What are the different types of multiple myeloma. How are immunoglobulins related to myeloma classification. What is IgG kappa myeloma and why is it significant. How do doctors determine a patient’s specific myeloma subtype.

The Basics of Multiple Myeloma and Immunoglobulins

Multiple myeloma is a cancer of plasma cells, which are a type of white blood cell responsible for producing antibodies. In multiple myeloma, cancerous plasma cells produce abnormal proteins called monoclonal immunoglobulins. Understanding the structure and types of immunoglobulins is crucial for classifying and treating multiple myeloma.

Structure of Immunoglobulins

Immunoglobulins are complex proteins composed of four chains:

• Two heavy chains
• Two light chains

The heavy chains determine the class of immunoglobulin, while the light chains can be either kappa (κ) or lambda (λ) type.

Types of Immunoglobulin Heavy Chains

There are five types of immunoglobulin heavy chains:

1. IgG
2. IgA
3. IgD
4. IgE
5. IgM

Each type of heavy chain has specific functions in the immune system. In multiple myeloma, the cancerous plasma cells typically produce one specific type of immunoglobulin.

IgG Kappa Myeloma: The Most Common Subtype

IgG kappa myeloma is the most prevalent subtype of multiple myeloma. In this form, the myeloma cells produce an immunoglobulin composed of two IgG heavy chains bound to two kappa light chains. This subtype accounts for a significant portion of multiple myeloma cases.

Characteristics of IgG Kappa Myeloma

IgG kappa myeloma has several distinctive features:

• Overproduction of IgG immunoglobulins
• Presence of kappa light chains
• Detectable monoclonal protein in serum tests
• Often associated with bone lesions and hypercalcemia

Are there specific symptoms associated with IgG kappa myeloma? While symptoms can vary among patients, common manifestations include bone pain, fatigue, frequent infections, and kidney problems. However, these symptoms are not exclusive to IgG kappa myeloma and can occur in other subtypes as well.

Other Common Subtypes of Multiple Myeloma

While IgG kappa is the most common, there are several other subtypes of multiple myeloma. Each subtype is defined by the specific immunoglobulin produced by the cancerous plasma cells.

IgA Myeloma

IgA myeloma is the second most common subtype. It can be further classified into IgA kappa or IgA lambda, depending on the light chain type. IgA myeloma often requires different monitoring techniques compared to IgG myeloma.

Light Chain Myeloma

Also known as Bence Jones myeloma, this subtype accounts for approximately 15-20% of myeloma cases. In light chain myeloma, the cancerous plasma cells produce only light chains (either kappa or lambda) without heavy chains.

Rare Subtypes of Multiple Myeloma

Some subtypes of multiple myeloma are less common but still significant in terms of diagnosis and treatment.

IgD, IgE, and IgM Myeloma

These subtypes are rare, collectively accounting for less than 5% of all myeloma cases. They can be challenging to diagnose and may require specialized treatment approaches.

Non-Secretory Myeloma

In this rare subtype (1-2% of cases), the myeloma cells produce little to no monoclonal protein. This can make diagnosis and monitoring more challenging, often requiring advanced testing methods.

Diagnostic Methods for Identifying Myeloma Subtypes

Accurate identification of the myeloma subtype is crucial for proper treatment and monitoring. Doctors use various diagnostic tests to determine the specific subtype of multiple myeloma.

Serum Protein Electrophoresis (SPEP)

SPEP is a key test for detecting and quantifying monoclonal proteins in the blood. It’s particularly useful for identifying IgG and IgA myeloma subtypes.

Immunofixation Electrophoresis

This test helps identify the specific type of immunoglobulin produced by the myeloma cells, including both the heavy and light chain components.

Serum Free Light Chain Assay

This test measures the levels of free light chains in the blood, which is especially important for diagnosing and monitoring light chain myeloma.

How do these diagnostic tests impact treatment decisions? The results of these tests not only confirm the diagnosis of multiple myeloma but also guide treatment choices and help monitor the disease’s progression and response to therapy.

Clinical Implications of Myeloma Subtypes

The specific subtype of multiple myeloma can influence various aspects of the disease and its management.

Treatment Considerations

While the core treatment approach for multiple myeloma is similar across subtypes, certain modifications may be necessary based on the specific immunoglobulin involved. For example, light chain myeloma may require more aggressive kidney protection strategies.

Prognosis and Disease Monitoring

Different subtypes may have varying prognoses and require different monitoring approaches. For instance, non-secretory myeloma may need more frequent imaging studies for disease assessment compared to other subtypes.

Does the myeloma subtype affect long-term outcomes? While the subtype is one factor in determining prognosis, other factors such as genetic abnormalities, stage at diagnosis, and response to treatment also play crucial roles in long-term outcomes.

Related Plasma Cell Disorders

Several conditions related to multiple myeloma affect plasma cells and immunoglobulin production. Understanding these disorders is important for comprehensive myeloma care.

AL Amyloidosis

This condition occurs when light chains misfold and form deposits in various organs, leading to organ dysfunction. It can occur in association with multiple myeloma or as a separate entity.

Waldenström’s Macroglobulinemia

This rare condition is characterized by the overproduction of IgM protein. While similar to multiple myeloma, it’s classified as a type of lymphoma.

POEMS Syndrome

POEMS syndrome is a rare paraneoplastic disorder associated with plasma cell proliferation. It involves a complex set of symptoms including polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes.

How do these related disorders differ from multiple myeloma in terms of treatment and prognosis? While these conditions share some similarities with multiple myeloma, they often require specialized treatment approaches and can have different prognostic implications.

Emerging Research and Future Directions

The field of multiple myeloma research is rapidly evolving, with new insights into disease biology and novel treatment approaches emerging regularly.

Targeted Therapies

Researchers are developing therapies that target specific molecular pathways involved in myeloma cell growth and survival. Some of these therapies may be more effective for certain myeloma subtypes.

Immunotherapy Approaches

Immunotherapies, including CAR-T cell therapy and bispecific antibodies, are showing promise in clinical trials. These approaches may offer new options for patients with difficult-to-treat myeloma subtypes.

Personalized Medicine

Advances in genomic profiling are paving the way for more personalized treatment strategies based on the specific genetic characteristics of a patient’s myeloma cells.

How might future research change our understanding and treatment of different myeloma subtypes? As our knowledge of myeloma biology deepens, we may discover more subtype-specific treatment approaches, leading to improved outcomes and potentially even subtype-specific cure strategies.

The field of multiple myeloma is complex and rapidly evolving. Understanding the various subtypes, including the common IgG kappa myeloma, is crucial for proper diagnosis, treatment, and management of this disease. As research progresses, we can expect more refined and effective approaches to treating each subtype of multiple myeloma, offering hope for improved outcomes for patients with this challenging condition.

Types of Multiple Myeloma | International Myeloma Foundation

Multiple myeloma has different types and subtypes. These types are based on the immunoglobulin (protein) produced by the myeloma cell. The various immunoglobulins have different functions in the body. Each immunoglobulin is made up of two heavy chains and two light chains.

The five types of heavy protein chains are G, A, D, E, and M.
The two types of light protein chains are kappa (κ) and lambda (λ).

Furthermore, there are different subtypes of myeloma. 

Subtypes of immunoglobulins

• Normal plasma cells secrete immunoglobulins (antibodies) to fight infections. Immunoglobulins are proteins that attach to substances entering the body that the body recognizes as foreign. Normal immunoglobulins are called “polyclonal protein.” Myeloma cells, which are cancerous plasma cells, secrete monoclonal protein. Monoclonal protein is an abnormal immunoglobulin that cannot properly fight infection.
• Healthy plasma cells or myeloma cells can produce immunoglobulins. These immunoglobulins made up of two heavy chains and two light chains that are bound together. 

• The five possible types of immunoglobulin (abbreviated “Ig”) are heavy chains: IgG, IgA, IgD, IgE, and IgM.
• The possible types of light chains are either kappa (κ) or lambda (λ).
• Myeloma cells make immunoglobulins. These immunoglobulins are made up of only one type of heavy chain (G, A, D, E, or M) and one type of light chain (kappa or lambda). The most common type of myeloma is IgG kappa. In IgG kappa myeloma, the myeloma cells produce an immunoglobulin made from two IgG heavy chains bound to two kappa light chains.
• About 15% of patients have light chain myeloma. In this type of myeloma, the myeloma cells secrete only light chain protein and no heavy chains. It is also known as “Bence-Jones myeloma” (after the doctor who discovered it).
• One to two-percent of patients have “non-secretory myeloma.” In non-secretory myeloma, the myeloma cells produce very little or no monoclonal protein of any type.
• Your doctor will order tests to identify your type of myeloma. It’s important to know which type you have as you will be able to better understand your test results.You will be able to determine if your level of monoclonal protein is stable, increasing, or decreasing.

See the IMF’s Patient Handbook if you have been diagnosed with any of the following:

• AL amyloidosis
• Light chain deposition disease (LCDD)
• Waldenström’s macroglobulinemia
• POEMS syndrome

Types of Myeloma

What’s Next?

Types of myeloma | Cancer Research UK

There are different types of myeloma. The treatment you need is usually the same whichever type you have but the type can change how it affects you.

There are also some other conditions related to myeloma that affect plasma cells. 

