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)
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Fax: 818-487-7454
TheIMF@myeloma.org
myeloma.org
Table of Contents
Introduction
5
MultipleMyelomaandMonoclonalProtein 5
WhatAreFreeLightChains?
6
HowisMonoclonalProtein
DetectedandMeasured?
8
TheSerumFreeLightChainAssays:
NormalVersusAbnormal
13
TheKappa/LambdaRatio
14
HowCantheSerumFreeLightChain
AssaysHelpwithTreatment?
16
FreeliteLevelsandtheAssessment
ofResponsetoTreatment
20
PatientsWhoBenefittheMost
fromtheSerumFreeLightChainAssays 22
WillInsuranceCovertheCost
ofSerumFreeLightChainAssays?
23
AbouttheIMF
24
Glossary
27
Sponsored by an unrestricted educational grant from Binding Site.
©2011, International Myeloma Foundation, North Hollywood, California (vi11)
Introduction
You received this booklet to learn more about
a type of laboratory test cal ed the Serum
Free Light Chain Assays (SFLCA). 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 Freelite test help with diag-
nosis and monitoring response to treat-
ment 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 al
words 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,
5
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
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produced in excess, this is consistent with the
presence of a monoclonal protein.
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)
myeloma or plasma cel growth.
is performed to identify the subtype of
M-protein that is being produced by the
How is Monoclonal Protein
myeloma cel s. The subtype is identified by
bands on the IFE (see Figure 2), but it cannot
Detected and Measured?
Monoclonal proteins may be detected and
measured in blood and/or urine. When mea-
1
surements are taken in blood, al of the cel s
2
alb
3
are removed, leaving only the yel ow liquid
4
5
6
component that is cal ed serum. If multiple
7
SPE
lgG
lgA
lgM
1
2
l
2
3
4
5
6
myeloma is suspected, your doctor wil evalu-
ate for the presence of an abnormal mono-
clonal protein (M-protein). Several tests can
1
be ordered to detect the M-protein, including
2
3
4
serum protein electrophoresis (SPEP), urine
5
6
7
protein electrophoresis (UPEP), and/or the
alb
SPE
lgG
lgA
lgM
1
2
l
2
3
4
5
6
Serum Free Light Chain Assays (Freelite). If
Figure 2. Il ustrates SPEP (above left),
one type of light chain (kappa or lambda) is
UPEP (below left), and their respective IFEs (right).
8
9
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
Serum free light chain assays are best per-
SPEP, UPEP, or IFE. For example, the normal
formed on serum rather than urine because of
level of one type of free light chain in the
the filtering ef ects of the kidneys. Part of the
blood is approximately 10 mil igrams per
normal function of the kidneys is to prevent
liter (abbreviated mg/L). However, the free
protein loss from the body into the urine. As
light chain level in blood would have to be
a result, an elevated level of M-protein may
50 times the normal level to be detected by
be detected in the blood before it is detected
SPEP and at least 15 times the normal level
in the urine. Hence, the serum free light chain
to be detected by IFE.
assays have replaced the need for urine stud-
ies in the initial diagnosis of myeloma and
related plasma cel diseases, however, urine
studies are stil important in the initial diag-
nosis of AL amyloidosis and as part of serial
monitoring. Free light chain assays are more
sensitive in blood, 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 may be
used to diagnose and monitor the vast major-
ity 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: 5.7126.3 mg/L*
one advantage is greater sensitivity than is
· Kappa/lambda ratio: 0.261.65**
available with SPEP, UPEP, and IFE. Another
*Note: The units here are mg/L; dif erent
advantage is that the serum free light chain
laboratories use dif erent units. It is important to
assays are automated and therefore require
double-check the units used when comparing
less time to perform in the laboratory than
numbers in lab values.
SPEP, UPEP, and IFE. However, although the
**Further Note: In patients with renal impair-
serum free light chain assays are excel ent
ment, it is recommended to interpret the results
for detection of free light chains, they are
of the Kappa/Lambda ratio with a modified
unable to detect whole immunoglobulins.
reference range of 0.373.1.
