncbi.nlm.nih.gov/pubmed/18671704?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
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NPathogenesis and progression of monoclonal gammopathy of undetermined significance.
Bladé J, Rosiñol L, Cibeira MT, de Larrea CF.
Leukemia. 2008 Sep;22(9):1651-7. [Epub 2008 Jul 31.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18668131?ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors discuss the predictors of malignant transformation, including serum free light-chain ratio, in monoclonal gammopathy
of undetermined significance and multiple myeloma.
In Caucasians, monoclonal gammopathy of undetermined significance (MGUS) is an age-related condition with prevalence as high as
3% in persons older than 50 years. Compared with whites, blacks have around two- and threefold higher prevalence rates of MGUS and
multiple myeloma (MM), respectively. Risk of progression from MGUS to MM has been found to be very similar in whites and blacks.
On average, the transformation rate to a malignant monoclonal gammopathy is 1% per year, with the mechanisms of progression likely
related to bone marrow microenvironment and/or the cytokine network. Overall, the actuarial probability of progression at 25 years of
follow-up is about 30%. However, when the competing causes of death are taken into account, the actual rate of progression is only 11%.
The predictors of malignant transformation are the plasma cell mass (M-protein size and/or proportion of plasma cell in the bone mar-
row), IgA isotype, serum free light-chain ratio and `evolving' type and ratio between phenotypically aberrant and normal bone marrow
plasma cells. It is recommended to follow these patients, particularly those with high risk of progression, annually to detect MM before
complications, such as renal failure or extensive skeletal, involvement occur.
NMore studies are needed to assess the performance of serum free light chain measurement for the diagnosis
of B-cell disorders in routine clinical practice response to Vermeersch et al.
Pratt G, Holding S.
Br J Haematol. 2008 Sep 5;143(1):145-146. [Epub 2008 Jul 30.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18671705?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
No abstract available.
N`Light-chain escape-multiple myeloma'-an escape phenomenon from plateau phase: report of the largest
patient series using LC-monitoring.
Kühnemund A, Liebisch P, Bauchmüller K, Zur Hausen A, Veelken H, Wäsch R, Engelhardt M.
J Cancer Res Clin Oncol. 2008 Sep 18. [Epub ahead of print.]
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http://www.ncbi.nlm.nih.gov/pubmed/18802723?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This report suggests that early detection of light-chain escape (LCE) multiple myeloma by means of serial serum free-light chain measure-
ments may prevent unnecessary complications, allows physicians to detect unusual relapse manifestations in the era of intensive and
biological therapy options, and possibly also permits improved treatment results in LCE-multiple myeloma.
PURPOSE: More intensive and novel therapy options in multiple myeloma (MM) hold the promise to improve treatment outcome.
However, disease evolution, induced with long disease duration and extensive pretreatment, has resulted in changes in the biological
behaviour of MM and unusual relapse emergence, such as of extramedullary (EM) disease or a shift in secretion from intact immuno-
globulin (Ig) to free-light chains (FLCs) only. METHODS: We studied ten patients since 2004, thoroughly assessed relevant patient
characteristics, prominent similarities, SFLC-changes, therapy response, mode and speed of progression, and the incidence of light-chain
escape (LCE)-MM within our entire myeloma patient cohort. Serum FLCs (SFLCs) were determined via Freelite-assay (Dade-Behringer
Nephelometer). RESULTS: This report summarizes the to date largest series of ten patients, whose MM appeared stable, as judged by con-
ventional monitoring of intact Ig levels, but developed severe organ dysfunction as a consequence of initially undetected LC-progression.
Median number of anti-MM cycles before LCE occurrence was six, including autologous and/or allogeneic stem cell transplants and novel
drugs, predominantly thalidomide, in 4/10. Classic diagnostics, such as electrophoresis and quantitative Ig measurement proved futile to
detect LC-progression, whereas SFLCs were reliable markers. The LCE-MM prevalence within 407 MM patients treated in our institu-
tion between 2004 and 2007 was 2.46%. CONCLUSIONS: Our report suggests that early detection of LCE-MM by means of serial
SFLC measurements may prevent unnecessary complications, allows to detect unusual relapse manifestations in the era of intensive and
biological therapy options and possibly also permits to improve treatment results in LCE-MM.
