Abnormal serum free light chain ratio predicts poor overall survival in mantle cell lymphoma

Abstract Abstract 1828 Introduction: Intact immunoglobulin or fragments thereof (intact/fragmented Ig) can be found in the urine due to nephrotic injury or the preferential scavenging of albumin by the renal FcRn receptor leading to immunoglobulin catabolism. Until now the occurrence, frequency and clinical impact of this phenomenon has not been assessed in patients with multiple myeloma (MM). Here we determine the incidence of intact/fragmented Ig in urine and evaluate its prognostic relevance. Patients and Methods: 94 patients with MM, median age 70 years old (range 41–87) with a male / female ratio 28/66, ISS stage I (48), stage II (23), stage III (28), 69 IgG (43 IgGk/26 IgGl) and 25 IgA (15 IgAk/7 IgAl) were enrolled. Serum free light chain concentrations (sFLC) were measured using commercially available immunoassays (Freelite™, The Binding Site, Birmingham, UK) and compared to electrophoresis results (Hydrasys, Sebia, Paris, France). Overall survival was estimated by the product limiting method of Kaplan-Meyer and survival was compared by the log rank test. Results: Overall, sFLC ratios had a greater sensitivity than urine immunofixation (uIFE) for the detection of monoclonal light chains 86/94 vs. 46/94. In 13/46 (28%) uIFE positive patients intact immunoglobulins or significant fragments (intact/fragmented Ig) thereof were detected, 12 IgG, (12/69, 17%) and 1 IgA (1/25, 4%). Three of these patients had normal urine protein concentrations (<250mg/L) and 2/13 patients had glomerular injury identified by increased levels of albumin excretion. There was no difference in creatinine levels between patients with or without intact/fragmented Ig (p=0.673). Analysis of overall survival in patients stratified at presentation according to uIFE results, namely the presence of intact/fragmented Ig, abnormal serum free light chain ratio-, and negative uIFE results revealed significantly shorter overall survival for the intact/fragmented Ig group (median OS: 34.5 vs. 66.0, vs. 80.6 months, respectively, p< 0.048) (figure 1). Discussion: Our findings confirm the superiority of the serum free light chain assay for detection of monoclonal free light chains as compared to urine immunofixation. However, the serum free light chain assay is inadequate for detection of intact/fragmented Ig in urine. The most important finding presented here is the observation that intact and/or fragment immunoglobulin is present in a substantial number of patients with MM. This phenomenon is mainly restricted to IgG isotypes. There are two possible explanations for these findings: first, the presence of glomerular injury, but this phenomenon (increased albumin leakage) was only seen in two patients and hence is unlikely to account for this observation. The second explanation relies upon disruption of the FcRn receptor function in immunoglobulin scavenging. This receptor will preferentially scavenge albumin in the renal setting, but dysfunction may lead to increased immunoglobulin catabolism and the presence of intact and/or fragmented Ig (Sarav, JASN, 20: 1941–1952, 2009). The results may reflect a hitherto unidentified subtle renal dysfunction. In line with this notion overall survival in our patients intact/fragmented Ig was found to be significantly shorter. Conclusion: We observed an unexpected high incidence of intact/fragmented Ig in the urine of our patients with MM. Patients with urinary excretion of intact/fragmented immunoglobulin had significantly shorter survival. These findings should be validated in further studies. Disclosures: Young: Binding Site: Employment. Harding:Binding Site: Employment.

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Heavy/Light Chain Quantification Identifies Clonal Plasma Cell Disease in Patients with AL Amyloidosis and Normal Serum Free Light Chain Ratio

Blood ◽

10.1182/blood.v126.23.2956.2956 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2956-2956

Author(s):

Tatiana Prokaeva ◽

Brian Spencer ◽

Fangui Sun ◽

Nathaniel McConnell ◽

Richard M O'hara ◽

...

Keyword(s):

