Urinary Free Light Chains Research Articles

B-311 Relation of Free Immunoglobulin Ligh Chain Concentration to Overflow Proteinuria

Abstract Background Free immunoglobulin light chains are small proteins that undergo substantial glomerular filtration. When high serum concentrations of free light chains occur in multiple myeloma, the high filtered load of light chains exceeds the uptake capacity of proximal tubules, and overflow proteinuria ensues. Massive excretion of light chains can lead to cast formation and renal injury. The present study sought to determine the relation of serum light chain concentration to overflow proteinuria. Methods Results for patients with plasma cell disorders were reviewed as approved by an institutional review board. A Binding Site Optilite analyzer measured serum free light chain concentrations. Urine and serum protein electrophoresis were performed on Helena agarose gels. A total of 170 paired serum and 24-hour urine specimens were evaluated for 36 patients with increased kappa light chains and 26 patients with increased lambda light chains. Results Overflow proteinuria with either immunoglobulin light chain presented with light chain as the major urinary protein and limited increases of urinary albumin. Light chain excretion exceeded albumin excretion when light chain excretion surpassed 100 mg/d. Similar results were obtained for cases with increased kappa and lambda free light chains. There was a general relation of increased serum kappa and lambda light chains and urinary excretion of the corresponding light chain. Limited urinary excretion of light chains (<120 mg/d) was seen when the serum light chain concentration was < 250 mg/L, representing an approximate threshold for substantial overflow proteinuria. Overflow proteinuria exceeding 2,000 g/d was seen only when serum free light chain concentrations exceeded 800 mg/L. However, a few patients with high serum light chain values (>1,000/L) had low urinary light chain excretion that was discordant from the relation of serum light chain concentration to light chain excretion. Serum light chain values >4,000 mg/L (N = 10) were all associated with overflow proteinuria of > 1,500 mg/d and, in 7 cases, >10,000 mg/d. In a few cases, there was evidence that serum light chain assays overestimated light chain concentrations. In one case, the serum free light chain value was twice the total protein and about 12-fold higher than the serum M-spike, suggestive of substantial overestimation. Conclusions Defining the relation between serum free light chain concentrations and the magnitude of overflow proteinuria helps identify patients at low and high risk of massive overflow proteinuria that can cause renal injury. Limited overflow proteinuria (<120 mg/d) occurred when serum light chain concentration was < 250 mg/L, and substantial overflow proteinuria occurred when serum light chains exceeded 4,000 mg/L Serum free light chain concentrations above 250 mg/L were incompletely predictive of urinary free light chain excretion; a few discordant cases with high measured serum light chain concentrations (>1,000 mg/L) and low excretion of light chains were observed. Further investigation is indicated for cases with possible overestimation of free light chains or discordance between serum light chain values and urinary light chain excretion. Unexpected results in some cases could relate to polymerization of free light chains as previously reported.

A patient with AL amyloidosis presenting with refractory tuberculosis, chest tightness and hypotension: case report

IntroductionImmunoglobulin light chain (AL) amyloidosis presents a clinical spectrum characterized by diverse manifestations and involvement of multiple organs, posing a significant diagnostic challenge for physicians.Methods and resultsWe present a case of a patient admitted to our hospital due to recurrent cough and sputum, which was initially diagnosed as refractory tuberculosis. Throughout his hospitalization, the patient experienced distressing symptoms, including uncontrollable chest tightness, hypotension, and fever. Noteworthy observations included a persistent elevation in cardiac biomarkers, indicative of cardiac damage. Bronchoalveolar lavage revealed the presence of various pathogenic microorganisms, while bone marrow flow cytometry demonstrated the existence of clonal plasma cells. Additionally, the urine free light chain assay detected the presence of M protein, and the positive congo red staining of the abdominal wall fat biopsy confirmed amyloid deposition in the tissues. Taking into account the patient’s clinical presentation and the examination findings, we reached a conclusive diagnosis of immunoglobulin light chain (AL) amyloidosis.ConclusionThis case serves as a reminder for physicians to consider rare diseases like AL amyloidosis when patients present with symptoms involving multiple organ systems such as heart, lung and kidney that are unresponsive to conventional treatment options.

Evaluation of Urinary Free Light Chains as a Marker of Severity of HIV Disease and Its Correlation with CD4 Count: A Pilot Study.

Human immunodeficiency virus (HIV) infection weakens immunity. Monitoring the immune status of the patient has become an important aspect of evaluating the progression of the disease and informing follow-up after treatment. Estimation of CD4 counts is quite costly and requires expertise in flow cytometry. In certain pathologies, free light chains (FLCs) are secreted in serum and urine and the magnitude can be used to monitor the severity, progression, and therapeutic monitoring of the disease. Urine as a specimen proves cost-effective and presents reduced risks during sample collection. The stability of light chains in urine at room temperature over extended periods simplifies the management of sample transportation as well. Hence, a pilot cross-sectional study was planned to evaluate the levels of urinary immunoglobulins in patients with HIV. The study was conducted at PGIMER, Dr. Ram Manohar Lohia Hospital (presently ABVIMS), New Delhi. Sixty-nine consecutive ART-naive HIV patients aged between 18 and 40 years and 69 age- and sex-matched healthy controls were included in the study. Urinary FLC kappa (κ) and lambda (λ) were measured using an immunoglobulin ELISA kit. Baseline urinary κ light chain levels were significantly higher in cases when compared with controls (p < .001) and were found to be increased with increasing WHO immunological classes (p < .001) and inversely related to CD4 cell count. However, no significant difference in mean urinary λ immunoglobulin light chain between cases and controls was found and no correlation with CD4 cell count or with stages of WHO immunological classification of HIV disease was observed. It is suggested that urinary free κ chain measurements combined with serum light chain measurements may be a useful marker in the follow-up and monitoring of response to therapies in patients with HIV where testing by flow cytometry is not available.

