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Diagnosis of monoclonal gammopathies
Eliminating the need for urine monoclonal studies as a part of initial diagnostic studies (ie, rule-out monoclonal gammopathy)
Assessing risk of progression from monoclonal gammopathy of undetermined significance to multiple myeloma
Monoclonal proteins are markers of plasma cell proliferative disorders. It has been recommended that serum and urine protein electrophoresis (PEL) and immunofixation electrophoresis (IFE) be performed as the diagnostic algorithm (eg, MPSS / Monoclonal Protein Study, Serum and MPSU / Monoclonal Protein Study, 24 Hour, Urine): A monoclonal band (M-spike) on serum and/or urine PEL identifies a monoclonal process and quantitates the abnormality. IFE characterizes the type of monoclonal protein (gamma, alpha, mu, delta, or epsilon heavy chain; kappa [K] or lambda [L] light chain). IFE is also more sensitive than PEL for detecting small abnormalities that may be present in diseases such as light chain multiple myeloma, oligosecretory myeloma, and plasmacytomas.
With the addition of the serum free light chain (FLC) assay, the expanded monoclonal protein study provides even more diagnostic sensitivity for the monoclonal light chain diseases such as primary amyloid and light chain deposition disease--disorders that often do not have serum monoclonal proteins in high enough concentration to be detected and quantitated by PEL. The FLC assay is specific for free kappa and lambda light chains and does not recognize light chains bound to intact immunoglobulin. Importantly, the addition of the serum FLC assay to serum PEL and IFE makes the serum diagnostic studies sufficiently sensitive so that urine specimens are no longer required as part of initial diagnostic studies.
Monoclonal gammopathies may be present in a wide spectrum of diseases that include malignancies of plasma cells or B lymphocytes (multiple myeloma: MM, macroglobulinemia, plasmacytoma, B-cell lymphoma), disorders of monoclonal protein structure (primary amyloid, light chain deposition disease, cryoglobulinemia), and apparently benign, premalignant conditions (monoclonal gammopathy of undetermined significance: MGUS, smoldering MM). While the identification of the monoclonal gammopathy is a laboratory diagnosis, the specific clinical diagnosis is dependent on a number of other laboratory and clinical assessments.
If a monoclonal protein pattern is detected by IFE or FLC, a diagnosis of a monoclonal gammopathy is established. Once a monoclonal gammopathy has been diagnosed, the size of the clonal abnormality can be monitored by PEL and/or FLC and in some instances by quantitative immunoglobulins. In addition, if the patient is asymptomatic and has a diagnosis of MGUS, the expanded monoclonal protein study panel provides the information (size of M-spike, monoclonal protein isotype, FLC K/L ratio) needed for a MGUS progression risk assessment (see Interpretation).
> or =1 year: 6.3-7.9 g/dL
Reference values have not been established for patients that are <12 months of age.
Albumin: 3.4-4.7 g/dL
Alpha-1-globulin: 0.1-0.3 g/dL
Alpha-2-globulin: 0.6-1.0 g/dL
Beta-globulin: 0.7-1.2 g/dL
Gamma-globulin: 0.6-1.6 g/dL
An interpretive comment is provided with the report.
No monoclonal protein detected
KAPPA-FREE LIGHT CHAIN
LAMBDA-FREE LIGHT CHAIN
KAPPA/LAMBDA-FREE LIGHT-CHAIN RATIO
-A characteristic monoclonal band (M-spike) is often found on protein electrophoresis (PEL) in the gamma globulin region and, more rarely, in the beta or alpha-2 regions. The finding of an M-spike, restricted migration, or hypogammaglobulinemic PEL pattern is suggestive of a possible monoclonal protein. Immunofixation electrophoresis (IFE) is performed to identify the immunoglobulin heavy chain and/or light chain.
-A monoclonal IgG or IgA >3 g/dL is consistent with multiple myeloma (MM).
-A monoclonal IgG or IgA <3 g/dL may be consistent with monoclonal gammopathy of undetermined significance (MGUS), primary systemic amyloidosis, early or treated myeloma, as well as a number of other monoclonal gammopathies.
-A monoclonal IgM >3 g/dL is consistent with macroglobulinemia.