Immunoglobulins and your type of myeloma

Most people have a type of myeloma that causes the abnormal plasma cells to produce abnormal proteins. These proteins are called immunoglobulin (also called abnormal protein, paraprotein, monoclonal protein or monoclonal spike). As well as the whole immunoglobulin, often a small part called the free light chain (called Bence Jones protein in urine) is made in big amounts by the plasma cells.  

Each immunoglobulin is made up of 2 long protein chains (called heavy chains) and 2 shorter protein chains (called light chains). 

Immunoglobulins can be classified into one of 5 types depending on their heavy chains. These are A, G, M, D and E. Your type of myeloma is named after the abnormal immunoglobulin it is making.

Only one type of immunoglobulin (Ig) is overproduced when you have myeloma. The type of immunoglobulin this is varies from person to person. IgG is the most common. The next most common is IgA and light chain only. IgM, IgD and IgE are very rare. 

Light chain myeloma sometimes called Bence Jones myeloma

About 20 out of 100  people with myeloma (20%) do not produce complete immunoglobulins. They only produce part of the immunoglobulin called the light chain. 

There are 2 types of light chains – called kappa and lambda. The light chains can show up in the urine. Doctors call this the Bence Jones protein (BJP).

A blood test called a serum free light chain test can pick up small increases in the amount of free light chains in the blood. Doctors use this test to:

• measure the amount of each of the light chains in the blood
• to compare the amount of kappa light chains to the amount of lambda light chains, known as the ratio

Your doctor can use the test to diagnose and monitor your myeloma.

Non secretory myeloma

In about 3 out of every 100 people with myeloma (3%), the myeloma cells produce little or no immunoglobulin (also called paraprotein). This makes it harder to diagnose.

Doctors use bone marrow tests and scans (such as PET-CT) to diagnose and monitor non secretory myeloma.

Types of myeloma depending on gene changes

Myeloma develops because of changes in genes that become abnormal. Genes are the instruction manuals for cells ‘telling’ them how to behave. There are subtypes of myeloma based on the changes in their genes. Your genetic subtype depends on the changes there are in the genes of the myeloma cells.

Knowing the genetic subtype can help doctors know how your myeloma might progress.

Doctors are researching how particular genetic subtypes of myeloma might be treated differently in the future.

Other conditions related to myeloma

Monoclonal gammopathy of undetermined significance (MGUS)

If you have MGUS your plasma cells make too many large protein molecules known as immunoglobulins or paraproteins (also called abnormal protein, monoclonal protein or monoclonal spike). These show up in the blood.

MGUS is often found by chance, in blood tests for a routine check up, or tests for a different medical problem. This is because MGUS does not cause any symptoms, and does not generally affect your health.

MGUS is diagnosed if you have:

• a low level of abnormal paraprotein in your blood (less than 30 g/l)
• a low level of abnormal plasma cells in your bone marrow (less than 10%)
• no evidence of certain other related conditions
• no related problems with organs or tissues

Because it doesn’t usually cause any symptoms or cause problems, MGUS does not usually need treatment. Some people with MGUS go on to develop myeloma, so your specialist or GP will see you regularly for check ups. About 1 out of 100 people with MGUS (1%) develop myeloma each year.

Plasmacytoma

A plasmacytoma is a tumour made up of plasma cells together in a lump. They can be found in bone or soft tissue. You might have one area of plasmacytoma and this is called solitary plasmacytoma. Some people have more than one plasmacytoma and this is called multiple solitary plasmacytoma.

The areas of plasmacytoma are similar to the areas of plasma cells found in people with multiple myeloma.

More than half of people with bone plasmacytoma go on to develop myeloma later in life. Soft tissue (or extramedullary) plasmacytoma can also develop into myeloma but is less common.

Doctors usually treat plasmacytoma with radiotherapy.

Amyloidosis

This is a rare conditon. The plasma cells make an abnormal protein called amyloid. The amyloid collects in body organs, such as the kidneys or heart, and gradually causes damage.

About 10 to 15 out of every 100 people with myeloma (10 to 15%) develop amyloidosis. But it doesn’t always cause problems. However, it is rare for people with amyloidosis to develop myeloma. Doctors usually treat amyloidosis with chemotherapy, and use the same drugs that you would have for myeloma.

Monoclonal Gammopathies of Undetermined Significance (MGUS): Practice Essentials, Pathophysiology, Epidemiology

Kappa and Lambda Light Chains

Kappa/Lambda Light Chains in Multiple Myeloma

Multiple myeloma is a blood cancer of white blood cells called plasma cells. Plasma cells come from the bone marrow and they produce antibodies (also called immunoglobulins) that fight wide variety of infections. In myeloma, one of these antibodies grows out of control in the bone marrow, crowding out the other antibodies. This is called a monoclonal protein (also called M-protein or M-spike). 

Antibodies are made up of two parts: heavy chains and light chains. When myeloma progresses, the myeloma cells start to produce more light chains than heavy chains. This can be measured by the Free Light Chain Assay test on a blood specimen. In general, the higher the free light chains, the more aggressive the disease is. Therefore, the serum free light chain test is a better predictor of outcome than the amount of M-protein in the blood.

What are light chains? 

There are two types of light chains: kappa and lambda. If a patient has kappa myeloma, their doctor will watch for a rise in the kappa numbers. Likewise, if a patient has lambda myeloma, the lambda number will be watched. This balance of kappa and lambda together is called the kappa/lambda ratio which can also indicate a change in levels of disease. “The ratio or proportion between the kappa and lambda light chains indicates an excess production of one chain over the other, and therefore can be used as an indication of disease progression or remission,” said Dr. Christina Gasparetto of Duke University. 

What are heavy chains? 

There are five types of immunoglobulins: IgG, IgA, IgM, IgE and IgD. Approximately 60-70% of patients have IgG myeloma and about 20% have IgA myeloma. 

Heavy and light chain combinations

In total, there are 10 variations of these immunoglobulins for myeloma patients: IgA kappa, IgG kappa, IgM kappa, IgD kappa, IgE kappa, IgA lambda, IgG lambda, IgM lambda, IgD lambda, and IgE lambda.

Presence of heavy and light chains

There are instances where patients can lose the heavy chain and have “light chain only” myeloma. There are also instances where patients no longer produce light chains in the blood and their disease must then be monitored through a bone marrow biopsy. 

Oops! Page Not Found | VELCADE® (bortezomib)

How is VELCADE administered?

VELCADE is prescribed by a doctor experienced in the use of medications to treat cancer. It is administered by a healthcare professional as an injection into your vein (intravenously, or IV) or under your skin (subcutaneously, or SC). VELCADE must not be administered into your spinal fluid (intrathecally).

Who should not receive VELCADE?

Before you receive treatment with VELCADE, tell your doctor about all of your medical conditions. You should not receive VELCADE if you are allergic to bortezomib, boron, or mannitol.

What are the possible side effects of VELCADE?

VELCADE can cause serious side effects, including:

• Nerve problems (peripheral neuropathy).

  VELCADE can cause damage to the nerves, a condition called peripheral neuropathy. You may feel muscle weakness, tingling, burning, pain, and loss of feeling in your hands and feet, any of which can be severe. Tell your doctor if you notice any of these symptoms. Your doctor may change the dose and/or schedule of VELCADE or stop it altogether. If you have peripheral neuropathy before starting VELCADE, your doctor could consider giving you VELCADE subcutaneously.

• Low blood pressure (hypotension).

  VELCADE can cause a drop in blood pressure. Tell your doctor if you have low blood pressure, feel dizzy, or feel as though you might faint. If you are taking drugs that lower blood pressure, your medications might need to be adjusted. If you are not drinking enough liquids, your doctor may need to administer IV fluids.

• Heart problems (cardiac toxicity).

  Treatment with VELCADE can cause or worsen heart rhythm problems and heart failure. Your doctor may closely monitor you if you have, or are at risk for, heart disease. Tell your doctor if you experience chest pressure or pain, palpitations, swelling of your ankles or feet, or shortness of breath.

• Lung problems (pulmonary toxicity).

  There have been reports of lung disorders in people receiving VELCADE. Some of these events have been fatal. Tell your doctor if you experience any cough, shortness of breath, wheezing, or difficulty breathing.

• Brain swelling (Posterior Reversible Encephalopathy Syndrome— PRES).

  There have been reports of a rare, reversible condition involving the brain, called PRES, in people treated with VELCADE. People with PRES can have seizures, high blood pressure, headaches, tiredness, confusion, blindness, or other vision problems. Treatment with VELCADE should be stopped in cases of PRES. It is not known whether restarting VELCADE therapy in patients previously experiencing this complication is safe.

• Stomach and Intestinal problems (gastrointestinal toxicity).

  VELCADE treatment can cause nausea, vomiting, diarrhea, and constipation. If your symptoms are severe, your doctor may recommend IV fluids and/or medications.

• Low platelet counts (thrombocytopenia).

  VELCADE can cause low levels of platelets (clot-forming cells). If platelets become very low, there is an increased risk of bleeding. Your doctor may recommend a platelet transfusion or other supportive care.

• Lowered white blood cells (neutropenia).

  VELCADE can cause low levels of neutrophils which are a type of white blood cells that help to fight infections. If your white blood cells become low, you can be at higher risk for infections. Tell your doctor if you develop a fever or believe you have an infection.

You will have regular blood tests to check your cell counts during your treatment with VELCADE. If the number of these cells is very low, your doctor may change the dose and/or schedule of VELCADE.