Preliminary evaluation of concordance between Bence Jones protein and urine free light chain (FLC)

Preliminary evaluation of concordance between Bence Jones protein and urine free light chain (FLC)

Soluble B-Cell Maturation Antigen As a Disease Biomarker in Relapsed or Refractory Multiple Myeloma (RRMM): Evaluation from Elranatamab (ELRA) Magnetismm Studies

BACKGROUND B-cell maturation antigen (BCMA) is primarily expressed on the cell membranes of terminally differentiated B cells and malignant or normal plasma cells. BCMA is a validated target for the treatment of multiple myeloma (MM). The γ-secretase enzyme cleaves the extracellular domain and releases soluble BCMA (sBCMA) in the circulation. sBCMA is elevated in patients with (pts) MM vs healthy subjects. Response to treatment in MM is routinely measured by serum and urine M-protein and free light chain (FLC). sBCMA could serve as a useful biomarker for disease response enabling a more rapid disease assessment given its faster turnover compared to serum FLC and/or M-protein (half-life of sBCMA, FLC, and M-protein is ~1, 2.75, and 11.9 days, respectively). This work a) evaluated the correlation of baseline sBCMA in plasma with key disease biomarkers and subgroups, and b) investigated the correlation of changes from baseline sBCMA with responses over time. METHODS Data from 4 studies in RRMM were pooled for the evaluation of baseline correlation with key disease biomarkers. These studies were the first-in-human MagnetisMM-1 (NCT03269136) study, the Japan Phase 1 MagnetisMM-2 (NCT04798586) study, MagnetisMM-3 (NCT04649359) study, and a Phase 1/2 MagnetisMM-9 (NCT05014412) study. Data from MagnetisMM-3 Cohort A only was used to investigate the correlation of changes from baseline sBCMA with responses over time. Two assays were used to measure sBCMA levels in plasma: 1) an electrochemiluminescent (ECL) ligand binding assay for measuring free (ie, drug unbound) sBCMA, and 2) an immunoaffinity LC-MS/MS assay for measuring total sBCMA (ie, free sBCMA in addition to drug bound and sBCMA bound to APRIL or BAFF). Plasma samples were collected at baseline and at various timepoints on treatment. Key disease biomarkers included disease stage [a: derived International Staging System (ISS), b) Revised-ISS (R-ISS) based on investigator assessment, and c) Derived R-ISS], tumor burden (high vs intermediate/low) which is derived as High: plasma cell in bone marrow (PCBM) ≥80%, or serum M-spike ≥ 5 g/dL, or FLC ≥5000 mg/L; Low: PCBM &amp;lt;50%, or serum M-spike &amp;lt; 3 g/dL, or FLC &amp;lt; 3000 mg/L; Intermediate: neither High nor Low. Other factors included β-2 microglobulin, cytogenetics, and presence of extramedullary disease (EMD). Statistical comparisons were conducted using t-test and one-way ANOVA. Statistical significance was defined as P &amp;lt;0.01. Correlations between post baseline changes in sBCMA levels and responses were explored graphically. RESULTS Baseline sBCMA was higher in participants with ISS or R-ISS 3 &amp;gt; 2 &amp;gt; 1 [ P &amp;lt;0.001]. Similarly, pts with high tumor burden had higher baseline sBCMA vs those with intermediate or low tumor burden. A moderate correlation was observed between baseline sBCMA and β-2 microglobulin. Participants with BMPC ≥50% had higher baseline sBCMA than those with &amp;lt;50%. A trend for association was observed in pts with EMD ( P=0.047). There was no statistically significant difference in baseline sBCMA levels between participants with high vs standard risk cytogenetics ( P=0.29). Results from the two assays for the baseline correlation were generally comparable. In MagnetisMM-3, free sBCMA declined in the majority of responding participants within 2 to 3 cycles. Concentrations of sBCMA in non-responding participants remained largely unchanged or increased in some patients. 92.5% (86/93) of responding participants (who also had free sBCMA measured) experienced at least 50% reduction from their baseline free sBCMA level vs 17.9% (12/67) in non-responding participants by Cycle 2 Day 1 (C2D1). An increase (or lack of decline) from baseline levels was observed in &amp;gt;90% of non-responders. Participants with deeper responses had higher magnitude of free sBCMA reduction by C2D1. Total sBCMA concentrations increased in non-responders and declined in responders, however, the decline was observed at later timepoints (eg, C6) as total sBCMA levels are affected by ELRA half-life. CONCLUSIONS Results from MagnetisMM studies showed that sBCMA is a potential disease biomarker of myeloma disease stage and disease burden. ELRA induced deep and rapid declines in free sBCMA levels. These declines correlated with clinical activity in patients with RRMM, which is demonstrated by ≥50% reduction in free sBCMA levels in &amp;gt;90% of responders, and an increase from baseline (or lack of decline) in &amp;gt;90% of non-responders.

