Understanding
Serum Free
Light Chain
Assays
International Myeloma Foundation
12650 Riverside Drive, Suite 206
North Hol ywood, CA 91607 USA
Telephone:
800-452-CURE (2873)
(USA & Canada)
818-487-7455
Fax: 818-487-7454
TheIMF@myeloma.org
www.myeloma.org
6/07

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Table of Contents
Introduction
5
MultipleMyelomaandMonoclonalProtein 5
WhatAreFreeLightChains?
6
HowisMonoclonalProtein
DetectedandMeasured?
8
TheSerumFreeLightChainAssays:
NormalVersusAbnormal
13
TheKappa/LambdaRatio
14
HowCantheSerumFreeLightChain
AssaysHelpwithTreatment?
15
FreeliteTMLevelsandtheAssessment
ofResponsetoTreatment
20
PatientsWhoBenefittheMost
fromtheSerumFreeLightChainAssays 21
WillInsuranceCovertheCost
ofSerumFreeLightChainAssays?
22
AbouttheIMF
23
Glossary
26
©2007, International Myeloma Foundation, North Hollywood, California

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Introduction
You received this booklet to learn more about
a type of laboratory test cal ed the Serum
Free Light Chain Assays. These tests are
also known col ectively as FreeliteTM. After
reading this booklet, you should be able to
answer the fol owing questions:
n What are free light chains?
n How are free light chains related to
multiple myeloma?
n How does the FreeliteTM test help with
diagnosis and monitoring response to
treatment of multiple myeloma?
This booklet is intended to provide you with
general information only. It is not meant to
replace the advice of your doctor or nurse
who can answer questions related to your
specific treatment plan. The definitions of all
works in bold are found in the glossary at the
end of the booklet.
Multiple Myeloma and
Monoclonal Protein
Myeloma is a cancer of the plasma cel s in
the bone marrow. Myeloma is synonymous
with multiple myeloma. The function of
normal plasma cel s is to produce antibod-
ies, also known as immunoglobulins, which
have an important role in fighting infection.
Each type of plasma cel produces only one
type of immunoglobulin. There are many
dif erent types of plasma cel s in the body,
4
5
*Words appearing in italics are defined in the glossary at the end of the booklet.

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and each type of plasma cel produces only
let er. These five types are abbreviated as
one type of immunoglobulin. The result is
IgG, IgA, IgM, IgD, and IgE.
the production of a wide variety of dif erent
There are two types of light chains, and they
immunoglobulins.
are referred to as kappa () and lambda (
In multiple myeloma, one particular plasma
or L). Each plasma cel produces only one
cel (a clone) is duplicated a very large
type of heavy chain and one type of light
number of times, causing excess produc-
chain. Altogether, there are 10 subtypes of
tion of one type of immunoglobulin cal ed
normal immunoglobulins (see Table 1).
a monoclonal protein or M-protein ­ also
Table 1. Subtypes of Immunoglobulins.
cal ed myeloma protein, paraprotein, or the
IgG kappa
IgG lambda
M-spike. The identification of an M-protein
is important for diagnosis, and the measure-
IgA kappa
IgA lambda
ment of its level is an aid for monitoring the
IgM kappa
IgM lambda
ef ectiveness of treatment.
IgD kappa
IgD lambda
IgE kappa
IgE lambda
What Are Free Light Chains?
The heavy and light chains are produced
Structural y, normal immunoglobulins (abbre-
separately within the plasma cel s and are
viated Ig) are composed of smal er units
assembled to form a whole ("intact") immuno-
cal ed heavy chains and light chains, and
globulin. When the light chains are at ached
together they form a large complex (see
to the heavy chains, the light chains are
Figure 1). There are five types of heavy
referred to as bound light chains. However,
chains, and each type is assigned a specific
when the light chains are not at ached to
the heavy chains, they are cal ed free light
chains. For unknown reasons, the plasma
cel s typical y produce more light chains than
are required to create the whole immuno-
globulins or monoclonal proteins. The excess
light chains enter the bloodstream as free
light chains (that is, not at ached to the heavy
chains). Thus, both in the normal situation
and in individuals with myeloma and related
disorders such as monoclonal gammopa-
thy of undetermined significance (MGUS),
Figure 1. Structure of an immunoglobulin (antibody).
excess light chains enter the bloodstream
6
7