• Tumor Lysis Syndrome (TLS).

  TLS is a syndrome that causes a chemical imbalance in the blood that could lead to heart and/or kidney problems. TLS can occur with cancer treatments, and your doctor will be monitoring your blood and urine for any signs of this syndrome. If you develop TLS, your doctor will take appropriate steps to treat it.

• Liver problems (hepatic toxicity).

  If you have liver problems, it can be harder for your body to get rid of VELCADE. VELCADE has caused sudden liver failure in people who were taking many medications or had other serious medical conditions. Symptoms of liver problems include a yellow discoloration of the eyes and skin (jaundice) and changes in liver enzymes measured in blood tests. Your doctor will closely monitor you if you have liver disease. It is not known whether restarting VELCADE therapy in patients previously experiencing this complication is safe.

• Hematologic disease (Thrombotic Microangiopathy, TMA).

  VELCADE can lead to the formation of blood clots in small blood vessels. These clots can result in low platelets, kidney damage, confusion, and an increased risk of bleeding. Tell your doctor if you develop pinpoint-sized purple dots (petechiae), larger bruises, or you see blood in your urine. Your doctor may stop treatment with VELCADE. It is not known whether restarting VELCADE therapy in patients previously experiencing this complication is safe.

More than 1 in 5 people (20%) receiving VELCADE have experienced the following side effects in one or more clinical trials: neutropenia, thrombocytopenia, peripheral neuropathy, fatigue, nausea, diarrhea, leukopenia (low levels of white blood cells), anemia, constipation, neuralgia (nerve pain), vomiting, lymphopenia (low levels of a certain type of white blood cells), rash, pyrexia (fever), and anorexia.

What other information should you tell your doctor?

Women should avoid becoming pregnant while being treated with VELCADE as it could harm your unborn baby. Females should use effective birth control during treatment and for at least seven months after the final dose of VELCADE. If using hormonal contraceptives (for example, the pill), an additional barrier method of contraception (for example, diaphragm or condom) must be used. Males should use effective contraception during treatment with VELCADE and for four months following treatment. Tell your doctor immediately if you think you are pregnant. Do not breastfeed during treatment with VELCADE and for two months after your final dose of VELCADE.

You should also tell your doctor if you:

• Have kidney disease. If you are on dialysis, your doctor will administer VELCADE after the dialysis procedure.

• Are taking medication for diabetes. VELCADE can affect your blood glucose levels. Your doctor may require close monitoring of your blood glucose levels and change the dose of your diabetes medicine while you are being treated with VELCADE.

• Have liver disease.

• Are using any other medications, including prescription and nonprescription medications, herbal or dietary supplements, or holistic treatments. St. John’s wort should be avoided.

• Develop a rash of any type or have skin pain while receiving VELCADE.

The side effects of VELCADE may impair your ability to drive or operate machinery.

These are not all of the possible side effects with VELCADE. It is important to always contact your doctor if you experience any side effects while on VELCADE. If you have any questions about VELCADE, contact your doctor. Additional information is available on the website at VELCADE.com.

Please see accompanying VELCADE

^® (bortezomib) full Prescribing Information.

Making sense of serum protein bands

Serum protein bands (monoclonal gammopathy) will sometimes be found following serum protein
electrophoresis in patients presenting with classic signs or symptoms of multiple myeloma, e.g. bone pain. In other cases,
patients may have non-specific symptoms, meaning the discovery is more unexpected. Irrespective of how the band is discovered,
there are additional tests that can be performed to provide more information to help with the diagnosis and to guide management.
These tests include; immunofixation, Bence-Jones protein and serum free light chains.

While we may recognise the names of some of the tests, it can be confusing to know the situations in which they should
be requested, and even what the results mean. This article provides an overview of the clinical situations in which a
patient may have a monoclonal gammopathy in their serum, what these results mean, and the role of other related laboratory
tests.

In a general practice setting, test results showing increased protein in serum or urine are often incidental findings
when investigations have been requested for other reasons. Patients with clinical conditions such as multiple myeloma,
that increase the levels of protein in serum or urine, may present with a wide range of symptoms or may be asymptomatic.
In these patients serum protein electrophoresis may have been requested as part of the initial work-up.

Levels of protein in the serum change in a predictable way in response to many clinical conditions, such as inflammation,
trauma (including burns and chemical injury), malignancy, infarction and necrosis. ¹ Serum protein electrophoresis
is a laboratory test used to help identify patients with multiple myeloma and other serum protein disorders, by separating
serum proteins into their various components. Indications for serum protein electrophoresis are numerous and are based
on clinical, laboratory and occasionally radiological findings (see “Indications for requesting serum protein electrophoresis”).

Indications for requesting serum protein electrophoresis

^1,2,3

Indications based on clinical findings:

• Suspected multiple myeloma, Waldenström’s macroglobulinemia, primary amyloidosis or other related disorders
• Unexplained bone pain or fracture
• Recurrent infections
• Unexplained peripheral neuropathy (not able to be attributed to another condition, e.g. type 2 diabetes, chemotherapy)

Indications based on laboratory findings:

• High (or low) total serum globulin or immunoglobulin
• Extremely high percentage of lymphocytes
• Incidental finding of an increased total protein level
• Unexplained anaemia (multiple myeloma is a recognised cause of non-iron deficiency anaemia) or other persisting cytopaenias
  for which there is no other explanation
• Unexplained high ESR (>50) with a normal CRP
• Unexplained hypercalcaemia or renal impairment
• Red cell rouleaux formations noted on the peripheral blood smear
• Unexplained high urine protein with relatively low or normal urine albumin
• Presence of urine free light chains (Bence-Jones proteinuria)

Indications based on radiological findings:

• Lytic lesions in bone
• Unexplained osteopaenia (as not all patients with multiple myeloma will have osteolytic lesions)

Electrophoresis fractions

Serum protein electrophoresis separates serum proteins into the following fractions: albumin, alpha, beta and gamma
globulins. Approximately 60% of the total protein in the serum is albumin, while the remaining fractions are composed
mainly of globulins, predominantly immunoglobulins. The gamma fraction contains the largest portion of immunoglobulins,
hence an increase in gamma globulin is referred to as a gammopathy.

Gammopathies can be either polyclonal, characterised by a broad diffuse band in the electrophoresis pattern, or monoclonal
where the band is sharp and well defined. Making the distinction between a monoclonal and polyclonal gammopathy is important.

Monoclonal gammopathies are associated with excessive production of immunoglobulins from a single clone of cells that
is malignant or potentially malignant, whereas polyclonal gammopathies are characterised by a generalised increase in
immunoglobulins.¹ A polyclonal gammopathy can be caused by various infections, haematologic diseases, liver
disease, some malignancies and inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, temporal
arteritis and sarcoidosis.

This article focuses on monoclonal gammopathies, and provides guidance on the laboratory management of conditions associated
with these.

Monoclonal gammopathy

Monoclonal gammopathy is the name given to a “band” in serum protein electrophoresis, caused by the overproduction
of a population of plasma cells, which in turn produce a single immunoglobulin (the so-called “plasma cell dyscrasias”).
As there is a finite capacity in the bone marrow, an enlarging clone of plasma cells expands at the expense of other cells.
Levels of other normal immunoglobulins eventually fall, referred to as immune paresis. While this is most often associated
with multiple myeloma, it is quite frequently an unexpected discovery, and may be related to a number of conditions.

Conditions associated with monoclonal gammopathy

There are a number of conditions associated with monoclonal gammopathy. In the first instance, most GPs will think of
multiple myeloma, but this is less common, and most people will be found to have a monoclonal gammopathy of undetermined
significance (MGUS). Table 1 compares the incidence of these conditions.

Table 1: Conditions with monoclonal gammopathies6,7,8
Condition	Clinical Effect	Incidence
Monoclonal gammopathy of undetermined significance (MGUS)	Asymptomatic with risk of progression	1% >50 years, rising up to 8% >70 years
Multiple myeloma	Severe	40 per million, but increases to 300 per million for people >80 years
Waldenström’s macroglobulinaemia	Moderate	0. 1 per million at age <45 years and 36.3 per million at age >75 years.
Amyloidosis	Severe	8 per million

Monoclonal gammopathy of undetermined significance (MGUS)

MGUS is the most common monoclonal gammopathy. It describes the presence of a monoclonal protein without sufficient
clinical or laboratory evidence to diagnose one of the other associated conditions. It is the most frequent diagnosis
of a monoclonal gammopathy, and has an incidence approximately 60 times greater than multiple myeloma (1% in people aged
over 50 years, rising to up to 8% of people aged over 70 years).^4,5

Approximately 1% of patients per year with MGUS will progress to multiple myeloma, therefore periodic (usually annual)
monitoring should be done (with serum protein electrophoresis, immunoglobulins and complete blood count). There is no
plateau time, beyond which development of a condition such as multiple myeloma will not occur. However, reactive bands,
which can occur as part of the immune response to an inflammatory stimulus, often reduce or disappear when followed.

Multiple myeloma

Multiple myeloma is uncommon and has an incidence of approximately 40 per million people. It is rare under the age 40
years, but its incidence rises to over 300 per million in people aged over 80 years. The median age at diagnosis is 69
years with a slight male predominance.³

Patients with multiple myeloma can be classified as having asymptomatic (formerly known as smouldering) or symptomatic
(active) disease.

