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
1/06
Table of Contents
Introduction
5
Multiple Myeloma and Monoclonal Protein 6
What are Free Light Chains?
7
How is Monoclonal Protein Normally
Detected and Measured?
9
How Can the Serum Free Light Chain Assays
Help with Diagnosis and Treatment?
12
The kappa/lambda Ratio
16
FreeliteTM Levels and the Assessment of
Response to Treatment
18
Patients Who Can Benefit the Most from
Serum Free Light Chain Assays
19
Will Insurance Cover the Cost of
Serum Free Light Chain Assays?
22
About the IMF
23
Glossary
24
©2006, International Myeloma Foundation, North Hollywood, California
Introduction
You have been given this booklet to learn
more about a new type of laboratory test
cal ed the serum Free Light Chain assay. This
test is also known as the FreeliteTM test. 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 work?
n How does the FreeliteTM test help with
diagnosis and treatment of multiple
myeloma?
n Can the FreeliteTM test be used to assess
response to treatment?
This booklet is meant to provide you with
general information only. It is not meant to
replace the advice of your doctor or nurse.
Your doctor or nurse can answer questions
related to your specific treatment plan. The
definitions of al words in italics are found in
the glossary at the end of this booklet.
4
5
myeloma. The free light chains are derived
Multiple Myeloma and Monoclonal
from the monoclonal protein (See Figure 1).
Protein
Myeloma is a cancer of the plasma cel s in
What are Free Light Chains?
the bone marrow. Myeloma is synonymous
Immunoglobulins or monoclonal proteins are
with multiple myeloma and plasma cel .
composed of two types of smal er molecules,
neoplasm. Plasma cel s produce antibodies,
one cal ed a heavy chain and the other
also known as immunoglobulins, which are
cal ed a light chain (see Figure 1). There
proteins that help fight infection. Each type
are five types of heavy chains, referred to
of plasma cel produces only one type of
by let er, with the abbreviation for immu-
immunoglobulin. There are many dif erent
noglobulin (Ig) before the let er: IgG, IgA,
types of plasma cel s in the body, resulting
IgM, IgD, and IgE. There are two types of
in the production of a variety of dif erent
light chains, referred to as kappa () and
immunoglobulins. In multiple myeloma, one
lambda (). Each plasma cel produces only
particular type of plasma cel is duplicated a
one type of heavy chain and only one type
very large number of times, causing excess
of light chain.
production of one type of immunoglobulin,
which is referred to as a monoclonal pro-
The heavy and light chains are produced sep-
tein, or M-protein. M-protein is also cal ed
arately within the plasma cel and are then
myeloma protein, para-protein, or the protein
assembled to form a whole immunoglobulin.
spike. M-protein is important for diagnosis
When the light chains are at ached to the
and for monitoring treatment in multiple
heavy chains, the light chains are referred
to as bound light chains. However, 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 immunoglobulin or mono-
clonal protein. The excess light chains enter
the blood stream as free light chains (i.e.
unat ached to the heavy chains). Thus both
in the normal situation and in patients with
myeloma and monoclonal gammopathies
(e.g. MGUS, or monoclonal gammopathy
Figure 1. Structure of an immunoglobulin or
of undetermined significance), excess light
monoclonal protein
6
7
is present in increased amounts. But excess
light chains in the serum can also occur to
a greater or lesser extent with al types of
myeloma, not just light chain or Bence Jones
myeloma.
How is Monoclonal Protein
Normally Detected and Measured?
Monoclonal proteins can be detected and
measured in both blood and urine. Serum
is merely blood that has had the cel s
removed, leaving only the clear liquid. If
multiple myeloma is suspected, your doctor
wil screen for abnormal monoclonal protein
(M-protein) levels using a laboratory test
known as protein electrophoresis. When pro-
chains enter the blood stream as free light
tein electrophoresis is performed on serum
chains. The normal levels of free light chains
samples, it is referred to as serum protein
in serum have recently been reported, along
electrophoresis (SPEP), and when performed
with the normal ratio of kappa free light
on urine samples, it is cal ed urine protein
chains to lambda free light chains. Normal
electrophoresis (UPEP). SPEP and UPEP can
levels of kappa free light chains are between
3.3 and 19.4 mg/L, while normal levels of
lambda free light chains are between 5.71
1
and 26.3 mg/L. The kappa/lambda ratio,
2
alb
3
4
which is normal y between 0.26 and 1.65,
5
6
7
is as important for diagnosis and monitoring
SPE
lgG
lgA
lgM
1
2
l
2
3
4
5
6
of myeloma as are the levels of kappa and
lambda light chains. As one might suspect
in patients with active myeloma, the free
1
2
light chain levels are higher than normal. In
3
4
5
patients with myeloma in which only light
6
7
alb
SPE
lgG
lgA
lgM
chains are produced (Bence Jones myeloma),
1
2
l
2
3
4
5
6
the type of light chain corresponding to the
Figure 2. Il ustrates SPEP (above left),
type of myeloma, either kappa or lambda,
UPEP (below left), and their respective IFEs (right).
