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n CNE Article
Monoclonal Gammopathy of Undetermined Significance—Making It Understandable to Patients Pamela Rule, APRN, and Jeannine M. Brant, PhD, APRN, AOCN®
© iStockphoto.com/Thinkstock
Oncology nurses working in ambulatory care often encounter patients with nonmalignant hematologic disorders because the specialties of hematology and oncology are closely entwined. A variety of nonmalignant hematologic disorders can evolve into blood malignancies; therefore, close surveillance of nonmalignant hematologic disorders in an oncology/hematology clinic is important for early detection of malignancy. Monoclonal gammopathy of undetermined significance (MGUS) is one nonmalignant, hematologic disorder that is usually aproblematic; however, it can evolve into a blood malignancy such as multiple myeloma or be associated with other chronic conditions. This article provides an overview of MGUS with a focus on implications for the oncology nurse and patient education.
Pamela Rule, APRN, is an advanced practice nurse in the Department of Internal Medicine at Cornell Scott Hill Health Center in New Haven, CT, and Jeannine M. Brant, PhD, APRN, AOCN®, is an oncology clinical nurse specialist and nurse scientist at Billings Clinic in Montana. The authors take full responsibility for the content of the article. The authors did not receive honoraria for this work. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or editorial staff. Rule can be reached at [email protected], with copy to editor at [email protected]. (Submitted January 2013. Revision submitted May 2013. Accepted for publication May 12, 2013.) Digital Object Identifier:10.1188/13.CJON.614-619
M
onoclonal gammopathy of undetermined significance (MGUS) was first described by Jan Waldenström in 1960 after abnormal narrow hypergammaglobulinemia bands were noted on serum protein electrophoresis in the blood of healthy individuals (Kyle, Buadi, & Rajkumar, 2011). Robert Kyle used the term “monoclonal gammopathy of undetermined significance” in 1978 after detecting a correlation between MGUS and the development of other disorders such as multiple myeloma, Waldenström’s macroglobulinemia, amyloidisis, and chronic lymphocytic leukemia (Korde, Kristinsson, & Landgren, 2011). Therefore, MGUS is defined as the presence of an abnormal protein (monoclonal protein or M protein) in the blood or urine in the absence of end-organ damage. In 2010, the International Myeloma Working Group defined MGUS as a serum monoclonal protein under 3 g/dl with fewer than 10% clonal bone marrow plasma cells and an absence of end-organ damage, which can be attributed to the plasma cell proliferative disorder, examples include hypercalcemia, renal insufficiency, anemia, and bone lesions (Kyle et al., 2010).
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Prevalence and Risk A systematic review of 14 studies estimated that the prevalence of MGUS was about 3% in people older than 50 (Wadhera & Rajkumar, 2010). The prevalence increases with age and is estimated to be 7% in Caucasians older than 80. Additional risks include race (6% in Caucasians compared to 8% in African Americans) (Greenberg, Vachon, & Rajkumar, 2012), gender (4% of Caucasian men older than 50 years compared to 3% of Caucasian women), family history (Greenberg, Rajkumar, & Vachon, 2012), and immunosuppression. For immunosuppressed patients with HIV, a substantial risk exists ranging from 9%–45% (Wadhera & Rajkumar, 2010). Infection also has been associated with the development of MGUS. Sixty-eight percent of patients with MGUS also have had Helicobacter pylori infections, and the eradication of the infection led to resolution of monoclonal gammopathy in 11 of 39 patients (Kyle et al., 2011). Environmental exposure to toxins such as asbestos, pesticides, radiation, petroleum, aromatic hydrocarbons, fertilizers, and paints poses additional risk. However,
December 2013 • Volume 17, Number 6 • Clinical Journal of Oncology Nursing
TABLE 1. Risk Stratification Model for Monoclonal Gammopathy of Undetermined Significance Risk for progression
Definition
Low risk
Level of M protein < 1.5 g/dl; IgG subtype; light chain ratio is normal
Low-intermediate risk
One of the low criteria being abnormal
Intermediate-high risk
Any two of the low-risk criteria being abnormal
High risk
All three factors being abnormal.
IG—immunoglobulin Note. Based on information from Kyle et al., 2011.
although some populations may be at increased risk for MGUS, no evidence exists that they have a higher progression rate to multiple myeloma (Wadhera & Rajkumar, 2010).
Pathophysiology An understanding of the lymphocytic immune system, the body’s nonspecific defense mechanism, is essential to understanding the pathophysiology of MGUS. The lymphocytic immune system is comprised of the cell-mediated system of t cells and the humoral immune system of B cells. T cells are highly specialized cells that circulate in the blood and lymphatic system to fight infection and other foreign invaders. B cells produce plasma cells and antibodies in response to previous exposure to foreign antigens. Plasma cells secrete antibodies (e.g., IgM, IgA, IgG) that recognize the foreign antigen. MGUS is a condition that occurs when these plasma cells produce an abnormal type of antibody called a monoclonal protein or M protein. Although normal white blood cells produce antibodies to fight infection, M proteins cannot fight infections and can accumulate in blood and urine. MGUS is believed to be a result of an abnormal response to antigenic formation. This abnormal response leads to cytogenic abnormalities such as hyperdiploidy (the most common) or genetic translocations (Kyle et al., 2010). Another finding is a chromosome 13 deletion that appears in MGUS as well as in multiple myeloma. However, whether that increases the rate of progression to multiple myeloma is not known (Greenberg, Rajkumar, et al., 2012; Klincová et al., 2011). Three main clinical types of MGUS exist: non-IgM (IgA or IgG) MGUS, IgM MGUS, and light chain MGUS. About 15%–20% of MGUS tumors are the IgM subtype and are phenotypically lymphoid or lymphoidplasmacytoid. These tumors most commonly progress to lymphoprolifertive disorders such as Waldenstron’s macroglobulinemia and lymphoma. The non-IgM MGUS tumors have a plasma cell phenotype and are most likely to progress to plasma cell disorders such as multiple myeloma (Kyle et al., 2011; Landgren, 2010). MGUS can be stratified into risk categories to suggest progression, but reliable biologic predictors are lacking. The main risk factor for progression to multiple myeloma is the size and amount of serum M protein and presence of an abnormal
serum-free light chain ratio (Wadhera & Rajkumar, 2010). For example, at 10 years of age, people with MGUS and an initial M protein of 0.5 g/dl had a 6% progression rate, and people with an initial M protein of 2.5 g/dl had a 24% rate (Kyle et al., 2011). A risk stratification model provides a template for risk (Kyle et al., 2011) (see Table 1). An abnormal serum-free light chain ratio, non-IgG MGUS, and a high serum M protein level (> 1.5) are the three risks identified that may predict progression to multiple myeloma. However, an abnormal light chain ratio increases the risk regardless of the type of M protein involved (Kyle et al., 2011; Wadhera & Rajkumar, 2010).