Anaemia and bone marrow failure, infections, renal impairment, bone pain and pathological fractures are common clinical
features. The differential diagnosis of multiple myeloma is shown in Table 2.

Less common associations of monoclonal gammopathies

Lymphomas: monoclonal gammopathy is a common feature of primary lymphoproliferative conditions such
as chronic lymphocytic lymphoma.

Waldenström’s macroglobulinaemia: a type of small cell lymphoma associated with production
(often large amounts) of monoclonal IgM. The median age at presentation is 63 years, and over 60% of patients are male.
Clinical features include enlargement of liver and spleen and anaemia, due to increasing concentration of IgM, and hyperviscosity
syndrome.³

Amyloidosis: Primary amyloidosis is associated with a monoclonal gammopathy in 85% of cases and is
characterised by pathological deposits of monoclonal light-chain fragments in various tissues such as heart, liver, bone
marrow, lymph nodes and bowel.

Plasmacytoma: refers to a localised solid collection of plasma cells in the body outside the bone marrow.

Laboratory tests for monoclonal gammopathies

There are number of laboratory tests which are useful for determining the presence of a monoclonal gammopathy, and then
eventually characterising it.

Serum total protein and albumin

These are relatively crude tests, but will often be abnormal if a monoclonal gammopathy and/or immune paresis is present.
A large band may show as a high serum total protein with a raised calculated globulin result. If the total serum protein
is very high, e.g. >90 g/L, protein electrophoresis may be performed on a reflex basis by the laboratory.

Immunoglobulins

A person with a monoclonal gammopathy will have an increase in a particular class of immunoglobulin: IgG, IgA, IgM or
IgD (IgE monoclonal gammopathy is extremely rare). Quantitation of immunoglobulins (routinely IgG, IgA and IgM) is performed
if a new monoclonal gammopathy is detected. It is also usually performed when following a known monoclonal gammopathy,
to provide information about progression.

Serum protein electrophoresis

Serum protein electrophoresis is a means of separating serum proteins. A small amount of serum is placed on a specific
medium (such as agarose) and an electrical charge is applied. The proteins then migrate across the medium in a characteristic
manner, due to the net charge and size and shape of the protein.

In routine serum protein electrophoresis, the protein will separate into five main components (Figure 1), identified
as albumin and the globulins (alpha1, alpha2, beta and gamma) . The gamma region contains the largest portion of globulins,
therefore monoclonal gammopathies are most frequently encountered in this portion of the electrophoresis.

Immunofixation

When serum protein electrophoresis identifies a mono-clonal gammopathy, the laboratory will automatically perform immunofixation
(i.e. reflex test) to further determine the exact type of monoclonal protein. The heavy chain of the immunoglobulin will
be identified as IgA, IgG or IgM (most commonly) or IgD (or IgE rarely). The light chains will be identified as kappa
or lambda (κ or λ). In a minority of cases only light chains (without heavy chains) are produced. Light chain-only
monoclonal gammopathy are often barely visible in serum but may show as large amounts of monoclonal light chains excreted
in the urine; hence the need to consider urine testing when clearly suspecting a monoclonal gammopathy.

Urine free light chain testing (Bence-Jones protein)

Even in disease-free people, light chains are produced in small excess over heavy chains, creating a surplus of (polyclonal)
free light chains. In a person with a monoclonal gammopathy this is often more marked, due to dysregulation of light versus
heavy chain production. All of the excess light chains also have an identical class and mobility. Excess free light chains
are frequently detectable in the urine by electrophoresis and immunofixation. The presence of monoclonal urine light chains,
often referred to as Bence-Jones protein, is found nearly exclusively in patients with lymphoproliferative processes such
as multiple myeloma.

Serum free light chains

Serum free light chain assays can detect normal levels of light chains in the blood, as well as elevated levels, even
when those levels are undetectable by serum protein electrophoresis and immunofixation. Both free κ and λ chains
are measured and the ratio is calculated. Excessive free κ or λ increases the likelihood a of monoclonal
plasma cell disorder.

Some evidence suggests that in patients with newly identified MGUS, an abnormal light chain ratio increases the likelihood
of progression independent of other factors such as band size and type. However, formal guidelines differ as to the use
of serum free light chains in this setting. Recent British Haematology Society guidelines do not recommend their use,
other than in patients who are otherwise at higher risk of progression (see “Monitoring monoclonal
gammopathy” below) and those where a malignant plasma cell disorder is otherwise clearly suspected.

Serum free light chains are useful in certain specific and uncommon settings, e.g. concern over a possible non-secretory
myeloma or amyloidosis, after specialist consultation. Light chains are sometimes used in specialist settings to monitor
the response of mutiple myeloma to treatment.

Serum free light chains are not recommended as a first line routine test for plasma cell disorders. There is also no
current evidence to support their use in long-term monitoring,⁹ except for monitoring response of mutiple myeloma
to treatment.

Clinical presentation of monoclonal gammopathy

Asymptomatic patients with chance findings

Approximately 30% of patients with monoclonal gammopathy are asymptomatic at diagnosis. In these cases the diagnosis
is made due to an unusual result being noticed by either the laboratory or the GP. Some of the more suspicious laboratory
findings include:

• Unexplained raised ESR (a monoclonal gammopathy does not increase CRP)
• Increased rouleaux formation on the blood film
• Increased serum total protein and/or calculated globulin (total protein minus albumin)
• Elevated immunoglobulin result

N.B. ESR and immunoglobulins are not recommended screening tests for monoclonal bands, which are only detected by electrophoresis

Symptomatic patients

Although the diagnosis of multiple myeloma is often made by chance, a significant number of people will present with
symptoms.

Two-thirds of patients complain of bone pain, frequently located in the back, long bones, skull and pelvis. In addition,
patients often have a range of non-specific (constitutional) symptoms, including fatigue, weight loss, chronic infections,
paresthesia and symptoms related to hypercalcaemia.

As many patients with multiple myeloma present with lower back pain, a number of “red flags” have been identified
in the assessment of patients with acute lower back pain. Multiple myeloma should be considered as a diagnosis in patients
aged over 50 years with back pain persisting more than one month, if one or more red flags are identified (Table 3).

Testing for monoclonal gammopathy

In patients with a possible monoclonal gammopathy, the following investigations are required:

• Serum protein electrophoresis
• Urine free light chain testing

If a band is identified by serum electrophoresis or if immune paresis is noted then immunofixation, immunoglobulins
and band quantification are recommended. A casual urine sample for protein and albumin and free light chains (Bence-Jones
protein) should be collected. Other tests which should also be requested in this clinical situation are complete blood
count, corrected calcium, creatinine (eGFR) and electrolyte measurements.

Monitoring monoclonal gammopathy

Periodic monitoring and watching for clinical and laboratory features of change is of key importance when managing patients
with a monoclonal gammopathy. This is because transformation can occur, e.g. a patient may transition from MGUS to asymptomatic
myeloma to multiple myeloma.

Approximately 1% of people with MGUS develop multiple myeloma, amyloidosis or Waldenström’s macroglobinaemia
annually, although most (especially those who are older at diagnosis) die of other diseases.¹¹

The follow-up for patients with MGUS depends on the risk of progression. Both the British/Nordic Study Group (2009)⁹ and
the International Myeloma Working Group (IMWG, 2010)¹² have recently published guidelines. These differ in
detail, but their common thread is that it is important to fully investigate patients at high risk, whereas those with
low risk can be spared unnecessarily invasive initial investigations and need less frequent long-term monitoring.

The patient should be informed about the range of possible symptoms and advised to report new symptoms such as bone
pain, weight loss, fatigue or other symptoms of progression. They should be aware that the risk of progression is life-long
and does not plateau. The risk of eventual progression is higher for a young fit person with more years of life expectancy,
than for an older person with other significant co-morbidities.

Low risk MGUS: The majority of patients with MGUS are at low risk of progression, judged by:

• Small band size (IgG <15 g/L OR IgA or IgM <10 g/L)
• They are asymptomatic
• No other abnormal results (normal adjusted calcium, creatinine and eGFR, blood count).

These patients should be followed-up several times in the first year, and this interval can be extended to six to 12
monthly and up to two to three yearly in long-term stable patients.^9,12

High risk MGUS: These patients should be referred to a haematologist and require more active initial
evaluation and closer long-term monitoring. Risk factors include one or more of the following:

• Band size IgG > 15 g/L OR IgA or IgM > 10 g/L
• Any IgD or IgE monoclonal gammopathy regardless of concentration
• Symptoms or signs of a suspected multiple myeloma or lymphoproliferative disorder, e.g. bone pain or pathological
  fractures, constitutional symptoms such as weight loss, peripheral neuropathy, nephrotic syndrome
• Other unexplained laboratory or radiology abnormalities regardless of band size, e.g. hypercalcaemia, renal impairment,
  anaemia, lytic lesions or significant osteopaenia
• The presence of Bence-Jones proteinuria, immune suppression, age and sex are not in themselves prognostic. However,
  significant Bence-Jones proteinuria (>500 mg/L) should prompt haematologist referral because of the risk of development
  or progression of renal impairment.

Further evaluation usually includes bone marrow aspirate and trephine biopsy. Serum free light chains and beta-2 microglobulin
may also be helpful in stratifying these patients – a normal light chain ratio and low beta-2 microglobulin level carries
lower risk.