-An abnormal serum free light chain (FLC) K/L ratio in the presence of a normal IFE suggests a monoclonal light chain process and should be followed by MPSU / Monoclonal Protein Study, 24 Hour, Urine.
-The initial identification of a serum M-spike >1.5 g/dL on PEL should be followed by MPSU / Monoclonal Protein Study, 24 Hour, Urine.
-The initial identification of an IgM, IgA, or IgG M-spike >4 g/dL, >5 g/dL, and >6 g/dL respectively, should be followed by VISCS / Viscosity, Serum.
- After the initial identification of a monoclonal band, quantitation of the M-spike on follow-up PEL can be used to monitor the monoclonal gammopathy. However, if the monoclonal protein falls within the beta region (most commonly an IgA or an IgM) quantitative immunoglobulin levels may be more a useful tool to follow the monoclonal protein level than PEL. A decrease or increase of the M-spike that is >0.5 g/dL is considered a significant change.
-Patients with monoclonal light chain diseases who have no serum or urine M-spike may be monitored with the serum FLC value.
-Patients suspected of having a monoclonal gammopathy may have normal serum PEL patterns. Approximately 11% of patients with MM have a completely normal serum PEL, with the monoclonal protein only identified by IFE. Approximately 8% of MM patients have hypogammaglobulinemia without a quantifiable M-spike on PEL but identified by IFE and/or FLC. Accordingly, a normal serum PEL does not rule out the disease and PEL alone should not be used to screen for the disorder if the clinical suspicion is high.
-Low-risk MGUS patients are defined as having an M-spike <1.5 g/dL, IgG monoclonal protein, and a normal FLC K/L ratio (0.25-1.65), and these patients have a lifetime risk of progression to MM of <5%.
-High-risk MGUS patients (M-spike >1.5, IgA or IgM, abnormal FLC ratio) have a lifetime risk of progression to MM of 60%.
Other Abnormal PEL Findings:
-A qualitatively normal but elevated gamma fraction (polyclonal hypergammaglobulinemia) is consistent with infection, liver disease, or autoimmune disease.
-A depressed gamma fraction (hypogammaglobulinemia) is consistent with immune deficiency and can also be associated with primary amyloidosis or nephrotic syndrome.
-A decreased albumin (<2 g/dL), increased alpha-2 fraction (>1.2 g/dL), and decreased gamma fraction (<1 g/dL) is consistent with nephritic syndrome and, when seen in an adult older than 40 years, should be followed by MPSU / Monoclonal Protein Study, 24 Hour, Urine.
-In the hereditary deficiency of a protein (eg, agammaglobulinemia, alpha-1-antitrypsin [A1AT] deficiency, hypoalbuminemia), the affected fraction is faint or absent.
-An absent alpha-1 fraction is consistent with A1AT deficiency disease and should be followed by a quantitative A1AT assay (AAT / Alpha-1-Antitrypsin, Serum).
Protein electrophoresis (PEL) alone is not considered an adequate screen for monoclonal gammopathies.
Very large IgG M-spikes (>4 g/dL) may saturate the protein stain. In these situations, quantitative IgG assays more accurately determine M-spike concentrations for monitoring disease progression or response to therapy.
Although the PEL M-spike is the recommended method of monitoring monoclonal gammopathies, IgA and IgM proteins that are contained in the beta fraction may be more accurately monitored by quantitative immunoglobulins.
Fibrinogen will migrate as a distinct band in the beta-gamma fraction but will be negative on immunofixation electrophoresis.
Hemolysis may augment the beta fraction.
Penicillin may split the albumin band.
Radiographic agents may produce an uninterpretable pattern.
1. Kyle RA, Katzmann JA, Lust JA, Dispenzieri A: Clinical indications and applications of electrophoresis and immunofixation. In Manual of Clinical Laboratory Immunology. Sixth edition. Edited by NR Rose, RG Hamilton, B Detrick. Washington DC. ASM Press, 2002, p 66-70
2. Rajkumar SV, Kyle RA, Therneau TM, et al: Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005;106:812-817
3. Katzmann JA, Dispenzieri A, Kyle RA, et al: Elimination of the need for urine studies in the screening algorithm for monoclonal gammopathies by using serum immunofixation and free light chain assays. Mayo Clin Proc 2006;81(12):1575-1578