Production Of Free Light Chains Research Articles

B-319 Kappa and Lambda Free Light Chains Quantification in Serum Samples with 3 or 4 Monoclonal Components Detected by Serum Immunofixation

Abstract Background Serum free light chain (FLC) quantification is a diagnostic criterion for monoclonal gammopathy. Oligoclonal expansion is defined when two or more small bands are detected in the gamma region of serum protein electrophoresis (SPEP) or immunofixation (SIFE) within the context of infectious diseases, autoimmune diseases, or some lymphoproliferative processes. This study aims to investigate the frequency of FLC disturbances in samples with oligoclonal pattern of 3 or 4 monoclonal bands observable in SIFE. Methods We have analyzed 7553 consecutive samples during the period of January to December 2023 in which both determination of FLC and SIFE were ordered in a large central laboratory at São Paulo, Brazil. FLC quantification and SIFE analysis were performed with FreeLite assay and Optilite system (The Binding Site, UK) and SPIFE 3000 (Helena Laboratories, USA), respectively. Results In our analysis, 119 samples (50 males, 69 females, median age 69 years (range 37-90)), with 3 or 4 monoclonal bands were identified, constituting 1.57% of the overall study population. These samples were then categorized into two groups. The first group had normal FLC Ratio (range 0.26 to 1.65) and the second group had altered FLC Ratio (outside 0.26-1.65 range). Seventy-seven samples (65%) had altered FLC ratio, with kappa elevation being the most common alteration (51 samples). Within these samples, median FLC ratio was 2.99 (range 1.72-719.05). Lambda elevation was present in 26 samples, with median FLC ratio 0.04 (range 0.005-0.16). Conclusions Presence of 3 or more oligoclonal bands in SIFE analysis may be indicative of various pathological processes (benign and malignant) and also be observed in post-transplantation. In this study, we have observed that most of these samples present altered FLC ratio, which indicate monoclonal disturbances in the production of free light chains. Those disturbances may be associated with a lymphoproliferative disease (e.g. multiple myeloma) or may be transient. Clinicians should be aware of the need for follow-up of these cases.

Hantavirus infection-induced B cell activation elevates free light chains levels in circulation.

In humans, orthohantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). An earlier study reported that acute Andes virus HPS caused a massive and transient elevation in the number of circulating plasmablasts with specificity towards both viral and host antigens suggestive of polyclonal B cell activation. Immunoglobulins (Igs), produced by different B cell populations, comprise heavy and light chains; however, a certain amount of free light chains (FLCs) is constantly present in serum. Upregulation of FLCs, especially clonal species, associates with renal pathogenesis by fibril or deposit formations affecting the glomeruli, induction of epithelial cell disorders, or cast formation in the tubular network. We report that acute orthohantavirus infection increases the level of Ig FLCs in serum of both HFRS and HPS patients, and that the increase correlates with the severity of acute kidney injury in HFRS. The fact that the kappa to lambda FLC ratio in the sera of HFRS and HPS patients remained within the normal range suggests polyclonal B cell activation rather than proliferation of a single B cell clone. HFRS patients demonstrated increased urinary excretion of FLCs, and we found plasma cell infiltration in archival patient kidney biopsies that we speculate to contribute to the observed FLC excreta. Analysis of hospitalized HFRS patients' peripheral blood mononuclear cells showed elevated plasmablast levels, a fraction of which stained positive for Puumala virus antigen. Furthermore, B cells isolated from healthy donors were susceptible to Puumala virus in vitro, and the virus infection induced increased production of Igs and FLCs. The findings propose that hantaviruses directly activate B cells, and that the ensuing intense production of polyclonal Igs and FLCs may contribute to acute hantavirus infection-associated pathological findings.