Other possible investigations for higher risk patients include; spine/pelvic MRI scan for possible lytic lesions, abdominal
CT for retroperitoneal lymph nodes (in patients with IgM bands), and renal investigations including; possible renal/tissue
biopsy for patients with unexplained nephrotic proteinuria or renal impairment (looking for amyloidosis).

Long-term patients with a high risk MGUS should usually be monitored at least several times in the first year, then
annually for life. New symptoms or laboratory abnormalities should prompt earlier review. An increase in band size of
more than 25% over three months (minimal 5 g/L) is regarded as significant.

Patients with asymptomatic multiple myeloma have significant risk (about 10% annually) of progression
to symptomatic disease, and should be under haematologist review. A skeletal survey and a bone marrow aspirate and biopsy
should be carried out at baseline. Laboratory tests and clinical work-up should be done at diagnosis including baseline
MRI of the spine and pelvis. Tests should be repeated two to three months after the initial recognition of the diagnosis.
If the results are stable, the studies should be repeated every four to six months for one year and, if stable, evaluation
intervals can be lengthened to every six to 12 months. A skeletal survey should be performed if there is evidence of progression.

Understanding immunoglobulins

Plasma cells produce immunoglobulins which are composed of heavy and light chains. Each plasma cell produces only one
type of heavy chain (IgA, IgD, IgG, IgM and IgE) and one type of light chain (either kappa or lambda [κ or λ]).
After the chains are produced they are assembled within the plasma cell to form a whole immunoglobulin.

Figure 2: Immunoglobulin (showing light and heavy chains).

A PCP’s Guide to Screening for Monoclonal Gammopathy of Undetermined Significance – Consult QD

By Jack Khouri, MD, Christy Samaras, DO, Jason Valent, MD, Alex Mejia Garcia, MD, Beth Faiman, PhD, CNP, Saveta Mathur, CNP, Kim Hamilton, CNP, Megan Nakashima, MD, and Matt Kalaycio, MD

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services Policy

The monoclonal gammopathies encompass a number of disorders characterized by the production of a monoclonal protein (M protein) by an abnormal clone of plasma cells or other lymphoid cells. Monoclonal gammopathy of undetermined significance (MGUS) is the most common of these disorders. The diagnostic criteria for MGUS are listed below.

Its clinical relevance lies in the inherent risk of progression to hematologic malignancies such as multiple myeloma or other lymphoproliferative disorders, or of organ dysfunction due to the toxic effects of the M protein. An M protein may consist of an intact immunoglobubin (Ig) molecule — i.e., two light chains and two heavy chains (most commonly IgG type followed by IgA and IgM) — or a light chain only (kappa or lambda).

MGUS is present in 3 to 4 percent of the population over age 50 and is more common in older men, African-Americans and Africans.

The overall risk of progression to myeloma and related disorders is less than or equal to 1 percent per year depending on the subtype of the M protein (higher risk with IgM than non-IgM and light-chain MGUS). While the risk of malignant transformation is low, multiple myeloma is almost always preceded by the presence of an asymptomatic and often unrecognized monoclonal protein.

When should we look for an M protein?

An M protein is typically an incidental finding when a patient is being assessed for any of a number of presenting symptoms or conditions. A large retrospective study found that screening for MGUS was mostly performed by internal medicine physicians. The indications for testing were anemia, bone-related issues, elevated creatinine, elevated erythrocyte sedimentation rate and neuropathy.

Routine screening for an M protein in the absence of clinical suspicion is not recommended, given the low risk of malignant progression, lack of effect on patient outcomes, the accompanying emotional burden and lack of treatment options. Evaluation for monoclonal gammopathy may be considered as part of the workup of associated clinical symptoms and signs and laboratory and imaging findings.

A low anion gap is not a major indicator of an M protein unless in a high concentration, in which case other manifestations would be present, such as renal failure, which would guide the diagnosis. Polyclonal hypergammaglobulinemia as a cause of low anion gap is far more common than MGUS.

Serum protein electrophoresis is an initial test used to identify an M protein and has a key role in quantifying it. An M protein appears as a narrow spike on the agarose gel and should be distinguished from the broad band seen in polyclonal gammopathies associated with cirrhosis and chronic infectious and inflammatory conditions, among others. A major disadvantage of serum protein electrophoresis is that it cannot detect an M protein in very low concentrations or determine its identity.

Serum immunofixation is more sensitive than serum protein electrophoresis and should always be ordered in conjunction with it, mostly to ensure detecting tiny amounts of M protein and to identify the type of its heavy chain and light-chain components.

The serum free light-chain assay is also considered an essential part of the screening process to detect light-chain MGUS and light-chain myeloma. As many as 16 percent of myeloma patients secrete only light chains, which may not be identified on serum immunofixation. In general, a low kappa-lambda ratio (< 0.26) indicates the overproduction of lambda light chains, and a high ratio (> 1.65) indicates the overproduction of kappa light chains.

The serum free light-chain assay helps detect abnormal secretion of monoclonal light chains before they appear in the urine once the kidney tubules become saturated and unable to reabsorb them.

Of note, the free light-chain ratio can be abnormal (< 0.26 or > 1.65) in chronic kidney disease. Thus, it may be challenging to discern whether an abnormal light-chain ratio is related to impaired light-chain clearance by the kidneys or to MGUS. In general, kappa light chains are more elevated than lambda light chains in chronic kidney disease, but the ratio should not be considerably skewed. A kappa-lambda ratio below 0.37 or above 3 is rarely seen in chronic kidney disease and should prompt workup for MGUS.

Tests in combination. The sensitivity of screening for M proteins ranges from 82 percent with serum protein electrophoresis alone to 93 percent with the addition of serum immunofixation and to 98 percent with the serum free light-chain assay. The latter can replace urine protein electrophoresis and immunofixation when screening for M protein, given its higher sensitivity. An important caveat is that urine dipstick testing does not detect urine light chains.

Once an M protein is found, immunoglobulin quantification, a complete blood cell count, and serum creatinine and calcium measurements are also recommended to look for anemia, renal failure and hypercalcemia, which can be associated with symptomatic myeloma.

Future posts will discuss the differential diagnosis of MGUS as well as risk stratification.

Dr. Khouri is a fellow in the Department of Hematology and Medical Oncology. Drs. Samaras, Valent and Mejia Garcia are staff in the Department of Hematology and Medical Oncology. Dr. Faiman, Ms. Mathur and Ms. Hamilton are clinical nurse practitioners in the Department of Hematologic Oncology and Blood Disorders. Dr. Nakashima is staff in the Department of Clinical Pathology. Dr. Kalaycio is Chairman of the Department of Hematology and Medical Oncology.

This abridged article was originally published in Cleveland Clinic Journal of Medicine.

90,000 Free kappa and lambda chains of immunoglobulins in serum, IgG

Quantitative study of free kappa and lambda chains of immunoglobulins in the blood, used for diagnosis, assessment of prognosis and control of treatment of monoclonal gammopathies and some other lymphoproliferative diseases.

Russian synonyms

Free κ and λ chains of immunoglobulins in the blood; free light chains of immunoglobulins in the blood.

Synonyms English

Free Light Chains, FLCs; FLCs, κ and λ; Serum FLC, sFLC.

Research method

Enzyme-linked immunosorbent assay (ELISA).

Units

μg / ml (micrograms per milliliter).

Which biomaterial can be used for research?

Venous blood.

How to properly prepare for the study?

• Eliminate physical and emotional stress for 30 minutes before the study.
• Do not smoke for 30 minutes prior to examination.

General information about the study

Monoclonal gammopathies are a group of diseases in which monoclonal proliferation of plasma cells is observed (multiple myeloma, Waldenstrom’s macroglobulinemia, monoclonal gammopathy of unclear significance, and others). As a rule, in these diseases, altered plasma cells secrete immunoglobulins or their components (the common name is paraproteins), which determine the clinical picture of the disease and can be measured for diagnostic purposes.

Different types of plasma cell tumors secrete different paraproteins:

• Monoclonal immunoglobulin is a complete immunoglobulin molecule composed of light and heavy chains. Hypersecretion of IgG immunoglobulin is most often detected.
• Light chains. In this case, complete assembly of immunoglobulins does not occur, and tumor cells secrete only (or predominantly) light chains of immunoglobulins. These light chains are called free, in contrast to light chains associated with heavy chains in the immunoglobulin molecule.Immunoglobulin free light chains are also called Bence Jones protein. A myeloma that secretes only light chains is known as Bence Jones myeloma. For a long time, the identification of free light chains was impossible, since there were no methods to differentiate free and bound light chains. Subsequently, with the invention of such methods, it became known that overproduction of free light chains is observed not only in multiple myeloma, but also in some other diseases, including AL-type amyloidosis and diseases of light chain deposition.
• Non-secreting plasma cell tumors. Despite the proliferation of plasma cells, they do not secrete either immunoglobulins or their individual fragments.

The following laboratory methods can be used to diagnose monoclonal gammopathies:

• electrophoresis and immunofixation of serum proteins;
• electrophoresis and immunofixation of urine proteins, including determination of Bens-Jones protein;
• Determination of free light chains of immunoglobulins in serum or urine using enzyme-linked immunosorbent assay (ELISA).

