Malcolm Brigden, MDCM, FRCPC, FACP, Chris Venner, MD, FRCPC

Monoclonal gammopathy and primary care

Even though most patients diagnosed with monoclonal gammo- pathy of undetermined significance will never develop malignant disease, follow-up is needed to identify those patients at risk of progression.

ABSTRACT: With an aging popula- finding of monoclonal gam- What is monoclonal gammo­pathy, tion in Canada, a rise in malignant mopathy (M-spike) becomes and when can it be encountered in plasmaproliferative disease can be A increasingly common with general clinical practice? expected. In the majority of cases, patient age. The presence of mono- is the in­­ this is preceded by monoclonal gam- clonal protein (M-protein) is found in creased production of immunoglobu- mopathy. However, not all cases of approximately 3% to 4% of those over lin secreted by an abnormally expand- monoclonal gammopathy progress age 50, 5% over age 65, and almost ed clone of B-cells in an amount that to malignant disease over time. 10% of those 85 or older.1-4 When can be identified by serum protein Primary care providers can benefit considered as a group, patients with electrophoresis (SPE) or immunofix- from considering common concerns monoclonal gammopathy of undeter- ation of the serum and or urine.1,2 The related to management and follow- mined significance (MGUS) have an monoclonal protein found can con- up of monoclonal gammopathy of approximately 1% cumulative chance sist of light chains attached to heavy undetermined significance (MGUS): per year of ultimately developing a chains (whole immunoglobulin) or When is MGUS likely to be encoun- malignant plasmaproliferative disor- free light chains (FLC) alone. The tered in general practice? What in- der such as (MM), discovery of a monoclonal protein vestigations should be undertaken? Waldenstrom can occur in a wide variety of clinical How should MGUS be managed? (WM), or systemic AL amyloidosis. situations.1-4 What indicates a risk of progression from MGUS to malignant disease? In Common concerns Dr Brigden is medical director of the Jack established MGUS, what follow-up Given the aging population in Cana- Ady Cancer Centre in Lethbridge, Alberta. investigations should be undertak- da, primary care providers are likely He is also a clinical associate professor at en? When should the possibility of to require some familiarity with the the University of Calgary and associate ad- systemic AL amyloidosis be investi- investigation, natural history, follow- junct professor at the University of Leth- gated? Answers to these questions up, and timing of possible subspecial- bridge. Dr Venner is a hematologist at the based on consensus guidelines and ist referral for patients with MGUS. Cross Cancer Institute and a clinical assis- recommendations can help primary As virtually no randomized trial data tant professor at the University of Alberta. care providers play a significant role exist in relation to this topic, litera- He was the recipient of the first Conjoint in managing patients with monoclo- ture-based consensus guidelines and Plasma Cell Dyscrasia Fellowship with the nal gammopathy of undetermined recommendations can help facilitate /BMT program of British Colum- significance, especially those pa- a problem-oriented approach when bia and the London School of Medicine, St. tients found to be at low risk for monoclonal protein is found.1-3 Bartholomew’s Hospital. He also served as progression. locum consultant at the National Amyloi- dosis Centre, University College London, This article has been peer reviewed. before assuming his current position.

