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  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.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

Literature Search

The literature search yielded 3036 citations (Figure 2). Of these, 2711 were excluded at the abstract level. The remaining 325 articles were retrieved for full-text review, upon which 310 were excluded. Most of the exclusions were studies that did not meet all of the predefined PICO criteria and/or did not provide data comparing the performance of the SFLC assay with the predefined traditional tests (serum or urine tests [SPEP, UPEP, SIFE, or UIFE], bone marrow evaluation, or skeletal survey). (See Appendix B for the list of rejected articles and the rationale for their rejection.) A total of 15 studies that were both comparative and met all the CER eligibility criteria were included.

Figure 2 is a flow chart that summarizes the search and selection of articles: There were 3036 citations identified by searching MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, with 2711 excluded at the abstract level. The remaining 325 articles were retrieved for full-text review, upon which 310 were excluded. Most of the exclusions were because studies did not meet all of the predefined PICO criteria and/or did not provide data comparing the performance of the SFLC assay with the predefined traditional tests. A total of 15 studies that were both comparative and met all the CER eligibility criteria were included.

Figure 2

Summary of search and selection of articles. FLC=free light chain; KQ=Key Question; PCD=plasma cell dyscrasia; PICO=population, intervention (diagnostic test/disease monitoring), comparator, and outcome; SFLC=serum free light chain

All included studies either used the Freelite assay for measuring SFLCs or referred to measurement of SFLCs or to a nephelometric technique for their measurement. We targeted any data describing, or permitting the inference of, a comparison between any single or group of traditional tests (SPEP, UPEP, SIFE, or UIFE) used to detect PCDs (particularly MGUS, MM [including LCMM and NSMM], or AL amyloidosis) and the same single test or group of tests with an SFLC assay added. Studies of diagnosis, progression, and treatment of PCDs were all of interest.

Study Quality Grade and Overall Strength of Evidence

Table 1 summarizes the relevance and quality of the 15 studies reviewed in detail. The studies are organized by which KQ they addressed and the quality grade they were assigned. The criteria met by each study and its quality grade are provided in Appendix C.

Table 1. Distribution and quality of the 15 studies addressing a KQ.

Table 1

Distribution and quality of the 15 studies addressing a KQ.

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?

Results

Three studies31-33 evaluated the addition of SFLC testing to traditional testing for the diagnosis of PCDs in undiagnosed patients suspected of having a PCD. The study characteristics and findings are listed in Tables 2, 3, and 4.

Table 2. Characteristics of studies addressing KQ1.

Table 2

Characteristics of studies addressing KQ1.

Table 3. Characteristics of patients in studies addressing KQ1.

Table 3

Characteristics of patients in studies addressing KQ1.

Table 4. Results of studies addressing KQ1.

Table 4

Results of studies addressing KQ1.

Each study was rated B quality because of the retrospective design and because formal statistical comparisons and confidence intervals were not provided. All three studies compared test results with the diagnosis of disease verified by medical records on the basis of a panel of criteria. One study reported industry-associated funding and also was the only study of the three to report the demographic characteristics of the study population 31

Abadie 200631 examined the diagnostic accuracy of the SFLC assay, with or without SPEP, in 312 consecutive, predominantly male veterans without a prior diagnosis of PCD. Fifteen percent of the patients were found on diagnostic testing to have a malignant PCD. The use of SPEP alone had a diagnostic sensitivity of 0.88 and a specificity of 0.98, with 15 false negatives (12 for MM and 1 each for Waldenstrom's macroglobulinemia, AL amyloidosis, and lymphoma). SPEP used in combination with the SFLC assay increased the sensitivity to 1.00 and the specificity to 0.99, although use of the SFLC assay alone showed four false negatives (two for MM and two for “potential MM”).

Piehler 200832 measured SFLCs, as well as performing SPEP, in 332 patients suspected of having monoclonal gammopathy (i.e., a PCD or other conditions such as hematological disorders associated with a monoclonal band). Twenty-seven percent of patients had a PCD, including 2.1 percent with LCMM, 6.6 percent with MM, 0.6 percent with amyloidosis, and 13.6 percent with MGUS. Use of the SFLC assay plus SPEP resulted in a diagnostic sensitivity of 0.96 and specificity of 0.78; whereas SPEP alone had a sensitivity of 0.87 and specificity of 0.98.