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or lambda) is produced in excess this is con-
sistent with a monoclonal production.
Serum and urine Protein electroPhoreSiS
Two tests that are widely performed to
measure M-protein levels and to monitor
responses to treatment are SPEP and UPEP.
The M-protein is identified as a "spike" on
the SPEP or UPEP tracing (see Figure 2). SPEP
and UPEP measure the amount of M-protein
in a sample, but cannot identify the type of
M-protein that is present. That is, the test can
not identify the subtype as IgG kappa, IgA
lambda, etc (Table 1).
immunofixation electroPhoreSiS
as free light chains. The amount of free light
A second type of electrophoresis, referred
chain production is linked to the activity of
to as immunofixation electrophoresis (IFE) is
myeloma or plasma cel growth.
performed to identify the subtype of M-pro-
tein that is being produced by the myeloma
How is Monoclonal Protein
cel s. The subtype is identified by bands on
the IFE (see figure 2). but general y, it can not
Detected and Measured?
Monoclonal proteins may be detected and
measured in blood and/or urine. When
1
measurements are taken in blood, al of the
2
alb
3
cel s are removed, leaving only the yel ow
4
5
6
liquid component that is cal ed serum. If
7
SPE
lgG
lgA
lgM


1
2

l
2
3
4
5
6
multiple myeloma is suspected, your doctor
wil evaluate for the presence of an abnor-
mal monoclonal protein (M-protein). Several
1
tests can be ordered to detect the M-pro-
2
3
4
tein, including serum protein electrophoresis
5
6
7
(SPEP), urine protein electrophoresis (UPEP),
alb
SPE
lgG
lgA
lgM


1
2

l
2
3
4
5
6
and/or the Serum Free Light Chain Assays
Figure 2. Il ustrates SPEP (above left),
(FreeliteTM). If one type of light chain (kappa
UPEP (below left), and their respective IFEs (right).
8
9

