Case 2 Extent Of Evaluation
A 78-year-old woman was evaluated for chronic progressive right-shoulder pain, limiting her joint mobility. She was a farmer and engaged in heavy lifting. A shoulder x-ray showed advanced degenerative arthritis and no lytic lesion. Laboratory tests revealed a normal complete blood count, calcium, and creatinine, but total protein was elevated at 8.7 g/dL . Further testing showed IgG M-protein of 1.7 g/dL, FLC of 8.61 mg/dL , FLC of 0.63 mg/dL , and / ratio of 13.67 . Because the M-protein and FLC were substantially elevated, additional work-up was performed. A bone marrow biopsy showed 6% -restricted plasma cells. A low-dose whole-body computed tomography scan did not show lytic lesions. She was diagnosed with MGUS.
Components Of Serum Protein Electrophoresis
The pattern of serum protein electrophoresis results depends on the fractions of two major types of protein: albumin and globulins. Albumin, the major protein component of serum, is produced by the liver under normal physiologic conditions. Globulins comprise a much smaller fraction of the total serum protein content. The subsets of these proteins and their relative quantity are the primary focus of the interpretation of serum protein electrophoresis.1,3
Albumin, the largest peak, lies closest to the positive electrode. The next five components are labeled alpha1, alpha2, beta1, beta2, and gamma. The peaks for these components lie toward the negative electrode, with the gamma peak being closest to that electrode. Figure 1 shows a typical normal pattern for the distribution of proteins as determined by serum protein electrophoresis.
Typical normal pattern for serum protein electrophoresis.
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.
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What Are The Minimum Tests Necessary During The Initial Evaluation Of Monoclonal Gammopathy
Once an M-protein is detected, the extent of further evaluation to rule out LPM depends on the pretest probability of the latter and whether or not an alternative explanation for the signs or symptoms that prompted the screening was found. We generally order the following tests, if not yet done, at the time of hematology consult: complete blood count, serum calcium, creatinine, FLC, immunofixation, and 24-h urine protein electrophoresis.
I Got Bloodwork Done And This Was The Result: Immunofixation Serum Monoclonal Protein Identified As Faint Igm Kappa What Does This Mean Thank You
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Conditions Related To M Proteins
Most cases of multiple myeloma start out as a usually harmless condition called monoclonal gammopathy of undetermined significance . One sign of MGUS is the presence of M proteins in the blood. Yet, with MGUS, the level of M proteins in the body is low and doesnt cause damage.
In the United States, MGUS affects about 3 percent of people above age 50. About 1 percent of these people go on to develop multiple myeloma or a similar blood cancer. So, the vast majority of people with MGUS dont go on to develop any disease.
Whether or not MGUS will progress into a more serious condition is difficult to determine. Some people are more at risk than others.
The more M proteins in your blood and the longer youve had MGUS, the higher your risk of developing one or more related conditions. Besides multiple myeloma, presence of M proteins in your blood may result in:
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How Do We Interpret Light
Because serum FLCs are cleared by the kidneys, their concentrations rise as the glomerular filtration rate falls. Generally, both polyclonal and FLC levels are elevated and produce an FLC ratio that is within the normal range . In patients with chronic kidney disease, studies show that FLC levels tend to be higher, resulting in a revised renal reference range for FLC ratio of 0.37 to 3.1. Thus, to consider that an increase in the serum FLCs is a result of clonal plasma cell disorder, the serum FLC ratio must be < 0.37 or > 3.1 in patients with renal impairment. If the FLC ratio falls within the renal range but the index of suspicion for an underlying monoclonal gammopathy remains high, we add urine protein electrophoresis and urine immunofixation for confirmation.
Quantitative Immunoglobulin Testing Or Qig
Quantitative immunoglobulins testing is often done as part of early screening for MM. It is usually done if the total protein level is elevated. QIg measures total immunoglobulin protein in the blood, both normal and abnormal. If QIg detects an increase an immunoglobulin, you must undergo further testing with IFE. The goal is to see if the increase is from abnormal protein.
Some doctors also use QIg to follow patients with IgA myeloma because it’s difficult to assess IgA with SPEP.
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What Are The Other Complications That Can Result From Mgus Besides Progression To Lpm
MGUS has been reported to be associated with > 130 different diseases in addition to progression to malignancy. Because of the high prevalence of MGUS in the general population, most of these reported associations are likely coincidental. However, some associations have been verified and are now considered to be causally related to MGUS. These include monoclonal gammopathyassociated peripheral neuropathy, monoclonal immunoglobulin deposition disease, and monoclonal gammopathyassociated proliferative glomerulonephritis., In addition, some studies show that patients with MGUS may be at a higher risk of fractures and deep vein thrombosis. Awareness of these known disease associations and exclusion of other causes of these syndromes are important for accurate diagnosis .
