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Miscellanious Information

You may be wondering why you feel so tired and cannot do many of the things you want to do, or used to do. You may also be wondering if there is anything you can do to feel better, be more productive, and regain your energy. Your healthcare team may have told you that you have anemia, which may explain, in part, why you feel so tired and lack the energy necessary to perform your
daily activities. Anemia and fatigue can be caused by multiple myeloma itself or by the treatment for the disease. You have been given this booklet to learn more about fatigue and anemia and how they relate to multiple myeloma and its treatment. In this booklet, you will also learn about what you can do
and which medications are available to help you better manage your fatigue and anemia and enable you to feel better and participate in more activities. After reading this booklet, you should know the following:

What fatigue and anemia are and how they relate to multiple myeloma;
When anemia and fatigue should be treated;
How anemia and fatigue are treated;
The possible side effects of treatment of anemia and fatigue;
If treatment for anemia interferes with your treatment for multiple myeloma;
What else you can do to feel less tired.

A short overview of multiple myeloma will be presented first, so that you can see how fatigue and anemia are related to the disease and its treatment, and better understand why it is so important that they be managed properly.
This booklet is meant to provide you with general information only. It is not meant to replace the advice of your doctor, nurse, or other healthcare practitioner. Your healthcare team can answer questions related to your specific treatment plan. All words that appear in bold type are defined in a glossary at the end of this booklet.

What Is Multiple Myeloma?

Multiple myeloma (also known as “myeloma” and “plasma cell neoplasm”) is a
malignancy of the immunoglobulin-producing plasma cells found in the bone marrow. It is a hematologic malignancy that resembles leukemia. However, the malignant plasma cells, or myeloma cells, rarely enter the blood stream as they do in a true leukemia. Instead, the myeloma cells accumulate in the bone
marrow, causing the following:

Disruption of normal bone marrow function, most commonly causing anemia (a low level of red blood cells in the bloodstream), although reduction in white blood cell and platelet counts can also occur;
Damage to bone surrounding accumulated myeloma cells;
Release of an abnormal protein, monoclonal protein (M protein), into the bloodstream;
Suppression of normal immune function; observed as reduced levels of normal immunoglobulins and increased susceptibility to infection.

Myeloma cells can also grow in the form of localized tumors or plasmacytomas.
Plasmacytomas may be single or multiple, and either medullary (confined within bone marrow and bone) or extramedullary (outside of the bone). When there are multiple plasmacytomas inside or outside bone, this condition is also called multiple myeloma.

Confronted with a diagnosis of multiple myeloma, it is important for your doctor to determine the stage of the disease. Disease staging will help determine what parts of the body have been affected and to what extent. This will allow the doctor to decide the best treatment option.

The Stages of Multiple Myeloma

Stage I (low cell mass): Early disease. The bone structure appears normal or close to normal on x-ray images; the number of red blood cells and amount of calcium in the blood are normal or close to normal and the amount of M protein is very low.

Stage II (intermediate cell mass): An intermediate stage between stage I and III.

Stage III (high cell mass): More advanced disease that includes one or more
of the following:

Anemia
A high level of calcium in the blood
More than 3 areas of advanced lytic bonelesions
A high level of M protein in the blood or urine.

Multiple myeloma is a serious malignancy, but it is treatable. Many patients experience a series of responses, relapses, and remissions. New treatments may extend the average survival of 5 years for patients diagnosed
with multiple myeloma.

Following diagnosis, several options are available for initial or frontline therapy. For patients who may be candidates for highdose therapy with stem cell transplant, various induction regimens can be considered, including thalidomide with dexamethasone, dexamethasone alone, other dexamethasonecontaining
combinations, or combinations containing other adrenocortical steroids. The
combination of the alkylating agent melphalan plus prednisone, a simple oral therapy, is an option for patients not considering highdose melphalan with autologous stem cell transplant. At the time of treatment, newer agents are frequently required to achieve further response. Revlimid (lenalidomide) and
VELCADE® (bortezomib) are important new agents available for use in this setting.

What Is Fatigue?

In healthy people, fatigue is typically characterized by extreme exhaustion or feelings of tiredness that interfere to some extent with normal everyday activities. It usually occurs after excessive stimulation or prolonged exertion of some kind and is temporary. Rest and refraining from strenuous activity can help restore energy and make a person feel better. Fatigue that is related to cancer, however, is different and more severe than normal fatigue and tends to last longer. Simply resting does not alleviate the fatigue. This type of fatigue has been defined by the National Comprehensive Cancer Network as “a distressing, persistent, subjective sense of tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.” In patients with multiple myeloma, fatigue
often is a symptom that anemia is present.