Diagnosis MGUS may remain subclinical for years; however, each year about 1% of patients with MGUS progress to multiple myeloma or another proliferative disorder. When this occurs, myeloma cells accumulate in the bone marrow and crowd out normal cells, which slow the blood marrow production of normal white blood cells, platelets, and red blood cells. A diagnosis is confirmed with a serum monoclonal protein (> 3 g/dl IgG or IgA), bone marrow plasma cells (> 10%), and the presence of end-organ disease such as skeletal lesions or renal compromise. Smoldering multiple myeloma also may occur, differentiated from myeloma by the absence of end-organ disease (Landgren, 2010). MGUS often is detected as an incidental finding on blood work during a routine physical examination. A high serum total protein can prompt an initial workup for MGUS. Initially, total serum protein measurement, total urine protein measurement, and complete blood count should be evaluated. If abnormal, a second level evaluation including a chemistry panel with calcium, serum and urine protein electrophoresis, and beta-2 microglobulin should be ordered. Evaluation of both serum and urine is important because the M protein in some patients may be located in only one fluid. If the second-level laboratory testing reveals abnormalities, then additional laboratory testing including serum immunofixation (IFE), urine immunofixation, quantitative immunoglobulin, and serumfree light chain should follow. The IFE must be performed to identify the M protein through serum protein electrophoresis. IFE is more sensitive than screening electrophoresis. If this additional testing reveals at least one abnormal result, then MGUS requires more diligent monitoring. A list of laboratory analyses for diagnosis and surveillance are included in Table 2 (Korde et al., 2011). Once an M protein spike is discovered, evaluation is needed to rule out diseases associated with increased M proteins. A diagnosis of MGUS is assigned in the absence of other pathology;
Implications for Practice u
Check for progression of disease by examining for physical changes such as pain or constipation.
u
Ask friends and caregivers for signs that the patient is resting or sleeping more than usual.
u
Be aware of increased bruising on skin or after blood draws.
Clinical Journal of Oncology Nursing • Volume 17, Number 6 • Monoclonal Gammopathy of Undetermined Significance
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TABLE 2. Laboratory Tests for Monoclonal Gammopathy of Undetermined Significance (MGUS) Laboratory Test Beta-2 microglobulin
Sub Test –
Normal Value 1.1–2.4 mg/L
Implications Found on the surface of all cells; increased in patients with malignancy and other immunosuppressive diseases.
ease suggests multiple myeloma. See Figure 1 for early screening for monoclonal gammopathies.
Treatment and Follow-Up
People with MGUS do not require treatment, but they do require close monitoring. The risk Bone marrow Plasma cells Less than 10% Healthy people can have up to 3% biopsy plasma cells in the bone marrow, 3%– for progression is ever present 10% is indicative of MGUS, greater and does not decrease over the than 10% is diagnostic of myeloma. course of the disease; however, death from other comorbidities Calcium – 9–10.5 mg/dl Hypercalcemia can indicate bone reis more common than death from sorption and onset of myeloma. MGUS. Complete blood White blood cells 5,000–10,000 If MGUS progresses, abnormal proteins In most cases, MGUS is asympcount crowd out normal cells in the bone tomatic, and individuals with Red blood cells 12–18 marrow, resulting in neutropenia, aneMGUS have normal blood counts, mia, and thrombocytopenia. Platelet cells 150,000–400,000 calcium levels, kidney function, and bone and organ function. Quantitative IgA 68–378 mg/dl Monitors specific levels of each imWhen MGUS is low risk, M proimmunoglobulin munoglobulin, a systemic marker of IgG 768–1632 mg/dl MGUS, also can differentiate between teins should be monitored at MGUS and myeloma; increased risk six months and then every one IgM 60–263 mg/dl of progression to myeloma with IgM or two years if no changes are spike. IgE 2–549 mg/dl detected. Most people who are symptomatic seek a provider IgD Less than 1–11.2 mg/dl with complaints of bone pain, Serum-free light Kappa 3.3–19.4 mg/L M proteins are composed of heavy fatigue, or recurrent infection. chain chain immunoglobulins and light Symptoms appear because of Lambda 5.71–26.3 mg/L chain kappa and lambda components. M protein (plasma cell) overJoined they are not a problem, but too production and the subsequent Kappa/lambda many free light chains may contribute 0.26–1.65 mg/L ratio crowding of bone marrow cells, to renal damage. resulting in a decreased proSerum or urine – Negative for Identifies the type of immunoglobulin duction of normal blood cells. immunofixation immunoproteins proteins present; 24-hour urine collecSome complications related to electropheresis tion needs to be refrigerated. the increase in proteins include Serum protein – Negative for Measures the total amount of proteins anemia, infection, neuropathies, electrophoresis abnormal protein and the amount of abnormal proteins osteopenia, and thromboemboin the blood; elevated in MGUS. lism. MGUS also puts the person at higher risk for bone loss and Total serum protein Protein 6.4–8.3 g/dl Total protein includes albumin and globulin; elevated globulin occurs skeletal problems, particularly Albumin 3.5–5 g/dl with MGUS. vertebral and hip fractures (Berenson et al., 2010). After the Globulin 2.3–3.4 g/dl initial skeletal survey, patients Total urine protein – Negative for Measures the total amount of proteins should be monitored with peabnormal protein and the amount of abnormal proteins