Some types of myeloma secrete only whole
Light chains produced by myeloma cel s wil
immunoglobulins. Therefore it is often best
be exclusively kappa or lambda, depend-
to perform SPEP and IFE to detect elevated
ing upon the type of myeloma. Thus, if the
levels of intact immunoglobulins in combina-
myeloma cel s produce kappa light chains,
tion with the serum free light chain assays to
the level of kappa free light chains wil
detect free light chains as recommended by
increase in the blood. If, on the other hand,
the International Myeloma Working Group.
the myeloma cel s produce lambda light
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chains, the level of lambda free light chains
there may be a persistent low level of
wil increase in the blood. Your doctor wil
active myeloma with excess production of
need to interpret the results of the serum
the abnormal light chains.
free light chain assays together with other
n A normal kappa/lambda ratio after treat-
clinical information in order to make a final
ment is a particularly good remission and
interpretation of the results. A specialist in
is termed a stringent complete response.
hematology/oncology is highly qualified to
Normalization of the kappa/lambda ratio
make this decision.
correlates with possible longer remissions,
and studies are in progress to investigate
The Kappa/Lambda Ratio
more about the nature of this relationship.
n The SFLCA kappa/lambda ratio is as
important for diagnosis and monitoring of
myeloma as are the levels of kappa and
lambda
n When the level of either kappa or lambda
is very high and the other chain is normal
or low, then the ratio is abnormal and
indicates that the myeloma is active
n If levels of both kappa and lambda
light chains are increased, the ratio may
be within the normal range, and this
general y indicates a disease other than
myeloma, such as poor kidney function.
When the kidneys are not working prop-
erly, both types of light chains are retained
in the blood and are not removed by the
kidneys. The result is increased levels of
both kappa and lambda in the blood. In
this situation, in general, the abnormal y
increased levels are not themselves a
direct result of currently active myeloma
n If the kappa and lambda levels are both
within the normal range, sometimes the
ratio may be abnormal. In this situation,
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before the increases in IgG and IgA and
How Can the Serum Free Light
other immunoglobulins can be detected by
Chain Assays Help with Treatment?
SPEP or IFE. Imaging tests, such as FDG-PET
Serum free light chain assays can help in
or CT-PET, are also useful in the assessment
several ways:
of minimal amounts of disease.
1. evaluation of early response and early relapse
2. monitoring patients with low levels of
Because free light chains are filtered by
myeloma protein (m-protein)
the kidneys rather quickly (within just a few
Myeloma that produces low levels of
hours), changes in blood levels in response
M-protein has traditional y been referred to
to treatment occur rapidly. Thus, with a
as nonsecretory or hyposecretory. Two new
good response to treatment, myeloma cel s
terms are used today: oligosecretory and
wil die, they wil stop producing free light
paucisecretory. Approximately 70% to 80%
chains, and the blood levels of the free light
of people with this type of myeloma have
chains wil decrease within a few hours to
measurable abnormalities of M-protein using
days. In this situation, the decrease in free
the serum free light chain assays. The Freelite
light chains occurs much more quickly than
test has been incorporated into response
the decrease in IgG or IgA, because these
criteria to assist in assessing ef ectiveness of
compounds are broken down much more
slowly by the body. Decreases in free light
chain levels can therefore be a very sensi-
tive indicator of early response. Typical y,
response to treatment can be detected by
serum free light chain assays in a mat er of
hours to days, whereas it may take one to
three weeks to detect response using SPEP
and IFE.
At the time of relapse, the sensitivity of the
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, may increase
16
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treatment in people with low-level M-protein
4. indicator of disease activity
myeloma (see Table 2 below).
A study from the Mayo Clinic showed that
patients with monoclonal gammopathy of
Table 2. Response to Treatment
Using Freelite in Hyposecretory Myeloma
undetermined significance (MGUS) who also
have an abnormal free light chain ratio are
Stringent
Normalized free light
more likely to progress and develop active
Complete
chain ratio
myeloma or a related malignant condition.