Serum free light chains

Serum free light chain estimations entered most clinical laboratory test menus from September 2008. Their main clinical utility is in the identification of persons who might have a light chain only plasma cell dyscrasia. Other reasons clinicians request these assays are for the monitoring of persons with myeloma and monitoring progression of renal impairment. Increased sensitivity for detection of excessive free light chain production over urine protein electrophoresis and immunofixation may earlier identify persons with AL amyloid or myeloma. Non-compliance by patients with requests for urine EPG-IFE can be offset by serum free light chain estimations. Serum free light chain assays are unable to define clonality in a person with abnormal free light chain levels unlike serum or urine protein electrophoresis. Measurements can be insensitive to prozone effects, potentially underestimating light chain levels despite careful testing strategies. Some monoclonal free light chain bands may have idiosyncratic charge and other physical characteristics that can frustrate good assay systems. Physician responses to abnormal results may vary according to clinical context in terms of known monoclonal bands, renal impairment, suspicion of AL amyloid, immunosuppressive treatments. Robust and reliable serum free light chains have earned a mature role in serum protein studies with strong support by clinician users.

Serum free light chains

Serum free light chain estimations entered most clinical laboratory test menus from September 2008. Their main clinical utility is in the identification of persons who might have a light chain only plasma cell dyscrasia. Other reasons clinicians request these assays are for the monitoring of persons with myeloma and monitoring progression of renal impairment. Increased sensitivity for detection of excessive free light chain production over urine protein electrophoresis and immunofixation may earlier identify persons with AL amyloid or myeloma. Non-compliance by patients with requests for urine EPG-IFE can be offset by serum free light chain estimations. Serum free light chain assays are unable to define clonality in a person with abnormal free light chain levels unlike serum or urine protein electrophoresis. Measurements can be insensitive to prozone effects, potentially underestimating light chain levels despite careful testing strategies. Some monoclonal free light chain bands may have idiosyncratic charge and other physical characteristics that can frustrate good assay systems. Physician responses to abnormal results may vary according to clinical context in terms of known monoclonal bands, renal impairment, suspicion of AL amyloid, immunosuppressive treatments. Robust and reliable serum free light chains have earned a mature role in serum protein studies with strong support by clinician users.

Next generation flow cytometry for MRD detection in patients with AL amyloidosis

The treatment of AL amyloidosis aims to eradicate the plasma cell clone and eliminate toxic free light chain production. Only in a minority of patients the plasma cell clone is completely eradicated; residual light chain production may still exist while clonal relapse may occur. We used sensitive next-generation flow cytometry (NGF) to detect minimal residual disease (MRD) in AL amyloidosis patients at complete haematologic response. MRD evaluation was feasible in 51 of 52 (98%) tested patients and at a median sensitivity of 2.3 × 10−6 MRD was undetectable in 23 (45%). An organ response occurred in 86% of MRDneg vs 77% in MRDpos; renal response in 15/17(88%) of MRDneg vs in 14/16(87.5%) of MRDpos and cardiac response in 10/10(100%) of MRDneg vs 11/15(73%) of MRDpos patients. After a median follow-up of 24 months post MRD testing, no MRDneg patient had a haematologic relapse vs 6/28(21%) MRDpos (p = .029). Pooling haematologic and organ progressions, 9 (32%) MRDpos patients had disease progression vs only 1 (4%) MRDneg patient (p = .026). In conclusion, MRD detection using NGF has profound clinical implications, so that AL patients with undetectable MRD have a very high probability of organ response and a very low probability of haematologic relapse.

Concentrations of immunoglobulin free light chains in cerebrospinal fluid predict increased level of brain atrophy in multiple sclerosis.