8
9
measure the amount of M-protein in a sam-
would have to be at least 50 times the normal
ple, but cannot identify the type of M-protein
level to be detected by SPEP, and at least 15
in the sample. A second type of electro-
times the normal level to be detected by IFE.
phoresis test, referred to as immunofixation
An alternative test method, the serum free
electrophoresis (IFE), is performed in order
light chain assay, is capable of detecting
to identify the type of M-protein that is being
free light chains at their normal levels in
produced by the myeloma cel s. Typical y, an
blood serum. Thus, the serum free light chain
SPEP is performed first, to determine if, and
assays can detect elevated levels of free light
how much, of an M-protein is present. If the
chains, even when these levels are unde-
SPEP demonstrates evidence of an M-protein,
tectable by SPEP and IFE. This means that
an IFE wil be done to determine what type of
multiple myeloma could be detected earlier
M-protein is there.
in the course of disease than is possible with
SPEP, UPEP, and IFE have both advantages
either SPEP or IFE or in cases where smal
and disadvantages. Among the disadvan-
amounts of light chains are produced by the
tages is that they are relatively insensitive for
myeloma.
the detection of free light chains, in that the
The free light chain assays are best per-
free light chain level must typical y be many
formed on serum rather than urine because
times the normal level in order to be detected.
of the filtering ef ects of the kidneys. Part
For instance, the normal level of one type of
of the normal function of the kidneys is to
free light chain in blood is approximately 10
prevent losing proteins from the body into
mil igrams per liter (abbreviated as mg/L).
urine. As a result, an elevated level of a
However, the free light chain level in blood
protein, such as M-protein, wil be present in
blood serum before being present in urine.
Hence, the serum free light chain assays may
completely replace the 24-hour urine tests for
M-protein: not only are the free light chain
assays more sensitive in serum, but a 24-
hour urine sample is dif icult to col ect and is
more dif icult to store than serum.
Like other assays to detect M-protein, the
serum free light chain assays have both
advantages and disadvantages. As dis-
cussed above, one advantage is greater
sensitivity than is available with SPEP, UPEP,
10
11
and IFE. Another advantage is that the serum
free light chain assays are automated and
require less time to perform than do SPEP,
UPEP, and IFE. However, although the serum
free light chain assays are excel ent for detec-
tion of free light chain immunoglobulins, they
are unable to detect whole immunoglobulins.
Some myeloma patients secrete only whole
immunoglobulins. Therefore, it is best to per-
form both SPEP (to detect elevated levels of
whole immunoglobulins) and the serum free
light chain assays (to detect free light chains)
in combination.
How Can the Serum Free Light
Chain Assays Help with Diagnosis
and Treatment?
Serum free light chain assays can help in
three ways:
1. Monitoring patients with low levels of
required for ful interpretation and/or assess-
myeloma protein (M-component)
ment of the monitored results. The major
Patients with low levels of M-component
concept to keep in mind is that myeloma is
are cal ed non-secretory or hypo secretory.
a monoclonal disease. Thus the light chains
Approximately 70-80% of such patients have
produced by the myeloma cel s wil be exclu-
light chains that are measurable by the free
sively free kappa or free lambda, depending
light chain assay test. Guidelines have been
upon the type of the myeloma.
established to assess response to treatment
The production of one type of light chain,
using the FreeliteTM test (See Table 1 below).