Quantification of Free Immunoglobulin Light Chains in Urine.

The serum-free immunoglobulin light chain assay has been recommended as a screening test for monoclonal gammopathy. We evaluated the usefulness of urine free immunoglobulin light concentration for selection of specimens for immunofixation electrophoresis. Using kits from The Binding Site for Freelite ®, we validated examination of urine for measuring free κ and λ light chains. The results of urine free light chain concentrations were evaluated to ascertain if the results could be used to reduce the number of specimens requiring urine protein immunofixation electrophoresis. In the 515 specimens examined, there was no evidence of monoclonal gammopathy or history of monoclonal gammopathy in 331. Monoclonal κ or λ light chains were detectable in 42 and 30 specimens, respectively. There was history of κ or λ chain associated monoclonal gammopathy in 62 and 50 patients, respectively. In the 38 monoclonal κ positive urine specimens, with light chain data, κ/λ ratio was >5.83 in all specimens. In 27 specimens positive for monoclonal λ light chains, with light chain data, the urine λ/κ ratio was > 0.17 in 24 of 27 specimens and > 0.041 in all specimens. In patients without monoclonal gammopathy all specimens had a κ/λ ratio of >5.83 or λ/κ ratio >0.17. The Freelite ® assay from The Binding Site is suitable for quantification of free light chains in urine. In patients with known history of monoclonal gammopathy, urine immunofixation electrophoresis may be omitted in specimens with κ/λ ratio of <5.83 for κ associated lesions and λ/κ ratio of <0.041 for λ associated lesions. However, the results do not support using this test for first-time urine testing for monoclonal light chains as it is not predictive of positive result, nor does it exclude a monoclonal light chain in urine.

A new challenge for urinary free light chains: assessment of the upper reference limit in healthy subjects.

Free light chains (FLCs) can be measured in both urine (uFLC) and serum (sFLC) in immunochemistry. We aim to compare FLC levels in serum and urine assessed among healthy volunteers and measured upper reference limits (URLs) of urinary FLC to creatinine ratio (uFLC/uCr) in mg/g to compare with the manufacturer's recommended URLs. Eligibility criteria: normal serum and urine FLC measure and negative serum/urinary immunofixation. Immunoturbidimetry was used to assess both κ and λ FLCs. The URLs were calculated with the 97.5th percentile of uFLC concentrations according to the Clinical and Laboratory Standards Institute recommendations. 126 healthy subjects (median age 46 years, 62% females) met the inclusion criteria. Median concentrations of κ and λ sFLCs were similar both for males and females without significant differences. κ and λ uFLCs were significantly higher in males than in females (p < 0.001 and p = 0.004, respectively). Slower clearance for λ FLC compared to κ FLC was observed with an increased κ/λ uFLC ratio in both males and females. URLs for male and female subjects: κ uFLC mg/g uCr = 34.35 vs. 23.18, and λ uFLC mg/g uCr = 3.59 vs. 1.96, respectively compared well with manufacturer's URLs. FLC catabolism is gender-dependent and occurs less rapidly in λ FLC than in κ FLC. The determination of the URL of uFLC, as uFLC/uCr, in healthy subjects in morning urine, proved to be consistent with the manufacturer's recommendations, but with a significant difference according to gender.

Soluble B-cell maturation antigen as a monitoring marker for multiple myeloma.

Objective: Response to treatment in multiple myeloma (MM) is routinely measured by serum and urine M-protein and free light chain (FLC), as described by the International Myeloma Working Group (IMWG) consensus statement. A non-negligible subgroup of patients however present without measurable biomarkers, others become oligo or non-secretory during recurrent relapses. The aim of our research was to evaluate soluble B-cell maturation antigen (sBCMA) as a monitoring marker measured concurrent with the standard monitoring in MM patients at diagnosis, at relapse and during follow up, in order to establish its potential usefulness in oligo and non-secretory disease. Method: sBCMA levels were measured in 149 patients treated for plasma cell dyscrasia (3 monoclonal gammopathy of unknown significance, 5 smoldering myeloma, 7 plasmacytoma, 8 AL amyloidosis and 126MM) and 16 control subjects using a commercial ELISA kit. In 43 newly diagnosed patients sBCMA levels were measured at multiple timepoints during treatment, and compared to conventional IMWG response and progression free survival (PFS). Results: sBCMA levels among control subjects were significantly lower than among newly diagnosed or relapsed MM patients [20.8 (14.7-38.7) ng/mL vs. 676 (89.5-1,650) and 264 (20.7-1,603) ng/mL, respectively]. Significant correlations were found between sBCMA and the degree of bone marrow plasma cell infiltration. Out of the 37 newly diagnosed patients who have reached partial response or better per IMWG criteria, 33 (89%) have had at least a 50% drop in sBCMA level by therapy week 4. Cohorts made similarly to IMWG response criteria-achieving a 50% or 90% drop in sBCMA levels compared to level at diagnosis-had statistically significant differences in PFS. Conclusion: Our results confirmed that sBCMA levels are prognostic at important decision points in myeloma, and the percentage of BCMA change is predictive for PFS. This highlights the great potential use of sBCMA in oligo- and non-secretory myeloma.