The ELISA method is relatively new (it was developed in 2001), however, due to its advantages, it was included in the standard algorithm for examining patients with suspected monoclonal gammopathy. The method is based on identifying epitopes of light chains that are available in molecules of free light chains and hidden in molecules of immunoglobulins, which makes it specific for free light chains. Both blood and urine can be analyzed for free light chains.

The main advantage of ELISA determination of FLCs is its higher sensitivity compared to other methods. So, for example, using serum electrophoresis, it is possible to determine monoclonal immunoglobulin at a level of 500-2000 mg / l. The sensitivity of the method of immunofixation of serum proteins is about 10 times higher. Electrophoresis and immunofixation of urine proteins are more sensitive methods with a resolution of 20-50 mg / l. These methods, however, are still not sensitive enough to detect diseases in which the concentration of FLCs is low (Bens-Jones myeloma, AL-type amyloidosis and light chain deposition diseases).Using the ELISA method, it is possible to determine FLCs in the blood serum at a concentration of only 1.5-3 mg / L.

In 80% of cases, plasma cell tumors secrete enough immunoglobulins that can be easily measured using electrophoretic methods. Although, as a rule, these tumors also secrete FLCs, in this group of patients, the study of FLCs using ELISA does not add significant diagnostic information. This study allows monoclonal gammopathies, secreting low concentrations of light chains, to be avoided by electrophoretic methods.

It should be noted that an increase in the concentration of free light chains does not always indicate the presence of monoclonal gammopathy. Their concentration also increases with polyclonal gammopathies observed in some infectious diseases or impaired renal function. In polyclonal gammopathies, however, there is a proportional increase in both kappa and lambda chains and the κ / λ ratio remains normal. With monoclonal gammopathies, the concentration of only one of the two types of light chains increases and the κ / λ ratio changes.Therefore, for the differential diagnosis of mono- and polyclonal gammopathies when an increased concentration of free light chains is detected, it is advisable to separately determine the concentration of kappa and lambda chains and calculate their κ / λ ratio.

The concentration of FLCs and the κ / λ ratio can be used as prognostic factors in assessing the risk of progression of unclear monoclonal gammopathy or asymptomatic myeloma to symptomatic myeloma. In addition to monoclonal gammopathies, FLCs can be used to predict some B-cell lymphomas.

The determination of FLCs by ELISA can be used to monitor the treatment of monoclonal gammopathies. Due to the short half-life of FLCs (2-6 hours compared to intact immunoglobulin – 21 days), FLCs are a more dynamic clinical and laboratory marker, which can be used to assess the response to treatment faster. This is especially true for monitoring Bence Jones myeloma. Usually, to control the treatment of this disease, multiple studies of the Bence-Jones protein in daily urine are performed, which is inconvenient for both the doctor and the patient.The ELISA test for serum FLCs has been shown to reflect tumor volume even better than Bens-Jones proteinuria and is likely to replace this assay altogether.

The study result is evaluated taking into account additional clinical, laboratory and instrumental data.

What is the research used for?

• For diagnostics, assessment of prognosis and control of treatment of monoclonal gammopathies (multiple myeloma, primary amyloidosis, monoclonal gammopathy of unclear significance) and some other lymphoproliferative diseases.

When is the study scheduled?

• If you suspect multiple myeloma or other diseases from the group of monoclonal gammopathies;
• in assessing the prognosis of some B-cell lymphomas.

What do the results mean?

Reference values ​​

Free kappa chains of immunoglobulins in serum: 3.25 – 15.81 μg / ml

Free lambda chains of immunoglobulins in serum: 3.23 – 28.05 μg / ml

Index of kappa / lambda light chains of immunoglobulins: 0.3 – 1.9

Reasons for the increase:

• multiple myeloma;
• primary systemic amyloidosis;
• solitary plasmacytoma;
• monoclonal gammopathy of unclear significance;
• chronic lymphocytic leukemia;
• B-cell lymphoma;

90,041 kidney disease;

90,041 infectious diseases;

• autoimmune diseases.

Reasons for downgrade:

• Disease control during treatment.

What can influence the result?

• Renal dysfunction;
• concomitant infectious and inflammatory or autoimmune diseases.

Download an example of the result

Important notes

• An increase in the concentration of free light chains does not always indicate the presence of monoclonal gammopathy;
• research results should be interpreted taking into account additional clinical, laboratory and instrumental data.

Also recommended

[20-018] Free lambda chains of immunoglobulins in serum

[20-015] Free kappa chains of immunoglobulins in serum

[06-035] Total whey protein

[06-038] Total protein in urine

[08-010] Total immunoglobulins G (IgG) in serum

[08-011] Total immunoglobulins M (IgM) in serum

[06-011] Protein fractions in whey

[13-101] Bens-Jones protein, quantitative (urine immunofixation)

[13-056] Immunofixation of serum immunoglobulins with antisera IgG, A, M K, L with quantitative determination of paraprotein

Who orders the study?

General practitioner, oncologist, hematologist.

Literature

• Tosi P, Tomassetti S, Merli A, Polli V. Serum free light-chain assay for the detection and monitoring of multiple myeloma and related conditions. Ther Adv Hematol. 2013 Feb; 4 (1): 37-41. doi: 10.1177 / 2040620712466863.
• Jenner E. Serum free light chains in clinical laboratory diagnostics. Clin Chim Acta. 2014 Jan 1; 427: 15-20. doi: 10.1016 / j.cca.2013.08.018. Epub 2013 Aug 30.

Free kappa and lambda chains of immunoglobulins in urine, IgG

Quantitative study of free κ – kappa and lambda – λ chains of immunoglobulins in urine, used to diagnose monoclonal gammopathies.

Russian synonyms

Free κ and λ chains of immunoglobulins in urine

Free light chains of immunoglobulins in urine

Synonyms English

Free Light Chains, FLCs

FLCs, κ and λ

Urine FLCs

Research method

Enzyme-linked immunosorbent assay (ELISA).

Units

μg / ml (micrograms per milliliter).

Which biomaterial can be used for research?

Daily urine.

How to properly prepare for the study?

• Eliminate alcohol from the diet within 24 hours before the study.
• Avoid (in consultation with your doctor) taking diuretics within 48 hours before urine collection.

General information about the study

Monoclonal gammopathies are a group of diseases in which monoclonal proliferation of plasma cells is observed (multiple myeloma, Waldenstrom’s macroglobulinemia, monoclonal gammopathy of unclear significance, and others).As a rule, in these diseases, altered plasma cells secrete immunoglobulins or their components (the common name is paraproteins), which determine the clinical picture of the disease and can be measured for diagnostic purposes.

Different types of plasma cell tumors secrete different paraproteins:

• Monoclonal immunoglobulin is a complete immunoglobulin molecule composed of light and heavy chains. Hypersecretion of IgG immunoglobulin is most often detected.
• Light chains. In this case, complete assembly of immunoglobulins does not occur, and tumor cells secrete only (or predominantly) light chains of immunoglobulins. These light chains are called “free”, in contrast to light chains associated with heavy chains in the immunoglobulin molecule. Free light chains of immunoglobulins – Bens-Jones protein. A myeloma that secretes only light chains is known as Bence Jones myeloma. For a long time, the identification of free light chains was impossible, since there were no methods to differentiate free and bound light chains.Subsequently, with the invention of such methods, it became known that overproduction of free light chains is observed not only in multiple myeloma, but also in some other diseases, including AL-type amyloidosis and diseases of light chain deposition.
• Non-secreting plasma cell tumors. Despite the proliferation of plasma cells, they do not secrete either immunoglobulins or their individual fragments.

The following laboratory methods can be used to diagnose monoclonal gammopathies:

• electrophoresis and immunofixation of serum proteins;
• electrophoresis and immunofixation of urine proteins, including determination of Bens-Jones protein;
• Determination of free light chains of immunoglobulins in serum or urine using enzyme-linked immunosorbent assay (ELISA).

The ELISA method is based on the identification of epitopes of light chains that are available in molecules of free light chains and hidden in molecules of immunoglobulins, which makes it specific for free light chains.

Both blood and urine can be tested for free light chains. In urine, free light chains of immunoglobulins polymerize, forming dimers and tetramers, and can also break down into smaller fragments. The process of polymerization / fragmentation of light chains in urine depends on parameters such as their concentration and urine pH, and is poorly predictable, which ultimately has a significant impact on the accuracy of the test result.For this reason, the study of free light chains in urine is considered as an additional analysis.

In 80% of cases, plasma cell tumors secrete an amount of immunoglobulins that can be easily measured using electrophoretic methods. Although these tumors typically also secrete FLCs, ELISA studies of FLCs in this group of patients do not add any diagnostic information. This study allows electrophoretic methods not to miss monoclonal gammopathies secreting intact immunoglobulins or light chains in low concentration.

It should be noted that an increase in the concentration of free light chains does not always indicate the presence of monoclonal gammopathy. Their concentration also increases with polyclonal gammopathies observed in some infectious diseases or impaired renal function. In polyclonal gammopathies, however, there is a proportional increase in both kappa and lambda chains and the κ / λ ratio remains normal. With monoclonal gammopathies, the concentration of only one of the two types of light chains increases and the κ / λ ratio changes.Therefore, for the differential diagnosis of mono- and polyclonal gammopathies when an increased concentration of free light chains is detected, it is advisable to separately determine the concentration of kappa and lambda chains and calculate their κ / λ ratio.

What is the research used for?

• For the diagnosis of monoclonal gammopathies (multiple myeloma, primary amyloidosis, monoclonal gammopathy of unclear significance).