Structure Of Monoclonal Antibodies
Each antibody is made up of four parts. There are two long chains on the inside, and two shorter chains on the outside. In the image, you can see a plasma cell with an antibody and many other tiny antibodies in the background.
The light chains, or the shorter, outside lines in the “blue Y” in the picture, are also called a Bence Jones proteins, or free immunoglobulin light chains. In this case, it is just a small piece of the huge antibody. When the M protein is a light chain, it is small enough, in fact, that it may pass through the kidneys and enter into the urine. So, if only a blood test is done the light chains can be missed since they have entered the urine.
On the other hand, if the M protein is a whole immunoglobulinthe whole big Y in the picturethen it can be detected in the blood since it is too large to pass to the urine. And because these large proteins are retained, excessive buildup of such M protein in the kidney may cause kidney disease.
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Where It Comes From
In multiple myeloma, the M protein comes from a great excess of plasma cells. Ordinarily, plasma cells will produce a wide range of antibodies. In the normal or healthy state, the population of plasma cells capable of producing a wide array of different antibodiesso-called polyclonal antibodies, or polyclonal immunoglobulins. When plasma cells become cancerous, often there is a single, very bad cell that has given rise to many identical minions. All of the minions are clones of the same cell, and they make only the same monoclonal proteins. Since there are a lot of plasma cells, multiplying abnormally, they make a lot of this monoclonal protein. The abundance, or spike, in the volume of just one protein, can be detected in lab tests.
Myeloma: Complications And Management
Myeloma causes a wide spectrum of complications, including significant bone destruction in the form of osteoporosis and lytic lesions. Often these lesions are in the spine, ribs, clavicles , pelvis, or in a long bone such as the humerus or femur . Small fractures or even major fractures may occur, causing pain, loss of height, more difficulty breathing, or difficulty walking. Although specific therapy for myeloma may slow this process down, specific agents have also been developed which are intended to slow down the destructive process, heal the bones, and even prevent fractures. Supportive medications for improving bone metabolism include supplemental calcium and vitamin D.
Bisphosphonates: Pamidronate and zoledronate are drugs which are approved for the treatment of the bone disease associated with myeloma. They have been shown in Phase III randomized trials to reduce the risk of fracture, such that for every 10 patients treated, 1 fracture is prevented.
These agents can also be used very effectively to treat hypercalcemia.
Long-term utilization of these drugs does have moderate risk. Kidney function must be monitored constantly and there is also a risk of osteonecrosis of the jaw, a condition in which the bone supporting the teeth becomes eroded. Symptoms include pain, swelling, loose teeth, exposed bone, drainage, and infection. This occurs in somewhere between 1 % and 5% of people who have been on the drugs for many years.
Therapy for the Spine
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What Are Monoclonal Gammopathies
Monoclonal gammopathies are conditions in which abnormal proteins are found in the blood. These proteins grow from a small number of plasma cells in the bone marrow. Plasma cells are a type of white blood cell. Their main job is to fight off infection.
The most common condition linked with these abnormal proteins is monoclonal gammopathy of undetermined significance . It is not cancer. But people with MGUS have a greater risk of getting serious diseases of the bone marrow and blood.
Serum Heavy/light Chain Assay Or Hevylite Test
The Hevylite® assay is a blood test that measures the intact immunoglobulins. It measures:
- the intact heavy and light chain protein made by the myeloma cells
- the heavy- and light-chain-bound immunoglobulin protein made by normal plasma cells
If your myeloma protein is, for example, IgA kappa, the intact immunoglobulin that is its normal counterpart will be IgA lambda.
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Case 5 Screening For Monoclonal Gammopathy In Asymptomatic Patients
A 61-year-old man was referred to hematology because of a strong family history of MM. His mother was diagnosed with active MM at the age of 70 and died 8 years later, and his sister was found to have the same diagnosis just 3 months before the visit. Neither his mother nor sister had risk factors. Prior to hematology referral, he had an SPEP and FLC performed, and no M-protein was detected.
Current practice guidelines do not recommend routine screening for MGUS in the general population because of the lack of proven benefit and absence of curative or preventive therapy. Although this rationale appears to be sound, the counterargument also has merits. It is notable that only 20% of prevalent MGUS cases are clinically recognized and fewer than 10% of MM, AL amyloidosis, or WM patients have a prior clinical diagnosis of MGUS.,, Therefore, approximately 80% of prevalent MGUS cases are not clinically recognized. Although this group of individuals should be at similar risk of progression to LPM, we neither seek them out nor follow their clinical course. A randomized controlled trial of MGUS screening is currently ongoing in Iceland to determine whether screening of the general population will be of clinical benefit,.