591 SEQUENCE OF DIAGNOSTIC TESTING IN CARDIAC AMYLOIDOSIS: EARLY MONOCLONAL PROTEIN STUDY IS ASSOCIATED WITH BETTER OUTCOMES IN AL AMYLOIDOSIS

Abstract Background Isolated cardiac amyloidosis (CA) is a complex diagnostic scenario, highlighting the need for physician awareness in differential diagnosis. Among the different types of amyloidosis, nearly all cases of CA are caused by light chain (AL) and transthyretin amyloidosis (ATTR). Patients with suspect CA without monoclonal components (MC) in both serum and urine and normal free light chain (FLC) ratio can have a non-biopsy diagnosis of ATTR amyloidosis with bone scintigraphy (1). However, in all suspected CA with a MC (approximately 20% of patients with ATTR amyloidosis), amyloid typing is mandatory. Thus, the diagnostic pathway of CA diverges based on MC-studies. We aim to assess if different sequence of diagnostic tests can affect outcomes in patients with cardiac AL amyloidosis. Methods Pavia Amyloidosis prospectively maintained database was searched for patients with isolated cardiac AL amyloidosis referred to our Centre from January 2016 to December 2020. Patients with a known monoclonal gammopathy (MG) and with multiple organ involvement were excluded. We searched for the date of symptom onset and first suspect of CA (i.e. recognition of clinical, imaging or laboratory signs of CA). In addition, we recorded the date of the different diagnostic tests performed: i.e. echocardiogram; serum and urine immunofixation and FLC measurement (MC-study); bone scintigraphy and cardiac magnetic resonance (defined as advanced cardiac imaging). We calculated the interval between those time-points and the final diagnosis: (a) from symptom onset to diagnosis, (b) from first suspect to final diagnosis, (c) from first suspect to MC-study and (d) to advanced cardiac imaging tests. We then searched for possible intervals of time amongst those, that were able to predict death at 3 months, by means of a ROC analysis. Results A total of 94 patients were included in the analysis (25% of all patients with cardiac AL amyloidosis diagnosed in the study period). Six (6%) patients died &amp;lt;1 month from diagnosis, and 27 (29%) died &amp;lt;3 months. Median overall survival (OS) of the whole cohort was 8 months, and the median follow-up of living patients was 39 months (range 16-73). The median time from symptom onset to diagnosis was 9 months (range 1-44) and the median time from the first suspect to diagnosis was 2 months (range 0-9). An interval from the first suspect to MC-study ≥6 weeks was the only predictor of death at 3 months. None of the other tested periods were associated with a significant ability to predict survival. A delay in MC-study ≥6 weeks identified patients with more advanced cardiac stage (50% vs. 25% were stage IIIb, P=0.02) and was associated with a significantly worse outcome (median survival 13 months vs. 4 months, P=0.012). In the whole cohort, a total of 76 (81%) patients underwent at least one advanced imaging examination. Amongst those, 37 (49%) performed the imaging tests before MC-study with a higher percentage of patients who had a delay in MC-studies evaluation (69% vs. 27%; P&amp;lt;0.001). Conclusion In patients who present with isolated cardiac AL amyloidosis with previously unknown MG, a relatively short delay in identifying the amyloid MC results in a considerable reduction of survival. A delay in MC-study was associated with more advanced cardiac stage. MC studies should be the first step in the work-up of patients with suspected CA to guide biopsy vs. non-biopsy diagnostic approach.

An echo score raises the suspicion of cardiac amyloidosis in Chinese with heart failure with preserved ejection fraction.

Transthyretin cardiac amyloidosis (ATTR-CA) has been realized as an important cause of heart failure with preserved ejection fraction (HFpEF). We aim to provide insights into its prevalence in Chinese HFpEF patients, which is not known to date, using increased wall thickness (IWT) score by echocardiography. Consecutive patients with HFpEF (EF≥40%) and IWT (≥12mm) were prospectively screened. Echocardiography was performed, and the IWT score incorporated relative wall thickness, E/e' ratio, longitudinal strains, and tricuspid annular plane systolic excursion, and septal apical-to-base ratio was calculated. ATTR-CA was defined as score ≥8 in the absence of serum and urine free light chain. Six hundred twenty-four HFpEF patients from January 2019 to December 2021 were enrolled, of which 65.2% were males and the median (interquartile range [IQR]) age was 66 (IQR 57, 73) years. Thirty-three patients (5.3%, 95% CI 3.5-7.0%) were with score ≥8, and 33.3% were females. They were younger (58 vs. 69years, P<0.001), had higher NT-proBNP (6525.0 vs. 1741.5pg/mL, P<0.001) and troponin I (105.2 vs. 27.7pg/mL, P=0.001) level, and lower LVEF (47% vs. 57%, P<0.001) compared with the patients with score <5. In the internal cohort (82 patients) who had undergone scintigraphy, the IWT score ≥8 was shown to have a sensitivity of 85.7% (95% CI 56.2-97.5%) and a specificity of 92.6% (95% CI 83.0-97.3%) for diagnosing CA, and the IWT score <5 had great accuracy in excluding CA with the negative predictive value of 100%, supporting the clinical usefulness of the IWT score to guide further dedicated testing for ATTR-CA. The IWT score by echocardiography was an excellent tool for screening ATTR-CA in HFpEF. In Chinese HFpEF patients associated with a hypertrophic phenotype, the proportion of highly suspected ATTR-CA as detected by IWT score ≥8 was 5.3%, lower than the reported prevalence of ATTR-CA in non-Asian patients with the disease.