What Is Anemia?

Anemia is an abnormally low level of red blood cells (RBCs) in your body. RBCs contain hemoglobin. Hemoglobin is a protein found in RBCs that contains iron and transports much-needed oxygen from the lungs to tissues and organs throughout the body. If the number of RBCs is low, however, then the hemoglobin count is low, and the body does not receive the amount of oxygen that it needs to function properly. Anemia can have multiple causes: it may be caused by some underlying disease that interferes with normal RBC production and functioning, or it may be the result of the negative effects of chemotherapy on RBC production.

What Causes Fatigue and Anemia in Patients with Multiple Myeloma?

Fatigue: You’re Not Alone

Fatigue associated with multiple myeloma usually is caused by underlying anemia. This type of fatigue severely affects patients’ quality of life and everyday functioning. The continued interference with normal functioning
is what sets cancer-related fatigue apart from normal fatigue. Fatigue is very common in patients with multiple myeloma and is estimated to affect 90%–100% of patients with the disease. Patients need to understand that
fatigue is a symptom of their disease and is not necessarily a sign that their condition is getting worse. Even though cancer-related fatigue is very common in patients with multiple myeloma, the exact physiologic mechanisms
that cause the fatigue are not known. It is known, however, that it is related to the patient’s anemia, and there are ways to manage it and help you cope.

Anemia: The Case of Missing RBCs

Anemia occurs in patients with multiple myeloma because plasma cells in bone marrow grow faster than normal, increase in number, and produce tumors in the marrow. These tumors interfere with the blood-producing activities of bone marrow, leading to a shortage of red blood cells (RBCs). This shortage
is known as anemia.

There are a number of causes of anemia in patients with multiple myeloma. The disease itself suppresses the body’s ability to make enough RBCs, resulting in low RBC counts. Unfortunately, the chemotherapy that kills the cancer cells in patients with multiple myeloma also destroys normal RBCs, thus also increasing the chances of developing anemia. Anemia is very common in patients
with multiple myeloma. In fact, at least 60%–70% of patients with multiple myeloma have anemia at the time they are diagnosed with the disease.

How are Fatigue and Anemia Diagnosed?

Fatigue: Give Them Something to Talk About

It can be difficult to diagnose fatigue associated with multiple myeloma for a number of reasons. There are no laboratory tests that can be used to diagnose fatigue; hence, information about fatigue provided by patients is very important. Your healthcare team will need to evaluate your situation and try to identify the source of your fatigue and ways to manage it most effectively. Patients need
to openly discuss their feelings of fatigue with members of their healthcare team. Do not think that your fatigue is not important enough to mention at your appointments. Although fatigue is an expected symptom with multiple myeloma, you do not have to accept it. There are things that you and your healthcare team can do that will help you feel better. Make notes for yourself when you
feel fatigued or when anything in particular makes you feel better or worse. Keep track of how limiting your fatigue is by noting to what extent it interferes with your daily activities. Your healthcare team will be asking questions
about your fatigue and any input you can provide will be very helpful. In addition to their screening, they need your feedback so that they can determine the severity of your fatigue and develop strategies to help you manage it. Based on your feedback, your healthcare team will rate your fatigue on a scale of 0 to 10 (with 0=no fatigue and 10=worst fatigue imaginable) and then classify your fatigue as one of the following:

Mild (0–3)
Moderate (4–6)
Severe (7–10).

Examples of things that you should be looking at and want to report to your healthcare team include (but are not limited to) the following:

Time when fatigue is most noticeable
Medications that you are taking
Emotional stress, anxiety, and depression
Presence and location of physical pain
Existence of other conditions or illnesses
Sleep disturbances
Dietary changes
Changes in weight
Changes in activity or daily routine
Changes in health.

If there are any changes or other factors that you think could be adding to
your fatigue, do not hesitate to bring them to the attention of your healthcare
team. There are factors that may not be obvious that could be making your fatigue worse. Many factors that contribute to fatigue are treatable. There are things that can be done to alleviate your fatigue, and your healthcare team can work with you and your family and caregiver(s) to develop a plan for you.