riodic bone density scanning in the urine. every year if osteopenia or osteoNote. Based on information from Mayo Clinic, 2013. porosis is present and every two years if normal. If indicated by the evaluation, oral or IV bisphosphonates should be used as part of the follow-up treatment. If therefore, the diagnosis of MGUS is by exclusion (Wadhera & IV zoledronic acid is used, it can be given yearly or every six Rajkumar, 2010). M protein spikes greater than 1.5 g/dl should months (Minter, Simpson, Weiss, & Landgren, 2011; Wong & be investigated further via a bone marrow biopsy. Abnormal Wiffen, 2002). light chain ratios may indicate light chain diseases such as light chain myeloma, systemic amyloidosis, or systemic light chain diseases. Light chain diseases affect the kidneys by occluding renal tubules; therefore, patients with light chain disease may The population of Americans aged 65 years and older is require a renal biopsy. A skeletal series is recommended if the higher than at any other time in the United States’ history and individual has any complaints of bone pain. Positive lytic dis-
Implications for Nursing
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December 2013 • Volume 17, Number 6 • Clinical Journal of Oncology Nursing
Clinical Journal of Oncology Nursing • Volume 17, Number 6 • Monoclonal Gammopathy of Undetermined Significance
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PLUS
b
Note. From Early Screening of Monoclonal Gammopathy of Undetermined Significance by the International Myeloma Foundation, 2010. Retrieved from http://myeloma.org/pdfs/flowchartENG-early-screening_o1 -type.pdf. Copyright 2010 by the International Myeloma Foundation. Reprinted with permission.
FIGURE 1. Early Screening of Monoclonal Gammopathy of Undetermined Significance
b
Or the patient may be asymptomatic and discovered to have a monoclonal gammopathy when abnormal test results are noted at the time of a routine checkup. Chemical panel = glucose, sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, calcium, albumin from serum protein electrophoresis, and liver function tests c Congo red stain of biopsy material d http://myeloma.org/pdfs/flowchart_ENG_monitoring_n1.pdf
a
No abnormalities
At least one abnormal result
Complementary tests
is expected to increase more rapidly over the next decade as more baby boomers start to turn 65 years of age. With this demographic shift comes the increased likelihood of individuals living with increased comorbidities, one of which may be MGUS. Although patients with MGUS need to know that they have certain risk factors predisposing them to a malignancy, they also need to be reassured that they may or may not be in danger of progression. In addition, with available risk identification, clinicians can attempt to identify which patients require closer follow-up and which ones may remain asymptomatic. Fortunately, MGUS is an uncommon hematologic disorder; however, because of its obscurity, education is important. Information conquers uncertainty, which plays an important role in the anxiety surrounding the diagnosis. Initially, patients should receive basic information regarding diagnosis, treatment options, and side effects (see Figure 2). The timing of the information given and the level of detail and content varies depending on the patient’s readiness to learn and preferred
Definition Monoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of an abnormal protein (monoclonal protein or M protein) in the blood. M protein is produced by plasma cells, a type of white blood cell. MGUS usually causes no problems. In some people, it can be associated with another disease or can progress over years to other disorders. Who will progress is difficult to predict. Only 1% of the population progresses each year. M proteins are monitored usually once a year to check for progression. If no increase in the protein occurs, MGUS does not require treatment. Risk Factors Genetic changes appear to play a role in MGUS, as do environmental triggers, such as being exposed to certain pesticides or to radiation from an atomic bomb. Other factors that increase your risk of MGUS include: • Your age: The risk of MGUS increases as you get older. About 1% of people aged 25 years and older and 5% of people aged 70 years and older have M protein in their blood. The highest incidence is among adults aged 80 years and older. • Your race: African Americans are more likely to experience this condition than Caucasians. • Your gender: MGUS is more common in men than in women. • A family history: If other people in your family have MGUS, your risk of developing the disorder may be higher. • Your weight: People with a body mass index greater than 30 (a level considered obese) have a greater risk of developing MGUS. Your risk of developing a more serious condition increases the longer you have had MGUS.
learning style. Patients and families should have knowledge of the disease and anticipate the next steps in the surveillance and treatment of the disease. Developing rapport and a bond enables individualized teaching to the patient’s level of understanding or the level of information the patient desires. The focus of the journey should be directed toward patients living their lives, not on fear of disease progression. Fortunately, most of these patients live a normal life span without progressing to a more serious disease.
Conclusion MGUS is an uncommon hematologic disorder, but often is a complex and easily misunderstood disease. Patients are initially anxious about a new diagnosis of MGUS, and the nurse plays a key role in educating the patient and family in an understandable manner, alleviating fear, and serving as a guide as patients and families journey through this obscure illness.