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NQuantitation of Serum Free Light Chains in Combination with Protein Electrophoresis and Clinical
Information for Diagnosing Multiple Myeloma in a General Hospital Population.
Piehler AP, Gulbrandsen N, Kierulf P, Urdal P.
Clin Chem. 2008 Sep 18. [Epub ahead of print.]
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http://www.ncbi.nlm.nih.gov/pubmed/18801937?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors evaluate serum free light chain (SFLC) measurements in combination with serum protein electrophoresis (SPE) and clinical
information for diagnosing multiple myeloma in a hospital population and conclude that the combined use of SPE, SFLC measurements,
and clinical criteria allows myeloma to be efficiently diagnosed or excluded based on serum measurements only.
BACKGROUND: Serum free light chain (SFLC) measurements have recently come into use as an aid for diagnosing monoclonal gam-
mopathy. We evaluated SFLC measurements in combination with serum protein electrophoresis (SPE) and clinical information for
diagnosing multiple myeloma (MM) in a hospital population. METHODS: We measured SFLCs in 3818 sera received for SPE over a
1-year period when patient symptoms or biochemical findings suggested myeloma-related tissue damage (n = 1067). We reviewed SPE
and SFLC results from 489 patients together with their final diagnoses obtained from the hospital information technology department.
RESULTS: SFLC measurement, combined with SPE and clinical information, allowed identification of 95% of patients (38 of 40) with
previously undiagnosed MM, macroglobulinemia, or primary amyloidosis. Additionally, we identified 45 patients with monoclonal gam-
mopathy of undetermined significance (MGUS) and 4 with plasmacytoma. Of patients followed at our hospital in whom SFLCs were
not measured, only 1 patient was diagnosed with MM. This patient had anemia and was mistakenly not tested for SFLCs. An abnormal
kappa/lambda ratio was found in 26 of 29 patients with MM but also in 36 of 203 patients with renal impairment, polyclonal immuno-
response, or other nonhematological diagnoses. None of the 203 patients with nonhematological disease had a kappa/lambda ratio <0.05
or >10. CONCLUSIONS: The combined use of SPE, SFLC measurements, and clinical criteria allows MM to be efficiently diagnosed
or excluded based on serum measurements only.
NSerum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure.
Hutchison CA, Plant T, Drayson M, Cockwell P, Kountouri M, Basnayake K, Harding S, Bradwell AR, Mead G.
BMC Nephrol. 2008 Sep 22;9:11.
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http://www.ncbi.nlm.nih.gov/pubmed/18808676?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
This study evaluates the diagnostic sensitivity and specificity of the immunoassays in myeloma patients with severe renal failure and con-
cludes that measurement of serum free light chain (FLC) concentrations and calculation of the serum kappa/lambda ratio is a convenient,
sensitive, and specific method for identifying monoclonal FLC production in patients with myeloma and acute renal failure.
BACKGROUND: Monoclonal free light chains (FLCs) frequently cause rapidly progressive renal failure in patients with multiple
myeloma. Immunoassays which provide quantitative measurement of FLCs in serum, have now been adopted into screening algorithms
for multiple myeloma and other lymphoproliferative disorders. The assays indicate monoclonal FLC production by the presence of an
abnormal kappa to lambda FLC ratio (reference range 0.26-1.65). Previous work, however, has demonstrated that in patients with renal
failure the FLC ratio can be increased above normal with no other evidence of monoclonal proteins suggesting that in this population
the range should be extended (reference range 0.37-3.1). This study evaluated the diagnostic sensitivity and specificity of the immunoas-
says in patients with severe renal failure. METHODS: Sera from 142 patients with new dialysis-dependent renal failure were assessed by
serum protein electrophoresis (SPE), FLC immunoassays and immunofixation electrophoresis. The sensitivity and specificity of the FLC
ratio's published reference range was compared with the modified renal reference range for identifying patients with multiple myeloma;
by receiver operating characteristic curve analysis. RESULTS: Forty one patients had a clinical diagnosis of multiple myeloma; all of these
patients had abnormal serum FLC ratios. The modified FLC ratio range increased the specificity of the assays (from 93% to 99%), with
no loss of sensitivity. Monoclonal FLCs were identified in the urine from 23 of 24 patients assessed. CONCLUSION: Measurement of
serum FLC concentrations and calculation of the serum kappa/lambda ratio is a convenient, sensitive and specific method for identifying
monoclonal FLC production in patients with multiple myeloma and acute renal failure. Rapid diagnosis in these patients will allow early
initiation of disease specific treatment, such as chemotherapy plus or minus therapies for direct removal of FLCs.