Anemia

If your doctor suspects you have anemia, he or she performs tests for it and determines its severity. You will be asked questions about your health in general. Remember to report any of the following symptoms:

Shortness of breath
Lack of energy and motivation
Rapid heartbeat
Swelling in the legs, especially in the ankles
Dizziness
Headache
Chills
Change in appetite
Decreased libido.

A physical examination will be performed. After the examination, your healthcare team will ask you questions in an attempt to identify and uncover the source of your fatigue. It is wise to have a family member or caregiver with you at your appointment. He or she may be able to add to the information you provide.
A simple blood test is used to determine what your hemoglobin level is. Hemoglobin levels are used to measure the number of RBCs in the body. Low hemoglobin levels indicate anemia. Severity of anemia is determined by hemoglobin level, measured in units designated as grams of RBCs per deciliter
(g/dL). Normal hemoglobin levels are 14 to 18 g/dL for men and 12 to 16 g/dL
for women. The National Cancer Institute (NCI) has developed the following scale that determines the degree of severity of anemia through relative levels of hemoglobin.

Grade	Severity	Hemoglobin Level (g/dL)
0	None	Normal value
1	Mild	10 to normal value
2	Moderate	8–10
3	Severe	6.5–7.9
4	Life-threatening	Less than 6.5

When Should Anemia and Fatigue be Treated?

It is important that you discuss your symptoms and how you are feeling with members of your healthcare team. Do not hesitate to mention that you feel tired or aren’t feeling particularly well. Let them know how much your fatigue is disrupting your everyday activities. Fatigue typically is a sign of some underlying problem; it needs to be treated as soon as possible. Left unmanaged, fatigue
can have a dramatic effect on your daily life and on your health. Your healthcare team will start treating your anemia as soon as it is diagnosed. They will want to begin restoring your RBC count as soon as possible. Your health and response to other treatments depend upon holding these levels to as
near-normal as possible. In some instances, in attempts to increase RBCs before anemia fully develops, treatment may be started in patients identified as being at high risk for developing anemia.

What Treatments Are Available for Fatigue and Anemia?

There are a number of treatments and things you can do for fatigue and anemia that will improve your health and make you feel better. Treatment of your anemia and fatigue will be based on the severity of each. All patients are not candidates for all treatments. Your healthcare team will determine which treatment regimen is best suited to and safest for you.

Fatigue

Your healthcare team will determine if there are contributing factors to your fatigue. Depending on their findings, they may do the following:

Adjust your medications;
Change or modification of your dietary intake;
Improve your fluid and electrolyte (sodium, potassium, calcium, andmagnesium) intake;
Treat the underlying cause(s) as is appropriate;
Create strategies for coping and managing your fatigue.

Anemia

For a number of years, the primary treatment option for anemia has been blood transfusion. Transfusions replace and replenish the RBCs that you have lost and are recommended when immediate correction of the anemia is desired. Although transfusions have an immediate effect that is beneficial for patients, the increase in hemoglobin levels may not be very large and may last only
up to a few weeks, so repeated transfusions may be necessary. Another option for anemia that needs to be treated but that does not have to be corrected
immediately involves treatment with a class of medications known as erythropoietic agents (epoetin alfa, epoetin beta, and darbepoetin alfa). These agents stimulate erythropoiesis, which is another name for the formation of
new RBCs, and are used to treat anemia caused by a variety of conditions, including multiple myeloma. These drugs have been used to treat anemia associated with cancer since the early 1990s. They are biologically equivalent to erythropoietin, a hormone that is found naturally in your body. This hormone
stimulates your bone marrow to produce RBCs. Administering erythropoietic agents thus signals your body to make RBCs, which helps to restore normal levels. You should be aware that it may take several weeks for these medications to take effect, so you may not feel better right away. Treatment with erythropoietic agents can also reduce the number of transfusions patients need. Thus, treatment with this class of drugs may be initiated to increase hemoglobin levels, reduce or eliminate the need for blood transfusions, and make patients who have been suffering from anemia feel better. In some patients, an erythropoietic agent and transfusion may be given together.

Erythropoietic agents may also be beneficial in patients who have been identified by their healthcare team as being at high risk for developing anemia.

You may also be given iron supplements to restore your iron levels to as near normal as possible. Iron is needed to produce RBCs, and iron supplements are often given during erythropoietic treatment.

How Are These Treatments administered?

