International Myeloma

Working Group (IMWG)

Guidelines for Serum
Free Light Chain
Analysis in Multiple
Myeloma and Related
Disorders
By imwg On July 9, 2010 Add Comment In Diagnosis, Staging & Monitoring, Guidelines
For the more than 3% of myeloma patients who have non-secretory or
oligosecretory disease, and for the majority of patients with AL amyloidosis (AL),
the traditional methods of measuring circulating monoclonal immunoglobulins
(electrophoresis, immunoelectrophoresis, immunofixation electrophoresis, and
nephelometric measurement of immunoglobulin heavy chains of serum) are not
adequate. The development of an assay that measures serum immunoglobulin-
free light chains has demonstrated utility for monitoring these patients and for
other specific indications, such as monitoring heavily-pretreated patients at
relapse.

The following guidelines from the International Myeloma Working Group describe
the potential uses of the serum free light chain (SFLC) assay and distinguish
which uses have proved their utility and which are still undergoing investigation.
SFLC assay for screening at diagnosis
The combination of serum immunoelectrophoresis (IFE), serum protein
electrophoresis (PEL), and serum free light chain (SFLC) assay are
recommended for screening at diagnosis.
For the purpose of screening for monoclonal proteins for all diagnoses
except AL, the SFLC assay can replace the 24-hour urine IFE, BUT after
diagnosis, the 24-hour urine for PEL and IFE should be done. For AL
screening, the urine IFE should still be done in addition to the serum tests,
including SFLC.
Prognostic value of the SFLC assay
Baseline values of the serum SFLC ratio are prognostic for:
MGUS (monoclonal gammopathy of undetermined significance)
Smoldering myeloma
Symptomatic myeloma
Solitary plasmacytoma
AL amyloidosis
The FLC assay in response assessment
Treatment-related immunosuppression of the uninvolved light chain (lambda
for kappa patients, and vice versa) can make the assay unreliable for
monitoring response in patients with secretory disease.
Routine serial use of the SFLC assay is recommended for oligosecretory
disease; hematologic response can therefore be best assessed with SFLC
assay in:
AL amyloidosis
Non-secretory myeloma (not yet fully validated)
Light chain deposition disease (not yet fully validated)
Response Criteria for FLC

Minimum deemed
PR CR sCR Progression
measurable

Normal rFLC and

AL without 50% reduction of 50% increase o
CR by IFE and ND
measurable serum iFLC > 100mg/l iFLC iFLC to > 100 mg
bone marrow
or urine M-protein

AL with
ND ND ND ND ND
measurable serum
or urine M-protein

Normal rFLC & CR

MM without 50% reduction of 50% increase o
iFLC > 100mg/l ND by IFE and bone
measurable serum dFLC dFLC
and rFLC abnormal marrow
or urine M-protein

Normal rFLC & CR

Use of FLC not Use of FLC not Use of FLC not Use of FLC not
MM with by IFE and bone
recommended recommended recommended recommended
measurable disease marrow

Abbreviations: iFLC, inv- restricted disease; dFLC, difference between iFLC and
uninvolved FLC; rFLC ,free light chain ratio; ND, not defined.
aMeasurable M protein includes serum M protein of at least 1 g per 100 ml or a
urine M-protein of at least 200 mg/24 h for myeloma patients (100 mg/24 h for AL
patients).

The FLC assay in the context of renal insufficiency

Although renal failure increases the levels of both kappa and lambda light
chains, it does not result in an abnormal ratio.
Interpreting serial measurements of iFLC in patients with oligosecretory
myeloma. LCDD, or amyloidosis who are on dialysis or who have markedly
abnormal renal function is very challenging, and response assessment has
 not been validated. However, following the dFLC or iFLC while noting the
uninvolved light chains can provide information.
Caveats with the free light chain (FLC) assay
Clinical
The test must be interpreted in the context of a clinical situation. If a
patient is in the midst of an infection or a flare-up of a rheumatologic
condition, the test should be repeated at a later date.
Technical
There can be lot-to-lot variation between batches of polyclonal FLC
antisera, which can produce inconsistent results.
Some monoclonal light chains (particularly kappa) do not dilute in a
linear fashion and may be underestimated.
Changes in the amino acid sequence of the light chain may render
certain light chain epitopes unrecognizable to the FLC reagents.
Extreme polymerization can cause an overestimation of light chains by
as much as 10-fold.
Very high levels of light chains can cause antigen excess, which in turn
can result in falsely low SFLC results with nephelometric techniques.
For large multi-center clinical trials, using a centralized lab is an option to
avoid lot-to-lot variation issues.
1
A Dispenzieri et al. International Myeloma Working Group guidelines for serum
free light chain analysis in multiple myeloma and related
disorders. Leukemia (2008), 1-10.
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Related
Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering
(Asymptomatic) Multiple Myeloma: IMWG Consensus Perspectives Risk Factors for
Progression and Guidelines for Monitoring and ManagementJune 24, 2010In "Diagnosis,
Staging & Monitoring"
IMWG Guidelines on Imaging Techniques in the Diagnosis and Monitoring of Multiple
MyelomaMarch 1, 2010In "Diagnosis, Staging & Monitoring"
The use of biochemical markers of bone remodeling in multiple myeloma: a report of the
International Myeloma Working GroupOctober 24, 2010In "IMWG Publications"

T A G G E D W I T H disorder serum free light chain

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