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Initially, monoclonal gammopa- thy may be discovered: Differential diagnosis for monoclonal • Entirely by chance. gammopathy • As part of an investigation for a clinical condition such as nephrotic Malignant syndrome, peripheral neuropathy, Plasma cell disease or congestive heart failure. • Monoclonal gammopathy of undetermined significance • During the investigation of skeletal • Multiple myeloma symptoms or findings such as back • Smouldering multiple myeloma pain, compression fractures, osteo- • AL amyloidosis porosis without known risk factor, • Other rarer malignant plasma cell disorders or lytic bone lesions. • With laboratory follow-up of hyper- B-cell (usually IgM) disease gammaglobulinemia or hypogamma- • Lymphoplasmacytic /Waldenstrom macroglobulinemia globulinemia. • Chronic lymphocytic leukemia • With laboratory follow-up of an • Small lymphocytic lymphoma elevated erythrocyte sedimentation • Marginal zone lymphoma rate. • Other indolent (rare) • With laboratory follow-up of abnor- mal values for individual serum im- Benign munoglobulins (IgG, IgA, IgM). Autoimmune/inflammatory disease • As part of an investigation for a • Rheumatoid arthritis, ankylosing spondylitis collagen vascular disease or inflam- • Systemic lupus erythematosis, scleroderma, Sjogren syndrome matory arthritis such as rheumatoid • Vasculitis, polymyalgia rheumatica arthritis, polymyalgia rheumatica, • Paraprotein-associated neuropathies scleroderma, or systemic lupus. • As part of an investigation for sus- Infectious disease pected immunodeficiency or unex- • Viral infections (EBV, CMV, HIV, HBV, HCV) plained chronic infections. • Severe acute infections • As part of the staging process for • Subacute or chronic infections (osteomyelitis, endocarditis, abscess) common hematological malignan- cies such as chronic lymphocytic Posttransplant effect leukemia, Hodgkin disease, or non- • Response to stem cell or solid organ transplantation . • As part of an investigation for suspected myeloma, Waldenstrom bone lesions, or unexplained periph- When monoclonal protein is macroglobulinemia, or systemic AL eral neuropathy are often screened found, what investigations amyloidosis. for the presence of an M-protein.2-4 should be undertaken? A monoclonal protein is often dis- Many malignant and benign medical Past studies have found there was no covered incidentally on routine conditions commonly encountered in follow-up in over 50% of cases where testing in an outpatient setting when clinical practice may be associated a monoclonal protein was discovered completing the workup for patients with monoclonal gammopathy (see incidentally.6 Today we recognize that with or box1,2,4). On very rare occasions, an serum protein electrophoresis should hypogammaglobulinemia, an elevat- M-protein may be detected and then be used to investigate in all cases of ed sedimentation rate, or an asymp- not be found in subsequent follow-up hypogammaglobulinemia or hyper- tomatic rise in serum protein levels. investigations. This is most likely to gammaglobulinemia, or when there Patients who present with back pain, occur when only a very small amount are abnormally low serum levels of anemia, renal insufficiency, signifi- of M-protein is detected and detection total immunoglobulins, including cant proteinuria, hypercalcemia, age- is by immunofixation alone.5 individual Ig classes.1-3 Serum protein inappropriate osteopenia, osteolytic electrophoresis is usually performed

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Albumin Alpha-1 globulinAlpha-2 globulinBeta globulinGamma

Figure 2. A serum immunofixation result showing specific antisera for heavy and light chains. Immunofixation confirms the monoclonal protein spike originally seen on serum protein Figure 1. Densitometer tracing (lower illustration) of a typical serum protein electrophoresis electrophoresis and identifies the M-protein result (upper illustration) revealing a monoclonal gammopahty or M-spike (arrow). as IgG kappa (arrows).

on an agarose gel. If a monoclonal ized hypogammaglobulinemia, but no lambda serum FLC ratio can be used protein is identified, it appears as a detectable serum monoclonal protein as a surrogate marker for the secretion sharply defined spike ( Figure 1 ). If on SPE, immunofixation should also of monoclonal free light chains. An the cause of the hypergammaglo­ be performed, along with serum FLC abnormal kappa-lamda ratio is defined bulinemia is actually polyclonal in analysis.1-3 Urine protein electropho- as less than 0.26 or greater than 1.65. nature, as in the case of a chronic resis (UPE) and immunofixation of an This ratio is often abnormal even infectious or inflammatory state such aliquot from a 24-hour urine specimen when the renal reabsorption threshold as cirrhotic liver disease, a broad- may not be necessary on initial screen- for light chains has not been exceed- based curve rather than a sharp spike ing, but these tests must be performed ed, meaning that very small amounts will be seen. when a serum or urine monoclonal of free light chains do not appear in The identification of an M-spike is protein is found in order to complete the urine.1,2,7 This makes serum FLC always followed by immunofixation, the baseline workup.2 testing ideal for detecting and moni- which is performed with specific anti- The relatively recent introduction toring the rarer cases of myeloma with sera against the various classes of of sensitive methods to measure low very little immunoglobulin secretion immunoglobulin to confirm the pres- levels of free light chains in serum (oligosecretory MM) as well as for ence of a monoclonal protein and iden- has established that both normal identifying AL amyloidosis, where tify specific associated heavy and light and malignant plasma cells secrete the amount of monoclonal protein is chain types, such as kappa or lambda free light chains as well as whole also often minute. Thus, during the ( Figure 2 ). In cases with low serum immunoglobulin.2,7 It has also been initial investigation of a monoclonal immunoglobulin levels or general- established that an abnormal kappa to gammopathy, in addition to blood