Recent studies showed that B cells play a major role in the pathogenesis of neurodegeneration in multiple sclerosis (MS). In this study, we aimed to determine the possible link between immunoglobulin free light chains (FLC) and brain atrophy in patients with MS. Ninety-two patients (32 males and 60 females) with MS were included. Kappa and lambda FLC concentrations in serum and cerebrospinal fluid (CSF) samples of MS patients were measured using ELISA assay. FLC quotients (Q-k and Q-λ, respectively) were calculated. In a cross-sectional group (n = 92), the MRI data were acquired within 6months from the date of the lumbar puncture. Twenty patients from this cohort performed a follow-up MRI after 1year of observation. Brain volumes were calculated with SIENAX and the brain atrophy (percentage brain volume change (PBVC)) was assessed with SIENA. Spearman's test was performed to assess correlations. We have shown statistically significant correlation of Expanded Disability Status Scale (EDSS) level with normalized brain volume (NBV, r = - 0.2721, p = 0.0062), white matter volume (WMV, r = - 0.2425, p = 0.015), and gray matter volume (GMV, r = - 0.216, p = 0.0309). Multiple Sclerosis Severity Score (MSSS) score correlated with NBV (r = - 0.2521, p = 0.0352) and WMV (r = - 0.315, p = 0.0079). Neither EDSS, nor MSSS scores correlated with the age of patients and relapse rate during the first year and 5years. In our study, we found statistically significant correlations of k-FLC in the CSF with NBV (r = - 0.311, p = 0.003) and with GMV (r = - 0.213, p = 0.0423). Q-k correlated only with NBV (r = - 0.340, p = 0.006) and Q-λ were negatively correlated with WMV (r = - 0.366, p = 0.003). We did not find correlations of k-FLC in CSF, λ-FLC in CSF, Q-k, and Q-λ with duration of MS course, EDSS, MSSS, number of relapses during the first year, and during the first 5years of disease. Additionally, we subdivided the study population in accordance with level of k-FLC CSF, Q-k, and Q-λ on the 25th and 75th percentile subgroups (25-k-FLCCSF/75-k-FLCCSF; 25-λ-FLCCSF/75-λ-FLCCSF; 25-Q-k/75-Q-k; 25-Q-λ/75-Q-λ). We found statistically significant difference of NBV and GMV between 25-k-FLCCSF and 75-k-FLCCSF subgroups (p = 0.0047, p = 0.0297 respectively), NBV between 25-Q-k and 75-Q-k subgroups (p = 0.038), and NBV and WMV between 25-Q-λ and 75-Q-λ subgroups (p = 0.0446, p = 0.0026 respectively). PBVC in the prospective group showed negative correlation with kappa FLC in the CSF (r = - 0.4853, p = 0.0301) and Q-k (r = - 0.6132, p = 0.0224), but not with other clinical, epidemiological data. In this study, we showed a strong negative correlation of k-FLC, Q-k, and Q-λ with brain atrophy in MS patients. Additionally, patients with high concentration of FLC had lower brain volumes. We did not find correlations of FLC with the relapse rate, age of patients, and MS time course. In the prospective group, the rate of atrophy was correlated with k-FLC and Q-k. We suggest that level of intrathecal production of FLC can be a good prognostic biomarker for MS.

Hemodiálisis en Pacientes con Mieloma Múltiple: a propósito de dos casos

El Mieloma múltiple es una patología hematológica en la que existe una proliferación de células plasmáticas a nivel de la médula ósea, causan un exceso de producción de cadenas ligeras, la presencia de estas cadenas ligeras libres incompletas es la causa principal de insuficiencia renal. Caso clínico: Presentamos dos casos de pacientes de 56 y 73 años con mieloma múltiple con cadenas Lambda y Kappa y con fracaso renal agudo. Fueron tratados en la unidad de diálisis del Hospital Rey Juan Carlos con hemodiálisis largas utilizando el filtro Filtryzer BK-2.1F®. Ambos precisaron de terapia combinada de quimioterapia y hemodiálisis largas y diarias con dializador de poro ancho. Se apreció que con las sesiones de hemodiálisis las cadenas ligeras disminuyeron considerablemente y que los dos pacientes mejoraron el filtrado glomerular sin precisar sesiones de hemodiálisis. La complicación más frecuente fue la coagulación del circuito extracorpóreo. Se resalta la importancia iniciar un diagnóstico y tratamiento precoz para reducir el riesgo de insuficiencia renal crónica.

