Comparison of Serum Free Light Chain Levels and 24 Hour Urinary Monoclonal Protein Secretion in Patients with Myeloma: Concordant Changes with Response to Therapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5064-5064 ◽  
Author(s):  
Shaji Kumar ◽  
S. Vincent Rajkumar ◽  
Matthew Plevak ◽  
Robert A. Kyle ◽  
Jerry A. Katzmann ◽  
...  
Keyword(s):  
Light Chain ◽  
Protein Level ◽  
Free Light Chain ◽  
Response To Therapy ◽  
M Protein ◽  
Serum Free ◽  
Protein Levels ◽  
Serum Free Light Chain ◽  
Data Points ◽  
Over Time

Abstract Background: The measurement of monoclonal (M) protein in the serum and urine is critical for response assessment and disease evaluation in patients with multiple myeloma (MM). The serum free light chain (FLC) assay offers a new and sensitive method of assessing response to therapy. An important question that has not been adequately addressed is the correlation between 24 hour urine M protein levels and serum FLC measurements, and the extent to which response to therapy estimated using the FLC assay correlates with that assessed using the 24 hour urine M protein level. Methods: A total of 2194 sets of data, with simultaneous UPEP and serum FLC measurement, were studied. These included 752 unique patients, with individual patients having 1–23 paired assessments over time. FLC estimation was carried out using the serum FLC assay (Freelite; The Binding Site Limited, UK) performed on a Dade-Behring Nephelometer. Based on the established reference range, kappa/lambda FLC ratio <0.26 or >1.65 were defined as abnormal indicating the presence of monoclonal lambda and kappa FLC, respectively. The monoclonal light chain isotype was considered the involved FLC isotype, and the opposite light chain type as the uninvolved FLC type. The Urine M protein by UPEP was compared to the serum levels of the involved light chain using Spearman Rank Correlation. For comparisons in individual patients over time, those with at least 10 measurements each were studied. Results: The median involved FLC level in patients with an undetectable urine M protein was 2.3 mg/dl compared to 32.2 mg/dL among those with a detectable urine M protein (P<0.001). Among the 1676 points with an abnormal FLC ratio, only 75% had an M protein detected in the urine, P < 0.001. Conversely, among patients with a positive urine M-protein, 91% had an abnormal FLC ratio. When all the 2194 data points were considered together, there was a significant correlation between the urine M protein level and the FLC levels (FLC level calculated as the difference between involved and uninvolved levels), rho=0.763, P < 0.001. The correlation did not change when patients with a serum creatinine of over 2.5 were excluded. The correlation between FLC levels and urinary M protein can be affected by several factors such as renal function that will differ across patients. Therefore, we examined whether the correlation between the two variables is stronger when the variations introduced by inter-patient differences in the relationship between the two variables are eliminated. In order to do this, we studied individual patients on whom multiple data points over time were available. One patient who had the maximum number of paired assessments (23 pairs) of serum FLC level and urinary M protein; the correlation between the two variables over time was highly significant, rho 0.981, p<0.001. Similarly 26 other patients who had measurable urine M protein levels in whom 10 nor more paired observations over time were available, also showed significant correlations, rho, range 0.726–0.981, p<0.01. Conclusion: There is a significant correlation between urine M-protein and serum free light chain across patients and the correlation is stronger in individual patients in whom the effect of inter-patient variation in other confounding factors can be eliminated. These data if confirmed in a clinical trial setting would support the use of serum FLC levels instead of urinary M protein measurements to assess response to therapy.

scholarly journals Excluding myeloma diagnosis using revised thresholds for serum free light chain ratios and M-protein levels

Haematologica ◽  
2019 ◽  
Vol 105 (4) ◽  
pp. e169-e171
Author(s):  
Jennifer L. J. Heaney ◽  
Alex Richter ◽  
Stella Bowcock ◽  
Guy Pratt ◽  
J. Anthony Child ◽  
...  
Keyword(s):  
Light Chain ◽  
Free Light Chain ◽  
M Protein ◽  
Serum Free ◽  
Protein Levels ◽  
Serum Free Light Chain

scholarly journals High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 827-832 ◽  
Author(s):  
Frits van Rhee ◽  
Vanessa Bolejack ◽  
Klaus Hollmig ◽  
Mauricio Pineda-Roman ◽  
Elias Anaissie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Prognostic Significance ◽  
Complete Response ◽  
High Serum ◽  
Free Light Chain ◽  
Response To Therapy ◽  
Rapid Reduction ◽  
Serum Free ◽  
Serum Free Light Chain