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Table 1. Defining features of the common beta cell clonal disorders, including monoclonal gammopathy of undetermined significance (MGUS).

Asymptomatic Symptomatic MGUS Smoldering Multiple myeloma Waldenstrom AL amyloidosis or other multiple macroglobulinemia clonal protein deposition myeloma disease

M-spike IgG or IgA IgG or IgA IgG or IgA Any IgM monoclonal Any monoclonal < 30 g/L ≥ 30 g/L ≥ 30 g/L gammopathy gammopathy or abnormal serum free light chain assay results Bone marrow clonal < 10% clonal > 10% clonal Any clonal plasma cell 10% lymphoplasmacytic Any clonal plasma cell or cell population plasma cells plasma cells population infiltration B-cell lymphoma population CRAB criteria* None None At least one Not a defining feature May or may not be present Related organ or None None Hypogammaglobulinemia Anemia Any fibril induced end-organ tissue impairment Occult bone disease Other cytopenias dysfunction: Hyperviscosity Neuropathy • Renal (often proteinuria) Cytopenias Hyperviscosity • Cardiac • Liver Retinopathy • Nerve (peripheral or Fatigue autonomic) • Soft tissue

*C alcium: > 0.25 mmol/L above the upper limit of normal or > 2.75 mmol/L Renal insufficiency: creatine >173 mmol/L Anemia: Hb 20 g/L below the lower limit of normal or Hb < 100 g/L Bone lesions: lytic lesions or with compression fractures1,2,4,8 counts, routine chemistries, SPE, and hypercalcemia, renal insufficiency, cal of MM are found to be present in immunofixation, a serum FLC assay anemia, bone lesions. Various defin- a high proportion of MGUS patients. should also be performed since virtu- ing features of MGUS, smoldering This suggests a complex evolutionary ally 100% of cases of MM, WM, AL MM, MM, and WM are compared in etiology, including the accumulation amyloidosis, and MGUS can initially Table 1 .2,8 of successive genetic “hits,” possibly be identified with these three non­ As noted earlier, the incidence of combined with a progressive altera- invasive tests.1,2,7 MGUS increases with age; MGUS tion and deregulation of the bone is also more common in males than marrow microenvironment.2,3,8 What distinguishes MGUS in females, and almost three times from frankly malignant more prevalent in African Ameri- How should MGUS be managed? plasmaproliferative disease? cans than Americans of European Studies have shown that MGUS MGUS by definition is a monoclo- descent.2-4 While the precise cause of patients have increased osteoclasto- nal gammopathy characterized by MGUS remains unknown, as in the genesis as well as an abnormally high a serum monoclonal protein of less case of MM, there is higher incidence rate of bone reabsorption.9,10 Not sur- than 30 g/L, plasma cells of less than in agricultural workers and those prisingly, patients with MGUS also 10% in the bone marrow, and, most with a history of significant expo- experience a much higher degree importantly, by the absence of end- sure to insecticides, herbicides, and of bone loss and fracture than age- organ damage that can be attributed fungicides.2-4 Prior radiation is also a and sex-matched controls.2-4,9 Spe- to the malignant plasma cell prolif- risk factor, and there is familial ten- cifically, there is an increased like- eration seen in multiple myeloma or dency, with a 3.3-fold increased risk lihood of developing vertebral and the hyperviscosity, lymphadenopa- in relatives of a propositus.1-3 Interest- hip fractures.9,10 For this reason, the thy, and hepatosplenomegaly seen in ingly, although conventional cyto- Nordic Myeloma Study Group and Waldenstrom macroglobulinemia.2-4 genetics rarely detect an abnormality the UK Myeloma Forum have both In MM, end-organ damage is defined in MGUS, with FISH analysis, the recommended that anyone with age- by the so-called CRAB features: same cytogenetic abnormalities typi- inappropriate bone loss or vertebral