The Role of Assay of Free Immunoglobulin Light Chains in the Diagnosis of the Onset of Multiple Sclerosis

Objective. To assess the diagnostic value of assaying immunoglobulin (IgG) light chains at the onset of multiple sclerosis (MS). Materials and methods. A total of 226 patients took part in the study; group 1 (n = 111) were patients with clinically isolated syndrome (CIS) with development to MS within the first two years; group 2 (n = 49) were patients with CIS who did not progress to MS in the first two years; group 3 (n = 20) consisted of patients with inflammatory diseases of the central nervous system. The reference group (group 4, n = 46) consisted of patients with noninflammatory CNS diseases. The following immunological indicators were assessed in the patients: the clonal nature of cerebrospinal fluid (CSF) IgG and the concentrations of free ϰ and λ light chains in the CSF and their ratio. Results. Synthesis of free light chains was significantly greater in group 1 than groups 2 and 4. Free light chain synthesis in group 3 was significantly greater than that in groups 2 and 4 but was not significantly different from that in group 1. Free light chain production was significantly greater in patients with oligoclonal IgG synthesis than in patients without oligoclonal synthesis. The level of production of free light chains in patients of group 1 was significantly greater than that in group 2, regardless of whether or not oligoclonal IgG was produced. The most valuable diagnostic markers were the concentration and the coefficient of CSF:serum concentrations of κ light chains. Use of these parameters along with assessment of the clonality of IgG synthesis produced a 50% reduction in number of false negative results. Independently of other factors, increases in κ chain levels led to a 9.718-fold increase in the probability of a diagnosis of MS. Conclusions. Assay of free light chains as a lab marker increases the accuracy of diagnoses of MS and provides an indirect evaluation of the risk that CIS will progress to complete MS in the next two years.

NILAI RUJUKAN FREE LIGHT CHAIN SERUM DENGAN IMUNOTURBIDIMETRI

The light chains of immunoglobulin are produced in larger quantity rather than heavy chains, therefore small amount of free lightchains (FLC) can be found in the blood of healthy individuals. Free light chain production is increased in the clone's proliferation ofmalignant B cells, i.e. in myeloma. Therefore the FLC level measurement can be used for diagnosis aid of myeloma and related B cellsdisorders. The aim of this study is to establish reference range of serum FLC κ, FLC λ, and κ/λ ratio in population ≥40 year's old usingimmunoturbidimetry assay. Serum FLC κ, FLC λ and κ/λ ratio were measured in 240 healthy male and female attending medical checkup in MMC hospital. Healthy subjects were determined by anamnesis and physical examination, with routine haematology, ESR, andserum creatinine level within normal ranges. The serum FLC assays were performed in the Clinical Pathology Laboratory, RSCM, usingHitachi 912 with immunoturbidimetry method. The results were analyzed by SPSS 11.5 program. Serum FLC normal reference valuein 40-84 years old healthy subjects are: FLC κ 11.7–30.6 mg/L, FLC λ 9.7–25.0 mg/L, and κ/λ ratio 0.79–1.75. This research is thefirst study for finding serum FLC values in the Indonesian population. The normal reference value found is similar with another studyusing the same platform analyzer.

Free light chains of immunoglobulins in patients with systemic sclerosis: correlations with lung involvement and inflammatory milieu

AimHumoral immunity and B cells are thought to play an important role in the pathophysiology of the systemic sclerosis (SSc). The production of free light chains (FLC) of immunoglobulins is...

Prolonged renal survival in light chain amyloidosis: speed and magnitude of light chain reduction is the crucial factor

Renal involvement causing progressive chronic kidney disease (CKD) is present in 70% of patients with systemic Iglight-chain (AL) amyloidosis at diagnosis. Chemotherapy thatsubstantially suppresses free light chain production is associated with improved patient survival, but its benefit in delaying the onset of renal replacement therapy among patients who present with established advanced CKD has notbeen studied. To evaluate this, we studied 1000 patients enrolled in the prospective UK AL amyloidosis chemotherapy study (ALchemy). Of these, 84 patients had advanced amyloid-related CKD defined by an estimated glomerular filtration rate (eGFR) under 20 ml/min/1.73 m2. We determined outcomes among these 84 patients, who had a median eGFR of 10 ml/min/1.73 m2, in relation to response to chemotherapy evaluated at three, six, and 12 months from baseline. Patients who achieved suppression of 90% or more in their amyloidogenic free light chain (dFLC) within three months of baseline had significantly better overall survival, prolonged time to dialysis, and prolonged time to the composite endpoint of 'death or dialysis' compared to those who achieved lesser degrees of clonal response at the same time point. Even when this target of greater than 90% dFLC response was achieved but was delayed beyond 3 months, it was associated with worse outcomes. Cox regression analyses confirmed that a 90% or better dFLC response within 3 months was the only significant independent predictor of all three of these outcome measures. Thus, renal survival among patients with systemic immunologic light chain amyloidosis who present with advanced CKD is strongly dependent upon the magnitude and speed with which the underlying hematologic disorder is suppressed by chemotherapy.