but not the other, wil result in an abnor-
Since the FreeliteTM test has been introduced
mal kappa/lambda ratio, which is normal y
only within the last two years, most hematol-
between 0.26 and 1.65. If the level of kappa
ogy/oncology groups are just learning ful y
free light chains is too high, while the level of
about the test and establishing their own
lambda free light chains is either normal or
procedures. Specialist consultation may be
low, the kappa/lambda ratio wil be higher
12
13
than normal (higher than 1.65). If, on the
to treatment occur rapidly. Thus if a patient
other hand, the concentration of lambda free
is responding wel to treatment, the free light
light chains is too high, but the kappa free
chain level wil drop within a few days. This is
light chain level is normal or low, the kappa/
much faster than IgG or IgA drops, because
lambda ratio wil be lower than normal (less
these larger molecules are broken down
than 0.26). If levels of both kappa and
much more slowly by the body. Increases
lambda light chains are elevated, resulting in
in free light chain levels can thus be a very
a ratio that is within the normal range, then
sensitive indicator of early response. Studies
this indicates a disease other than myeloma,
are ongoing to assess the reliability of using
such as impairment of kidney function.
free light chain measurements in this way to
track early response.
2. Evaluation of early response and early
relapse
At the time of relapse, the sensitivity of the
free light chain assay becomes most signifi-
Since serum free light chains are broken
cant. Even very smal amounts of myeloma
down and/or excreted by the kidneys rather
that start to grow as part of relapse produce
quickly, changes in blood levels in response
measurable amounts of free light chains.
Studies are ongoing to compare the sensitiv-
ity of FDG-PET or CT-PET scanning versus free
light chain measurements in detecting very
early relapse.
3. Free light chain level as an indicator of
disease activity
A recent study from the Mayo Clinic has
shown that patients with MGUS who also
have elevated levels of free light chains
in the blood are more likely to progress
and develop active myeloma. FreeliteTM is
therefore a useful test in that set ing. In addi-
tion, early studies suggest that changes in
FreeliteTM levels may be useful in tracking the
disease status for myeloma patients overal ,
not just those with Bence Jones (light chain)
myeloma or non-secretory disease. Further
clinical trials are needed to clarify the use of
14
15
FreeliteTM in myeloma patients throughout the
IFE. Typical y, responses to treatment can be
disease course.
detected by serum free light chain assays in
a mat er of one or two days, whereas it may
take one to three weeks to detect responses
The kappa/lambda Ratio
using SPEP and IFE. In some cases, response
n The importance of the kappa/lambda
to treatment can be detected by the serum free
ratio is not immediately obvious.
light chain assays in a mat er of hours.
n When the levels of abnormal kappa or
Lastly, the serum free light chain assays may
lambda are very high, then obviously the
af ord the ability to identify relapse earlier
ratio is very abnormal.
than may be the case with other tests. Part
of the definition of complete remission is
n However, if the levels of both the abnormal
that the M-protein not be detected by IFE.
light chain (e.g. kappa) and the other light
However, as discussed above, the serum free
chain (e.g. lambda) are both elevated,
light chain assays are more sensitive in the
then the ratio may be normal. This indi-
detection of light chains than is IFE. Hence,
cates that the levels are elevated because
the serum free light chain assays can often
of poor kidney function resulting in reten-
detect an increase in free light chain levels
tion of both types of light chains within
before the increase can be detected by IFE.
the blood stream. This is therefore not
in itself a direct result of currently active
myeloma.
n Conversely, if the kappa and lambda lev-
els are both within the normal range, the
ratio may continue to be abnormal. This
indicates that there is indeed a persistent
low level of active myeloma with excess
production of the abnormal light chain. If
the ratio also becomes normal, this reflects
an especial y good remission and corre-
lates with possible longer remission.
Monitoring treatment can be greatly facilitated
by the use of serum free light chain assays. The
reason for this is that the serum free light chain
assays can reveal responses to treatment wel
before they can be detected using SPEP and
16
17
FreeliteTM Levels and the Assessment
n Serum free light chain assays, along with
of Response to Treatment
other laboratory tests, can provide valu-
able information on prognosis of MGUS
Serum FreeliteTM levels can be used in the
patients.
same way as monoclonal protein mea-
n Use of serum free light chain assays to
surements to assess response to treatment.
monitor treatment reveals responses to
Recently, specific criteria have been estab-
treatment more rapidly than do other labo-
lished and are summarized in Table 1.
ratory tests.