Vermeersch 200833 explored the use of the SFLC assay in 833 consecutive patients suspected of having a PCD and compared various tests and combinations of tests (Table 4). Three percent of patients had a malignant PCD and 19 percent had MGUS. The highest diagnostic sensitivity, 0.94, was achieved by using the SFLC assay plus SIFE. SIFE alone had a sensitivity of 0.92. The SFLC assay plus SPEP (with SIFE performed only if SPEP was positive, for confirmation) achieved a sensitivity of 0.82, whereas SPEP plus SIFE without the SFLC assay had a sensitivity of 0.79. SPEP plus SIFE had a specificity of 1.00, as did SIFE alone; the SFLC assay plus either SPEP (with SIFE for confirmation) or SIFE had a specificity of 0.97.

Summary

Three retrospective studies evaluated the SFLC assay in combination with traditional tests in undiagnosed patients suspected of having a PCD. The addition of the SFLC assay to traditional tests in a diagnostic panel increased the sensitivity of the assay for detection of PCDs in all three studies (from 0.64–0.87 to 0.96–1.00 for SPEP and to 0.92–0.94 for SIFE). The statistical significance of the increase in sensitivity was not addressed in any of the studies; the effect on specificity was inconsistent. The studies were heterogeneous with regard to design and comparator, such that meta-analysis could not be performed for quantitative data synthesis. We rated the strength of evidence to evaluate the effect of adding SFLC testing to traditional testing on diagnostic performance as insufficient.

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

No studies compared the use of the SFLC assay with traditional tests to determine whether the use of the SFLC assay predicts progression from MGUS to MM. Therefore, we rated the strength of evidence as insufficient for this question.

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)?

No studies compared the use of the SFLC assay with traditional tests to determine whether treatment decisions were different with regard to timing, duration, or type of treatment. Therefore, we rated the strength of evidence as insufficient for this question.

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)?

Results

Eleven studies evaluated the SFLC assay and traditional testing in parallel and examined their relationship to clinical outcomes in PCDs.13,34-42 43 No direct comparisons between the SFLC assay and traditional tests were performed. Three studies were conducted in patients with AL amyloidosis13,38,40 and eight in patients with MM.34-37,39,41-43 Three studies38,40,43 reported industry-associated funding or authorship. Nine studies were retrospective13,34-36,38-42 and one was prospective43; the remaining study37 lacked enough detail to determine the study design. Followup times varied from 3 months to 13 years, with sample sizes of 40 to 443 patients. Among studies reporting patient characteristics, the median age ranged from 54 to 72 years and the study populations were 44 to 65 percent male.

Patients With AL Amyloidosis

Three retrospective studies examined the SFLC assay in patients with AL amyloidosis and reported the use of SFLC assay in evaluating treatment response and predicting prognosis: Kumar 2011,38 Lachmann 2003, 40 and Sanchorawala 2005.13 These studies measured SFLC responses and paraprotein responses to treatment with traditional testing (electrophoresis or IFE) and examined their relationship to outcomes. Paraprotein reduction was usually reported as part of a “hematologically complete” response.22

The sample sizes were 66, 262, and 443 patients (Tables 5–7). Followup times were 21 months to 5 years. Kumar 2011 and Lachmann 2003 reported industry-associated funding or authorship. All three studies reported explicit diagnostic criteria. Lachmann 2003 reported enrolling referred patients; the other two studies did not describe the enrollment method. The median age of study participants was 54 to 64 years and, in the two studies with data on patient sex, one had 61 percent men and the other, 63 percent men. All three studies were rated as quality C; none of the three studies performed direct statistical comparisons of the relative strength of prediction, providing only unadjusted estimates for each predictor.

Table 5. Characteristics of studies addressing KQ4.

Table 5

Characteristics of studies addressing KQ4.

Table 6. Characteristics of patients in studies addressing KQ4.

Table 6

Characteristics of patients in studies addressing KQ4.

Table 7. Results of studies addressing KQ4.

Table 7

Results of studies addressing KQ4.

All three studies showed that patients with greater reductions in abnormal SFLC concentrations (a >50 percent reduction40 or >90 percent reduction,13,38 vs. lesser reductions) after treatment (either chemotherapy or stem-cell transplantation) had better survival outcomes.

Although Kumar 201138 did not find quantitative paraprotein concentrations to be a good predictor (unlike SFLC concentrations), Lachmann 200340 found the paraprotein concentration to be significantly related to survival; however, the relationship seemed to be weaker than that of SFLC reduction to survival. In Kumar 2011, some patients with PCD did not have “measurable disease,” (i.e., they did not have elevated SFLC concentrations before treatment), which precluded use of the SFLC assay as a marker of disease and treatment response, limiting the assay's utility. Sanchorwala 200513 found that a reduction in SFLC concentration by more than 90 percent and achievement of a complete response were both predictive of a lower mortality and both provided independent predictive information.