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compression fractures, but with- What clinical features of MGUS urine light chain nor the presence of out definitive known risk factors, indicate a risk of progression? an associated reduction in the nonin- should undergo monoclonal pro- In a series of longitudinal studies volved immunoglobulin classes (each tein screening.1-3 Similarly, MGUS conducted over 50 years, Kyle and abnormality exists in approximately patients with T scores less than 21.0 other researchers confirmed that vir- 30% of newly diagnosed MGUS) has should maintain a minimum oral tually all cases of MM are preceded been found to be predictive for later intake of 1000 IU of vitamin D daily by MGUS, with a median duration progression.2-4 as well as a calcium intake between of more than 10 years.3,4,8 Interest- Low-risk patients, those with none 1000 and 1500 mg/per day.2,3 Those ingly, patients were found to be at of the three risk factors, are known to identified with frank osteoporosis risk for progression even after 30 to have an absolute risk of progression should be treated with bisphospho- 40 years of follow-up.2,3 However, to a plasma proliferative disorder at nates or other appropriate therapy9,10 it was simultaneously recognized 20 years of only 5%. Approximately There is an increased risk of that despite an average overall risk 70% of patients with new, inciden- peripheral neuropathy with MGUS. for progression of 1% per year, not tally discovered MGUS will fall into Accordingly, the various expert con- all patients with MGUS ultimately this category. The low-intermediate- sensus groups have suggested that developed symptomatic malignant risk patients, those with one risk fac- patients presenting with idiopath- MM, WM, or AL amyloidosis.1-3 This tor, have a 21% risk of progression. ic peripheral neuropathy should be realization has stimulated efforts to The intermediate-risk patients, those screened for MGUS. With screen- discover which factors might help with two risk factors, have a 37% risk ing, approximately 10% of patients to stratify the risk for progression in of progression, while risk increases presenting with idiopathic periph- individual cases. A Spanish group to 58% for patients in the high-risk eral neuropathy will be found to recently found that a preponderance group, who have three risk factors.3,4 have monoclonal gammopathy.2-4 of phenotypically abnormal plasma Population-based cohort studies have cells on bone marrow flow cytometry In established MGUS, what suggested that MGUS patients may were associated with significant risk follow-up testing should be not have a higher risk of develop- for progression.4,8 However, such an undertaken? ing peripheral neuropathy, and most approach requires both invasive bone For those patients with MGUS that associated cases are unlikely to be marrow sampling and an adequate does progress, the median time to pro- caused by the actual MGUS.11 How- sample. gression is around 5 years, and overall ever, patients with an IgM-related Kyle and other researchers ulti- progression risk is highest in the first neuropathy are often found to have mately found a way to stratify MGUS 5 years.3,8,13 No uniformly predict- serum-antimyelin-associated glyco- patients into four groups at low, low- able pattern for progression has been protein on testing, and may intermediate, intermediate, and high identified, with only 50% of patients respond to appropriate therapies such yearly risk for progression.3,8 To do ultimately developing MM. Five dif- as and the administra- this, they identified three easily quan- ferent patterns of progression from tion of cytotoxic agents or the mono- tifiable risk factors: baseline monoclonal protein levels clonal rituximab.11 • An M-protein level greater than ( Figure 3 ) have been identified by Other investigations have shown 15 g/L. Kyle: that MGUS patients are also more • The presence of IgA or IgM (i.e., • Sudden, rapid increase. likely to experience thromboembolic non-IgG) protein. • Gradual, steady increase. events such as deep vein thrombo- • An abnormal FLC ratio. • Initial stability followed by gradual sis.12 One study identified a relative Kyle also confirmed that the pres- increase. risk of 3.3 for DVT with MGUS, with ence of more than 5% plasma cells • Initial stability followed by sudden the greatest risk existing during the in a bone marrow aspiration biopsy increase. first year after diagnosis.2,3,12 Despite sample was an independent risk factor • Ongoing relative stability over a this observation, there is no evidence for progression, although the invasive number of years followed by the de- to date that any unique prophylactic nature of such a procedure eliminat- velopment of lytic lesions, anemia, measures should be taken. ed this factor from the list of “easily or renal insufficiency/progressive quantifiable” risk factors.3,4 Interest- M-protein proteinuria. ingly, neither the presence or type of The existence of this last group