Response
Changes in Freelite levels are useful for track-
Partial
50% decrease in the
ing the disease status in almost al people
Response
dif erence between the
with myeloma, not just those with light chain
light chain produced by
(Bence Jones) myeloma or nonsecretory dis-
the myeloma cel s and the
ease.
other light chain
5. assessment of stringent complete response
to treatment
3. enrol ment in clinical trials
One of the goals of myeloma treatment is
Clinical trials are the only route by which
to reduce the level of M-protein as much
new medicines are made available and a
as possible and sometimes to eliminate it
potential cure discovered. People with myelo-
entirely. If the free light chain ratio becomes
ma may participate in clinical trials to help
normal after treatment then this provides a
test the safety and ef ectiveness of new treat-
very good and sensitive indication that treat-
ments. In order for a patient with myeloma to
ment has been highly ef ective, and means
be eligible to participate in a trial, there must
that the level of light chain paraprotein
be a way to monitor their M-protein levels in
has been reduced as much as possible. If
the blood or urine. People with hyposecreto-
the free light chain ratio normalizes with
ry (formerly "nonsecretory") disease used to
treatment, then this result is cal ed stringent
be excluded from clinical trials because there
complete response. This type of response is
was no method to monitor their M-protein
the best possible response according to the
levels. With the availability of the serum free
International Response Criteria in Multiple
light chain assays, the M-protein level can
Myeloma. By definition, a stringent complete
be monitored in the blood of the majority of
response also includes a normal SPEP, a
these people. Therefore, people with hypo-
normal UPEP, a normal IFE, and no evidence
secretory (oligosecretory or paucisecretory)
of myeloma cel s in the bone marrow using
disease may now be eligible to participate
special tests.
in clinical trials.
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Freelite Levels and the Assessment
In summary, the serum free light chain assays
of Response to Treatment
of er several advantages for diagnosis and
monitoring of treatment:
Serum free light chain levels, as measured
n Inclusion of serum free light chain assays
by the Freelite test, can be used in the same
can improve the sensitivity of screening
way as monoclonal protein measurements
protocols for detection and diagnosis of
to assess response to treatment, but they
myeloma
can also be used more frequently in the
early weeks of treatment. Some people with
n The serum free light chain assays along
myeloma find it helpful to track their own
with other tests can provide valuable infor-
serum free light chain values using tables or
mation for people with MGUS
spreadsheets just like people with diabetes
n Use of serum free light chain assays to
track their blood sugar. A powerful tool to fol-
monitor treatment reveals responses to
low the results of al laboratory tests as wel
treatment earlier than other laboratory
as to display and print tables is the Myeloma
tests such as SPEP
ManagerTM software available at www.man-
ager.myeloma.org.
Specific criteria to assess stringent complete
response and complete response have been
established by the International Myeloma
Working Group and are summarized in
Table 3.
Table 3. Stringent Complete Response
and Complete Response
Stringent
Complete Response as defined
Complete
below and Normalization of
Response
the free light chain ratio with
no evidence of myeloma cel s
in the bone marrow.
Complete
Negative immunofixation in
Response
the serum and urine, disap-
pearance of any plasmacy-
toma, and 5% plasma cel s
in the bone marrow
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n The improved sensitivity of serum free light
n People with deposits of light chains in the
chain assays over IFE may al ow earlier
form of AL amyloidosis. People with AL
detection of a relapse of myeloma
amyloidosis may or may not have active
n The serum free light chain assay is rec-
myeloma. Tracking the light chain levels
ommended for use in diagnosis, prog-
is very helpful to assess the disease status.
nosis, and monitoring in the guidelines
n People with light chain only myeloma
published by the International Myeloma
(Bence Jones myeloma). The major advan-
Working Group.
tages of the serum free light chain assays
n The NCCN Clinical Practice Guidelines
for these people are:
in Oncology recommend the use of
· Ease of blood testing versus 24-hour
polyclonal serum free light chain assays
urine col ection*
(Freelite®) in the initial diagnostic workup
· The much greater sensitivity of blood
of myeloma and related disorders.
testing: mildly increased levels may be
detected in the blood but not detected
Patients Who Benefit the Most
in the urine.
From the Serum Free Light Chain
* It is important to note that periodic 24-hour
Assays Are:
urine testing is stil recommended and neces-
sary, both to double-check the light chain
n People with myeloma who have abnormal
excretion level and monitor for any evidence
serum free light chain results at the start
of kidney damage.
of treatment. Monitoring with the serum
free light chain assays often al ows a
Will Insurance Cover the Cost of
rapid assessment of the ef ectiveness of
treatment.
Serum Free Light Chain Assays?
n People with very low levels of light chains
In the United States, the serum free light
with other tests such as SPEP, UPEP, and IFE.
chain assays are reimbursed by Medicare.