Abstract Serum-free light chain (SFLC) levels are useful for diagnosing nonsecretory myeloma and monitoring response in light-chain–only disease, especially in the presence of renal failure. As part of a tandem autotransplantation trial for newly diagnosed multiple myeloma, SFLC levels were measured at baseline, within 7 days of starting the first cycle, and before both the second induction cycle and the first transplantation. SFLC baseline levels higher than 75 mg/dL (top tertile) identified 33% of 301 patients with higher near-complete response rate (n-CR) to induction therapy (37% vs 20%, P = .002) yet inferior 24-month overall survival (OS: 76% vs 91%, P < .001) and event-free survival (EFS: 73% vs 90%, P < .001), retaining independent prognostic significance for both EFS (HR = 2.40, P = .008) and OS (HR = 2.43, P = .016). Baseline SFLC higher than 75 mg/dL was associated with light-chain–only secretion (P < .001), creatinine level 176.8 μM (2 mg/dL) or higher (P < .001), beta-2-microglobulin 297.5 nM/L (3.5 mg/L) or higher (P < .001), lactate dehydrogenase 190 U/L or higher (P < .001), and bone marrow plasmacytosis higher than 30% (P = .003). Additional independent adverse implications were conferred by top-tertile SFLC reductions before cycle 2 (OS: HR = 2.97, P = .003; EFS: HR = 2.56, P = .003) and before transplantation (OS: HR = 3.31, P = .001; EFS: HR = 2.65, P = .003). Unlike baseline and follow-up analyses of serum and urine M-proteins, high SFLC levels at baseline—reflecting more aggressive disease—and steeper reductions after therapy identified patients with inferior survival.

scholarly journals Comparing the Performance of Serum Free Light Chain Measurements with Urine Electrophoresis and Immunofixation for Monitoring and Assessing Response to Therapy in Patients with Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3347-3347 ◽  
Author(s):  
Thomas Dejoie ◽  
Michel Attal ◽  
Philippe Moreau ◽  
Jean-Luc Harousseau ◽  
Herve Avet-Loiseau
Keyword(s):  
Light Chain ◽  
Conflicts Of Interest ◽  
Free Light Chain ◽  
Response To Therapy ◽  
Stage I ◽  
Reference Ranges ◽  
Serum Free ◽  
Post Transplant ◽  
Serum Free Light Chain ◽  
Measurable Disease

