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Editorials |
Department of Laboratory Medicine and Pathology, Department of Internal Medicine, Mayo Clinic, Rochester, MN,
aAddress correspondence to this author at:, 210 Hilton, Mayo Clinic, Rochester, MN 55905, Fax 507-266-4088, E-mail katzmann{at}mayo.edu
In this issue of Clinical Chemistry, Piehler et al. (1) present data on the use of serum protein electrophoresis (SPE),1 clinical history, and selective use of serum immunoglobulin free light chain (FLC) assay as a diagnostic screening algorithm for multiple myeloma (MM) in a general hospital population and conclude that this algorithm allows for efficient diagnosis or exclusion of multiple myeloma. The authors investigated clinical histories and sera of the 3818 samples sent to their laboratory for SPE over a 1-year period. These samples translated into 2854 unique patients: 2302 who did not have either an abnormality detected on SPE or a clinical history that included unexplained anemia, renal disease, hypercalcemia, increased sedimentation rate, and/or osteolysis, bone pain, or fractures; and 545 who met at least 1 of these criteria. Of the 545, 157 were excluded because their monoclonal protein had been previously recognized, leaving 332 patients: 83 who had a newly identified monoclonal band on SPE and 249 who had no monoclonal band detected. These 332 patients were subsequently screened with the FLC assay. Of the group without a monoclonal protein detected by SPE, 56 patients had an abnormal FLC ratio, and only 14% of these had a plasma cell disorder. Using this methodology, the authors "missed" only 4 diagnoses—2 myelomas and 2 plasmacytomas—and conclude that their algorithm detected 95% of all cases of MM, Waldenstrom macroglobulinemia, or primary amyloidosis.
The authors should be congratulated on this endeavor, but there are 2 major limitations of their study that must be addressed. The first is that clinical diagnosis rather than immunofixation electrophoresis (IFE) was used as the gold standard to assess the performance of their algorithm. Certainly clinical information is important, but in this instance the clinical gold standard of final diagnosis is highly reliant on their laboratory testing. Second, one must be cognizant that the abnormal expansion of a plasma cell clone in bone marrow is not typically appreciated until a secondary effect or symptom becomes apparent. The exceptions to this rule are the times when a high serum or urine total protein triggers further evaluation with protein electrophoresis and other tests that then may detect the secreted monoclonal immunoglobulin. The clinical signs and symptoms for the multitude of plasma cell dyscrasias, however, will vary significantly depending on the diagnosis. As the authors recognize, in the case of multiple myeloma, the clinical presentation includes anemia, bone lesions, renal impairment, or hypercalcemia. For Waldenstrom macroglobulinemia, the hallmarks are anemia, lymphadenopathy, and occasionally signs of hyperviscosity. However, for other, low-tumor-burden plasma cell disorders like immunoglobulin light chain amyloidosis (AL), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein skin changes), cryoglobulinemia, and immunoglobulin light chain deposition disease, the symptoms are more protean, and recognition of a small monoclonal protein is essential to send the clinician down the right diagnostic path. The testing algorithm employed by Piehler et al. does not take this into account. By not performing IFE in patients, it is impossible to estimate how many patients with one of these alternate diagnoses remain undiagnosed and will suffer from either a delayed diagnosis or a completely missed diagnosis.
IFE has been recommended for screening owing to its increased sensitivity not only for these rarer conditions, but also for picking up the 15%–20% of patients with either oligosecretory or light chain myeloma—i.e., those patients whose malignant plasma cells secrete immunoglobulin light chain without associated heavy chain. Free immunoglobulin light chains rapidly transit the blood because of renal clearance and are more easily detected in urine than blood by electrophoretic methods, but can frequently be detected in the serum by IFE. In addition, in 2001, sensitive quantitative assays for serum 
and 
free light chains became commercially available (2), and it has been repeatedly demonstrated that the ratio of to FLC in serum is very sensitive to clonal expansion of plasma cells that secrete excess FLC (3)(4)(5). Moreover, the quantitative FLC assay enables disease monitoring in the absence of a quantifiable M-spike (6)(7). Surprisingly, FLC quantification has also proven to be prognostic for progression of the premalignant conditions of monoclonal gammopathy of undetermined significance and smoldering multiple myeloma (8)(9) as well as for survival in MM, plasmacytoma, and primary amyloidosis (10)(11)(12). Because of these findings, many clinicians are now ordering protein electrophoresis, immunofixation electrophoresis, and serum FLC. As demonstrated by the initiative of Piehler et al., clinicians and laboratorians are trying to identify the best combination of serum and urine tests to use in initial testing for monoclonal gammopathies.
The approach used by Piehler et al. substitutes the laboratory’s review of medical history for the ordering physician’s judgment and for routine IFE and FLC testing. In this study (and in routine laboratory medicine practice), it is not always clear why physicians order SPE; approximately 75% of samples had no indication in the medical record that suggested multiple myeloma. Although clinicians should understand that population-based screening for monoclonal gammopathies is not appropriate, serious diseases still may need to be ruled out. If clinicians order SPE to rule out monoclonal gammopathies other than MM, then the laboratory’s criteria for further testing will need to be expanded beyond the clinical presentations associated with MM. For most laboratories, it is impractical to review medical records for all SPE requests, and if the clinical criteria are expanded, this difficulty significantly increases.
The minimal laboratory testing approach proposed by Piehler et al. is different from other published algorithms. The current screening recommendations for patients suspected of having MM are protein electrophoresis and IFE of both serum and urine. Because of the sensitivity of serum FLC quantification for clonal FLC excess, it has been suggested to test serum SPE, IFE, and FLC as the initial screening algorithm (13). If a monoclonal gammopathy is identified, urine studies may then be needed for the final diagnosis. An alternative approach is the use of SPE and FLC with IFE and urine studies triggered if an abnormality is detected (14). Although this algorithm will not detect small monoclonal proteins that are obscured in the β fraction, it is likely that a small monoclonal protein with no excess FLC is not clinically significant. The elimination of urine studies and of serum IFE from first-line monoclonal gammopathy screening similar to that proposed by Piehler et al. will reduce laboratory complexity and cost, but systematic studies validating these approaches have not been published.
As we extend FLC measurements into the general hospital population, we have to recognize potential false positives in the group of minimally abnormal FLC ratios (1)(14)(15). An efficient screening algorithm for monoclonal gammopathies remains to be finalized and may depend on the distribution of patients in the individual medical practice. At this point, there are 2 clear conclusions regarding screening for monoclonal gammopathies: 1) population-based screening should not be performed and clinical judgment is integral to test ordering, and 2) if serum FLC is part of the approach, then urine assays are not needed as part of the initial evaluation.
Acknowledgments
Author Contributions: Each author confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors’ Disclosures of Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
Footnotes
1 Nonstandard abbreviations: SPE, serum protein electrophoresis; FLC, free light chain; MM, multiple myeloma; IFE, immunofixation electrophoresis. 
References
The following articles in journals at HighWire Press have cited this article:
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  R. B Fulton and S. L Fernando Serum free light chain assay reduces the need for serum and urine immunofixation electrophoresis in the evaluation of monoclonal gammopathy Ann Clin Biochem, September 1, 2009; 46(5): 407 - 412. [Abstract] [Full Text] [PDF]
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 A. J. Bakker, A. Bierma-Ram, C. Elderman-van der Werf, M. L. Strijdhaftig, and J. J. van Zanden Quantitation of Serum Free Light Chains Clin. Chem., August 1, 2009; 55(8): 1585 - 1587. [Full Text] [PDF]
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