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makes it essential that MGUS follow- up include not only laboratory testing Sudden rapid increase (15%) Stable with gradual increase (12%) but also periodic history taking and Gradual steady increase (12%) Stable with sudden increase (25%) 3,13 physical examination. In fact, a 60 study of MGUS patients experiencing optimal follow-up found that sched- uled visits detected changes leading 50 to the diagnosis of MM or WM in only 16% of cases, while myeloma- 40 related complications (bone pain/ fractures, anemia/fatigue, hypercal- cemia, renal failure) were responsible 30 for diagnosis in 45% of cases, and findings from diagnostic workup for

Serum M-spike (g/L) 20 less serious symptoms accounted for another 25%.14 Patients with low-risk MGUS 10 do not require initial bone marrow examination, skeletal survey, or oth- 0 er imaging studies unless there are 0 5 10 15 20 25 30 accompanying CRAB features, such Years from MGUS diagnosis as bone pain, anemia, or abnormal renal function. If there are no CRAB Figure 3. Patterns of protein increase in monoclonal gammopathy of undetermined features and screening test results for significance (MGUS) AL amyloidosis and WM are nega- Four patterns of protein increase in monoclonal gammopathy of undetermined significance tive, then patients may be followed (MGUS) are observed in relation to the development of a malignant plasma cell disorder. The plotted curves represent the composite values over time for all individuals in a particular with SPE (serum FLC optional) at 6 patient group. A fifth pattern (not illustrated) is characterized by the development of lytic lesions, months initially, and then annually if anemia, or renal insufficiency despite ongoing relative stability of the monoclonal protein level. they remain stable ( Figure 4 ). Alter- Data from Rajkumar SV, Kyle RA, Therneau TM, et al.,13 used with permission. natively, a longer follow-up period of 2 to 3 years or even a symptom-based compression is suspected, magnetic annually for life. recall may suffice.2-4 Repeat annual resonance imaging of the spine should At the time of follow-up, radio- visit testing should include history also be performed.8,15 In this situa- logical re-evaluation should be per- taking and physical examination, rou- tion, the patient should be considered formed only if there have been symp- tine chemistries, and SPE, with serum to have MM rather than MGUS. MRI toms and signs suggestive of bone FLC optional, unless the initial clon- may also prove helpful in confirming disease development or progression. al protein discovered is light chain suspected progression from MGUS to Patients with MGUS and known os­ alone. It is important to note that the MM15 because an abnormal signal on teoporosis or osteopenia should have test of choice for those patients with T1- or T2-weighted images strongly a follow-up bone density study every light chain alone MGUS is serum suggests pathological bone marrow 2 years, and be assessed for response FLC. In these instances, the SPE and infiltration.15 Patients with interme- to any anti-resorptive therapy.9,10 UPE results can be misleading. diate- or high-risk MGUS with an Patients followed regularly should Patients with intermediate-risk IgM monoclonal protein should have be referred for subspecialty evaluation and high-risk MGUS should have a an initial abdominal CT scan, since when symptoms compatible with the bone marrow aspiration biopsy with unsuspected asymptomatic retro- diagnosis of MM, lymphoma, WM, conventional cytogenetics and FISH peritoneal lymphadenopathy may be or AL amyloidosis develop. Referral analysis, as well as a skeletal survey. present. If the results of these tests might also be considered with devel- Early specialist referral may also be are normal, patients with IgM MGUS opment of unexplained new onset considered for this group. If impend- may be followed with SPE and rou- anemia, cytopenias, hypercalcemia, ing vertebral fracture or spinal cord tine blood work in 6 months, and then albuminuria, CHF, neuropathy, or an