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measure the amount of the M-protein subtype
Serum free light chain aSSayS
that is present in the sample. An SPEP may
The serum free light chain assays are capable
be performed first to determine if, and how
of detecting free light chains at their normal
much, of an M-protein is present. If the SPEP
(non-elevated) levels in the blood. Importantly,
demonstrates the presence of an M-protein,
these assays can detect mildly increased lev-
an IFE wil be done to determine what sub-
els of free light chains even when these levels
type of M-protein is present.
are undetectable by SPEP and IFE. This means
that multiple myeloma could be detected ear-
SPEP, UPEP, and IFE have advantages and
lier than might be possible with either SPEP
disadvantages. Among the disadvantages
or IFE and it is particularly useful in instances
are that they are relatively insensitive for the
when only smal amounts of light chains are
detection of free light chains, in that the free
produced by the myeloma.
light chain level must typical y be many times
the normal level in order to be detected with
The free light chain assays are best per-
SPEP, UPEP, or IFE. For example, the normal
formed on serum rather than urine because
level of one type of free light chain in the
of the filtering ef ects of the kidneys. Part of
blood is approximately 10 mil igrams per
the normal function of the kidneys is to pre-
liter (abbreviated mg/L). However, the free
vent protein loss from the body into the urine.
light chain level in blood would have to be
As a result, an elevated level of M-protein
50 times the normal level to be detected by
may be detected in the blood before it is
SPEP and at least 15 times the normal level
detected in the urine. Hence, the serum free
to be detected by IFE.
light chain assays may replace the need
for urine studies in the initial diagnosis of
myeloma and related plasma cel diseases,
however, urine studies are stil important as
part of serial monitoring. Serum free light
chain assays are more sensitive in serum,
the 24-hour urine sample is dif icult to col ect
and transport, and the specimen is more
dif icult to store than serum, however, urine
studies do show other aspects of myeloma
disease, like kidney damage.
Like other tests that detect M-protein, the
serum free light chain assays have advantag-
es and disadvantages. As discussed above,
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In people with a myeloma that produces only
light chains (Bence Jones myeloma), there is
an increased amount of kappa or lambda
light chain, depending upon the light chain
produced by the myeloma. But excess light
chains can also occur to a greater or lesser
extent with al types of myeloma, not just light
chain or Bence Jones myeloma. Therefore,
measurement of free light chains can be used
to diagnose and monitor the vast majority
of people with myeloma regardless of the
subtype of the myeloma.
The Serum Free Light Chain Assays:
Normal Versus Abnormal
Normal levels of serum free light chains are*:
· Kappa: 3.3­19.4 mg/L*
· Lambda: 5.7­26.3 mg/L*
· Kappa/lambda ratio: 0.26­1.65
one advantage is greater sensitivity than is
*Note: The units here are mg/L; dif erent
available with SPEP, UPEP, and IFE. Another
laboratories use dif erent units. It is important
advantage is that the serum free light chain
to double-check the units used when compar-
assays are automated and therefore require
ing numbers in lab values.
less time to perform in the laboratory than
Light chains produced by myeloma cel s will
SPEP, UPEP, and IFE. However, although the
be exclusively kappa or lambda, depend-
serum free light chain assays are excel ent
ing upon the type of myeloma. Thus, if the
for detection of free light chains, they are
myeloma cel s produce kappa light chains,
unable to detect whole immunoglobulins.
the level of kappa free light chains will
Some types of myeloma secrete only whole
increase in the blood. If, on the other hand,
immunoglobulins. Therefore it is often best
the myeloma cel s produce lambda light
to perform SPEP or IFE to detect elevated
chains, the level of lambda free light chains
levels of intact immunoglobulins in combina-
wil increase in the blood. Your doctor will
tion with the serum free light chain assays to
need to interpret the results of the serum
detect free light chains.
free light chain assays together with other
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clinical information in order to make a final
be within the normal range, and this
interpretation of the results. A specialist in
general y indicates a disease other than
hematology/oncology is highly qualified to
myeloma, such as poor kidney function.
make this decision.
When the kidneys are not working prop-
erly, both types of light chains are retained
The Kappa/Lambda Ratio
in the blood and are not removed by the
kidneys. The result is increased levels of
n The kappa/lambda ratio is as important
both kappa and lambda in the blood. In
for diagnosis and monitoring of myeloma
this situation, in general, the abnormal y
as are the levels of kappa and lambda
increased levels are not themselves a
n When the level of either kappa or lambda
direct result of currently active myeloma
is very high and the other chain is normal
n If the kappa and lambda levels are both
or low, then the ratio is abnormal and
within the normal range, sometimes the
indicates that the myeloma is active
ratio may be abnormal. In this situation,
n If levels of both kappa and lambda
there may be a persistent low level of
light chains are increased, the ratio may