Abstract The introduction of the serum free light chain (sFLC) changed the diagnostic paradigm for patients with B cell disorders. IMWG guideline recommends the assay as a replacement for 24h urine at diagnosis, however with the exception of oligosecretory disease the assay is not recommended as a tool to monitor patients. One rationale for this recommendation is that to date, studies have compared the concentrations of FLC as measured by the two tests rather than determine which test provides the more reliable clinical assessment. Here we compare the sensitivities of FLC and 24h urine and comment on the reliability of each to monitor patients. Sequential sera from 25 LCMM (14 FLCκ, 11 FLCλ; stage I: 10, II: 10, III: 5) and 157 IIMM patients (79 IgGκ, 34 IgGλ, 26 IgAκ, 18 IgAλ; Stage I: 46, II: 75, III: 35, 1 missing) enrolled onto the IFM 2007-02 MM trial were analysed. Serum FLCκ and FLCλ levels were measured by Freelite® in samples collected at presentation, after cycles 2 and 4 of therapy and post ASCT. Results were compared to previously published sFLC reference ranges (sFLCκ 3.3-19.4 mg/L, sFLCλ 5.7-26.3 mg/L, sFLCκ/λ ratio 0.26-1.65), SPEP, UPEP sIFE and uIFE. IMWG guidelines were used to define measurable disease and to assess response the therapy. Quadratic Weighted Kappa (WK) analysis was performed to assess agreement in responses assigned by sFLC and urine tests. All 25 LCMM patients had abnormal sFLC ratios (14 FLCκ, 11 FLCλ) and measurable disease at presentation (iFLC 3620 (689-22000) mg/L). Similarly, all patients were positive by uIFE and had measurable disease by UPE (1940 (490-42000) mg/24h). However, in keeping with previous reports quantitative correlation between the two assays was poor (r=0.27). Responses assigned by sFLC and UPEP were concordant in 11/25 (44%) patients, although in 4/11 (40%) timing of the response was different (UPEP 89 (58-118) days; sFLC 226 (216-227) days). In the remaining 14/25 patients the responses assigned using the two tests differed. In 7/14 patients UPEP and uIFE became negative whilst the FLC ratio remained abnormal; in 1/7 patient sIFE confirmed the presence of the M protein. In 3 patients FLC identified relapse, while UPEP was negative or indicated response. In a further 2 patients FLC identified no response whilst UPEP initially identified a response and subsequent relapse. Overall, a moderate concordance was identified between the responses assigned by sFLC and urine tests (WK (95% CI): 0.59 (0.36-0.82)). At presentation, 154/157 (98%) IIMM patients had abnormal FLC ratios (FLCκ ratio 57 (2-33191); FLCλ ratio 0.009 (0.00003-0.25)), whereas only 85/157 (54%) patients were positive by uIFE and 67/157 (43%) by UPEP. 98/157 (62%) had measurable disease using sFLC (κFLC 491 (101-15600) mg/L; λFLC 441 (101-14100) mg/L), and 55/157 (35%) had measurable disease by UPEP (1000 (210-9200) mg/24h). 53/157 (34%) patients had measurable disease by both methods. The correlation between sFLC and UPEP measurements was poor (r=0.36) as was the correlation between intact immunoglobulin measurements by SPEP and sFLC (r=-0.06) or UPEP (r=-0.26). In 53 IIMM patients with measurable disease by both FLC and UPEP, sFLC ratios normalised in 14/53 patients (in 8/14 sIFE remained positive) while uIFE became negative in 33/53 patients (20/33 remained sIFE positive). WK showed better agreement for response assignment between intact immunoglobulin and sFLC measurements (WK (95% CI): 0.63 (0.48-0.79); substantial agreement) than with urine tests (0.49 (0.27-0.72); moderate agreement). Additionally, there was an association between depth of response by sFLC pre- and post-transplant: patients achieving >VGPR before transplant were more likely to achieve >VGPR post-transplant compared with patients who achieved <VGPR prior to transplant (96.2% vs. 63.2%, respectively; p=0.001). Finally 5/157 IIMM patients were oligosecretory and had measurable levels of disease by both UPEP and sFLC, but not by SPEP. In all 5 patients UPEP became negative by cycle 2; however, an abnormal sFLC ratio and positive sIFE indicated persistent disease. sFLC was a more sensitive tool and showed a greater degree of concordance with IFE and SPEP than UPEP in LCMM and IIMM patients respectively during patient monitoring. Furthermore, >90% reduction in sFLC prior to transplant was associated with post-transplant response in IIMM patients. Larger studies with patient outcome are required to validate our findings. Disclosures No relevant conflicts of interest to declare.

Significance of Serum Free Light Chain Estimation with Detectable Serum Monoclonal Protein on Immunofixation Electrophoresis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5048-5048
Author(s):  
Jayesh Mehta ◽  
Regina Stein ◽  
Eric Vickrey ◽  
William Resseguie ◽  
Seema Singhal
Keyword(s):  
Light Chain ◽  
Free Light Chain ◽  
Response To Therapy ◽  
Oligoclonal Bands ◽  
Serum Samples ◽  
Serum Free ◽  
Monoclonal Protein ◽  
Serum Free Light Chain ◽  
Small Series ◽  
Immunofixation Electrophoresis

Abstract The serum free light chain (SFLC) assay is useful in detecting monoclonal protein when there no detectable M protein on immunofixation electrophoresis (IFE). There are limited data on its value when IFE is positive. In a small series of 5 patients achieving CR, normalization of SFKLR was found to precede IFE negativity by a few weeks (Moesbauer et al. ASH 2005). Results on 231 serum samples from myeloma patients (most on therapy) where serum IFE showed IgA κ (n=33), IgA λ (n=13), IgG κ (n=153), or IgG λ (n=32), and where simultaneous SFLC and immunoglobulin (Ig) estimation had been performed were analyzed. Samples with &gt;1 monoclonal band or multiple oligoclonal bands were excluded. The serum free κ:λ ratio (SFKLR; normal 0.26–1.65) was abnormal in 113 (49%) and normal in 118 (51%). IgG and IgA levels were compared in the context of normal versus abnormal SFKLR within each of the 4 isotypes (IgA κ, IgAλ, IgG κ, IgG λ). The table below shows that involved Ig levels were higher with abnormal than with normal SFKLR. However, uninvolved Ig levels were higher with normal than with abnormal SFKLR suggesting that normalization of SFKLR may mark a response to therapy - improved uninvolved Ig levels being evidence of response. Monoclonal protein Immunoglobulin Abnormal SFKLR Normal SFKLR P IgA kappa IgA 1640 (190–4000) 515 (102–2230) 0.048 IgA kappa IgG 419 (118–1120) 404 (197–1740) 0.39 IgA lambda IgA 408 (159–696) 704 (180–779) 0.17 IgA lambda IgG 619 (495–1510) 1530 (533–1700) 0.025 IgG kappa IgA 42 (7–225) 94 (7–642) 0.0009 IgG kappa IgG 1490 (585–5560) 1260 (327–2690) 0.004 IgG lambda IgA 32 (7–121) 96 (19–562) 0.047 IgG lambda IgG 2060 (555–12300) 1050 (432–2830) 0.018 However, does normalization of SFKLR universally herald IFE negativity? This is an important unanswered question because SFKLR is normal in a high proportion of samples which still show monoclonal protein on IFE. The figures below show scatter plots of IgG and IgA for each of the 4 isotypes for normal vs abnormal SFKLR. Within each plot, there is no obvious pattern distinguishing normal (x) from abnormal (o) SFKLR. However, there are a number of normal SFKLR points with high involved and low uninvolved Ig levels where a normal SFKLR is difficult to explain. Figure Figure Figure Figure We conclude that the SFLC assay often reveals normal SFKLR even when there is a detectable monoclonal protein in the serum. Whether this always predicts eventual paraprotein clearance and achievement of IFE negativity in patients on therapy is unknown, and needs to be studied prospectively.