Serum Free Light Chains
This blood test can measure the light chain levels in the blood and is done when looking for myeloma or light chain amyloidosis.
This is most helpful in the rare cases of myeloma in which no M protein is found by SPEP. Since the SPEP measures the levels of intact antibodies, it cannot measure the amount of light chains only.
This test also calculates thelight chain ratio which is used to see if there is one type of light chain more than the other. There are 2 kinds of light chains: kappa and lambda. Normally, they are present in equal amounts in the blood, giving a ratio of 1 to 1. If there is more of one type of light chain than the other, the ratio will be different, which can be a sign of myeloma.
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Other References To M Protein
In the context of myeloma, M protein refers to the abnormal production of your body’s antibody-producing plasma cells. Unfortunately, “M protein” may be laden with different meanings in medicine, depending on the topic or illness that is being discussed.
The M protein may also be described using terms as follow:
- Monoclonal protein
- The M spike
- The M-component
In this article, we are talking mostly about the M protein that relates to cancerand, more specifically, to certain types of blood cancer and precancerous conditions of the blood and bone marrow. However, some other notable M proteins occur in medicine, especially in regard to infectious pathogens as shown here:
- M protein may stand for viral matrix protein as in the M1 protein of the influenza virus.
- M protein may be used in referring to a specific bacterium, streptococcus pyogenes.
- M protein, or actually “protein M,” is relevant to the bacterium mycoplasma genitalia.
When Do We Test For Monoclonal Gammopathy
In general, we test for the presence of monoclonal gammopathy in patients who have clinical symptoms and signs concerning for the presence of MM, AL amyloidosis, or WM. However, with the exception of diffuse lytic bone lesions, macroglossia, infiltrative cardiomyopathy, and engorgement of retinal veins, most presenting symptoms and signs of LPMs are nonspecific. As a result, in most instances when testing for M-proteins is performed, an alternative explanation for the clinical presentation is typically found, and patients with positive tests are labeled as having an incidental diagnosis of MGUS. Because MGUS is common and LPMs are rare ,, the chance of identifying LPM in day-to-day practice is very low. In a study of 7090 patients without a history of LPM who had SPEP performed for various indications, 3% were found to have MGUS, and only 1% were diagnosed with LPM. The majority of tests were performed by nonhematologists. It is estimated that, on average, a hematologist-oncologist in the United States sees 2 new MM cases annually and 1 new case of AL and WM every 10 years. These numbers are expected to be far less in general medical practice. We also look for monoclonal gammopathy if a patient has a nonmalignant disease known to be a cause of, or associated with, monoclonal gammopathy, especially if the treatment requires control or eradication of the plasma cell clone .
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Blood And Marrow Conditions That Have An Increased M Protein
Conditions that may result in an elevated level of M proteins on a urine test include:
- Myeloma – A urine test will be positive for M protein in 50 to 80% of people with myeloma.
- MGUS – Monoclonal gammopathy of undetermined significance may have an elevated level.
- Waldenstrom’s macroglobulinemia – This cancer, which involves cells which are precursors of plasma cells, may have an elevated M protein level.
In some cases, cells causing the M-protein are malignant, and they may invade the bone, lymph nodes, liver, spleen, or other organs. This is the case in multiple myeloma, solitary plasmacytoma, and Waldenström macroglobulinemia.
In other cases, the M-protein is produced by a small, limited, pre-malignant clone of cells that has expanded, and this causes no symptoms. This is the case in monoclonal gammopathy of undetermined significance MGUS.
Complications Of M Proteins
A lot of the time, M proteins don’t cause any problems. You may not realize that you have them in your body. But as the abnormal or cancerous plasma cells spread, they may crowd out healthy blood cells. This can lead to complications, such as:
Anemia. Symptoms of anemia like shortness of breath is one of the more common presentations cause the BM is so crowded with abnormal plasma cells that red blood cells are crowded out. So are platelets that are formed in the bone marrow, so bruising is common.
Infections. When plasma cells make more M proteins, there are fewer functional antibodies to fight infections.
Bone loss or damage. Bones are weakened by dysfunctional plasma cells, both cause of decreased bone density and because of actual collections of cancer cells in the bone. You can suffer from bone fractures from minimal activity . This is called a pathologic fracture.
Kidney problems. Your kidneys have to work overtime to filter out the M proteins and calcium in your blood. Your kidneys might not work as well as they should, or you might even have kidney failure.
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