Transfusions

Transfusions are administered as intravenous infusions in a hospital or other healthcare facility. A trained healthcare professional will give the transfusion. It is recommended that a caregiver or family member drive you to and from the transfusion center. The entire process can take a few hours.

Erythr opoietic Agents

Erythropoietic agents are administered as subcutaneous injections by a healthcare professional. The amount of medication, frequency of injections, and schedule of your injections will be determined by your healthcare team.

Iron Supplements

Iron supplements are available in oral and intravenous formulations. However, oral products are used most often. Intravenous products are helpful in patients who, for various reasons, cannot use the oral forms.

What Are Some of the Possible Side Effects of Treatment?

Possible Side Efects With Transfusions

There are a number of possible side effects that can occur after receiving a blood transfusion. Some patients may have a mild fever or develop a rash or hives. These reactions are temporary and usually not severe.

In very rare instances, patients may experience serious incompatibility reactions. These reactions will be managed immediately by the healthcare team. Strict screening processes are used to prevent the spread of viral infections transmitted in blood during infusions. Such transmissions were more of a
concern in earlier years when screening was not so common or stringent.

Possible Side Efects With Erythr opoietic Agents

Erythropoietic agents generally are well tolerated by patients. The most commonly reported side effects experienced by patients treated with these drugs are

Fever
Diarrhea
Nausea
Vomiting
Swelling at the injection site
Fatigue

Allergic reactions tend to be rare; when they do occur, they tend to be mild in nature. Remember that not all patients treated with erythropoietic agents experience any or all of the reactions that have been reported by other patients. Similarly, patients do not experience side effects to the same degree.
However, at the first sign of any reaction, patients should contact a member of their healthcare team immediately.

Will Treatment for Fatigue and Anemia Interfere with Treatment for Multiple Myeloma?

Treatments chosen by healthcare teams to manage your fatigue and anemia will not interfere with treatments for multiple myeloma. Treatments approved to treat anemia and fatigue can be done safely and in conjunction with treatment for multiple myeloma.

What Else Can Be Done to Help Patients with Anemia and Fatigue Feel Better?

Along with transfusions, medications, and other adjustments, there are also a number of other things you can do to manage and cope with your fatigue and anemia, including the following:

Exercise (walking, cycling, swimming)
Developing coping strategies (distractions)
Modification of activities (naps, reestablishment of priorities, use of labor-saving devices)
Counseling.

Patient education can help you understand anemia and fatigue. Ask members of your healthcare team if they have any information that they can pass on to you or if they can direct you to other sources of information. Your healthcare team can also work with you to develop a general strategy for managing your fatigue. Involve your family and caregivers. They can be great support. Do not be ashamed or afraid to talk about your fatigue and the impact it has on your life. For more information on multiple myeloma and treatment options, contact the IMF.

About the IMF

“One person can make a difference,
Two can make a miracle.”
Brian D. Novis
IMF Founder

Myeloma is a little-known, complex, and often misdiagnosed bone marrow cancer that attacks and destroys bone. Myeloma affects approximately 75,000 to 100,000 people in the United States, with more than 15,000 new cases diagnosed each year. Although there is presently no known cure for myeloma, doctors have many approaches to help myeloma patients live better and longer.
The International Myeloma Foundation (IMF) was founded in 1990 by Brian and Susie Novis shortly after Brian’s myeloma diagnosis at the age of 33. It was Brian’s dream that future patients would have easy access to medical information and emotional support throughout their battle with myeloma.
He established the IMF with the three goals of treatment, education, and research. He sought to provide a broad spectrum of services for patients and, their families, friends, and health- care providers. Although Brian died four years after his initial diagnosis, his dream did not. Today, the IMF reaches out to an international membership of more than 135,000. The IMF was the first organization dedicated solely to myeloma, and today it remains the largest.

The IMF provides programs and services to aid in the research, diagnosis, treatment, and management of myeloma. The IMF ensures that no one must brave the myeloma battle alone. We care for patients today, while working toward tomorrow’s cure

How Can the IMF Help You?

PATIENT EDUCATION

Information Package
Our free IMF InfoPack™ provides comprehensive information about myeloma, treatment options, disease management, and IMF services. It includes our acclaimed Patient Handbook.

Internet Access
Log on to www.myeloma.org for 24-hour access to information about myeloma, the IMF, education, and support programs.

