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Rao M, Yu WW, Chan J, et al. Serum Free Light Chain Analysis for the Diagnosis, Management, and Prognosis of Plasma Cell Dyscrasias [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Aug. (Comparative Effectiveness Reviews, No. 73.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Serum Free Light Chain Analysis for the Diagnosis, Management, and Prognosis of Plasma Cell Dyscrasias

Serum Free Light Chain Analysis for the Diagnosis, Management, and Prognosis of Plasma Cell Dyscrasias [Internet].

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Introduction

Plasma Cell Dyscrasias

Plasma cell dyscrasias (PCDs) are a group of neoplastic disorders characterized by the uninhibited expansion of a monoclonal population of malignant plasma cells.1 Multiple myeloma (MM) is the most common malignant plasma cell tumor, accounting for about 1 percent of all cancer types,1 and the second most common hematologic malignancy in the United States. With an age-adjusted incidence rate of 5.5 cases per 100,000 population,2 the American Cancer Society estimated that there were 19,900 new diagnoses and 10,790 deaths due to myeloma in 2007.3 Although the median survival has improved to 5 years with current standards of treatment,4 the annual costs of modern therapies can range from $50,000 to $125,000 per patient.5,6

Plasma cells arise from B cells in the bone marrow and produces immunoglobulins that constitute the body's normal humoral immune response. The immunoglobulin molecule is composed of a heavy chain and a light chain. Plasma cells normally produce light chains in excess that do not bind to heavy chains to form a complete immunoglobulin molecule and instead enter the bloodstream as free light chains (FLCs).

In PCDs, each abnormally expanded clone of malignant plasma cells produce an excess of either intact immunoglobulin or FLCs of a single type; either type of excess molecule is called a monoclonal protein (M protein) or paraprotein. Measurement of M proteins (either complete immunoglobulins or FLCs) is integral to diagnosing PCDs, monitoring disease response to therapy and adjusting treatment, and determining disease progression or relapse.

PCDs range in severity. The mildest and most common PCD is the precancerous monoclonal gammopathy of undetermined significance (MGUS), affecting approximately 3 percent of the general population 50 years of age or older.1 MGUS can progress to asymptomatic MM (also called smoldering or indolent MM) or symptomatic MM. The M proteins produced in MM are either intact immunoglobulins or FLCs or both. Rarer MM variants include light chain MM (LCMM, formerly known as Bence Jones myeloma), characterized by expanded FLC-producing clones, and oligosecretory or nonsecretory MM (NSMM), in which few detectable light- or heavy-chain M proteins are secreted. Other PCDs include systemic (primary) AL amyloidosis, (also called light chain amyloidosis) in which amyloid [A] proteins derived from immunoglobulin light chains [L] are deposited in tissue, as well as macroglobulinemia, solitary plasmacytoma, and plasma-cell leukemia. AL amyloidosis can be a complication of MM but is often considered a distinct disorder related to a relatively stable, slow-growing plasma-cell clone and organ dysfunction.

SFLC Assay, Guidelines, and Current Use

SFLC Assay

The serum free light chain (SFLC) assay (the Freelite™ Assay, The Binding Site Ltd., Birmingham, United Kingdom) was introduced in 2001 to measure the FLC component in serum.7 The assay works by recognizing an epitope that is detectable only on light chains that are not bound to the heavy chain of the immunoglobulin molecule—the FLCs—in the serum. This is the sole SFLC assay approved by the U.S. Food and Drug Administration (FDA) and is classified as an immunoglobulin light chain-specific immunological test system. It measures kappa and lambda light chains separately and detects low concentrations of FLCs—less than 1 mg/dL in serum and less than 200 mg/day in urine.8 The other main advantage is the ability to measure the ratio of kappa chains to lambda chains, for which the normal range is 0.26 to 1.65.9 An abnormal ratio provides a useful index of clonality, as clonal disorders produce disproportionately high concentrations of a single type of light chain. In a given case of PCD, if kappa chains are in excess, the kappa/lambda ratio is greater than 1.65; if the lambda chains are in excess, the ratio is less than 0.26.

Guidelines

The International Myeloma Working Group (IMWG) recommends the following actions and tests for evaluation of a patient suspected of having a myeloma7: a complete history taking and physical examination; routine laboratory testing including serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE), nephelometric quantitation of immunoglobulins, and measurement of serum FLCs (SFLCs); bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization; and imaging. Thus, testing for M protein is only one part—albeit an integral part—of a suite of tests done to diagnose PCDs.

M protein measurement and typing are traditionally achieved through the use of SPEP and/or urine protein electrophoresis (UPEP) and SIFE and/or urine immunofixation electrophoresis (UIFE), plus immunoglobulin quantification. These traditional tests have relatively low sensitivity, especially regarding concentrations of SFLCs. This lack of sensitivity results in many undetected cases of PCDs involving excess FLCs. It is likely that up to 3 percent of cases of NSMM, LCMM, or AL amyloidosis are not detected by traditional tests.10 To increase the chance of detection of FLCs in urine, 24-hour urine collection has been recommended, along with procedures to concentrate urine samples. Yet these adaptations can be cumbersome for patients and providers, affecting compliance and test accuracy.