Popeye's sign and transthyretin amyloidosis.

A 76-year-old man with a history of cervical open-door laminoplasty for ossification of the posterior longitudinal ligament presented to our hospital with a symptom of exertional dyspnoea. A 12-lead electrocardiogram revealed I-degree atrioventricular block (PQ interval 262 ms), left axis deviation, and complete right bundle branch block (Panel A). A transthoracic echocardiogram indicated left ventricular hypertrophy with a maximum wall thickness of 17 mm and a left ventricular ejection fraction of 61% (Panel B1). Strain echocardiogram using speckled tracking showed marked diminution of global longitudinal strain with apical sparing (Panel B2). Physical examination found subconjunctival hemorrhage in right eye, several purpuric lesions in upper extremities, and a large bulge on his left upper arm when he flexed his arm, so-called Popeye’s sign, indicating a hallmark of biceps tendon rupture (see Supplementary material online, Video S1; Panel C; arrow). A monoclonal component was not detected by serum and urine immune-electrophoresis and free light chain assays. 99mTc-labelled bone scintigraphy showed grade 3 myocardial uptake (Panel D). Eventually, endomyocardial biopsy and genetic sequencing analysis of the transthyretin gene confirmed the patient as a wild-type transthyretin amyloidosis (Panel E). Popeye’s sign is uncommon, but pivotal to diagnose transthyretin amyloidosis.

69-Year-Old Man With Dysuria and Right Lower Abdominal Pain

69-Year-Old Man With Dysuria and Right Lower Abdominal Pain

Prevalence of cardiac amyloidosis in patients undergoing transcatheter edge-to edge mitral valve repair

Abstract Introduction Cardiac amyloidosis (CA) is associated with severe aortic stenosis, however, its prevalence in patients with severe mitral regurgitation in elderly patients is unknown. Methods Patients scheduled for transcatheter edge-to edge mitral valve repair (TMVR) were prospectively screened for CA using 99m technetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) bone scintigraphy and subsequent serum as well as urine free light-chain quantification in case of a positive DPD scan, defined as visual cardiac update based on the Perugini grading scale. Results Out of 100 patients undergoing TMVR, 28 patients (28.0%) had a positive DPD-scan (DPD+). 14 patients (14.0%) showed Perugini grade I enhancement, 9 patients (9.0%) grade II enhancement, and in 5 patients (5.0%), grade III enhancement was present. 28 patients suffered from TTR and two from AL- amyloidosis (one patient had a combination of TTR and AL-amyloidosis). When compared to patients with a negative scan (DPD-), DPD+ patients presented with similar baseline characteristics such as age (DPD- vs DPD+ 76y/o vs 77y/o, p=0.44), gender (female; 62.7% vs 50.0%, p=0.25), coronary artery disease (59.7% vs 42.9%, p=0.13), previous valve surgery (25.4% vs 14.3%, p=0.24) and atrial fibrillation (68.7% vs 78.6%, p=0.33). Also, NYHA functional class and EuroScore II were similar (NYHA ≥ III; 85.1% vs 82.1%, p=0.72, and EuroScore II 9.9±9.8% vs 7.0±4.8%, p=0.21, respectively). On echocardiography, DPD+ patients presented with more pronounced left and right ventricular hypertrophy (interventricular septum: 15mm vs 13mm, p&amp;lt;0.01) but similar left ventricular ejection fraction (44.9% vs 42.3%, p=0.34). At 3-months after TMVR, DPD+ patients showed significant improvement in BNP serum levels when compared to DPD- patients (DPD+ vs DPD-: +315±2569pg/ml vs −2404±8696pg/ml, p=0.03), while NYHA functional class remained unchanged (NYHA improvement ≥1 class: 57.6% vs 50.0%, p=0.52) Conclusions In this single centre experience, CA was highly prevalent among elderly patients with severe mitral regurgitation scheduled for TMVR. TMVR in CA patients resulted in significant improvement of NT-pro BNP levels. Future studies need to clarify the prognostic relevance of CA in this specific patient population. Funding Acknowledgement Type of funding sources: None.