Complications A small percentage of people with MGUS develop a more serious condition, such as multiple myeloma or other cancers or blood disorders. Your doctor will take into account several factors when determining your risk, including: • The amount of M protein in your blood • The type of M protein • The amount of plasma cells in your bone marrow • The presence of protein in your urine Other complications associated with MGUS include fractures and blood clots. Preparing for Your Appointment MGUS is detected and monitored with blood tests. The blood tests require no preparation on your part. If you are found to have MGUS, you may be referred to a hematologist, a doctor who specializes in blood disorders. Prior to your appointment to help you get ready you can: • Write down any symptoms you are experiencing, including any that may seem unrelated to the reason for which you scheduled the appointment. • Write down key personal information, including any major stresses or recent life changes. • Make a list of all medications, as well as any vitamins or supplements you are taking. Or bring the original bottles your medications came in with you. • Ask a family member or friend to come with you. Sometimes it can be difficult to remember all of the information provided to you during an appointment. Someone who accompanies you may remember something that you missed or forgot. • Write down questions to ask your doctor.
Tests and Diagnosis • Blood tests: Once an abnormal protein is discovered, another test called serum protein electrophoresis (SPE) is ordered. The SPE test separates your blood proteins into five parts and can show any abnormal proteins as well as unusual amounts of normal proteins. Another test, the free light chain assay, is often done at the same time as the SPE, and it looks at the smaller parts of the M protein. Also ordered are tests to count your blood cells, to look for decline in kidney function, and to determine the amount of calcium in your blood. • X-rays: X-rays will help your doctor look for bone abnormalities that may indicate another type of plasma cell disorder. • Bone marrow test: During a bone marrow test, your doctor uses a hollow needle to remove a portion of your bone marrow from the back of one of your hip bones. The bone marrow is then analyzed to determine what percentage of plasma cells it contains. This test is generally only done when doctors suspect that someone is at risk of developing a more serious disease, or in people with unexplained anemia, kidney failure, bone lesions, or high calcium levels. Treatment and Drugs MGUS does not require treatment, but your doctor is likely to recommend frequent checkups every 6–12 months. If you have a risk of developing a more serious condition, your doctor may recommend more frequent checkups so that if a disease such as multiple myeloma develops, it can be treated as early as possible. If you have MGUS and bone loss, your doctor may recommend treatment with medications called bisphosphonates that help increase your bone density.
FIGURE 2. Patient Information for Monoclonal Gammopathy of Undetermined Significance Note. Based on information from Mayo Clinic, 2013. 618
December 2013 • Volume 17, Number 6 • Clinical Journal of Oncology Nursing
References Berenson, J.R., Anderson, K.C., Audell, R.A., Boccia, R.V., Coleman, M., Dimopoulos, M.A., . . . Kyle, R.A. (2010). Monoclonal gammopathy of undetermined significance: A consensus statement. British Journal of Haematology, 150, 28–38. doi:10.1111/j.1365 -2141.2010.08207.x Greenberg, A.J., Rajkumar, S.V., & Vachon, C.M. (2012). Familial monoclonal gammopathy of undetermined significance and multiple myeloma: Epidemiology, risk factors, and biological characteristics. Blood, 119, 5359–5366. doi:10.1182/blood-2011-11-387324 Greenberg, A.J., Vachon, C.M., & Rajkumar, S.V. (2012). Disparities in the prevalence, pathogenesis and progression of monoclonal gammopathy of undetermined significance and multiple myeloma between blacks and whites. Leukemia, 26, 609–614. doi:10.1038/ leu.2011.368 Klincová, M., Sandecká, V., Mikuláiová, A., Radocha, J., Maisnar, V., & Hájek, R. (2011). Monoclonal gammopathy of undeterminated significance: Introduction and current clinical issues. Klinická Onkologie, 24, S14–S17. Korde, N., Kristinsson, S.Y., & Landgren, O. (2011). Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): Novel biological insights and development of early treatment strategies. Blood, 117, 5573–5581. doi:10.1182/blood-2011-01-270140 Kyle, R.A., Buadi, F., & Rajkumar, S.V. (2011). Management of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Oncology, 25, 578–586. Kyle, R.A., Durie, B.G., Rajkumar, S.V., Landgren, O., Bladé, J., Merlini, G., . . . Boccadoro, M. (2010). Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia, 24, 1121–1127. doi:10.1038/leu.2010.60
Landgren, O. (2010). Monoclonal gammopathy of undetermined significance and smoldering myeloma: New insights into pathophysiology and epidemiology. Hematology, 2010(1), 295–302. doi:10.1182/asheducation-2010.1.295 Mayo Clinic. (2013). Monoclonal gammopathy of undetermined significance. Retrieved from http://www.mayoclinic.com/health/ monoclonal-gammopathy/DS00870 Minter, A.R., Simpson, H., Weiss, B.M., & Landgren, O. (2011). Bone disease from monoclonal gammopathy of undetermined significance to multiple myeloma: Pathogenesis, interventions, and future opportunities. Seminars in Hematology, 48, 55–65. doi:10.1053/j.seminhematol.2010.11.001 Wadhera, R.K., & Rajkumar, S.V. (2010). Prevalence of monoclonal gammopathy of undetermined significance: A systematic review. Mayo Clinic Proceedings, 85, 933–942. doi:10.4065/ mcp.2010.0337 Wong, R., & Wiffen, P.J. (2002). Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database of Systematic Reviews, 2, CD002068. doi:10.1002/14651858.CD002068
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Being Prepared Is Essential to Self-Care and Quality of Life, p. 255 Patient Satisfaction With Survivorship Care Plans, p. 266 Improving Nurses’ Communication Skills for Difficult Conversations, p. 279 Developing a Cancer Survivorship Care Plan, p. 280 Adolescent and Young Adult Oncology: An Emerging Specialty, p. 292 Reducing Central Line–Associated Bloodstream Infections in Transplantation Recipients, p. 297 Managing Indolent Lymphoma With Bendamustine, p. 303 Ruxolitinib for the Treatment of Myelofibrosis, p. 312 Strategies to Relieve Fatigue in Patients Receiving Radiation Therapy, p. 319 Lymphedema Following Breast Cancer, p. 325
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n CNE Article
Monoclonal Gammopathy of Undetermined Significance—Making It Understandable to Patients Pamela Rule, APRN, and Jeannine M. Brant, PhD, APRN, AOCN®
© iStockphoto.com/Thinkstock
Oncology nurses working in ambulatory care often encounter patients with nonmalignant hematologic disorders because the specialties of hematology and oncology are closely entwined. A variety of nonmalignant hematologic disorders can evolve into blood malignancies; therefore, close surveillance of nonmalignant hematologic disorders in an oncology/hematology clinic is important for early detection of malignancy. Monoclonal gammopathy of undetermined significance (MGUS) is one nonmalignant, hematologic disorder that is usually aproblematic; however, it can evolve into a blood malignancy such as multiple myeloma or be associated with other chronic conditions. This article provides an overview of MGUS with a focus on implications for the oncology nurse and patient education.