In general, for diagnosis, SPEP is estimated to detect an immunoglobulin peak in 82 percent of patients with MM.10 The addition of SIFE increases the sensitivity to 93 to 95 percent,4,5 which is further increased to 97 percent by performing UPEP and UIFE.10

It has been suggested that the SFLC assay could play an adjunctive role in screening, diagnosis, monitoring, and prognosis of PCDs in high-risk populations. The IMWG currently considers the SFLC assay to be an adjunct to traditional tests.11 The assay could allow for quantitative monitoring of response and remission after treatment and provide prognostic information,12,13 potentially reducing the need for frequent bone marrow biopsy for purposes of quantifying plasma cells, which is required as part of stringent monitoring for MGUS progression to MM or defining disease remission.11 It could potentially be used in conjunction with SPEP and SIFE to replace urine tests that require 24-hour collection (UPEP and UIFE), which could simplify diagnosis and disease monitoring.9,11 The SFLC assay may also be the only means of detecting a disease marker in some disease settings: NSMM, where SFLCs are often the only marker of the disease14; AL amyloidosis, where low M protein concentrations may not be detected by means of conventional techniques; and LCMM, where the M protein consists only of FLCs.11 Thus, in addition to detecting a wider spectrum of PCDs than traditional tests, the assay may help detect earlier stages of the disease, and because of the short half-life of SFLCs (2 to 6 hours, vs. 21 days for complete immunoglobulins15), the assay may also help detect relapses and treatment failures earlier than by reliance on M protein concentrations alone.10

Clinical Effectiveness and Use in Practice

Although the SFLC assay has been in use for a decade, how best to incorporate it into practice remain unclear.16 The test appears to have been widely adopted by clinicians as an adjunct to the panel of tests used to diagnose PCDs, given the assay's biological validity and ease of use as compared with cumbersome urine collections. Its use is also being evaluated in patient management. The SFLC assay has successfully been used to define disease subcategories and improve risk stratification.17,18 The test is efficient in the diagnosis of AL amyloidosis,19-21 as is reflected in the International Society of Amyloidosis Consensus Response criteria.22

But uncertainties regarding the optimal use of the SFLC assay remain. PCDs are a heterogeneous group of disorders that require a panel of tests for accurate diagnosis. Different tests will perform differently across the variety of disease subgroups and across different disease settings, and their results need to be evaluated with this in mind. Ascertainment of its comparative effectiveness will allow for the use of the assay to be refined and recommendations optimized; these aspects are addressed in the present comparative effectiveness review (CER). Evaluations of clinical utility should take into consideration different clinical settings and phases of disease as well as different disease populations.

Context of This Comparative Effectiveness Review

The aim of this CER is to evaluate the body of evidence that exists to address the relative effectiveness of the SFLC assay as compared with traditional tests for the diagnosis, management, and prognosis of PCDs. We sought to answer a set of questions focusing on the SFLC assay versus traditional testing in specific clinical settings to focus on comparative effectiveness. Our goals were to evaluate the SFLC assay as an add-on test in diagnostic settings and to compare it with existing tests in other settings such as for disease monitoring and prognosis. These questions were vetted by panels of Key Informants and Technical Experts who assisted in identifying the important areas for evidence review (as discussed in the Methods section). To address these areas in an unbiased way that would permit summary of the relevant data, studies had to meet a specific, predefined set of criteria related to population, intervention (diagnostic test/disease monitoring), comparator, and outcome (PICO). Many articles in the literature address clinical but not comparative effectiveness and therefore did not meet our stated goals.

Key Questions

Five KQs were formulated in consultation with American Association for Clinical Chemistry (AACC) and the Agency for Healthcare Research and Quality (AHRQ).

KQ1. Does adding the SFLC assay and the kappa/lambda ratio to traditional testing (serum/urine electrophoresis or IFE), compared with traditional testing alone, improve the diagnostic accuracy for PCDs (MGUS, MM, NSMM, or AL amyloidosis) in undiagnosed patients suspected of having a PCD?

KQ2. As compared with traditional tests, how well does the SFLC assay independently predict progression to MM in patients with MGUS?

KQ3. In patients with an existing diagnosis of PCD (MM, NSMM, or AL amyloidosis), does the use of the SFLC assay result in different treatment decisions as compared with traditional tests?

  • Does the use of the SFLC assay affect the management of patients by allowing for earlier institution of specific therapies?
  • Does the use of the SFLC assay influence the duration of treatment?
  • Does the use of the SFLC assay influence the type of treatment (e.g., radiation therapy)?

KQ4. In patients with an existing diagnosis of PCD (MM, NSMM, or AL amyloidosis), is the SFLC assay better than traditional tests in indicating how the patient responds to treatment and of outcomes (overall survival, disease-free survival, remission, light chain escape, and quality of life)?

KQ5. In patients with an existing diagnosis of PCD (MM, NSMM, or AL amyloidosis), does the use of the SFLC assay reduce the need for other diagnostic tests (e.g., bone marrow biopsy)?

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