active myeloma with excess production of
the abnormal light chains.
n A normal kappa/lambda ratio after treat-
ment is a particularly good remission and
is termed a stringent complete response.
Normalization of the kappa/lambda ratio
correlates with possible longer remissions,
and studies are in progress to investigate
more about the nature of this relationship.
How Can the Serum Free Light
Chain Assays Help with Treatment?
Serum free light chain assays can help in
several ways:
1. evaluation of early response and early relapse
Because free light chains are broken down
and/or excreted by the kidneys rather
quickly (within just a few hours), changes
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in blood levels in response to treatment
people with non-secretory or hyposecretory
occur rapidly. Thus, with a good response
myeloma have measurable abnormalities of
to treatment, myeloma cel s wil die, they
M-protein using the serum free light chain
wil stop producing free light chains, and
assays. The FreeliteTM test has been incor-
the blood levels of the free light chains will
porated into response criteria to assist in
decrease within a few hours to days. In this
assessing ef ectiveness of treatment in people
situation, the decrease in free light chains
with hyposecretory myeloma (see Table 2
occurs much more quickly than the decrease
below).
in IgG or IgA, because these compounds
Table 2. Response to Treatment
are broken down much more slowly by the
Using FreeliteTM in Hyposecretory Myeloma
body. Decreases in free light chain levels
Stringent
Normalized free light
can therefore be a very sensitive indicator of
Complete chain ratio
early response. Typical y, response to treat-
Response
ment can be detected by serum free light
Partial
50% decrease in the
chain assays in a mat er of hours to days,
Response
dif erence between the
whereas it may take one to three weeks to
light chain produced by
detect response using SPEP and IFE.
the myeloma cel s and the
At the time of relapse, the sensitivity of the
other light chain
free light chain assays is also very impor-
tant. Even very smal amounts of myeloma
that start to grow as part of relapse produce
measurable amounts of free light chains in
most instances. The serum free light chain
levels of either kappa or lambda, depending
upon the type of myeloma, often increase
before the increases in IgG and IgA and
other immunoglobulins can be detected by
SPEP or IFE. Imaging tests, such as FDG-PT
or CT-PET, are also useful in the assessment
of minimal amounts of disease.
2. monitoring patients with low levels of
myeloma protein (m-protein)
Myeloma that produces low levels of M-
protein is cal ed non-secretory or hyposecre-
tory disease. Approximately 70% to 80% of
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3. enrol ment in clinical trials
as possible ­ and sometimes to eliminate it
Clinical trials are the only route by which
entirely. If the free light chain ratio becomes
new medicines are made available and a
normal after treatment then this provides a
potential cure discovered. People with myelo-
very good and sensitive indication that treat-
ma may participate in clinical trials to help
ment has been highly ef ective, and means
test the safety and ef ectiveness of new treat-
that the level of light chain paraprotein
ments. In order for a patient with myeloma to
has been reduced as much as possible. If
be eligible to participate in a trial, there must
the free light chain ratio normalizes with
be a way to monitor their M-protein levels in
treatment, then this result is cal ed stringent
the blood or urine. People with hyposecreto-
complete response. This type of response is
ry (formerly "non-secretory") disease used to
the best possible response according to the
be excluded from clinical trials because there
International Response Criteria in Multiple
was no method to monitor their M-protein
Myeloma. By definition, a stringent complete
levels. With the availability of the serum free
response also includes a normal SPEP, a
light chain assays, the M-protein level can
normal UPEP, a normal IFE, and no evidence
be monitored in the blood of these people.
of myeloma cel s in the bone marrow using
Therefore, people with hyposecretory dis-
special tests.
ease may now be eligible to participate in
clinical trials.
4. indicator of disease activity
A study from the Mayo Clinic showed that
patients with monoclonal gammopathy of
undetermined significance (MGUS) who also
have an abnormal free light chain ratio are
more likely to progress and develop active
myeloma. Changes in FreeliteTM levels are
useful for tracking the disease status in almost
al people with myeloma, not just those with
light chain (Bence Jones) myeloma or non-
secretory disease.
5. assessment of stringent complete response
to treatment
One of the goals of myeloma treatment is
to reduce the level of M-protein as much
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FreeliteTM Levels and the Assessment
n Inclusion of serum free light chain assays
of Response to Treatment
can improve the sensitivity of screening
protocols for detection and diagnosis of
Serum Freelite levels can be used in the
myeloma
same way as monoclonal protein measure-
n The serum free light chain assays along
ments to assess response to treatment, but
with other tests can provide valuable infor-
they can also be used more frequently in the
mation for people with MGUS
early weeks of treatment. Some people with
myeloma find it helpful to track their own
n Use of serum free light chain assays to
serum free light chain values using tables or