Online Myeloma Forum
Join the IMF Internet Discussion Group at www.myeloma.org/listserve.html to share your thoughts and experiences.

Myeloma Minute™
Subscribe to this free weekly email newsletter for up-to-the-minute information about myeloma.

IMF Patient & Family Seminars ™
Meet with leading experts in myeloma treatment to learn more about recent advances in therapy and research.

Myeloma Matrix™
On our website and in print, this document is a comprehensive guide to drugs in development for myeloma.

Myeloma Today ™ Newsletter
Our quarterly newsletter is available free of charge by subscription.

SUPORT
Myeloma Hotline: 800-452-CURE (2873)
Toll-free throughout the United States and Canada, the IMF Hotline is staffed by trained information specialists and is in frequent interaction with members of our Scientific Advisory Board.

Support Groups
A worldwide network of more than 100 myeloma support groups hold regular meetings for members of the myeloma community. The IMF conducts annual retreats for leaders of myeloma support group leaders.

RESEARCH

BANK ON A CURE®
This DNA bank will provides genetic data research in new drug development.
The Int ernational Stag ing Syst em (ISS) This updated staging system for myeloma enhances physicians’ ability to select the most appropriate treatment for each patient.

Research Grants
Leading the world in collaborative research and achieving extraordinary results, the IMF Grant Program supports both junior and senior researchers working on a broad spectrum of projects. The IMF has attracted many young investigators into the field of myeloma; they have remained in the field and are actively
pursuing a cure for this disease.

Glossary

Adrenal corticosteroid: Any of the steroidal hormones produced by the adrenal cortex or their synthetic equivalents. Also known as adrenocorticoids, glucocorticosteroid, or corticosteroid.

Alkylating agent: An agent that prevents the growth and division of new cancer cells by inhibiting their ability to replicate DNA.

Anemia: A low level of red blood cells in the bloodstream.

Antibody: A protein produced by some of the body’s white blood cells that helps fight infection.

Bone marrow: A soft spongy tissue found in most large bones that produces red and white blood cells and platelets.

Cell: The smallest unit of life. Millions of microscopic cells comprise each body organ.

Cytokine: A growth factor produced by T-cells that stimulates the growth of T-cells and B-cells.

Enzyme: A type of protein that causes chemical reactions in other substances without undergoing change in the process.

Erythropoiesis: The formation of new red blood cells. Hematologic malignancy: A cancer of the blood or bone marrow.

Immunoglobulin: An antibody.

Interleukins: Various cytokines involved in the growth and survival of myeloma cells.

Lytic (lysis): Dissolution or destruction of cells.

Monoclonal protein (M protein): An abnormal protein produced by myeloma cells that accumulates in and damages bone and bone marrow. A high level of
M protein indicates that myeloma cells are present in large numbers.

Multiple myeloma: A cancer arising from the plasma cells in the bone marrow. The plasma cells in patients with multiple myeloma form abnormal antibodies, possibly damaging the bone, bone marrow, and other organs.

Plasma cell: A type of white blood cell that produces antibodies.

Plasmacytoma: A tumor made up of cancerous plasma cells.

Platelet: An element in the blood that helps with clotting, which in turn helps repair damaged blood vessels.

Proteins: A group of compounds that are the main components of a cell.

Red blood cell (RBC): A blood cell that carries oxygen from the lungs throughout the body.

White blood cell: A cell made by the bone marrow that helps fight infection and/or disease.

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Understanding Serum Free Light Chain Assays

Introduction

You received this booklet to learn more about a type of laboratory test called the Serum Free Light Chain Assays. These tests are also known collectively as Freelite™. After reading this booklet, you should be able to answer the following questions:

What are free light chains?
How are free light chains related to multiple myeloma?
How does the Freelite™ 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 cells in the bone marrow. Myeloma is synonymous with multiple myeloma. The function of normal plasma cells is to produce antibodies, also known as immunoglobulins, which have an important role in fighting infection. Each type of plasma cell produces only one type of immunoglobulin. There are many different types of plasma cells in the body, and each type of plasma cell produces only one type of immunoglobulin. The result is the production of a wide variety of different immunoglobulins.

In multiple myeloma, one particular plasma cell (a clone) is duplicated a very large number of times, causing excess production of one type of immunoglobulin called a monoclonal protein or M-protein – also called myeloma protein, paraprotein, or the M-spike. The identification of an M-protein is important for diagnosis, and the measurement of its level is an aid for monitoring the effectiveness of treatment.