The Utility of Serum Free Light Chain Measurement in Myeloma Patients with Oligoclonal Bands on Serum or Urine Immunofixation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5121-5121 ◽  
Author(s):  
E. Vickrey ◽  
S. Allen ◽  
J. Krishnamurthy ◽  
V. Singh ◽  
J. Mehta ◽  
...  
Keyword(s):  
Light Chain ◽  
Free Light Chain ◽  
M Protein ◽  
Oligoclonal Bands ◽  
Oligoclonal Band ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Immunofixation Electrophoresis ◽  
Relationship Of ◽  
The Relationship

Abstract During treatment, patients with myeloma can develop restricted bands in the serum or urine that are different from the original M protein on serum (SIFE) and urine (UIFE) immunofixation electrophoresis. These so-called oligoclonal bands represent transient aberrant recovery of the immune system, and are not associated with any adverse implications. Unless SIFE/UIFE are checked and the bands identified as oligoclonal, a mistaken diagnosis of persistent or recurrent disease may be made. It is not known if the pattern of serum free light chain (SFLC) levels helps differentiate between oligoclonal bands and persistent/recurrent M protein. Data on 219 myeloma patients with serial follow-up were evaluated to identify 3537 encounters which fulfilled the following criteria: available SFLC levels, and 1 or more restricted bands identified on SIFE or UIFE. Patients with non-secretory and biclonal disease were excluded. If a heavy or light chain not part of the original M protein was seen, the presence of an oligoclonal band was diagnosed. If the original M protein was identified intact (e.g. the detection of IgG kappa in a patient with IgG kappa myeloma) or its constituent heavy or light chain were identified in an unbound fashion (e.g. the detection of free IgG or free kappa in a patient with IgG kappa myeloma), the original M protein was felt to be present. Results with oligoclonal bands were further characterized by the additional presence or absence of the original M protein. Only the original M protein was seen in 2661 (75%), 352 (10%) had oligoclonal bands without the original M protein, and an oligoclonal band was seen with the original M protein in 524 (15%). The SFLC ratio was normal (0.26–1.65) in 1306 (37%) and abnormal in 2231 (63%). The relationship of the nature of the restricted bands seen with the SFLC ratio was assessed in two ways in preliminary analysis. In the first, the SFLC ratio was classified as normal or abnormal. In the second, abnormal ratios were classified further as concordant (&lt;0.26 for lambda disease and &gt;1.65 for kappa disease) or discordant (&lt;0.26 for kappa disease and &gt;1.65 for lambda disease). Discordant ratios were grouped with normal because they did not reflect an excess of the abnormal light chain associated with the original M protein. The following table shows the relationship between the nature of the restricted bands and the SFLC ratio: SFLC ratio SFLC ratio Restricted band category Normal Abnormal Normal or discordant abnormal Concordant abnormal Original M protein only 843 (32%) 1818(68%) 919 (35%) 1742 (65%) Oligoclonal band(s) only 185 (53%) 167(47%) 215 (61%) 137 (39%) Oligoclonal band(s) with original M protein 278 (53%) 246 (47%) 302 (58%) 222 (42%) P &lt;0.0001 &lt;0.0001 As the table shows, the SFLC ratio was normal significantly more frequently when oligoclonal bands were present. This appeared to be unaffected by the presence of bands resembling the original M protein. As the SFLC ratio can be affected by treatment-induced suppression of the uninvolved free light chain, the data were also analyzed as follows: concordant abnormal SFLC ratio with elevated involved free light chain (1890; 53%) versus the rest (1647; 47%). Finally, based on the hypothesis that elevated uninvolved free light chain levels are less likely to be seen with active disease, readings with elevated uninvolved free light chains were transferred from the former category into the latter. The following table shows the relationship between the nature of the restricted bands and the above categories: SFLC ratio SFLC ratio Restricted band category Normal (All others) Abnormal (Concordant abnormal with elevated involved free light chain) Normal (All others) Abnormal (Concordant abnormal with elevated involved free light chain; excluding elevated uninvolved free light chain) Original M protein only 1246 (47%) 1415 (53%) 1299 (49%) 1362 (51%) Oligoclonal band(s) only 247 (70%) 105 (30%) 257 (73%) 95 (27%) Oligoclonal band(s) with original M protein 343 (65%) 181 (35%) 361 (69%) 163 (31%) P &lt;0.0001 &lt;0.0001 Once again, as the table shows, the SFLC ratio was normal (or equivalent of normal) significantly more often when oligoclonal bands were present. We conclude that the SFLC ratio is significantly more likely to be normal when oligoclonal bands are present in patients with myeloma. However, the differences between patients with and without oligoclonal bands are not definitive enough to predict the nature of the bands seen. SIFE and UIFE remain the only definitive means of identifying the nature of the restricted bands seen in patients with myeloma on therapy.