Overall Survival ◽

Binding Site ◽

Plasma Cell ◽

Light Chain ◽

Free Light Chain ◽

Al Amyloidosis ◽

Cell Disease ◽

Serum Free ◽

Serum Free Light Chain ◽

Combined Use

Abstract Background: Serum and urine immunofixation electrophoreses (SIFE/UIFE) are routinely used for detection of clonal immunoglobulins (Ig) in AL amyloidosis. Serum free light chain (FLC) assays (Freelite®, The Binding Site Ltd., Birmingham, UK) have significantly improved the management of patients with AL amyloidosis by providing quantitative measure for the detection and monitoring of clonal plasma cell disease. However, up to 20% of patients with AL amyloidosis may have uninformative serum free light chain values. Objective: To assess the quantitative potential of serum Heavy/Light Chain (HLC) pairs (Hevylite®, The Binding Site Ltd., Birmingham, UK) assay in identification of clonal plasma cell disease in AL amyloidosis. Methods: One hundred and ninety-nine untreated patients with AL amyloidosis were included in this study. Patients with multiple myeloma or B cell lymphoproliferative diseases associated AL amyloidosis were excluded. Serum sampleswere obtained at initial evaluation and stored at -20°C. SIFE/UIFE were performed at the time of sample collection. HLC pairs were assessed by the Hevylite® assay. HLC κ/λ normal ratios (HLCR) were: 1.12-3.21 for IgG κ/λ; 0.78-1.94 for IgA κ/λ; and 1.18-2.74 for IgM κ/λ. FLCs were assessed by the Freelite® assay; FLC κ/λ normal ratio (FLCR) was 0.26-1.65. In 103 cases, FLC testing was performed at the time of sample collection; 96 cases were tested at The Binding Site. Vital status of patients was obtained from either medical records or Social Security Death Index. Follow-up ended in June 2014. Results: An abnormal HLCR was found in 74 (37.2%), an abnormal FLCR in 163 (81.9%), and SIFE/UIFE positivity in 187 (94%) of 199 patients with AL amyloidosis. Of 36 patients with a normal FLCR, 23 (63.9%) were noted with an abnormal HLCR compared to 51 (31.3%) patients in an abnormal FLCR group (P = 0.001). In total 186/199 (93.5%) patients with AL amyloidosis had abnormalities in either HLCR or FLCR, compared to 187/199 (94%) of patients who were SIFE/UIFE+ (Table 1). The combined use of both FLCR and HLCR yielded quantifiable information in 93.5% of cases; the use of both tests in combination with SIFE/UIFE identified plasma cell clonality in 100% of patients. Seventy-two cases presented with an abnormal HLCR for a single isotype and 2 in multiple Ig isotypes. In all cases, involved LC type of abnormal HLCR matched LC type identified by SIFE/UIFE. None of 12 cases that were negative on the SIFE/UIFE presented with an abnormal HLCR, however, all showed abnormalities in FLCR. Table 1. Comparative efficiency of FLCR, HLCR and Serum/Urine Immunofixation in AL Amyloidosis patients. SIFE/UIFE+ (n=187) SIFE/UIFE- (n=12) HLCR+/FLCR+ 51 (27.2%) - HLCR+/FLCR- 23 (12.3%) - HLCR-/FLCR+ 100 (53.5%) 12 (100%) HLCR-/FLCR- 13 (7%) - Overall survival was similar in patients with and without abnormal HLCR (Log rank p=0.092; Figure 1), whereas patients with an abnormal FLCR had a significantly inferior overall survival compared to those with a normal FLCR (Log rank p=0.027; Figure 2). Combined use of both HLCR and FLCR demonstrated a trend toward superior overall survival in a group of patients with an abnormal HLCR / normal FLCR (Wilcoxon p=0.037; Log rank p=0.107; Figure 3). Conclusions: The Hevylite® assay provided information in addition to other laboratory tests for clonal plasma cell disease in AL amyloidosis. The combined use of the HLCR and FLCR provided quantifiable information in 93.5% of patients. The use of both assays in combination with SIFE/UIFE detected clonal disease in all patients. HLCR has potential to quantify clonal disease in patients with uninformative FLCR results. An abnormal HLCR was not predictive of overall survival, while an abnormal FLCR was, in this series of patients. Combined use of HLCR and FLCR could be beneficial in prognostication of outcome in AL amyloidosis. Disclosures McConnell: The Binding SIte: Employment. O'hara:The Binding Site: Employment.

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Serum Free Light Chain Concentration (>1000mg/dl) at Diagnosis and at Relapse Predicts for Very Poor Prognosis in Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.5698.5698 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5698-5698

Author(s):

Abhishek Chilkulwar ◽

Prerna Mewawalla ◽

Anna Miller ◽

Gina Berteotti ◽

Entezam Sahovic ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Disease Progression ◽