When is the study scheduled?

• If you suspect multiple myeloma or other diseases from the group of monoclonal gammopathies.

What do the results mean?

Reference values ​​

Kappa chains: 0.4 – 20 μg / ml.

Lambda chains: 0.3 – 5 μg / ml.

Reasons for the increase:

• multiple myeloma;
• primary systemic amyloidosis;
• solitary plasmacytoma;
• monoclonal gammopathy of unclear significance;
• chronic lymphocytic leukemia;
• B-cell lymphoma;

90,041 infectious diseases;

• autoimmune diseases.

Reasons for downgrade:

• Disease control during treatment.

What can influence the result?

• Renal dysfunction;
• concomitant infectious and inflammatory or autoimmune diseases.

Download an example of the result

Important notes

• The study of free light chains in urine is inferior in accuracy to the study of blood and is currently considered as an additional analysis;
• research results should be interpreted taking into account additional clinical, laboratory and instrumental data.

Also recommended

[20-014] Free kappa chains of immunoglobulins in urine

[20-017] Free lambda chains of immunoglobulins in urine

[06-038] Total protein in urine

[06-011] Protein fractions in whey

[13-101] Bens-Jones protein, quantitative (urine immunofixation)

[13-056] Immunofixation of serum immunoglobulins with antisera IgG, A, M K, L with quantitative determination of paraprotein

Who orders the study?

General practitioner, oncologist, hematologist.

Literature

1. Tosi P, Tomassetti S, Merli A, Polli V. Serum free light-chain assay for the detection and monitoring of multiple myeloma and related conditions. Ther Adv Hematol. 2013 Feb; 4 (1): 37-41. doi: 10.1177 / 2040620712466863.

2. Jenner E. Serum free light chains in clinical laboratory diagnostics. Clin Chim Acta. 2014 Jan 1; 427: 15-20. doi: 10.1016 / j.cca.2013.08.018. Epub 2013 Aug 30.

3. Dispenzieri A et al. International Myeloma Working Group.International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009 Feb; 23 (2): 215-24.

4. Snyder MR, Clark R, Bryant SC, Katzmann JA. Quantification of urinary light chains. Clin Chem. 2008 Oct; 54 (10): 1744-6. doi: 10.1373 / clinchem. 2008.107599.

90,000 M-gradient, typing. Serum electrophoresis and immunofixation with a panel of antisera (IgG / A / M / kappa / lambda) with a quantitative assessment of the M-gradient

Method of determination

Electrophoresis and immunofixation with a panel of antisera (to IgG, IgA, IgM, kappa and lambda chains) with densitometry and assessment of the M-component content.

Study material
Blood serum

Synonyms : Electrophoretic separation of serum proteins; Clinical electrophoresis and immunofixation; Paraproteins (m-gradient) in blood serum.

Serum protein electrophoresis; Immunofixation electrophoresis (IFE); Detection of kappa and lambda light chain monoclonal proteins in human serum; Immunofixation for characterizing monoclonal proteins (M8proteins) in human serum.

Brief description of the test “M-gradient, typing. Serum electrophoresis and immunofixation with a panel of antisera (IgG / A / M / kappa / lambda) with a quantitative assessment of the M-gradient “

Detection and typing of monoclonal immunoglobulins.

Immunoglobulins – proteins with antibody activity (the ability to specifically bind certain antigens).

Unlike most serum proteins, which are produced in the liver, immunoglobulins are produced by plasma cells – the descendants of B-lymphocyte precursor stem cells in the bone marrow.According to structural and functional differences, 5 classes of immunoglobulins are distinguished – IgG, IgA, IgM, IgD, IgE and a number of subclasses. Polyclonal increases in immunoglobulins are the normal response to infections.

Monoclonal gammopathies are conditions when an abnormal amount of immunoglobulin is produced by a clone of plasma cells or B-lymphocytes (a population of cells originating from a single precursor B-cell). These conditions can be benign or a manifestation of a disease.Monoclonal gammopathies are detected by the appearance of an abnormal protein band on serum or urine electrophoresis.

Immunoglobulin molecules consist of one or more structural units built according to a single principle – two identical heavy chains and two identical light peptide chains – kappa or lambda. Varieties of heavy chains are the basis for dividing immunoglobulins into classes. Immunoglobulin chains have constant and variable regions, the latter being associated with antigenic specificity.

Immunoglobulin produced by one clone of cells has an identical structure – it represents one class, subclass, characterized by an identical composition of heavy and light chains. Therefore, if an abnormally large amount of monoclonal immunoglobulin is present in the serum, during the electrophoretic separation of serum proteins, it migrates in the form of a compact band, which stands out against the background of the standard distribution pattern of serum protein fractions. When describing the results of electrophoresis of serum proteins, it is also called paraprotein, M-peak, M-component, M-protein or M-gradient.According to its structure, such a monoclonal immunoglobulin can be a polymer, monomer, or a fragment of an immunoglobulin molecule (in the case of fragments, these are more often light chains, less often – heavy ones).

Light chains are capable of passing through a renal filter and can be detected by urine electrophoresis.

The detection of monoclonal paraproteins is based on the use of protein electrophoresis. Sometimes fibrinogen and CRP that migrate to beta or gamma fractions can be mistaken for paraproteins.The immunoglobulin nature of the identified monoclonal component is confirmed by immunofixation of the separated proteins with a specific polyvalent precipitating antiserum directed against immunoglobulins (test No. 4050). When confirming the presence of monoclonal immunoglobulin, densitometry is performed and its quantitative content is determined. Full identification (typing) of the monoclonal component requires a detailed study using electrophoresis and immunofixation with an expanded panel of antisera against IgG, IgA, IgM, kappa and lambda chains (test No. 4051).In the diagnosis and prognosis, the class of the identified paraprotein, its concentration at the time of diagnosis, and the rate of increase in its concentration in dynamics are taken into account. The presence of paraprotein is a marker of a number of hemato-oncological diseases.

What can affect the results of the test “M-gradient, typing. Serum electrophoresis and immunofixation with a panel of antisera (IgG / A / M / kappa / lambda) with a quantitative assessment of the M-gradient “

When examining patients using drugs based on monoclonal antibodies (can be used as antitumor therapy, immunosuppressants, etc.), it should be borne in mind that at peak concentrations after administration, such drugs can sometimes be the reason for the detection of small abnormal bands of an immunoglobulin protein during electrophoresis.

For what purpose is the study “M-gradient, typing. Serum electrophoresis and immunofixation with a panel of antisera (IgG / A / M / kappa / lambda) with a quantitative assessment of the M-gradient “

Multiple myeloma is a classic hematological disease caused by malignant proliferation of plasma cells secreting monoclonal immunoglobulin (paraprotein) or its fragments.Plasma cells more often proliferate diffusely in the bone marrow, the disease leads to osteolytic lesions of the bones, reduction of other bone marrow cells, which leads to anemia, thrombocytopenia, leukopenia, inhibits the development of normal clones of plasma cells. Patients may present with localized symptoms of bone pathology (pain, fractures) or nonspecific symptoms (weight loss, anemia, bleeding, recurrent infections, or kidney failure). In most patients, at the time of diagnosis, the concentration of paraprotein exceeds 25 g / l.In myeloma, serum paraprotein is most often IgG (60%), less often IgA (20%), and about 20% of cases are Bens-Jones myeloma associated with the production of free light chains kappa or lambda (20%), which can be found in urine. Sometimes in myeloma, a biclonal paraprotein, represented by immunoglobulins of different classes or of the same class, but containing light chains of different classes, can be noted. IgD and IgE myeloma is rarely noted. Determination of the concentration of paraprotein is used to monitor the effectiveness of myeloma treatment, such monitoring for myeloma during therapy should be carried out every 3 months.If the content of paraprotein has dropped below the detectable level, it is advisable to re-measure it after 6 or 12 months.

Waldenstrom’s macroglobulinemia is a lymphoma with overproduction of monoclonal IgM. Lymphoplasmacytic tumor cells with a characteristic immunophenotype are diffusely distributed in the lymph nodes, spleen and bone marrow. A high concentration of monoclonal IgM often exceeds 30 g / L and leads to an increase in blood viscosity and a number of clinical manifestations, including confusion, blindness, bleeding tendencies, heart failure, and hypertension.In macroglobulinemia, paraproteinemic polyneuropathy, cold hemolytic anemia, and cryoglobulins are common. In other types of lymphomas and chronic lymphocytic leukemia, paraproteins of the IgM class are observed in 20% of patients, but the concentration of paraprotein is usually lower than 30 g / l.

Heavy chain disease (Franklin’s disease) is accompanied by the synthesis of only the heavy chain IgG-gamma, without the accompanying light chain. This extremely rare disease is manifested by edema of the soft palate and lymphoid infiltration.Also rarely noted is the alpha heavy chain disease, in which chronic diarrhea occurs, malabsorption caused by lymphoid infiltration of the intestinal wall.

Monoclonal paraprotein can be detected in a number of non-neoplastic diseases, in particular, in essential cryoglobulinemia (usually IgM), paraproteinemic chronic polyneuropathy, cold hemolytic anemia, AL-amyloidosis of the kidneys (free lambda chains), and internal organs, diseases of the deposition of light chains.Serum paraprotein is also noted in Castelmann’s disease (IgM / lambda), POEMS syndrome (polyneuropathy with organ megalium) and myxedema lichen (IgG / kappa).