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increase in the concentration of the Investigations monoclonal protein by more than • CBC, Ca2, creatine, , LFTs 30% (minimum absolute increase of • Serum immunoglobulins CRAB features* present or 5 g/L). All patients should be asked • Serum immunofixation M-protein > 30 g/L • Serum free light chain to make contact immediately with any • Urinalysis (protein/creatine ratio) significant change, such as the occur- rence of bone pain and symptoms of fatigue.2-4,8 CRAB features absent and Investigations M-protein < 30 g/L • Bone imaging studies It is important to realize that inter- • BM aspirate and biopsy laboratory variation in serial mono- • Evaluate for MM, WM, clonal protein SPE, UPE, and FLC and subspecialist referral MGUS determinations can be as high as 25%. For individual values, the biological coefficient of variation is around 8% for SPE and approaches 30% for UPE IgG, IgA IgM, • Lymphadenopathy M-protein M-protein • Hepatosplenomegally and FLC. This means that for any • Constitutional or change between two serial observa- hyperviscosity symptoms tions to be truly significant, a 30% present • Assess patient for any symptoms or signs of AL amyloidosis difference would be required for SPE • If absent consider M-protein values, and more than 70% in the case class of UPE and FLC values.16

When should the possibility of IgG IgA AL amyloidosis be considered and further testing undertaken? In AL amyloidosis, the abnormal SMP < 15 SMP ≥ 15 SMP <15 monoclonal light chain (frequently g/L and g/L and/or g/L and FLC ratio FLC ratio FLC ratio lamda) causes systemic proteotox- normal abnormal normal icity by misfolding and aggregating in fibrils, thus interacting with and depositing in various tissues.4,8,17 The Low-intermediate, inter- Low risk mediate, and high risk clinical presentation in amyloidosis usually depends on the organ system involved predominantly ( Table 2 ). • BM aspirate and biopsy BM = bone marrow Hence, the differential diagnosis is • Skeletal survey FLC = serum free light chain • Consider specialist based on early recognition of organ referral MGUS = monoclonal damage. For instance, early renal gammopathy of undetermined significance biopsy should be strongly considered Repeat visit† Repeat visit† in MM = multiple myeloma for any patient with low-level pro- in 6 months 6 months and SMP = serum monoclonal teinuria and renal failure or, alterna- and 2–3 years yearly there- protein tively, heavy proteinuria/nephrotic thereafter after SPE = serum protein syndrome. Hepatomegaly, abnormal electrophoresis liver function, or liver failure related WM = Waldenstrom On repeat visit: macroglobulinemia to amyloid deposition may initially history, physical exam, CBC, Ca2, creatine, SPE present with nonspecific symptoms such as asthenia and unintentional Figure 4. Management of patient with monoclonal protein found on serum protein weight loss, or simply an unantici- electophoresis, positive immunofixation, or abnormal serum free light chain ratio. pated elevation in alkaline phospha- *CRAB features include hypercalcemia, renal failure, anemia, bone lesions tase. Gastrointestinal tract involve- †Repeat visits at more frequent intervals if M-protein value is progressively increasing ment may manifest with gut motility