COMPLETE RESPONSE
n The improved sensitivity of serum free light
chain assays over IFE may al ow earlier
n Reduction of kappa/lambda ratio
to normal range* of: 0.26-2.0
detection of a relapse of myeloma.
n IFE negative serum and urine
Patients Who Can Benefit the
PARTIAL RESPONSE
Most from Serum Free Light Chain
n Baseline FREELITE must be 100 mg/L**
n 50% decrease in FREELITE level
Assays are:
Table 1. Freelite: Guidelines for Response Criteria
n Patients with very low levels of light chains
with other tests such as SPEP, UPEP or IFE.
*The normal range for the ratio has been expanded
slightly to encompass patients with renal insuf iciency.
Such patients are often cal ed non-secre-
**If the Freelite level is < 100 mg/L, then no partial
tory. Approximately 80% of such patients
response assessment is possible.
These response criteria are being inte-
grated into previously published Myeloma
Management Guidelines (see IMF publica-
tions).
In summary, the serum free light chain assays
of er several advantages for diagnosis and
monitoring of treatment:
n Inclusion of serum free light chain assays
can improve the sensitivity of screening
protocols for detection and diagnosis of
myeloma.
18
19
can be successful y monitored using serum
About the IMF
free light chain assays.
"One person can make a dif erence,
n Patients with deposits of light chains in the
form of amyloidosis. Amyloidosis patients
Two can make a miracle."
may or may not have active myeloma.
Brian D. Novis
Tracking the light chain levels is very help-
IMF Founder
ful to assess the disease status.
Myeloma is a lit le-known, complex, and
n Patients with light chain only myeloma
often misdiagnosed bone marrow cancer
(Bence-Jones myeloma). The major advan-
that at acks and destroys bone. Myeloma
tages for these patients are:
af ects approximately 75,000 to 100,000
· Ease of blood testing versus 24-hour
people in the United States, with more than
urine col ection
15,000 new cases diagnosed each year.
While there is presently no known cure for
· The much greater sensitivity of the
myeloma, doctors have many approaches
blood testing, i.e. low levels detected
to help myeloma patients live bet er and
in the blood, but not picked up in
longer.
the urine.
The International Myeloma Foundation (IMF)
Will Insurance Cover the Cost of
was founded in 1990 by Brian and Susie
Novis shortly after Brian's myeloma diagno-
Serum Free Light Chain Assays?
sis at the age of 33. It was Brian's dream that
future patients would have easy access to
The serum free light chain assays are reim-
medical information and emotional support
bursed by Medicare. Please consult with
throughout their bat le with myeloma. He
your doctor and insurance provider regard-
established the IMF with the 3 goals of treat-
ing this issue.
ment, education, and research. He sought
to provide a broad spectrum of services for
patients, their families, friends, and health
care providers. Although Brian died 4 years
after his initial diagnosis, his dream didn't.
Today the IMF reaches out to an international
membership of more than 125,000. The IMF
was the first organization dedicated solely to
myeloma, and today it remains the largest.
22
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The IMF provides programs and services to
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Glossary
Antibody: A protein produced by plasma cel s (a type of
white blood cel ) which helps fight infection. Also known
Multiple myeloma: A cancer arising from the plasma cel s
as an immunoglobulin.
in the bone marrow. The plasma cel s in patients with
multiple myeloma form abnormal antibodies, possibly
Antigen: A substance that when introduced into the body
damaging the bone, bone marrow, and other organs.
stimulates the production of an antibody.
Antigens
include bacteria, viruses, fungi, toxins, foreign blood
Plasma cell: A type of white blood cel that produces
cel s, and the cel s of transplanted organs.
antibodies.
Bone marrow: A soft, spongy tissue found in most large
Plasmacytoma: A tumor made up of cancerous plasma
bones that produces red and white blood cel s and
cel s.
platelets.
Protein: A group of compounds that are the main compo-
Cell: The smal est unit of life. Mil ions of microscopic cel s
nents of a cel .
comprise each bodily organ.
Red blood cell: A blood cel that carries oxygen from the
Immunoglobulin: See "Antibody."
lungs throughout the body.
Monoclonal protein (M-protein): An abnormal protein pro-
White blood cell: A cel made by the bone marrow that
duced by myeloma cel s which accumulates in and dam-
helps fight infection and/or disease.
ages bone marrow. A high level of M-protein indicates
that myeloma cel s are present in large numbers.
Appointments
Kappa
Lambda
/
Date
Time
Important Notes
Level
Level
Ratio
24
25
Appointments
Kappa
Lambda
/
Date
Time
Important Notes
Level
Level
Ratio