These are people who general y have non-
Please consult with your doctor's of ice and
secretory (hyposecretory, oligosecretory, or
insurance provider regarding this issue.
paucisecretory) myeloma. Approximately
70% of people with nonsecretory myeloma
can have their disease monitored using the
serum free light chain assays.
22
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The IMF provides programs and services to
About the IMF
aid in the research, diagnosis, treatment,
"One person can make a dif erence,
and management of myeloma. The IMF
ensures that no one must brave the myeloma
Two can make a miracle."
bat le alone.
Brian D. Novis
IMF Founder
We care for patients today, while working
toward tomorrow's cure.
Myeloma is a lit le-known, complex, and
often misdiagnosed bone marrow cancer that
How Can the IMF Help You?
at acks and destroys bone. Myeloma af ects
approximately 75,000 to 100,000 people
Patient education
in the United States, with approximately
information PacKage
20,000 new cases diagnosed each year.
Our free IMF InfoPack provides comprehensive
Although there is presently no known cure
information about myeloma, treatment options,
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disease management, and IMF services. It
es to help myeloma patients live bet er
includes our acclaimed Patient Handbook.
and longer.
internet acceSS
Log on to www.myeloma.org for 24-hour
The International Myeloma Foundation (IMF)
access to information about myeloma, the IMF,
was founded in 1990 by Brian and Susie
education, and support programs.
Novis shortly after Brian's myeloma diagno-
online myeloma forum
sis at the age of 33. It was Brian's dream that
Join the IMF Internet Discussion Group at
future patients would have easy access to
www.myeloma.org/listserve.html to share your
medical information and emotional support
thoughts and experiences.
throughout their bat le with myeloma. He
myeloma minute
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Meet with leading experts in myeloma treat-
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Today, the IMF reaches out to an interna-
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tional membership of more than 195,000.
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myeloma matrix
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24
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myeloma today neWSletter
reSearch grantS
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Leading the world in col aborative research
charge by subscription.
and achieving extraordinary results, the IMF
SuPPort
Grant Program supports both junior and senior
researchers working on a broad spectrum of
myeloma hotline: 800-452-cure (2873)
projects. The IMF has at racted many young
Toll-free throughout the United States and
investigators into the field of myeloma who
Canada, the IMF Hotline is staf ed by trained
remain in the field and actively pursue a cure
information specialists and is in frequent inter-
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action with members of our Scientific Advisory
Board.
Glossary
SuPPort grouPS
Antibody: A protein produced by plasma cel s (a type
A worldwide network of more than 100 myelo-
of white blood cel ) that helps fight infection. Also
ma support groups holds regular meetings for
known as an immunoglobulin.
members of the myeloma community. The IMF
Bone Marrow: A soft, spongy tissue found in most
conducts annual retreats for myeloma support
large bones that produces red blood cel s, white
group leaders.
blood cel s, and platelets.
reSearch
Immunoglobulin: See "Antibody."
BanK on a cure®
Monoclonal protein (M-protein): An abnormal immu-
noglobulin produced by myeloma cel s. A high level
This DNA bank wil provide genetic data for
of M-protein indicates that large numbers of myeloma
research in new drug development.
cel s are present. The M-protein may consist of intact
international myeloma WorKing grouP (imWg)
immunoglobulin, free light chains, or both.
IMF's International Myeloma Working Group
Multiple myeloma: A cancer arising from the plasma
consists of 145 leading myeloma researchers
cel s in the bone marrow. The plasma cel s form
from around the world who col aborate on a
abnormal antibodies, possibly damaging the bone,
broad range of myeloma research projects.
bone marrow, and other organs.
With a goal to improve myeloma treatment
Plasma cell: A type of white blood cel that produces
options and diagnostic systems, their work
antibodies.
focuses on protocols to provide a more durable
Plasmacytoma: A tumor made up of cancerous plasma
remission for myeloma patients while improv-
cel s.
ing quality of life, addressing the needs of
Protein: A group of compounds that are the main
both myeloma patients and the physicians who
component of a cel .
treat them.
Stringent complete response: normalization of the free
the international Staging SyStem (iSS)
light chain ratio and absence of myeloma cel s in the
This updated staging system for myeloma wil
bone marrow fol owing treatment.
enhance physicians' ability to select the most
White blood cell: A cel made by the bone marrow that
appropriate treatment for each patient.
helps fight infection and/or disease.
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