Light Chain Glomerulopathy Causing Kidney Failure in Renal Cell Carcinoma

Light chain deposition disease(LCDD) is a rare cause of kidney failure. It is associated with multiple myeloma and is diagnosed by the evaluation of serum and urine free light chains. Patients who are diagnosed with this disease often develop rapidly progressive renal failure. To our knowledge, it does not have any association with other malignancies aside from multiple myeloma.We present a case that highlights a novel association between renal cell carcinoma and light chain-mediated renal disease. Our patient was admitted due to acute renal failure and underwent a comprehensive diagnostic evaluation with an eventual diagnosis of light chain glomerulopathy in the setting of metastatic renal cell carcinoma.

P-PN003. Refractory chronic inflammatory demyelinating polyneuropathy treated with subcutaneous bortezumib

Introduction. A 73-year-old man with underlying diabetes presented in May 2017 with progressive bilateral upper and lower limb weakness and numbness for 3 months. Examination revealed power of 2-3 on lower limbs and 3 on upper limbs. Reflexes were absent with gloves and stocking sensory loss. NCS showed diffused sensorimotor demyelinating polyneuropathy. Monoclonal IgG kappa was detected. Urine free light chain showed raised kappa. However, BMAT showed no evidence of myeloma. Abdominal fat pad biopsy showed no evidence of amyloidosis. Anti-ganglioside and paraneoplastic antibodies were not detected. Sural nerve biopsy showed axonal loss. CT NTAP was unremarkable. He responded initially with IVIG therapy but In July 2017, he had a relapse with worsening lower limb weakness. He was given IVIG 1 g/kg maintenance together with dexamethasone 4 weekly pulse therapy with some improvement. In Oct 2017, he presented again with worsening weakness. Besides, there was dysphagia and dysphonia. He developed type 2 respiratory failure requiring NIV and ICU admission, requiring 2 weekly plasmapheresis to rescue him from recurrent respiratory failure. IV Rituximab was tried but with little success even after 1 month of completion. Subcutaneous Bortezumib was given for 2 courses; Feb 2018 and Aug 2018. Results. After first course of Bortezumib, he improved significantly; with no more dysphagia and respiratory failure. He was subsequently discharged in Apr 2018, since then on monthly maintenance plasmapharesis and later 3 monthly. Upon latest review in Nov 2019, he was able to ambulate independently; muscle power improved with upper limbs proximal 5, distal 3; lower limbs proximal 5, distal 4. NCS showed improvement of motor CMAP especially in upper limbs. Conclusion. Bortezumib can be considered in refractory CIDP despite limited experience in the literature. However it should be reserved after conventional therapies have failed due to its neurotoxic side effects.

Comparison of Residual Neoplastic Plasma Cell Number Using Multicolor Flow Cytometry and Various Stages of International Myeloma Working Group-Defined Responses in Patients with Multiple Myeloma