monitor treatment reveals responses to
spreadsheets ­ just like people with diabetes
treatment earlier than other laboratory
track their blood sugar. A table that can be
tests such as SPEP
used to fol ow results of the serum free light
n The improved sensitivity of serum free light
assays is located at the end of this booklet.
chain assays over IFE may al ow earlier
Specific criteria to assess stringent complete
detection of a relapse of myeloma
response and complete response have been
established by the International Myeloma
Patients Who Benefit the Most
Working Group and are summarized in
From the Serum Free Light Chain
Table 3.
Assays Are:
Table 3. Stringent Complete Response
and Complete Response
n People with myeloma who have abnormal
serum free light chain results at the start
Stringent
Normalization of the free
of treatment. Monitoring with the serum
Complete light chain ratio and no
free light chain assays often al ows a
Response
evidence of myeloma cel s
rapid assessment of the ef ectiveness of
in the bone marrow
treatment.
Complete Negative immunofixation in
n People with very low levels of light chains
Response
the serum and urine, disap-
with other tests such as SPEP, UPEP, and
pearance of any plasmacy-
IFE. These are people who general y have
toma, and 5% plasma cel s
non-secretory (or hypo-secretory) myelo-
in the bone marrow
ma. Approximately 80% of people with
non-secretory myeloma can have their
In summary, the serum free light chain assays
disease monitored using the serum free
of er several advantages for diagnosis and
light chain assays.
monitoring of treatment:
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n People with deposits of light chains in the
About the IMF
form of AL amyloidosis. People with AL
amyloidosis may or may not have active
"One person can make a dif erence,
myeloma. Tracking the light chain levels is
Two can make a miracle."
very helpful to assess the disease status.
Brian D. Novis
n People with light chain only myeloma
IMF Founder
(Bence Jones myeloma). The major advan-
Myeloma is a lit le-known, complex, and
tages of the serum free light chain assays
often misdiagnosed bone marrow cancer that
for these people are:
at acks and destroys bone. Myeloma af ects
· Ease of blood testing versus 24-hour
approximately 75,000 to 100,000 people
urine col ection*
in the United States, with approximately
· The much greater sensitivity of blood
20,000 new cases diagnosed each year.
testing: mildly increased levels may be
Although there is presently no known cure for
detected in the blood but not detected
myeloma, doctors have many approaches
in the urine.
to help myeloma patients live bet er and
longer.
* It is important to note that periodic 24-hour
urine testing is stil recommended and neces-
The International Myeloma Foundation (IMF)
sary, both to double-check the light chain
was founded in 1990 by Brian and Susie
excretion level and monitor for any evidence
Novis shortly after Brian's myeloma diagno-
of kidney damage.
sis at the age of 33. It was Brian's dream that
future patients would have easy access to
medical information and emotional support
Will Insurance Cover the Cost of
throughout their bat le with myeloma. He
Serum Free Light Chain Assays?
established the IMF with the 3 goals of treat-
In the United States, the serum free light
ment, education, and research. He sought
chain assays are reimbursed by Medicare.
to provide a broad spectrum of services for
Please consult with your doctor's of ice and
patients, their families, friends, and health
insurance provider regarding this issue.
care providers. Although Brian died 4 years
after his initial diagnosis, his dream didn't.
Today, the IMF reaches out to an interna-
tional membership of more than 150,000.
The IMF was the first organization dedicated
solely to myeloma, and today it remains the
largest.
22
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internet acceSS
reSearch
Log on to www.myeloma.org for 24-hour
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Join the IMF Internet Discussion Group at
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for myeloma.
24
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Glossary
Appointments
Antibody: A protein produced by plasma cel s (a type of
date
time
Kappa
lambda
/
white blood cel ) that helps fight infection. Also known as


level
level
ratio
an immunoglobulin.
Bone Marrow: A soft, spongy tissue found in most large
bones that produces red blood cel s, white blood cel s,
notes
and platelets.
Immunoglobulin: See "Antibody."
notes
Monoclonal protein (M-protein): An abnormal protein pro-
duced by myeloma cel s which accumulates in and dam-
ages bone marrow. A high level of M-protein indicates
notes
that myeloma cel s are present in large numbers. The
M-protein may consist of intact immunoglobulin, free light
chains, or both.
notes
Multiple myeloma: A cancer arising from the plasma cel s
in the bone marrow. The plasma cel s form abnormal
antibodies, possibly damaging the bone, bone marrow,
notes
and other organs.
Plasma cell: A type of white blood cel that produces
antibodies.
notes
Plasmacytoma: A tumor made up of cancerous plasma
cel s.
Protein: A group of compounds that are the main com-
notes
ponent of a cel .
Stringent complete response: normalization of the free light
notes
chain ratio and absence of myeloma cel s in the bone
marrow fol owing treatment.
White blood cell: A cel made by the bone marrow that
notes
helps fight infection and/or disease.
notes
notes
notes
notes
26

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