What Are Free Light Chains?

Structurally, normal immunoglobulins (abbreviated Ig) are composed of smaller units called heavy chains and light chains, and together they form a large complex (see Figure 1). There are five types of heavy chains, and each type is assigned a specific letter. These five types are abbreviated as IgG, IgA, IgM, IgD, and IgE.

There are two types of light chains, and they are referred to as kappa (κ) and lambda (λ or L). Each plasma cell produces only one type of heavy chain and one type of light chain. Altogether, there are 10 subtypes of normal immunoglobulins (see Table 1).

Table 1. Subtypes of Immunoglobulins.

IgG kappa	IgG lambda
IgA kappa	IgA lambda
IgM kappa	IgM lambda
IgD kappa	IgD lambda
IgE kappa	IgE lambda

The heavy and light chains are produced separately within the plasma cells and are assembled to form a whole (“intact”) immunoglobulin. When the light chains are attached to the heavy chains, the light chains are referred to as bound light chains. However, when the light chains are not attached to the heavy chains, they are called free light chains. For unknown reasons, the plasma cells typically produce more light chains than are required to create the whole immunoglobulins or monoclonal proteins. The excess light chains enter the bloodstream as free light chains (that is, not attached to the heavy chains). Thus, both in the normal situation and in individuals with myeloma and related disorders such as monoclonal gammopathy of undetermined significance (MGUS), excess light chains enter the bloodstream as free light chains. The amount of free light chain production is linked to the activity of myeloma or plasma cell growth.

How is Monoclonal Protein Detected and Measured?

Monoclonal proteins may be detected and measured in blood and/or urine. When measurements are taken in blood, all of the cells are removed, leaving only the yellow liquid component that is called serum. If multiple myeloma is suspected, your doctor will evaluate for the presence of an abnormal monoclonal protein (M-protein). Several tests can be ordered to detect the M-protein, including serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and/or the Serum Free Light Chain Assays (Freelite™). If one type of light chain (kappa or lambda) is produced in excess this is consistent 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

A second type of electrophoresis, referred to as immunofixation electrophoresis (IFE) is performed to identify the subtype of M-protein that is being produced by the myeloma cells. The subtype is identified by bands on the IFE (see figure 2). but generally, it can not measure the amount of the M-protein subtype that is present in the sample. An SPEP may be performed first to determine if, and how much, of an M-protein is present. If the SPEP demonstrates the presence of an M-protein, an IFE will be done to determine what subtype of M-protein is present.

SPEP, UPEP, and IFE have advantages and disadvantages. Among the disadvantages are that they are relatively insensitive for the detection of free light chains, in that the free light chain level must typically be many times the normal level in order to be detected with SPEP, UPEP, or IFE. For example, the normal level of one type of free light chain in the blood is approximately 10 milligrams per liter (abbreviated mg/L). However, the free light chain level in blood would have to be 50 times the normal level to be detected by SPEP and at least 15 times the normal level to be detected by IFE.

Serum Free Light Chain Asays

The serum free light chain assays are capable of detecting free light chains at their normal (non-elevated) levels in the blood. Importantly, these assays can detect mildly increased levels of free light chains even when these levels are undetectable by SPEP and IFE. This means that multiple myeloma could be detected earlier than might be possible with either SPEP or IFE and it is particularly useful in instances when only small amounts of light chains are produced by the myeloma.

The free light chain assays are best performed on serum rather than urine because of the filtering effects of the kidneys. Part of the normal function of the kidneys is to prevent protein loss from the body into the urine. As a result, an elevated level of M‑protein may be detected in the blood before it is detected in the urine. Hence, the serum free light chain assays may replace the need for urine studies in the initial diagnosis of myeloma and related plasma cell diseases, however, urine studies are still important as part of serial monitoring. Serum free light chain assays are more sensitive in serum, the 24-hour urine sample is difficult to collect and transport, and the specimen is more difficult 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 advantages and disadvantages. As discussed above, one advantage is greater sensitivity than is available with SPEP, UPEP, and IFE. Another advantage is that the serum free light chain assays are automated and therefore require less time to perform in the laboratory than SPEP, UPEP, and IFE. However, although the serum free light chain assays are excellent for detection of free light chains, they are unable to detect whole immunoglobulins. Some types of myeloma secrete only whole immunoglobulins. Therefore it is often best to perform SPEP or IFE to detect elevated levels of intact immunoglobulins in combination with the serum free light chain assays to detect free light chains.