【Introduction】Urine and serum immunofixation electrophoresis (IFE) and free light chain (FLC) are used for measuring paraprotein levels produced by neoplastic plasma cells and are widely accepted as standard tests for diagnosis and monitoring of multiple myeloma (MM). Treatment response criteria defined by the International Myeloma Working Group (IMWG) largely relies on the decrease in paraprotein levels of intact immunoglobulin with or without serum FLC. However, the paraprotein levels vary widely between patients and even in the same patient during the course of the disease. Therefore, considerable discrepancy often exists between the extents of decrease in neoplastic tumour cell burden and paraprotein levels in response to chemotherapy. We retrospectively compared the bone marrow plasma cell (BM-PC) levels using 6- to 8-color flow cytometry (FCM) with various levels of IMWG-defined responses after treating patients with MM.【Methods】We included patients with MM (light chain only multiple myeloma (LCMM), n =35 ; intact immunoglobulin multiple myeloma (IIMM), n =115 ) who were treated at Kameda Medical Center, Japan and Kanazawa University Hospital, Japan, between April 2007 and June 2017. Among them, 130 patients (LCMM; n=35 , IIMM; n=95 ) who achieved partial response (PR) or better response were selected on the basis of the co-availability of serum and urine test data, FLC data, and multicolor flow cytometry (MFC)-generated BM-PC quantitation data. MFC-mediated assessment of BM-PCs was performed during diagnosis and when each IMWG-defined treatment response was obtained. The residual BM-PC level was compared with the IMWG-defined responses using Kruskal-Wallis analysis. Oligosecretary and non-secretary myeloma were excluded from this study. This study conformed to the principles of the Declaration of Helsinki.【Result】Complete data set of IFE, FLC, and MFC during diagnosis, PR, very good partial response (VGPR), complete response (CR), and stringent CR (sCR) were available in 37, 58, 10, and 50 samples in IIMM and in 4, 21, 15, and 21 samples in LCMM. Mean BM-PCs during diagnosis in IIMM and LCMM was 2.1 x 10-1 and 2.2 x 10-1, respectively. In patients with IIMM, mean residual BM-PCs at PR, VGPR, CR, and sCR in IIMM were 1.8 × 10-2 (range: 1.4 × 10-5-7.5 × 10-2), 2.0 × 10-3 (range: 1.4 × 10-5-2.9 × 10-2), 4.4 × 10-4 (range: 2.1 × 10-5-2.0 × 10-3), and 4.8 × 10-4 (range: 2.0 × 10-6-5.3 × 10-3), respectively. Although significant difference in residual BM-PC levels was observed between PR vs. VGPR (P < 0.01), there were no statistically significant difference between VGPR vs. CR (P = 0.08) and CR vs. sCR (P = 0.9). Of note, 58% patients had residual MM cells ≥ 10-4 even when they achieved sCR. The amount of involved intact immunoglobulin at diagnosis was significantly higher in these patients than those who achieved residual MM cells <10-4 (mean: 5206.1 vs. 3954.7 p = 0.04).In patients with LCMM, mean residual BM-PCs cells at PR, VGPR, CR, and sCR were 3.5 × 10-2 (range: 5.1 × 10-3-7.7 × 10-2), 8.9 × 10-3 (range: 4.0 × 10-4-8.9 × 10-2), 2.0 × 10-3 (range: 4.0 × 10-5-1.0 × 10-2), and 1.1 × 10-4 (range: 2.0 × 10-6-7.0 × 10-4), respectively. Significant difference in the amount of residual BM-PC was only observed between CR and sCR, but not in PR vs. VGPR and VGPR vs. CR (PR vs. VGPR: p = 0.08, VGPR vs. CR: p = 0.08, CR vs. sCR: p = 0.03). Normal FLC ratio was highly predictive of lower residual BM-PCs (> 10-4) in LCMM. (Figure 1)Figure 2 shows the proportion of residual BM-PCs at various IMWG responses. The percentages of samples with residual BM-PCs at the levels of ≥ 10-3, 10-3 > - ≥ 10-4 , and < 10-4 in IIMM were 86.8% (n = 32/37), 7.8% (n = 3/37), and 5.2% (n = 2/37) for PR, 31.0% (n = 18/58), 56.8% (n = 33/58), and 12.0% (n = 7/58) for VGPR, 20% (n = 2/10), 40% (n = 4/10), and 40% (n = 4/10) for CR, and 12% (n = 6/50), 46% (n = 23/50), and 42% (n = 21/50) for sCR, respectively. In the case of LCMM, these figures were 100% (n = 4/4), 0% (n = 0/4), and 0% (n = 0/4) for PR, 66.6% (n = 14/21), 33.3% (n = 7/21), and 0% (n = 0/21) for VGPR, 20% (n = 3/15), 66.6% (n = 10/15), and 13.3% (n = 2/15) for CR, and 0% (n = 0/21), 23.8% (n = 5/21), and 76.1% (n = 16/21) for sCR, respectively.【Conclusion】The depth of residual BM-PCs response did not parallel that of IMWG response, and ~20% patients with CR had high level of residual BM-PCs (≥ 10-3). Although paraprotein-based assessment is feasible for disease monitoring in MM, our data indicates that response to treatment could be better assessed by BM-PC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Serum and urine free light chains measurements in patients with systemic sclerosis: novel biomarkers for disease activity

Circulating free light chains (FLCs), considered biomarkers of B cell activity, are frequently elevated in patients affected by systemic inflammatory autoimmune diseases. As the systemic sclerosis (SSc) clinical course can be variable, this study is aimed at evaluating FLCs levels in affected individuals as biomarkers of disease activity. We assessed FLC levels in serum and urine of 72SSc patients and 30healthy controls (HC). Results were analyzed in comparison with overall clinical and laboratory findings, disease activity index (DAI) and disease severity scale (DSS). SSc patients displayed increased levels of κ and λ FLC in serum significantly higher than HC (p=0.0001) alongside the mean values of free κ/λ ratio and κ+λ sum (p=0.0001). SSc patients showed increased free κ in urine with a κ/λ higher than HC (p=0.0001). SSc patients with increased κ+λ in serum showed that erythro-sedimentation rate (p=0.034), C-reactive protein (p=0.003), DAI (p=0.024) and DSS (p=0.015) were higher if compared to SSc patients with normal levels of FLC. A positive linear correlation was found between serum levels of free κ and DAI (r=0.29, p=0.014). In addition, SSc patients with increased free κ in urine had higher DAI (p=0.048) than SSc patients with normal κ levels. Our results strengthen the role of serum FLC as useful biomarker in clinical practice to early diagnosis and monitor disease activity, showing for the first time that also urine FLC levels correlated with disease activity in SSc patients.

Urinary biopyrrins and free immunoglobin light chains are biomarker candidates for screening at-risk mental state in adolescents.

Early diagnosis of individuals' at-risk mental state (ARMS) is important for preventing their pathogenesis or, at least, delaying onset of overt psychosis. Traditional diagnosis of ARMS subjects is mainly based on structured interviews, but future diagnosis would be carried out together with biomarkers. In this study, we report urinary biopyrrins and free immunoglobin light chains κ and λ (κFLC and λFLC) as novel diagnostic biomarker candidates for screening ARMS subjects. Nineteen ARMS subjects and 21 age- and sex-matched healthy controls were enrolled in this study. Inclusion criteria of the ARMS subjects were based on a comprehensive assessment of Structured Interview for Prodromal Syndromes. We compared oxidative stress and immunological markers in the urine of ARMS subjects with those of healthy controls by ELISA protocol. Augmentation of biopyrrins and reduction of κFLC and λFLC were found in the ARMS samples, and their diagnostic performance was evaluated by receiver operating characteristic analysis, of which area under the curve was as large as 0.915 in combination. Our findings suggest that the ARMS subjects were under higher oxidative stress but lower in B cell activation, and that the combined assay of urinary biopyrrins and free immunoglobulin light chains would be useful for the early detection and screening of ARMS subjects among adolescents.