In screening examinations, the frequency of detection of paraproteinemia increases sharply in the population after reaching 50 years of age and reaches 4-10% in persons over 65 years of age. However, the majority of newly diagnosed paraproteinemias in the general population are asymptomatic monoclonal gammopathies of unexplained significance (MGNZ).The concentration of paraprotein at MGNZ is significantly lower than 30 g / l and usually does not exceed 10–15 g / l. In addition, with MGNZ, paraprotein is detected against the background of polyclonal immunoglobulins, i.e., inhibition of the normal synthesis of other immunoglobulins does not occur. The term “MGNZ” indicates cases of paraproteinemia without other signs of oncohematological disease, which require annual monitoring so as not to miss the moment when the process becomes glorified. When paraproteins are detected in patients under 50 years of age, even more frequent repeated examinations are required, since they have a high risk of developing multiple myeloma.If the concentration of M-protein is more than 15 g / L, regardless of age, it is recommended to conduct an extended examination, including electrophoresis of a 24-hour urine sample and immunofixation every 3-6 months, since the risk of malignant transformation is very high. Benign paraproteinemia is distinguished, which is characterized by the preservation of paraprotein without progression to multiple myeloma or other disease within 5 years of follow-up. In transient paraproteinemia, the paraprotein concentration is usually below 3 g / l.

Literature

1. Andreeva N.E., Balakireva T.V. Paraproteinemic hemoblastosis // Guide to hematology / ed. A.I. Vorobyov. 3rd ed., M., 2003. T. 2, p. 151-184.

2. Berenson J.R. Monoclonal gammopathy of undetermined significance: a consensus statement. Br. J. Haematol. 2010,150 (1): 28-38.

90,000 M-gradient, immunotyping with a panel of antisera (IgG / A / M / kappa / lambda) with a quantitative assessment of the M-gradient

Determination of quantitative and qualitative changes in the main fractions of blood protein used for diagnostics and control of treatment of acute and chronic inflammations of infectious and non-infectious genesis, as well as cancer (monoclonal gammopathies) and some other diseases.

With the proliferation of a clone of plasma cells, the synthesis of immunoglobulin is increased, represented by one class, subclass and isotype, which includes heavy and light protein chains of the same type. During the electrophoretic separation of blood serum proteins, this immunoglobulin migrates in the form of a compact band, which is determined against the background of other protein fractions. This immunoglobulin is called monoclonal immunoglobulin or paraprotein. In serum protein electrophoresis, it is called the M-gradient.Paraprotein is a tumor marker in a number of hemato-oncological diseases.

Multiple myeloma is a classic hematological disease caused by the proliferation of plasma cells secreting monoclonal immunoglobulin (paraprotein) or its fragments. In most cases, at the time of diagnosis, the concentration of paraprotein exceeds 25 g / l.

In myeloma, serum paraprotein is most often represented by IgG (60%), less often IgA (20%).The remaining about 20% of cases are Bens-Jones myeloma associated with the production of free light chains of kappa or lambda (20%). In 2–4% of myeloma cases, there may be a biclonal paraprotein, represented by immunoglobulins of different classes or one class, but containing light chains of different classes. Changes in paraprotein concentration serve as an indicator of the effectiveness of myeloma treatment. Monitoring the concentration of PP in myeloma during therapy should be carried out every 3 months. If the PP content has dropped below the detectable value, it is advisable to re-measure it after 6 or 12 months.

Waldenstrom’s macroglobulinemia is a lymphoma with overproduction of monoclonal IgM. Lymphoplasmacytic tumor cells with a characteristic immunophenotype are diffusely distributed in the lymph nodes, spleen and bone marrow. A high concentration of monoclonal IgM often exceeds 30 g / L and leads to an increase in blood viscosity and a number of clinical manifestations, including confusion, blindness, bleeding tendencies, heart failure, and hypertension.In macroglobulinemia, paraproteinemic polyneuropathy, cold hemolytic anemia, and cryoglobulins are common. In other types of lymphomas and chronic lymphocytic leukemia, paraproteins of the IgM class are observed in 20% of patients, but the concentration of paraprotein is usually lower than 30 g / l.

Heavy chain disease (Franklin disease) is accompanied by the synthesis of only the heavy chain IgG-gamma, without the accompanying light chain. This extremely rare disease is manifested by edema of the soft palate and lymphoid infiltration.Also rarely noted is the alpha heavy chain disease, in which chronic diarrhea occurs, malabsorption caused by lymphoid infiltration of the intestinal wall.

In screening examinations, the frequency of detection of paraproteinemia increases sharply in the population after reaching 50 years of age and reaches 4-10% in persons over 65 years of age. However, the majority of newly diagnosed paraproteinemias in the general population are asymptomatic monoclonal gammopathies of unexplained significance (MGNZ).The concentration of paraprotein at MGNZ is significantly lower than 30 g / l and usually does not exceed 10–15 g / l. In addition, with MGNZ, paraprotein is detected against the background of polyclonal immunoglobulins, i.e., inhibition of the normal synthesis of other immunoglobulins does not occur. The term “MGNZ” indicates cases of paraproteinemia without other signs of oncohematological disease, which require annual monitoring in order not to miss the moment of malignancy of the process. When paraproteins are detected in patients under 50 years of age, even more frequent repeated examinations are required, since they have a high risk of developing multiple myeloma.If the concentration of M-protein is more than 15 g / L, regardless of age, it is recommended to conduct an extended examination, including electrophoresis of a 24-hour urine sample and immunofixation every 3-6 months, since the risk of malignant transformation is very high. Benign paraproteinemia is distinguished, which is characterized by the preservation of paraprotein without progression to multiple myeloma or other disease within 5 years of follow-up. In transient paraproteinemia, the paraprotein concentration is usually below 3 g / l.

Indications for the appointment of the study:

1. Typing paraprotein.

2. Differential diagnosis of monoclonal gammopathies.

3. Evaluation of the effectiveness of the therapy for myeloma and other gammopathies.

Interpretation of results:

Positive:

• Monoclonal gammopathies of unexplained significance, benign paraproteinemia;
• Multiple myeloma;
• Waldenstrom’s macroglobulinemia;
• Lymphoma and chronic lymphocytic leukemia;
• Heavy chain disease;
• Paraproteinemic polyneuropathy;
• AL amyloidosis or light chain deposition disease;

Negative:

• Normal M-gradient is not detected in serum.

LOINC 74868-1 – IgG.kappa / IgG.lambda [Mass Ratio] in Serum or Plasma

Term Description

Measuring both the IgGκ and IgGλ, calculating the IgGκ / IgGλ ratio, and then comparing with normal subjects levels may provide a more sensitive indication of clonality. Usage of the IgGκ / IgGλ ratio may also compensate for any fluctuations in plasma volume and adjust for half-life variations. This term was based on, but not limited in use to, the Hevylite Human IgG Kappa and Lambda assays.
Source: Regenstrief LOINC

Fully-Specified Name

Component

IgG.kappa / IgG.lambda

Property

MRto

Time

Pt

System

Ser / Plas

Scale

Qn

Method

Additional Names

Short Name

IgG Kappa / G lambda SerPl

Display Name

IgG.kappa / IgG.lambda [Mass ratio]

Consumer Name
Alpha

IgG.kappa / IgG.lambda, Blood

Basic Attributes

Class

CHEM

Type

Laboratory

First Released

Version 2.48

Last Updated

Version 2.48

Order vs. Observation

Both

Formula (Readable)

IgG kappa (unit g / L) is divided by IgG lambda (unit: g / L) to calculate the IgG kappa / lambda-ratio.

Member of these Panels

Language Variants

Get Info

zh-CNChinese (China)

IgG.kappa / IgG.lambda: 质量 比率: 时间 点: 血清 / 血浆: 定量 型:

nl-NLDutch (Netherlands)

IgG.kappa / IgG.lambda: massaverhouding: moment: serum of plasma: kwantitatief:

fr-FRFrench (France)

Immunoglobuline G kappa / immunoglobuline G lambda: Masse ratio: Ponctuel: Sérum / Plasma: Numérique:

it-ITItalian (Italy)

IgG.kappa / IgG.lambda: MRto: Pt: Siero / Plasma: Qn:

pt-BR Portuguese (Brazil)

IgG.kappa / IgG.lambda: : Pt: Soro / Plas: Qn:

ru-RURussian (Russian Federation)

IgG.kappa / IgG. lambda: Mass: TchkVrm: Sew / Plas: Quantity:

es-ESSpanish (Spain)

IgG kappa / IgG lambda: Relacion de Masa: Punto temporal: Suero o Plasma: Qn:

tr-TRTurkish (Turkey)

IgG.kappa / IgG.lambda: KütlOr: Zmlı: Ser / Plaz: Kant:

Related Names

• Chemistry
• G lambda
• heavy chain
• IgG Kappa
• IgG lamba
• Immune globulin G
• Immunoglobulin G
• Mass concentration ratio
• Mass ratio
• MCRto
• Pl
• Plasma
• Plsm
• Point in time
• QNT
• Quan
• Quant
• Quantitative
• Random
• SerP
• SerPl
• SerPlas
• Serum
• Serum or plasma
• SR

Example Units

LOINC FHIR

^® API Example – CodeSystem Request Get Info

https: // fhir.