Summary for AL Amyloidosis

Although the three studies reported that the SFLC assay may aid in assessing treatment response and monitoring outcomes in AL amyloidosis patients, no direct comparisons with traditional tests (electrophoresis or IFE) were performed. All three studies were rated as quality C, owing to limitations in study design, including selection/spectrum bias as well as (in one study) small sample size. Overall, because of a lack of direct comparisons and poor study quality, current evidence on the effectiveness of the SFLC assay compared with traditional tests for assessment of treatment response and outcome is inconclusive. The strength of evidence underlying this comparison was therefore rated as insufficient.

Patients With MM

Eight studies34-37,39,41 42,43 enrolled patients with MM and compared the use of SFLC assay and other traditional tests in evaluating treatment response and predicting prognosis (Tables 5–7). Six of the eight—Dispenzieri 2008,34 Giarin 2009,35 Khoriaty 2010,36 van Rhee 2007,41 Kyrtsonis 2007,39, and Paiva 201142—were retrospective analyses of cohorts; one study, Dytfeld 2011,43 was prospective; and study design was not specified in the remaining study, Kroger 2010.37 Sample size ranged from 40 to 303, and median followup duration was 3 months to 13 years. Study quality was graded as B in three of the eight studies, owing to retrospective designs without adjustments for potential confounders,34,35,41 and C in the other five studies, owing to small sample sizes, limited information about study design, and/or potential selection bias.36,37,39,42,43 None of the three B-quality studies performed direct statistical comparisons of relative strength of prediction. The three outcome categories covered in the studies are discussed in the next paragraphs.

Assessment and Prediction of Treatment Response

Four studies34,36, 37,42 addressed the use of SFLC assay in the assessment of treatment response and one study43 addressed the prediction of treatment response. The traditional test comparators that were also used to assess treatment response (in parallel with the SFLC assay) differed in each study (i.e., SPEP, UPEP, total kappa/lambda ratio measured by nephelometry, bone marrow evaluation with immunophenotyping, or standard response criteria [e.g., from IMWG]).

Of the four studies that used SFLC test results to assess treatment response, one study, of C quality, found that 22 of 102 patients had discordant findings regarding achievement of a treatment response after induction therapy, defined according to the SFLC ratio and the immunophenotypic response.42 Another study, of B quality, found that after 2 months of therapy, treatment response was achieved by 23 percent of 139 patients using the paraprotein definition, compared with 62 percent using the SFLC definition.34 In a C-quality study, the majority (27 of 43 patients) achieved treatment response as defined by both M protein criteria and SFLC criteria at the same time; SFLC response occurred earlier than M protein response in eight other patients.36 A fourth study37 of unclear design reported an abnormal SFLC ratio before relapse and a positive IFE test in 9 of a subgroup of 10 patients. The quality of this study was rated as C because of the limited information about study design, SFLC response definitions, and results.

Only 1 study, of C quality, reported data on prediction of treatment response.43 Patients received VDD (bortezomib, pegylated liposomal doxorubicin, and dexamethasone) treatment for newly diagnosed, histologically confirmed MM. An SFLC and M protein–based prognostic model predicted that either a 90 percent or greater reduction in serum M protein level or involved SFLC level, or normalization of the SFLC ratio, predicted a very good partial response (VGPR) or better response with 92 percent sensitivity and 93 percent specificity after two cycles of VDD treatment. Sensitivity increased to 96 percent after three cycles of VDD treatment. Taking into account the heterogeneity of MM and its spectrum of M protein presentations, measurements of both the involved SFLC and M protein were needed to fully monitor response to treatment. Neither the rate of decline in M protein or involved SFLC concentration independently predicted VGPR at the end of six cycles of VDD (at 90 percent sensitivity and specificity). When the involved SFLC was replaced by urine M protein in the predictive model, the sensitivity, specificity, and predictive value were all less than 90 percent.