Diagnostic value of immunoglobulin free light chains at the debut of multiple sclerosis

To evaluate the diagnostic value of determination of free immunoglobulin light chains (IgG) in the debut of multiple sclerosis (MS). Data from 226 patients, including 111 patients with clinically isolated syndrome with conversion to multiple sclerosis within the first 2 years of the disease (group 1), 49 patients with clinically isolated syndrome who did not develop multiple sclerosis within the first 2 years of the disease (group 2), 20 patients with other inflammatory diseases of the central nervous system (group 3) were analyzed. The control group consisted of 46 patients with non-inflammatory diseases of the central nervous system. The clonality of immunoglobulins in the CSF, concentration of kappa and lambda free light chains and their ratio were studied. Concentrations of free light chains were significantly higher in the first group in comparison with group 2 and the control group, but didn't differ from group 3. In group 3, concentrations of free light chains were significantly higher compared to group 2 and controls. In oligoclonal-positive patients with clinically isolated syndrome (groups 1 and 2), concentrations of kappa and lambda free light chains were significantly higher than in oligoclonal-negative patients. The production of free light chains in patients from the first group was considerably higher than in group 2 regardless of the oligoclonal status. The concentration of kappa chains and quotient of kappa free light chains in the CSF had the best diagnostic characteristics. Their use, along with the evaluation of IgG clonality, reduced the risk of false-negative results by 50%. Regardless of other factors, elevated concentrations of kappa chains increase the likelihood of MS diagnosis by 9.718 times. The use of free light chains as a laboratory marker can increase the accuracy of MS diagnosis. These markers can help indirectly assess the risk of transformation of a clinically isolated syndrome into definite multiple sclerosis within the first 2 years of disease.

Minimal tumour burden in haematological diseases: a step forward with quantitative assessment of Bence-Jones in nephelometry?

Minimal tumour burden in haematological diseases: a step forward with quantitative assessment of Bence-Jones in nephelometry?

DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF INTRATHECAL SYNTHESIS OF IMMUNOGLOBULIN FREE LIGHT CHAINS IN MULTIPLE SCLEROSIS

Increased intrathecal synthesis and oligoclonal banding of immunoglobulins (Ig) in cerebrospinal fluid (CSF) are major immunological findings in multiple sclerosis. Free light chains are fragments of Ig molecules that are produced in parallel to oligoclonal Ig, and their production reflects total Ig synthesis within central nervous system. Assessment of intrathecal kappaand lambda free light chain production within CNS compartment will help to improve diagnosis and prediction of outcomes in multiple sclerosis. Concentrations of kappa and lambda free light chains and clonality of immunoglobulin pattern synthesis were studied in paired CSF and serum samples of 151 patients, including 92 patients with multiple sclerosis, and 33 patients with clinically isolated syndrome which later was transformed into the definite multiple sclerosis. A control group consisted of 26 patients with other inflammatory diseases of central nervous system. Several Ig parameters have been determined in the patients, i.e., Ig clonality in CSF; concentrations of free light chains (both kappaand lambda-) in CSF; as well as their indexes and ratios. It was established that synthesis of kappa free light chains were significantly elevated in patients with multiple sclerosis. Moreover, the amounts of free light Ig chains in patients with positive oligoclonality test were significantly higher than in cases without intrathecal oligoclonal synthesis. With respect to diagnostic significance, the kappa quotient proved the best available option for diagnosis of multiple sclerosis. Its combination with Ig oligoclonality assays caused a decrease in false-negative diagnostics by 42%. Diagnostic benefit of the kappa quotient could be also confirmed by the data of ROC analysis. Also concentration of lambda free light chains in cerebrospinal fluid showed a negative correlation with conversion terms of clinically isolated syndrome to evident multiple sclerosis. Therefore, the indexes of free Ig light chains enables more precise diagnostics, like as more efficient severity evaluation of multiple sclerosis.