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 all 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: 3.3–19.4 mg/L*
Lambda: 5.7–26.3 mg/L*
Kappa/lambda ratio: 0.26–1.65

*Note: The units here are mg/L; different laboratories use different units. It is important to double-check the units used when comparing numbers in lab values.

Light chains produced by myeloma cells will be exclusively kappa or lambda, depending upon the type of myeloma. Thus, if the myeloma cells produce kappa light chains, the level of kappa free light chains will increase in the blood. If, on the other hand, the myeloma cells produce lambda light chains, the level of lambda free light chains will increase in the blood. Your doctor will need to interpret the results of the serum free light chain assays together with other clinical information in order to make a final interpretation of the results. A specialist in hematology/oncology is highly qualified to make this decision.

The Kappa/Lambda Ratio

The kappa/lambda ratio is as important for diagnosis and monitoring of myeloma as are the levels of kappa and lambda
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
If levels of both kappa and lambda light chains are increased, the ratio may be within the normal range, and this generally indicates a disease other than myeloma, such as poor kidney function. When the kidneys are not working properly, 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 abnormally increased levels are not themselves a direct result of currently active myeloma
If the kappa and lambda levels are both within the normal range, sometimes the ratio may be abnormal. In this situation, there may be a persistent low level of active myeloma with excess production of the abnormal light chains.
A normal kappa/lambda ratio after treatment 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 in blood levels in response to treatment occur rapidly. Thus, with a good response to treatment, myeloma cells will die, they will stop producing free light chains, and the blood levels of the free light chains will decrease within a few hours to days. In this situation, the decrease in free light chains occurs much more quickly than the decrease in IgG or IgA, because these compounds are broken down much more slowly by the body. Decreases in free light chain levels can therefore be a very sensitive indicator of early response. Typically, response to treatment can be detected by serum free light chain assays in a matter 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 important. Even very small 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. M onitoring patients with low levels of myeloma protein (M-protein)

Myeloma that produces low levels of Mprotein is called non-secretory or hyposecretory disease. Approximately 70% to 80% of people with non-secretory or hyposecretory myeloma have measurable abnormalities of M-protein using the serum free light chain assays. The Freelite™ test has been incorporated into response criteria to assist in assessing effectiveness of treatment in people with hyposecretory myeloma (see Table 2 below).

Table 2. Response to Treatment Using Freelite™ in Hyposecretory Myeloma

Stringent Complete Response	Normalized free light chain ratio
Partial Response	≥ 50% decrease in the difference between the light chain produced by the myeloma cells and the other light chain

3. Enrollment in clinical trials

Clinical trials are the only route by which new medicines are made available and a potential cure discovered. People with myeloma may participate in clinical trials to help test the safety and effectiveness of new treatments. In order for a patient with myeloma to be eligible to participate in a trial, there must be a way to monitor their M-protein levels in the blood or urine. People with hyposecretory (formerly “non-secretory”) disease used to be excluded from clinical trials because there was no method to monitor their M-protein levels. With the availability of the serum free light chain assays, the M-protein level can be monitored in the blood of these people. Therefore, people with hyposecretory disease 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 Freelite™ levels are useful for tracking the disease status in almost all people with myeloma, not just those with light chain (Bence Jones) myeloma or nonsecretory disease.

5. A ssessment of stringent complete response to treatment

One of the goals of myeloma treatment is to reduce the level of M-protein as much as possible – and sometimes to eliminate it entirely. If the free light chain ratio becomes normal after treatment then this provides a very good and sensitive indication that treatment has been highly effective, and means that the level of light chain paraprotein has been reduced as much as possible. If the free light chain ratio normalizes with treatment, then this result is called stringent complete response. This type of response is the best possible response according to the International Response Criteria in Multiple Myeloma. By definition, a stringent complete response also includes a normal SPEP, a normal UPEP, a normal IFE, and no evidence of myeloma cells in the bone marrow using special tests.

Freelite™ Levels and the Assessment of Response to Treatment

Serum Freelite levels can be used in the same way as monoclonal protein measurements to assess response to treatment, but they can also be used more frequently in the early weeks of treatment. Some people with myeloma find it helpful to track their own serum free light chain values using tables or spreadsheets – just like people with diabetes track their blood sugar. A table that can be used to follow results of the serum free light assays is located at the end of this booklet.