Relationship Between Baseline SFLC Measurements and Survival

Two studies examined the relationship of baseline SFLC concentrations and survival; one followed 303 patients for 21 months and included concomitant evaluation of the predictive ability of traditional testing (in the form of measurement of baseline concentrations of serum and urine M protein),41 whereas the other followed 94 patients for 33 months and incorporated the clinical Durie–Salmon staging system and the International Staging System (ISS).39 In the former study, of B quality, the top tertile of SFLC concentrations (>75 mg/dL) were considered the risk category,41 whereas in the latter study, of C quality, patients were stratified according to whether the SFLC ratio was above or below the median (with the ratio calculated using the involved SFLC in the numerator, for a monotonic distribution).39 In both studies, patients with higher SFLC concentrations or ratio had significantly lower survival rates than did patients with lower SFLC concentrations or ratio. The former study did not find serum or urine M protein concentrations to be predictive of survival and reported significantly poorer overall and event-free survival rates among patients with a baseline SFLC level of greater than 75 mg/dL (vs. ≤75 mg/dL; p=0.016 and p=0.008, respectively).41 The latter study reported that while Durie–Salmon and ISS staging were independent predictors (both p<0.0001), an abnormal SFLC ratio was also significantly associated with 3- and 5-year disease-specific survival rates (p=0.0001).39

Relationship Between Post-Treatment SFLC Measurements and Survival

Three studies examined the relationship between post-treatment SFLC ratios and survival.35,41,42 One study42 of C quality analyzed the SFLC ratios after induction therapy among a subset of 102 patients enrolled in a previous trial. After stratification of patients on the basis of immunofixation status, the 3-year progression-free survival rate, time to progression, and overall survival did not differ between patients with normal and abnormal SFLC ratios post-treatment.42

A second study,35 of B quality, analyzed immunofixation results and SFLC ratios after stem-cell transplantation among 202 patients. Overall and event-free survival did not differ between patients with and those without a normal SFLC ratio or between patients with and those without a normal SIFE test.35 However, this study also reported that a normal SFLC ratio at 3 months post treatment was significantly associated with longer event-free survival (p=0.02) but not with overall survival (p=NS).

In a third study of 303 patients,41 also of B quality, patients with a percent reduction in SFLC concentration in the top tertile after transplantation had nearly twice the risk of death—that is, hazard ratios greater than 2 for overall or event-free survival—than patients with less of a percent reduction (after adjustment for serum lactate dehydrogenase concentration and cytogenetic abnormalities), despite a paradoxically better response to induction therapy. However, there was no significant relationship between the tertiles of percent reductions in serum and urine M protein values and overall or event-free survival.

Summary for MM

Eight studies reported on the use of the SFLC assay and traditional tests in measuring treatment response and predicting prognosis in patients with MM. However, none of the studies formally compared the predictive capability of the SFLC assay with that of traditional tests. Most (75 percent) were retrospective cohort studies, and only 3 were of quality B (with the rest being quality C). The studies were heterogeneous with respect to population, intervention (diagnostic test/disease monitoring), and comparator as well as degree of adjustment for confounders. Taken together, these factors limit the conclusions that can be drawn about the definitive use of the SFLC assay in prognosis prediction, and the strength of evidence was rated as insufficient for comparisons with traditional testing in patients with MM.

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)?

Results

We identified one C-quality retrospective cohort study assessing the need for bone marrow examination, with the SFLC assay used to define the completeness of response to treatment: Chee 200947 (Tables 8–10). As currently defined in the European Group for Blood and Marrow Transplantation and IMWG uniform response criteria, a complete response in a patient with MM requires a bone marrow examination showing less than 5 percent plasma cells, in addition to negative SIFE and UIFE results; the addition of normalization of the SFLC ratio defines stringently complete remission.22,27

Table 8. Characteristics of studies addressing KQ5.

Table 8

Characteristics of studies addressing KQ5.

Table 9. Characteristics of patients in studies addressing KQ5.

Table 9

Characteristics of patients in studies addressing KQ5.

Table 10. Results of studies addressing KQ5.

Table 10

Results of studies addressing KQ5.

Chee 2009 enrolled 92 patients with MM who achieved negative SIFE and UIFE tests after therapy and had a bone marrow aspirate or biopsy performed within 30 days before or after those tests. A subgroup of 29 patients also had data on the SFLC ratio; among those whose ratio normalized, the percentage of clonal plasma cells in the bone marrow was examined. Fourteen percent of patients with a negative IFE test had more than 5 percent plasma cells in bone marrow, as did 10 percent of patients with a normal SFLC ratio. Among patients with IFE-negative status, those with less than 5 percent plasma cells in the marrow had improved overall survival compared with those with 5 percent or more plasma cells (6.2 years vs. 2.3 years, respectively; p <0.01).

Summary

A single study was found that addressed whether IFE or SFLC testing would reduce the need for other diagnostic tests such as bone marrow examination; the authors concluded that it was not possible to eliminate such tests. Owing to the preliminary nature of the data, we rated the strength of evidence as insufficient for addressing this question.

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