Aggressive FLC Escape in a Patient with IgD Myeloma.

Background. Some patients who are stable or in remission from a myeloma secreting intact monoclonal immunoglobulin (+/− associated free light-chains (FLCs)) relapse with production of FLC. This FLC escape is one of the illustrations of the intraclonal heterogeneity of multiple myeloma. Results. We report FLC escape in a patient with IgD myeloma characterized by a severe outcome. We discuss parameters that negatively impacted prognosis in this patient, including bone lesions, biochemical parameters, and genomic abnormalities. Conclusion. This case illustrates the selective pressure exerted by therapeutic drugs and the variable sensitivity of subclones to these drugs; it also highlights the importance of FLC monitoring in treated MM patients.

Comparison of the free and total light chain assays in serum and urine samples with immunofixation electrophoresis for detecting monoclonal proteins in patients with monoclonal gammopathy

ABSTRACT Monoclonal protein (M-protein) is produced by a malignant clone of plasma cells. Detected in serum and/or urine, this typically indicates multiple myeloma (MM) or other monoclonal gammopathy (MG). In a majority of MM cases, with the production of intact monoclonal immunoglobulin (Ig), malignant plasmocytes and/or B lymphocytes often produce excessive amounts of free light chains (FLCs). Excessive synthesis of FLCs lowers the ability of renal proximal tubules to re-absorb FLCs, which results in abnormally high levels of FLCs in the urine (Bence Jones protein, BJP). In laboratory practice, there are tests available for the quantitative measurement of only FLCs κ and λ or for total light chains (TLCs). These tests measure both free forms and bound in the (Ig) molecules forms as light chains that are evident in the serum and in urine. The purpose of this study was to evaluate the FLCs and TLCs approaches in screening serum and urine samples of patients with MM, doing so in comparison to the results of immunofixation (IFE) assessment. A second purpose was to assess the suitability of the collected material for obtaining the most reliable results. The results of serum FLCs (sFLCs) assays suggest that this approach is of the highest reliability and diagnostic usefulness in the detection of MG with excess production of FLCs, in comparison to other available tests. In our work, when κ band light chains were detected in serum IFE (sIFE), 91% patients had their FLCs concentrations beyond the reference range, whereas 89% patients had increased λ FLCs when λ band light chains were detected in sIFE. We also found abnormal sFLC κ/λ ratios in 86.4% and 88.9% of all subject patients who had κ or λ band light chains detected in their sIFE, respectively.

44-Year-Old Man With Exertional Dyspnea, Weight Loss, and Palpitations

44-Year-Old Man With Exertional Dyspnea, Weight Loss, and Palpitations

Serum Free Light Chains Identify Patients With Monoclonal Gammopathy At Increased Risk Of Developing Renal Disease