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NPrognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into
the international staging system.
Snozek CL, Katzmann JA, Kyle RA, Dispenzieri A, Larson DR, Therneau TM, Melton LJ 3rd, Kumar S, Greipp PR, Clark RJ,
Rajkumar SV.
Leukemia. 2008 Oct;22(10):1933-7. [Epub 2008 Jul 3.]
:
http://www.ncbi.nlm.nih.gov/pubmed/18596742?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
To determine if the serum free light chain (FLC) ratio has prognostic value in patients with symptomatic multiple myeloma, the authors
test baseline serum samples from a well-characterized cohort of 790 newly diagnosed myeloma patients with the FLC assay. Their findings
suggest that the serum FLC ratio at initial diagnosis is an important predictor of prognosis in myeloma, and can be incorporated into the
International Staging System for improved risk stratification.
To determine if the serum free light chain (FLC) ratio has prognostic value in patients with symptomatic multiple myeloma (MM), base-
line serum samples from a well-characterized cohort of 790 newly diagnosed MM patients were tested with the FLC assay. FLC ratio was
calculated as kappa/lambda (reference range 0.26-1.65). On the basis of the distribution of values, a cutpoint kappa/lambda FLC ratio of
<0.03 or >32 was chosen for further analysis. Overall survival was significantly inferior in patients with an abnormal FLC ratio of <0.03
or >32 (n=479) compared with those with an FLC ratio between 0.03 and 32 (n=311), with median survival of 30 versus 39 months,
respectively. We incorporated abnormal FLC ratio with the International Staging System (ISS) risk factors (that is, albumin <3.5 g/dl and
serum beta(2)-microglobulin >or=3.5 g/l), to create a risk stratification model with improved prognostic capabilities. Patients with 0, 1, 2
or 3 adverse risk factors had significantly different overall survival, with median survival times of 51, 39, 30 and 22 months, respectively
(P<0.001). These findings suggest that the serum FLC ratio at initial diagnosis is an important predictor of prognosis in myeloma, and
can be incorporated into the ISS for improved risk stratification.
NImmunodiagnostic capabilities of anti-free immunoglobulin light chain monoclonal antibodies.
Davern S, Tang LX, Williams TK, Macy SD, Wall JS, Weiss DT, Solomon A.
Am J Clin Pathol. 2008 Nov;130(5):702-11.
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http://www.ncbi.nlm.nih.gov/pubmed/18854262?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_
DefaultReportPanel.Pubmed_RVDocSum
The authors develop monoclonal antibodies (mAbs) that specifically recognize the kappa or lambda free light chain (FLC) products of
all known human variable and constant region light chain genes and find through their studies that their anti-FLC mAbs, with their high
degree of reactivity and versatility, may provide an invaluable tool in the diagnosis and management of light chain-associated disease.
Overproduction of plasma cell-derived monoclonal free kappa or lambda immunoglobulin light chains (FLCs) is a hallmark of multiple
myeloma, AL amyloidosis, and light chain deposition disease. Because these components serve as unique cellular and serologic biomark-
ers, their detection and quantitation has diagnostic, therapeutic, and prognostic import. In this regard, we have developed monoclonal
antibodies (mAbs) that specifically recognize the kappa or lambda FLC products of all known human variable and constant region light
chain genes. We now report the results of our studies that have demonstrated the capability of these reagents to measure, in a modified
fluid-phase capture enzyme-linked immunosorbent assay (ELISA), serum kappa and lambda FLCs at concentrations as low as 5 and 15
ng/mL, respectively. The mAb-based ELISA has greater sensitivity and reproducibility than does the commercially available immunotur-
bidimetric assay that uses polyclonal anti-FLC antibodies. In addition, the mAbs can immunostain monoclonal FLC-producing plasma
cells and pathologic light chain-related amyloid and nonfibrillar tissue deposits. Our anti-FLC mAbs, with their high degree of reactivity
and versatility, may provide an invaluable tool in the diagnosis and management of light chain-associated disease.
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www.myeloma.org
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