Pamela Rule, APRN, is an advanced practice nurse in the Department of Internal Medicine at Cornell Scott Hill Health Center in New Haven, CT, and Jeannine M. Brant, PhD, APRN, AOCN®, is an oncology clinical nurse specialist and nurse scientist at Billings Clinic in Montana. The authors take full responsibility for the content of the article. The authors did not receive honoraria for this work. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or editorial staff. Rule can be reached at [email protected], with copy to editor at [email protected]. (Submitted January 2013. Revision submitted May 2013. Accepted for publication May 12, 2013.) Digital Object Identifier:10.1188/13.CJON.614-619
M
onoclonal gammopathy of undetermined significance (MGUS) was first described by Jan Waldenström in 1960 after abnormal narrow hypergammaglobulinemia bands were noted on serum protein electrophoresis in the blood of healthy individuals (Kyle, Buadi, & Rajkumar, 2011). Robert Kyle used the term “monoclonal gammopathy of undetermined significance” in 1978 after detecting a correlation between MGUS and the development of other disorders such as multiple myeloma, Waldenström’s macroglobulinemia, amyloidisis, and chronic lymphocytic leukemia (Korde, Kristinsson, & Landgren, 2011). Therefore, MGUS is defined as the presence of an abnormal protein (monoclonal protein or M protein) in the blood or urine in the absence of end-organ damage. In 2010, the International Myeloma Working Group defined MGUS as a serum monoclonal protein under 3 g/dl with fewer than 10% clonal bone marrow plasma cells and an absence of end-organ damage, which can be attributed to the plasma cell proliferative disorder, examples include hypercalcemia, renal insufficiency, anemia, and bone lesions (Kyle et al., 2010).
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Prevalence and Risk A systematic review of 14 studies estimated that the prevalence of MGUS was about 3% in people older than 50 (Wadhera & Rajkumar, 2010). The prevalence increases with age and is estimated to be 7% in Caucasians older than 80. Additional risks include race (6% in Caucasians compared to 8% in African Americans) (Greenberg, Vachon, & Rajkumar, 2012), gender (4% of Caucasian men older than 50 years compared to 3% of Caucasian women), family history (Greenberg, Rajkumar, & Vachon, 2012), and immunosuppression. For immunosuppressed patients with HIV, a substantial risk exists ranging from 9%–45% (Wadhera & Rajkumar, 2010). Infection also has been associated with the development of MGUS. Sixty-eight percent of patients with MGUS also have had Helicobacter pylori infections, and the eradication of the infection led to resolution of monoclonal gammopathy in 11 of 39 patients (Kyle et al., 2011). Environmental exposure to toxins such as asbestos, pesticides, radiation, petroleum, aromatic hydrocarbons, fertilizers, and paints poses additional risk. However,
December 2013 • Volume 17, Number 6 • Clinical Journal of Oncology Nursing
TABLE 1. Risk Stratification Model for Monoclonal Gammopathy of Undetermined Significance Risk for progression
Definition
Low risk
Level of M protein < 1.5 g/dl; IgG subtype; light chain ratio is normal
Low-intermediate risk
One of the low criteria being abnormal
Intermediate-high risk
Any two of the low-risk criteria being abnormal
High risk
All three factors being abnormal.
IG—immunoglobulin Note. Based on information from Kyle et al., 2011.
although some populations may be at increased risk for MGUS, no evidence exists that they have a higher progression rate to multiple myeloma (Wadhera & Rajkumar, 2010).