BackgroundMonoclonal gammopathy (MG) is frequently associated with kidney disease (monoclonal gammopathy of renal significance; MGRS). International guidelines recommend the use of the serum free light chain (FLC) assay when screening for monoclonal gammopathies; an abnormal FLC ratio and an elevation of at least one FLC isotype indicates an Ig LC clone. However it is not known if, in patients with normal kidney function, the presence of a FLC clone predisposes to the future development of kidney disease. Patients and MethodsA 22485 patient database with multiple laboratory tests and up to 15-year follow up (Regional Medical Laboratory, Tulsa, OK, USA) was analysed. There were 425 confirmed MG patients with no progression to multiple myeloma. Median age was 72 years (22-97 years) and M/F ratio was 177/248. FLC kappa and lambda were measured nephelometrically with Freelite® (The Binding Site Ltd, Birmingham, UK). Baseline was defined on the first available FLC measurement; this was available at inception in 258 (61%) patients and during follow-up in 167 (39%) patients. 128 patients with MG and an eGFR <60ml/min/1.75m2 and/or a clinical diagnosis of renal disease (ICD9 code) prior to and up to 100 days after baseline were excluded from the analysis. Statistical analyses, including Receiver Operating Characteristics (ROC) to identify monoclonal FLC (iFLC) cut-off were carried out using SPSS v21. Results297 (of 425) patients had a MG with normal renal function at baseline; 118 (40%) patients had an abnormal FLC ratio (88 kappa, median: 35.5 (7.7-2675) mg/L; 30 lambda, median: 83.6 (0.9-3552) mg/L). 21/297 (7%) patients developed renal impairment during the course of follow up (median: 852 (114-2388) days); 15/21 (71%) had monoclonal FLC production. In these patients there was no association between iFLC (median: 47.8 (0.9-3552) mg/L) and creatinine (median: 0.9 (0.5-1.5) mg/dL) levels (p=0.3966). Time to renal impairment (TTRI) was significantly shorter for patients with an abnormal v normal FLC ratio (75% TTRI: 1261 days v not reached (NR), hazard ratio (HR): 5.31; p<0.001). Age between groups was similar (median: 68 (22-97) v 72 (39-92) years; p=0.0544). In 118 patients withan abnormal FLC ratio, Cox regression analysis identified iFLC concentrations as being associated with the development of impaired renal function (p=0001). Furthermore, patients with iFLC>100mg/L (n=25) were at a significantly increased risk of developing renal impairment compared with patients with iFLC<100mg/L (n=93) (75% TTRI: 874 days v NR, respectively; HR: 6.10; p<0.001). ConclusionsThese results indicate that the presence of an Ig LC clone is associated with an increased risk of people with MG and normal kidney function progressing to renal disease. Disclosures:No relevant conflicts of interest to declare.

Plasma Markers of B-Cell Activation and Clonality in Pediatric Liver and Hematopoietic Stem Cell Transplant Recipients

Transplant recipients are at risk of posttransplant lymphoproliferative disease (PTLD). Thirty-six pediatric transplant recipients were evaluated (18 hematopoietic stem cell and 18 liver recipients; 12 had PTLD). We studied 207 longitudinal plasma samples from these recipients for three markers of B-cell activation or clonality: immunoglobulin free light chains (FLCs), soluble CD30 (sCD30), and monoclonal immunoglobulins (M-proteins). Kappa FLCs, lambda FLCs, and sCD30 were elevated in 20.8%, 28.0%, and 94.2% of plasma specimens, respectively. Free light chain and sCD30 levels increased significantly 1.18 to 1.82 fold per log10 Epstein-Barr virus (EBV) load in peripheral blood. Five PTLD cases manifested elevated FLCs with an abnormal kappa/lambda ratio, suggesting monoclonal FLC production. M-proteins were present in 91% of PTLD cases versus 50% to 67% of other recipients with high or low EBV loads (P=0.13). Concordance of FLCs, M-proteins, and PTLD tumor light chain restriction was imperfect. For example, one PTLD case with an IgG lambda M-protein had a tumor that was kappa restricted, and another case with an M-protein had a T-cell PTLD. In an additional case, an IgM kappa M-protein and excess kappa FLCs were both detected in plasma at PTLD diagnosis; although the tumor was not restricted at diagnosis, kappa restriction was present 5 years later when the PTLD relapsed. Plasma markers of B-cell dysfunction are frequent after transplantation and associated with poor EBV control. These abnormal markers may be produced by oligoclonal B-cell populations or PTLD tumor cells and could potentially help identify recipients at high risk of PTLD.