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problems, malabsorption, diarrhea, Heart failure is typically diastolic in an easier-to-obtain surrogate tissue or recurrent gastrointestinal bleed- nature with systolic dysfunction not can be biopsied (bone marrow or fat ing.4,17 Peripheral neuropathy is fre- appearing until late in the disease aspirate), but if the biopsy results are quently seen and is typically sensory course. Troponin T and the N-terminal negative, then tissue from an affected in nature. Carpal tunnel syndrome is fragment of pronatriuretic peptide organ is required. Congo red staining highly associated with amyloidosis, (NT-proBNP) are sensitive markers should be routinely performed on any although the syndrome is secondary of cardiac dysfunction in AL amyloi- bone marrow biopsy done as part of to soft tissue fibril deposits around dosis, with increases often noted sev- a workup for a newly discovered the carpal tunnel rather than to direct eral months before the onset of symp- M-protein. Importantly, AL amyloi- nerve damage. Autonomic neuropa- toms or detectable echocardiographic dosis is frequently associated with a thy may manifest with postural hypo- features.4 Unfortunately, elevations low-level monoclonal gammopathy, tension or symptoms of abnormal gut are not specific and may be noted in making it imperative that symptoms motility.17 a variety of other cardiac diseases. and signs typically associated with A high index of suspicion is espe- Since almost all patients with cardiac amyloid are actively pursued with cially important in the case of cardiac amyloidosis also have an abnormal M-proteins of any level.17 In addition, amyloidosis, since by the time clini- FLC ratio, a higher index of suspicion the monoclonal protein most often cal symptoms are evident, irrevers- for occult involvement has been sug- present is free lamda light chain alone. ible cardiac damage has frequently gested for all MGUS patients mani- Thus, if AL amyloid is suspected, an occurred.4,17 With cardiac amyloido- festing this abnormality.7 FLC assay should always be ordered sis, both conduction system and pump A definitive diagnosis requires the in addition to the UPE and SPE. function may be affected, producing identification by pathology of amyloid arrhythmias, heart failure, or both. deposition in affected organs.17 Often

Table 2. Possible presenting features of AL amyloidosis.

Symptoms Clinical presentation Red flags Approximate incidence

General Malnutrition Unexplained fatigue, dyspnea, or edema 75% Weight loss

Heart Nonischemic heart failure NT-proBNP > 332 ng/l (100% sensitivity) Arrhythmias Restrictive cardiac wall thickening BNP > 73 ng/L (90% sensitivity) 70% Low electrocardiographic voltage Late gadolinium enhancement at MRI

Kidney Nephrotic syndrome Proteinuria > 0.5 g/d Renal failure (predominantly albumin) 70%

Liver Hepatomegaly without scan defects Elevation of ALP or yGT in the absence of other causes 20%

PNS/ANS Nondiabetic symmetric ascending Neuropathic pain and loss of sensitivity to temperature peripheral neuropathy (small fibre, axonal) Erectile dysfunction 15% Postural hypertension Bladder and bowel dysfunction Onset of hypotension or resolution of hypertension

Soft tissue Purpura (periorbital) Carpal tunnel syndrome Macroglossia Claudication of the jaw 10% Muscular pseudohypertrophy Articular or soft tissue deposits

ALP = alkaline phosphatase, BNP = b-type natriuretic peptide, NT-proBNP = N-Terminal pro b-type natriuretic peptide, PNS/ANS = peripheral nervous system/autonomic nervous system, yGT = y-glutamyl transpeptidase.4,17