Pathophysiology An understanding of the lymphocytic immune system, the body’s nonspecific defense mechanism, is essential to understanding the pathophysiology of MGUS. The lymphocytic immune system is comprised of the cell-mediated system of t cells and the humoral immune system of B cells. T cells are highly specialized cells that circulate in the blood and lymphatic system to fight infection and other foreign invaders. B cells produce plasma cells and antibodies in response to previous exposure to foreign antigens. Plasma cells secrete antibodies (e.g., IgM, IgA, IgG) that recognize the foreign antigen. MGUS is a condition that occurs when these plasma cells produce an abnormal type of antibody called a monoclonal protein or M protein. Although normal white blood cells produce antibodies to fight infection, M proteins cannot fight infections and can accumulate in blood and urine. MGUS is believed to be a result of an abnormal response to antigenic formation. This abnormal response leads to cytogenic abnormalities such as hyperdiploidy (the most common) or genetic translocations (Kyle et al., 2010). Another finding is a chromosome 13 deletion that appears in MGUS as well as in multiple myeloma. However, whether that increases the rate of progression to multiple myeloma is not known (Greenberg, Rajkumar, et al., 2012; Klincová et al., 2011). Three main clinical types of MGUS exist: non-IgM (IgA or IgG) MGUS, IgM MGUS, and light chain MGUS. About 15%–20% of MGUS tumors are the IgM subtype and are phenotypically lymphoid or lymphoidplasmacytoid. These tumors most commonly progress to lymphoprolifertive disorders such as Waldenstron’s macroglobulinemia and lymphoma. The non-IgM MGUS tumors have a plasma cell phenotype and are most likely to progress to plasma cell disorders such as multiple myeloma (Kyle et al., 2011; Landgren, 2010). MGUS can be stratified into risk categories to suggest progression, but reliable biologic predictors are lacking. The main risk factor for progression to multiple myeloma is the size and amount of serum M protein and presence of an abnormal
serum-free light chain ratio (Wadhera & Rajkumar, 2010). For example, at 10 years of age, people with MGUS and an initial M protein of 0.5 g/dl had a 6% progression rate, and people with an initial M protein of 2.5 g/dl had a 24% rate (Kyle et al., 2011). A risk stratification model provides a template for risk (Kyle et al., 2011) (see Table 1). An abnormal serum-free light chain ratio, non-IgG MGUS, and a high serum M protein level (> 1.5) are the three risks identified that may predict progression to multiple myeloma. However, an abnormal light chain ratio increases the risk regardless of the type of M protein involved (Kyle et al., 2011; Wadhera & Rajkumar, 2010).
Diagnosis MGUS may remain subclinical for years; however, each year about 1% of patients with MGUS progress to multiple myeloma or another proliferative disorder. When this occurs, myeloma cells accumulate in the bone marrow and crowd out normal cells, which slow the blood marrow production of normal white blood cells, platelets, and red blood cells. A diagnosis is confirmed with a serum monoclonal protein (> 3 g/dl IgG or IgA), bone marrow plasma cells (> 10%), and the presence of end-organ disease such as skeletal lesions or renal compromise. Smoldering multiple myeloma also may occur, differentiated from myeloma by the absence of end-organ disease (Landgren, 2010). MGUS often is detected as an incidental finding on blood work during a routine physical examination. A high serum total protein can prompt an initial workup for MGUS. Initially, total serum protein measurement, total urine protein measurement, and complete blood count should be evaluated. If abnormal, a second level evaluation including a chemistry panel with calcium, serum and urine protein electrophoresis, and beta-2 microglobulin should be ordered. Evaluation of both serum and urine is important because the M protein in some patients may be located in only one fluid. If the second-level laboratory testing reveals abnormalities, then additional laboratory testing including serum immunofixation (IFE), urine immunofixation, quantitative immunoglobulin, and serumfree light chain should follow. The IFE must be performed to identify the M protein through serum protein electrophoresis. IFE is more sensitive than screening electrophoresis. If this additional testing reveals at least one abnormal result, then MGUS requires more diligent monitoring. A list of laboratory analyses for diagnosis and surveillance are included in Table 2 (Korde et al., 2011). Once an M protein spike is discovered, evaluation is needed to rule out diseases associated with increased M proteins. A diagnosis of MGUS is assigned in the absence of other pathology;
Implications for Practice u
Check for progression of disease by examining for physical changes such as pain or constipation.
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Ask friends and caregivers for signs that the patient is resting or sleeping more than usual.
u
Be aware of increased bruising on skin or after blood draws.
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TABLE 2. Laboratory Tests for Monoclonal Gammopathy of Undetermined Significance (MGUS) Laboratory Test Beta-2 microglobulin
Sub Test –
Normal Value 1.1–2.4 mg/L
Implications Found on the surface of all cells; increased in patients with malignancy and other immunosuppressive diseases.
ease suggests multiple myeloma. See Figure 1 for early screening for monoclonal gammopathies.
Treatment and Follow-Up
People with MGUS do not require treatment, but they do require close monitoring. The risk Bone marrow Plasma cells Less than 10% Healthy people can have up to 3% biopsy plasma cells in the bone marrow, 3%– for progression is ever present 10% is indicative of MGUS, greater and does not decrease over the than 10% is diagnostic of myeloma. course of the disease; however, death from other comorbidities Calcium – 9–10.5 mg/dl Hypercalcemia can indicate bone reis more common than death from sorption and onset of myeloma. MGUS. Complete blood White blood cells 5,000–10,000 If MGUS progresses, abnormal proteins In most cases, MGUS is asympcount crowd out normal cells in the bone tomatic, and individuals with Red blood cells 12–18 marrow, resulting in neutropenia, aneMGUS have normal blood counts, mia, and thrombocytopenia. Platelet cells 150,000–400,000 calcium levels, kidney function, and bone and organ function. Quantitative IgA 68–378 mg/dl Monitors specific levels of each imWhen MGUS is low risk, M proimmunoglobulin munoglobulin, a systemic marker of IgG 768–1632 mg/dl MGUS, also can differentiate between teins should be monitored at MGUS and myeloma; increased risk six months and then every one IgM 60–263 mg/dl of progression to myeloma with IgM or two years if no changes are spike. IgE 2–549 mg/dl detected. Most people who are symptomatic seek a provider IgD Less than 1–11.2 mg/dl with complaints of bone