scholarly journals The importance of bone marrow examination in determining complete response to therapy in patients with multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (13) ◽  
pp. 2617-2618 ◽  
Author(s):  
Cheng E. Chee ◽  
Shaji Kumar ◽  
Dirk R. Larson ◽  
Robert A. Kyle ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Light Chain ◽  
Plasma Cells ◽  
Complete Response ◽  
Free Light Chain ◽  
Response To Therapy ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Serum And Urine

Abstract The current definition of complete response in multiple myeloma includes a requirement for a bone marrow (BM) examination showing less than 5% plasma cells in addition to negative serum and urine immunofixation. There have been suggestions to eliminate the need for BM examinations when defining complete response. We evaluated 92 patients with multiple myeloma who achieved negative immunofixation in the serum and urine after therapy and found that 14% had BM plasma cells more than or equal to 5%. Adding a requirement for normalization of the serum-free light chain ratio to negative immunofixation studies did not negate the need for BM studies; 10% with a normal serum-free light chain ratio had BM plasma cells more than or equal to 5%. We also found that, on achieving immunofixation-negative status, patients with less than 5% plasma cells in the BM had improved overall survival compared with those with 5% or more BM plasma cells (6.2 years vs 2.3 years, respectively; P = .01).

Early Reduction of Serum Free Light Chain Can Predict Therapeutic Responses in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4742-4742
Author(s):  
Thanyaphong Na Nakorn ◽  
Phandee Watanaboonyongcharoen ◽  
Seksan Suwannabutra ◽  
Sunee Theerasaksilp ◽  
Nara Paritpokee
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Light Chain ◽  
Free Light Chain ◽  
M Protein ◽  
Therapeutic Monitoring ◽  
Serum Samples ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Therapeutic Responses

Abstract Background M protein as measured by serum protein electrophoresis (SPE) is usually required for the diagnosis and therapeutic monitoring of multiple myeloma. However, SPE may not be able to detect M protein in some cases such as light-chain disease or non-secretory myeloma. Serum free light chain (FLC) assay has been recently developed and shown to be very helpful in such situations. Here, we evaluate the usefulness of this new test in the diagnosis and therapeutic monitoring of myeloma patients treated with bortezomib plus dexamethasone at our institution. Methods Serial serum FLC assays were performed before and after each cycle of induction therapy. All patients were treated with bortezomib plus dexamethasone every 3 weeks for four cycles. Treatment responses were determined according to the European Group for Blood and Marrow Transplantation criteria. Results There were total of 25 patients in this analysis. Fifteen were male (60%); the median age was 54 years (range, 35–68 years). Abnormal ratio of serum FLC was detected in 88% of pre-treatment serum samples. After four cycles of induction therapy, nine patients (36%) had achieved complete remission. No baseline clinical and laboratory parameters could correctly predict the therapeutic responses in these patients. When serial FLC assays were taken into account, we found that a more-than-40% reduction in the abnormal serum FLC after the first cycle of treatment was significantly associated with achieving complete response at the end of treatment (Pearson Chi-square, p = 0.041). Conclusions Serum FLC assay is very useful for the diagnosis of multiple myeloma and allows a more rapid assessment of therapeutic response. Further studies are needed to establish the role of this test in the era of highly effective anti-myeloma therapy.

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