Light Chain ◽

Free Light Chain ◽

Light Chains ◽

Free Light Chains ◽

Serum Free ◽

Serum Free Light Chain ◽

Serum Free Light Chains

Abstract Background: There have been significant improvements in the outcomes for patients with multiple myeloma over the past 10 years. The course of the disease remains highly variable. While some patients experience 10-15 year survivals, others succumb to highly refractory disease within a few months. Many studies have focused on the description of prognostic factors capable of predicting this heterogeneity in survival. Baseline Serum free light chain concentration is a major prognostic indicator for plasma cell neoplasms and normalization of free light chain ratio with treatment has been reported as an indicator for favorable prognosis. High Baseline free light chain concentration at presentation indicates aggressive disease. Furthermore High serum free light chain ratio correlates with elevated serum creatinine, elevated LDH and extensive marrow infiltration. Objectives: To determine if serum free light chain concentration > 1000mg/dl at the time of diagnosis and at disease progression was an independent prognostic marker for multiple myeloma. Methods: The results of all the serum free light chain analyses of patients evaluated at western Pennsylvania hospital between 2007 -2015 were reviewed and patients with serum free light chain concentration >1000mg/dl at the time of initial diagnosis and disease progression were identified Retrospective chart review was done to study the survival in these patients. Results: Total of 15 patients in whom serum free light chain concentration was greater than 1000 mg/dl at diagnosis were identified. Median age at diagnosis was 60.81 years (45.2-77.3). The median survival in this population is 1.85 years (range 0.06-8.85 years), with 5 deaths. Of these 15, 9 patients received an autologous PBSCT as a part of their initial therapy. Six of them are alive with a median overall survival of 2.44 years and mean survival of 3.89 years (range 0.87-8.89). In the remaining 6 patients that did not undergo an auto PBSCT 3 of them are alive with median overall survival of 1.21 years and a mean survival 1.20 years (range 06-2.76 years). There is an overall trend toward very poor prognosis in this specific group of patients irrespective of the age, sex, stage at time of diagnosis, the immunoglobulin subtype and the free light chain subtype (kappa vs lambda). We also conducted a retrospective review of patients in whom serum free light chains concentration was greater than 1000mg/dl at disease progression. Twenty patients were identified all of whom are deceased with a median overall survival from the time of progression with serum free light chains greater than 1000 mg /dl was dismal at 0.27 years and mean survival was 0.53 years (range 0.04-2.52 years) Conclusion: Patients with multiple myeloma who presented with a serum free light chain concentration greater than 1000 mg/dl at diagnosis have very poor prognosis. These specific subgroups of patients should be identified and treated aggressively at the time of diagnosis to prevent complications from multiple myeloma and improve their overall survival. In our small cohort of patients those who underwent auto PBSCT as a part of their initial therapy tend to have better outcomes in terms of overall survival compared to patients who received therapy without auto PBSCT consolidation. Patients with serum free light chains greater than 1000 mg/dl at disease progression will need to be treated aggressively with perhaps a salvage auto PBSCT to improve their overall outcome. A larger study to evaluate elevated serum free light chains (greater than 1000 mg/dl) as a prognostic indicator at diagnosis and progression should be done to further validate these findings Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

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Normalization of the Serum Free Light Chain (FLC) Ratio Is Associated with Superior Overall Survival among Myeloma Patients Achieving Immunofixation Negative State: Results Support Incorporation of Serum FLC Ratio in Stringent CR Definition.

Blood ◽

10.1182/blood.v112.11.1692.1692 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1692-1692 ◽

Cited By ~ 4

Author(s):

Shaji Kumar ◽

Angela Dispenzieri ◽

Dirk Larson ◽

Colin Colby ◽

Robert Kyle ◽

...

Keyword(s):

Overall Survival ◽

Light Chain ◽

Median Overall Survival ◽

Free Light Chain ◽

Serum Free ◽

Monoclonal Protein ◽

Protein Levels ◽

Serum Free Light Chain ◽

Serum And Urine

Abstract Background: Traditionally response to therapy in multiple myeloma (MM) is based on changes in the serum and urine monoclonal protein by immunoelectrophoresis. Immunofixation allows for detection of small amounts of monoclonal protein that cannot be quantitated on immunoelectrophoresis. Serum immunoglobulin free light chain (FLC) assay allows for detection of unbound kappa and lambda free light chain and has allowed disease measurement in patients with oligosecretory myelomas and can potentially allow detection of low levels of tumor burden, below the threshold of the standard tests. We examined this hypothesis in patients who had obtained a negative immunofixation in serum and urine following treatment of their MM. Methods: For the purposes of the study, we included selected patients with MM who had measurable monoclonal (M) protein levels at baseline (defined as >1 gm/dL in the serum or >200 mg/24 hour in the urine or involved free light chain > 10 mg/dL) on protein electrophoresis; patients with non-secretory and oligo-secretory myeloma were excluded. We then identified patients who since 1995 had a negative immunofixation in the serum and urine, all done at the same time (within 30 days of each other). Baseline demographics and clinical characteristics; date of diagnosis, last follow up, and follow up status; serum and urine M protein levels at diagnosis; and results of serum and urine immunofixation, and serum free light chain (FLC) ratio within 30 days of the immunofixation were all collected from the existing databases. Results: Eighty-four patients met the criteria for the study, all of whom had measurable disease at baseline and subsequently achieved negative immunofixation in serum and urine. Among these, 46 patients (55%) also had a normal FLC ratio (K/L ratio; 0.26–1.65). Th median time from diagnosis to the documented immunofixation was 7.5 months (range, 1–157). The median overall survival from diagnosis among those with a normal FLC ratio along with negative immunofixation was not reached compared to 76 months for those with abnormal FLC ratio, P = 0.02. The median overall survival from the documentation of negative immunofixation was not reached for the group with normal FLC ratio compared to 46.5 months for those with an abnormal FLC, P = 0.03. Conclusion: Attainment of a normal FLC ratio at the time of serum and urine immunofixation negative status identifies a group of patients with better outcome. The presence of an abnormal FLC ratio likely represents persistence of the clonal population that is secreting none or very small amounts of monoclonal protein. The data presented here supports the inclusion of FLC measurements as part of response criteria for MM as has been done for the definition of stringent CR in the IMWG response criteria. Figure: Overall survival from diagnosis in patients with or with out a normal FLC ratio at the time of serum and urine immunofixation. Figure:. Overall survival from diagnosis in patients with or with out a normal FLC ratio at the time of serum and urine immunofixation.

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