pain, Serum-free light Kappa 3.3–19.4 mg/L M proteins are composed of heavy fatigue, or recurrent infection. chain chain immunoglobulins and light Symptoms appear because of Lambda 5.71–26.3 mg/L chain kappa and lambda components. M protein (plasma cell) overJoined they are not a problem, but too production and the subsequent Kappa/lambda many free light chains may contribute 0.26–1.65 mg/L ratio crowding of bone marrow cells, to renal damage. resulting in a decreased proSerum or urine – Negative for Identifies the type of immunoglobulin duction of normal blood cells. immunofixation immunoproteins proteins present; 24-hour urine collecSome complications related to electropheresis tion needs to be refrigerated. the increase in proteins include Serum protein – Negative for Measures the total amount of proteins anemia, infection, neuropathies, electrophoresis abnormal protein and the amount of abnormal proteins osteopenia, and thromboemboin the blood; elevated in MGUS. lism. MGUS also puts the person at higher risk for bone loss and Total serum protein Protein 6.4–8.3 g/dl Total protein includes albumin and globulin; elevated globulin occurs skeletal problems, particularly Albumin 3.5–5 g/dl with MGUS. vertebral and hip fractures (Berenson et al., 2010). After the Globulin 2.3–3.4 g/dl initial skeletal survey, patients Total urine protein – Negative for Measures the total amount of proteins should be monitored with peabnormal protein and the amount of abnormal proteins riodic bone density scanning in the urine. every year if osteopenia or osteoNote. Based on information from Mayo Clinic, 2013. porosis is present and every two years if normal. If indicated by the evaluation, oral or IV bisphosphonates should be used as part of the follow-up treatment. If therefore, the diagnosis of MGUS is by exclusion (Wadhera & IV zoledronic acid is used, it can be given yearly or every six Rajkumar, 2010). M protein spikes greater than 1.5 g/dl should months (Minter, Simpson, Weiss, & Landgren, 2011; Wong & be investigated further via a bone marrow biopsy. Abnormal Wiffen, 2002). light chain ratios may indicate light chain diseases such as light chain myeloma, systemic amyloidosis, or systemic light chain diseases. Light chain diseases affect the kidneys by occluding renal tubules; therefore, patients with light chain disease may The population of Americans aged 65 years and older is require a renal biopsy. A skeletal series is recommended if the higher than at any other time in the United States’ history and individual has any complaints of bone pain. Positive lytic dis-
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PLUS
b
Note. From Early Screening of Monoclonal Gammopathy of Undetermined Significance by the International Myeloma Foundation, 2010. Retrieved from http://myeloma.org/pdfs/flowchartENG-early-screening_o1 -type.pdf. Copyright 2010 by the International Myeloma Foundation. Reprinted with permission.
FIGURE 1. Early Screening of Monoclonal Gammopathy of Undetermined Significance
b
Or the patient may be asymptomatic and discovered to have a monoclonal gammopathy when abnormal test results are noted at the time of a routine checkup. Chemical panel = glucose, sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, calcium, albumin from serum protein electrophoresis, and liver function tests c Congo red stain of biopsy material d http://myeloma.org/pdfs/flowchart_ENG_monitoring_n1.pdf
a
No abnormalities
At least one abnormal result
Complementary tests
is expected to increase more rapidly over the next decade as more baby boomers start to turn 65 years of age. With this demographic shift comes the increased likelihood of individuals living with increased comorbidities, one of which may be MGUS. Although patients with MGUS need to know that they have certain risk factors predisposing them to a malignancy, they also need to be reassured that they may or may not be in danger of progression. In addition, with available risk identification, clinicians can attempt to identify which patients require closer follow-up and which ones may remain asymptomatic. Fortunately, MGUS is an uncommon hematologic disorder; however, because of its obscurity, education is important. Information conquers uncertainty, which plays an important role in the anxiety surrounding the diagnosis. Initially, patients should receive basic information regarding diagnosis, treatment options, and side effects (see Figure 2). The timing of the information given and the level of detail and content varies depending on the patient’s readiness to learn and preferred
Definition Monoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of an abnormal protein (monoclonal protein or M protein) in the blood. M protein is produced by plasma cells, a type of white blood cell. MGUS usually causes no problems. In some people, it can be associated with another disease or can progress over years to other disorders. Who will progress is difficult to predict. Only 1% of the population progresses each year. M proteins are monitored usually once a year to check for progression. If no increase in the protein occurs, MGUS does not require treatment. Risk Factors Genetic changes appear to play a role in MGUS, as do environmental triggers, such as being exposed to certain pesticides or to radiation from an atomic bomb. Other factors that increase your risk of MGUS include: • Your age: The risk of MGUS increases as you get older. About 1% of people aged 25 years and older and 5% of people aged 70 years and older have M protein in their blood. The highest incidence is among adults aged 80 years and older. • Your race: African Americans are more likely to experience this condition than Caucasians. • Your gender: MGUS is more common in men than in women. • A family history: If other people in your family have MGUS, your risk of developing the disorder may be higher. • Your weight: People with a body mass index greater than 30 (a level considered obese) have a greater risk of developing MGUS. Your risk of developing a more serious condition increases the longer you have had MGUS.
learning style. Patients and families should have knowledge of the disease and anticipate the next steps in the surveillance and treatment of the disease. Developing rapport and a bond enables individualized teaching to the patient’s level of understanding or the level of information the patient desires. The focus of the journey should be directed toward patients living their lives, not on fear of disease progression. Fortunately, most of these patients live a normal life span without progressing to a more serious disease.
Conclusion MGUS is an uncommon hematologic disorder, but often is a complex and easily misunderstood disease. Patients are initially anxious about a new diagnosis of MGUS, and the nurse plays a key role in educating the patient and family in an understandable manner, alleviating fear, and serving as a guide as patients and families journey through this obscure illness.