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Summary eloma Forum (UKMF) and Nordic Myelo- tween monoclonal gammopathy of unde- Since more than 70% of patients with ma Study Group (NMSG): Guidelines for termined significance and venous throm- MGUS discovered incidentally are in the investigation of newly detected M- boembolic disease. Thromb Res 2010; the low-risk category for progression, proteins and the management of mono- 125:216-219. and because MGUS itself occurs pre- clonal gammopathy of undermined sig- 13. Rajkumar SV, Kyle RA, Therneau TM, et dominantly in older individuals, more nificance (MGUS). Br J Haematol 2009; al. Serum free light chain ratio is an inde- than 90% of patients diagnosed with 147:22-42. pendent risk factor for progression of MGUS today will probably never 3. Kyle R, Buadi F, Rajkumar S. Management monoclonal gammopathy of undeter- develop multiple myeloma or anoth- of monoclonal gammopathy of undeter- mined significance. Blood 2005;106:812- er malignant plasmaproliferative mined significance (MGUS) and smolder- 817. disorder.2-4 Patients can be followed ing multiple myeloma (SMM). 14. Bianchi G, Kyle R, Colby C, et al. Impact using three established and easily 2011;25:578-586. of optimal follow-up of monoclonal gam- quantifiable risk factors: an M-spike 4. Merlini G, Palladini G. Differential diagno- mopathy of undetermined significance greater than 15 g/L, the presence of sis of monoclonal gammopathy of unde- on early diagnosis and prevention of non-IgG type protein, and an abnor- termined significance. Hematology Am myeloma-related complications. Blood mal FLC ratio.4,18 It is likely that most Soc Hematol Educ Program 2012;2012: 2010;116:2019-2025. patients in the low-risk category do not 595-603. 15. Walker R, Barlogie B, Haessler J, et al. require annual follow-up and could be 5. Murray D, Seningen J, Dispenzieri A, et al. Magnetic resonance imaging in multiple seen at less frequent intervals.18 Laboratory persistence and clinical pro- myeloma: Diagnostic and clinical implica- In the next few years, greater pre- gression of small monoclonal abnormali- tions. J Clin Oncol 2007;25:1121-1128. cision in identifying high-risk patients ties. Am J Clin Pathol 2012;138:609-613. 16. Katzmann J, Snyder M, Rajkumar S, et al. may allow for chemoprevention or 6. Vladutiu A. Prevalence of M-proteins in Long-term biological variation of serum complication prevention trials, espe- serum of hospitalized patients. Physi- protein electrophoresis M-spike, urine M- cially if more sensitive predictive cians’ response to finding M-proteins in spike, and monoclonal serum free light biomarkers for progression can be serum protein electrophoresis. Ann Clin chain quantification: Implications for mon- discovered.2,18 Whatever developments Lab Sci 1987;17:157-161. itoring monoclonal gammopathies. Clin are ahead, our aging population makes 7. Tosi P, Tomassetti S, Merli A, et al. Serum Chem 2011;57:1687-1692. it likely that primary care providers free light-chain assay for the detection and 17. Rosenzweig M, Landau H. Light chain will increasingly encounter and need monitoring of multiple myeloma and (AL) amyloidosis: Update on diagnosis to manage patients with MGUS. Using related conditions. Ther Adv Hem 2013; and management. J Hematol Oncol the guidelines and recommendations 4:37-41. 2011;10:4-47. now available, primary care providers 8. Bianchi G, Ghobrial I. Does my patient 18. Korde N, Kristinsson S, Landgren O. can play a significant role in managing with a serum monoclonal spike have mul- Monoclonal gammopathy of undeter- such patients, especially those found tiple myeloma? Hematol Oncol Clin North mined significance (MGUS) and smolder- to be at low risk for progression. Am 2012;26:383-393. ing multiple myeloma (SMM): Novel bio- 9. Kristinsson S, Tang M, Pfeiffer R, et al. logical insights and development of early Competing interests Monoclonal gammopathy of undeter- treatment strategies. Blood 2011;117: None declared. mined significance and risk of skeletal 5573-5581. fractures: A population based study. Blood Acknowledgments 2010;116:2651-2655. Serum protein electrophoresis and immuno­ 10. Berenson J, Yellin O, Boccia R, et al. Zole- electrophoresis strips kindly supplied by dronic acid markedly improves bone min- Allison Venner, PhD. eral density for patients with monoclonal gammopathy of undetermined signifi- References cance and bone loss. Clin Cancer Res 1. Berenson J, Anderson K, Audell R, et al. 2008;14:6289-6295. Monoclonal gammopathy of undeter- 11. Rajabally Y. Neuropathy and paraproteins: mined significance: A consensus state- Review of a complex association. Eur J ment. Br J Haematol 2010;150:28-38. Neurol 2011;18:1291-1298. 2. Bird J, Behrens J, Westin J, et al. UK My- 12. Cohen A, Sarid R. The relationship be-

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