Table 3. Stringent Complete Response and Complete Response

Stringent Complete Response	Normalization of the free light chain ratio and no evidence of myeloma cells in the bone marrow
Complete Response	Negative immunofixation in the serum and urine, disappearance of any plasmacytoma, and ≤5% plasma cells in the bone marrow

In summary, the serum free light chain assays offer several advantages for diagnosis and monitoring of treatment:

Inclusion of serum free light chain assays can improve the sensitivity of screening protocols for detection and diagnosis of myeloma
The serum free light chain assays along with other tests can provide valuable information for people with MGUS
Use of serum free light chain assays to monitor treatment reveals responses to treatment earlier than other laboratory tests such as SPEP
The improved sensitivity of serum free light chain assays over IFE may allow earlier detection of a relapse of myeloma

Patients Who Benefit the Most From the Serum Free Light Chain Assays Are:

People with myeloma who have abnormal serum free light chain results at the start of treatment. Monitoring with the serum free light chain assays often allows a rapid assessment of the effectiveness of treatment.
People with very low levels of light chains with other tests such as SPEP, UPEP, and IFE. These are people who generally have non-secretory (or hypo-secretory) myeloma. Approximately 80% of people with non-secretory myeloma can have their disease monitored using the serum free light chain assays.
People with deposits of light chains in the form of AL amyloidosis. People with AL amyloidosis may or may not have active myeloma. Tracking the light chain levels is very helpful to assess the disease status.
People with light chain only myeloma (Bence Jones myeloma). The major advantages of the serum free light chain assays for these people are:
- Ease of blood testing versus 24-hour urine collection*
- The much greater sensitivity of blood testing: mildly increased levels may be detected in the blood but not detected in the urine.

* It is important to note that periodic 24-hour urine testing is still recommended and necessary, both to double-check the light chain excretion level and monitor for any evidence of kidney damage.

Will Insurance Cover the Cost of Serum Free Light Chain Assays?

In the United States, the serum free light chain assays are reimbursed by Medicare. Please consult with your doctor’s office and insurance provider regarding this issue.

About the IMF

“One person can make a difference, Two can make a miracle.”
Brian D. Novis
IMF Founder

The International Myeloma Foundation (IMF) was founded in 1990 by Brian and Susie Novis shortly after Brian’s myeloma diagnosis at the age of 33. It was Brian’s dream that future patients would have easy access to medical information and emotional support throughout their battle with myeloma. He established the IMF with the 3 goals of treatment, 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 150,000. The IMF was the first organization dedicated solely to myeloma, and today it remains the largest.

The IMF provides programs and services to aid in the research, diagnosis, treatment, and management of myeloma. The IMF ensures that no one must brave the myeloma battle alone.

We care for patients today, while working toward tomorrow’s cure.

How Can the IMF Help You?

Internet Access
Log on to www.myeloma.org for 24-hour access to information about myeloma, the IMF, education, and support programs.

Online Myeloma Forum
Join the IMF Internet Discussion Group at www.myeloma.org/listserve.html to share your thoughts and experiences.

Myeloma Minute™
Subscribe to this free weekly email newsletter for up-to-the-minute information about myeloma.

Glossary

Antibody: A protein produced by plasma cells (a type of white blood cell) that helps fight infection. Also known as an immunoglobulin.

Bone Marrow: A soft, spongy tissue found in most large bones that produces red blood cells, white blood cells, and platelets.

Immunoglobulin: See “Antibody.”

Monoclonal protein (M-protein): An abnormal protein produced by myeloma cells which accumulates in and damages bone marrow. A high level of M-protein indicates that myeloma cells are present in large numbers. The M-protein may consist of intact immunoglobulin, free light chains, or both.

Multiple myeloma: A cancer arising from the plasma cells in the bone marrow. The plasma cells form abnormal antibodies, possibly damaging the bone, bone marrow, and other organs.

Plasma cell: A type of white blood cell that produces antibodies.

Plasmacytoma: A tumor made up of cancerous plasma cells.

Protein: A group of compounds that are the main component of a cell.

Stringent complete response: normalization of the free light chain ratio and absence of myeloma cells in the bone marrow following treatment.

White blood cell: A cell made by the bone marrow that helps fight infection and/or disease.