Complications A small percentage of people with MGUS develop a more serious condition, such as multiple myeloma or other cancers or blood disorders. Your doctor will take into account several factors when determining your risk, including: • The amount of M protein in your blood • The type of M protein • The amount of plasma cells in your bone marrow • The presence of protein in your urine Other complications associated with MGUS include fractures and blood clots. Preparing for Your Appointment MGUS is detected and monitored with blood tests. The blood tests require no preparation on your part. If you are found to have MGUS, you may be referred to a hematologist, a doctor who specializes in blood disorders. Prior to your appointment to help you get ready you can: • Write down any symptoms you are experiencing, including any that may seem unrelated to the reason for which you scheduled the appointment. • Write down key personal information, including any major stresses or recent life changes. • Make a list of all medications, as well as any vitamins or supplements you are taking. Or bring the original bottles your medications came in with you. • Ask a family member or friend to come with you. Sometimes it can be difficult to remember all of the information provided to you during an appointment. Someone who accompanies you may remember something that you missed or forgot. • Write down questions to ask your doctor.
Tests and Diagnosis • Blood tests: Once an abnormal protein is discovered, another test called serum protein electrophoresis (SPE) is ordered. The SPE test separates your blood proteins into five parts and can show any abnormal proteins as well as unusual amounts of normal proteins. Another test, the free light chain assay, is often done at the same time as the SPE, and it looks at the smaller parts of the M protein. Also ordered are tests to count your blood cells, to look for decline in kidney function, and to determine the amount of calcium in your blood. • X-rays: X-rays will help your doctor look for bone abnormalities that may indicate another type of plasma cell disorder. • Bone marrow test: During a bone marrow test, your doctor uses a hollow needle to remove a portion of your bone marrow from the back of one of your hip bones. The bone marrow is then analyzed to determine what percentage of plasma cells it contains. This test is generally only done when doctors suspect that someone is at risk of developing a more serious disease, or in people with unexplained anemia, kidney failure, bone lesions, or high calcium levels. Treatment and Drugs MGUS does not require treatment, but your doctor is likely to recommend frequent checkups every 6–12 months. If you have a risk of developing a more serious condition, your doctor may recommend more frequent checkups so that if a disease such as multiple myeloma develops, it can be treated as early as possible. If you have MGUS and bone loss, your doctor may recommend treatment with medications called bisphosphonates that help increase your bone density.
FIGURE 2. Patient Information for Monoclonal Gammopathy of Undetermined Significance Note. Based on information from Mayo Clinic, 2013. 618
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References Berenson, J.R., Anderson, K.C., Audell, R.A., Boccia, R.V., Coleman, M., Dimopoulos, M.A., . . . Kyle, R.A. (2010). Monoclonal gammopathy of undetermined significance: A consensus statement. British Journal of Haematology, 150, 28–38. doi:10.1111/j.1365 -2141.2010.08207.x Greenberg, A.J., Rajkumar, S.V., & Vachon, C.M. (2012). Familial monoclonal gammopathy of undetermined significance and multiple myeloma: Epidemiology, risk factors, and biological characteristics. Blood, 119, 5359–5366. doi:10.1182/blood-2011-11-387324 Greenberg, A.J., Vachon, C.M., & Rajkumar, S.V. (2012). Disparities in the prevalence, pathogenesis and progression of monoclonal gammopathy of undetermined significance and multiple myeloma between blacks and whites. Leukemia, 26, 609–614. doi:10.1038/ leu.2011.368 Klincová, M., Sandecká, V., Mikuláiová, A., Radocha, J., Maisnar, V., & Hájek, R. (2011). Monoclonal gammopathy of undeterminated significance: Introduction and current clinical issues. Klinická Onkologie, 24, S14–S17. Korde, N., Kristinsson, S.Y., & Landgren, O. (2011). Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): Novel biological insights and development of early treatment strategies. Blood, 117, 5573–5581. doi:10.1182/blood-2011-01-270140 Kyle, R.A., Buadi, F., & Rajkumar, S.V. (2011). Management of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Oncology, 25, 578–586. Kyle, R.A., Durie, B.G., Rajkumar, S.V., Landgren, O., Bladé, J., Merlini, G., . . . Boccadoro, M. (2010). Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia, 24, 1121–1127. doi:10.1038/leu.2010.60
Landgren, O. (2010). Monoclonal gammopathy of undetermined significance and smoldering myeloma: New insights into pathophysiology and epidemiology. Hematology, 2010(1), 295–302. doi:10.1182/asheducation-2010.1.295 Mayo Clinic. (2013). Monoclonal gammopathy of undetermined significance. Retrieved from http://www.mayoclinic.com/health/ monoclonal-gammopathy/DS00870 Minter, A.R., Simpson, H., Weiss, B.M., & Landgren, O. (2011). Bone disease from monoclonal gammopathy of undetermined significance to multiple myeloma: Pathogenesis, interventions, and future opportunities. Seminars in Hematology, 48, 55–65. doi:10.1053/j.seminhematol.2010.11.001 Wadhera, R.K., & Rajkumar, S.V. (2010). Prevalence of monoclonal gammopathy of undetermined significance: A systematic review. Mayo Clinic Proceedings, 85, 933–942. doi:10.4065/ mcp.2010.0337 Wong, R., & Wiffen, P.J. (2002). Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database of Systematic Reviews, 2, CD002068. doi:10.1002/14651858.CD002068
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Being Prepared Is Essential to Self-Care and Quality of Life, p. 255 Patient Satisfaction With Survivorship Care Plans, p. 266 Improving Nurses’ Communication Skills for Difficult Conversations, p. 279 Developing a Cancer Survivorship Care Plan, p. 280 Adolescent and Young Adult Oncology: An Emerging Specialty, p. 292 Reducing Central Line–Associated Bloodstream Infections in Transplantation Recipients, p. 297 Managing Indolent Lymphoma With Bendamustine, p. 303 Ruxolitinib for the Treatment of Myelofibrosis, p. 312 Strategies to Relieve Fatigue in Patients Receiving Radiation Therapy, p. 319 Lymphedema Following Breast Cancer, p. 325
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