Significant Activity of Lenalidomide-Dexamethasone in Multiple Myeloma (MM) Patients with Light Chain Induced Acute Renal Failure (LC-ARF)

AbstractAbstract 4031 Introduction:Excessive production of free light chains with affinity for uromodulin results in protein aggregates and toxic injury of distal renal tubules. The ensuing renal failure is a significant risk factor for infections, dependency on chronic hemodialysis and reduced survival. Management of this emergency includes rapid confirmation of the diagnosis and prompt installment of effective anti-myeloma therapy. Here, we assess the efficacy of lenalidomide-dexamethasone for treatment of patients with LC-ARF. Patients and Methods:32 patients with LC-ARF as formerly defined (J. Clin. Oncol. 2010 20; 28(30):4635-41) have been enrolled so far. Age (median): 66 years (range: 46–87 years), Gender: male/female: 17/15. All patients presented with ISS stage III. 26 (81.3%) had de novo MM and 6 (18.8%) previously treated, but relapsing disease. Median GFR was 19.9 ml/min (range 6.1 – 37.2 ml/min). ECOG performance status was 0 in 9, I-II in 18 and III-IV in 5 patients, respectively. Lenalidomide was given from d 1–21 with dose adaptation according to GFR as suggested in the prescribing information. Dexamethasone 40 mg was administered on d 1–4, 9–12, 17–20 during cycle 1; thereafter 1x/week. Cycles were repeated q 4 weeks. Results:Presently, 23 patients are evaluable for response (completed ≥2 cycles and fully documented). The median follow-up is 7.7 months, median number of cycles is 9 (range 2–9). CR was achieved in 5 (21.7%), nCR in 1 (4%), VGPR in 2 (8%) and PR in 13 (52%) patients, MR in 1 (3%), respectively, yielding an ORR (CR+nCR+VGPR+PR) of 91.3% for evaluable patients and 65.6% for the ITT population. Median time to first myeloma response was 28 (range 27–63 days) and to best response was 113 days (34–304 days). The cumulative incidence of all patients with myeloma and renal responses are shown in figure 1. Median PFS and OS were 13.8 and 31.2 months respectively in the evaluable patients and 7.4 and 31.2 months in the ITT population.Renal response was assessed as formerly defined (J Clin Oncol. 2010 20; 28(30):4635-41). 4 patients achieved CRrenal, 8 PRrenal and 3 MRrenal, yielding an ORRrenal in 15 patients (65.2% of the evaluable and 46.9% of the ITT population). Median time to first renal response was 28 (range: 27–34) days, and to best renal response 119 days (34–304 days). 5 of 13 dialysis dependent patients became dialysis independent.Median GFR of evaluable patients increased from 15.2 (range 6.1 – 35.1 ml/min) at baseline to a median best GFR of 31.4 ml/min (range 11.3 – 103.2 ml/min). In the 5 patients with CR a significant increase in GFR (median 26.7 to 60.9 ml/min) and in the 16 patients with nCR/VGPR/PR an increase from 13.5 to 30.1 ml/min was observed.Full documentation of adverse events is presently available in 32 patients. 5 patients died within the first 2 months, 2 (8.7%) each due to infection and cardiac arrest and 1 (4.3%) with apoplexia. Grade 3/4 anemia, thrombopenia and leucopenia, were seen in 17 (53.1%), 9 (28.1%), and 5 (15.6%) patients, respectively. Other common grade 3/4 toxicities were infection/sepsis in 13 (40.6%), and cardiac dysfunction in 8 (25%) patients, respectively. Exanthema G3 was seen in 3 patients (9.3%), pulmonary embolism, macula edema and multiple stroke syndrome in 1 (3.1%), potassium deficiency G3/4 in 5 (15.6%), and oral candidiasis in 2 patients (6.3%) each. Conclusions:LD showed significant anti-myeloma activity with an overall myeloma response rate (CR-PR) of 91.3% in the evaluable of 65.5% in the ITT cohort. Renal responses (CRrenal-PRrenal) were observed in 65.2% and 46.9% patients, respectively. Time to first myeloma and first renal response was fast (28 days each). The LD regimen with the lenalidomide dose adjusted to GFR was well tolerated. Updated results will be presented. [Display omitted] Disclosures:Ludwig:Janssen Cilag: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria. Off Label Use: Lenalidomide was used of label in combination with dexamethasone in this phase II study in patients with acute light-chain induced renal failure.