Epidemiology, Staging, and Management of Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell disorder that is on the rise throughout the world, especially in the US, Australia, and Western Europe. In the US, MM accounts for almost 2% of cancer diagnoses and over 2% of cancer deaths (more than double the global proportion). Incidence has risen by 126% globally and over 40% in the US since 1990, while global mortality has risen by 94% and US mortality has fallen by 18%. The 5 year survival in the US has more than doubled over the past decades with the introduction of new targeted therapies and transplant techniques. Risk factors for MM include age (average age of diagnosis is 69), race (African Americans are over double as likely to be diagnosed), sex (men are at a 1.5× risk), and family history. Diagnosis includes serum or urine electrophoresis and free light-chain assay but requires bone marrow biopsy. It is distinguished from smoldering myeloma and monoclonal gammopathy of undetermined significance by a high (>3 g/dL) level of M-protein (monoclonal light chains) and the presence of CRAB (Hypercalcemia, Renal failure, Anemia, Bone pain) symptoms, which include hypercalcemia, renal failure, anemia, and bone pain, suggesting an end-organ damage. International staging system staging involves beta 2 microglobulin and albumin levels, while the revised system considers prognostic factors such as lactate dehydrogenase levels and chromosomal abnormalities. Front-line management includes induction regimen, maintenance therapy and hematopoietic cell transplantation for eligible patients and bisphosphonates or bone-stimulating agents for the prevention of skeletal events. Treatment for relapsed disease includes newly approved monoclonal antibodies like the CD38-targeting daratumumab, proteasome inhibitors, immunomodulating agents, and investigational therapies such as B cell maturation antigen Chimeric antigen receptor T cells.

P0745URINE TIMP-2 AND IGFBP-7- NEW BIOMARKERS OF KIDNEY INJURY IN MULTIPLE MYELOMA PATIENTS

Abstract Background and Aims Urine tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) seem to be novel kidney injury related biomarkers, especially in tubular cells damage. Free light chains (FLCs) are associated with renal failure in multiple myeloma (MM) and appear to have a prognostic value and indicate stages in MM. The aim of the study was to investigate the correlation between new biomarkers and acclaimed parameters of renal failure and markers of MM stages and prognosis. Method The study included 124 patients with MM in the mean age of 66 +/- 10 years, with median time from MM diagnosis of 30 (lower; upper quartile 14; 63) months. There were 7(6%) patients with smoldering MM, 80(65%) with ISS stage 1, 22 (18%)with stage 2 and 15 (12%) with stage 3 MM. Mean eGFR was 71 +/- 25 ml/min/1.73 m2 and 30 (24%) patients had eGFR &amp;lt;60 ml/min/1.73 m2. The examined parameters included creatinine, urine NGAL, urine and serum cystatin-C, urine and serum FLC kappa and lambda, serum monoclonal protein, IGFBP-7 and TIMP-2 in serum and urine, WBC count, IL-6, NT-proBNP, serum albumin and β2-microglobulin. IGFBP-7 and TIMP-2 in serum were measured in a subgroup of 73 patients, including 26 (36%) with eGFR &amp;lt;60 ml/min/1.73 m2. The association between between these parameters were determined by multivariate stepwise regression analysis. The p-value &amp;lt;0.05 was considered statistically significant. Results Except for urine cystatin C and urine TIMP-2, all the studied markers were higher among patients with eGFR &amp;lt;60 ml/min/1.73m2: urine NGAL: 23.3 (9.2; 68.4) vs. 7.8 (3.9; 16.8) ng/ml; p&amp;lt;0.001; urine IGFBP-7: ; serum IGFBP-7: 86.2 (29.3; 125.0) vs. 33.7 (13.2; 61.5) ng/ml; p=0.003; and serum TIMP-2: 628 (498; 663) vs. 431 (360; 614) ng/ml; p=0.011, respectively. Serum and urine IGFBP-7 and urine NGAL were also higher among patients with ISS grade 3 comparing to the rest of the group (p=0.008, p&amp;lt;0.001 and p=0.033, respectively). Patients with smoldering myeloma did not differ from those with symptomatic disease. No differences in studied markers were observed between patients with newly diagnosed MM in comparison to those who had been treated with one or more schemes. Only urinary IGFBP-7 differed between patients who were on treatment at the time of samples’ collection (median ng/ml) in comparison to untreated (median ng/ml; p=0.009). No differences in TIMP-2 and IGFBP-7 levels in patients divided according to MM state were observed (remission vs stable vs progressive disease). In whole studied group, urinary markers of tubular injury were interrelated: cystatin C correlated positively with NGAL monomer (R=0.22; p=0.016), IGFBP-7 (R=0.26; p=0.004) and TIMP-2 (R=0.22; p=0.016), NGAL correlated positively with IGFBP-7 (R=0.39; p&amp;lt;0.001) and TIMP-2 (R=0.25; p=0.005), and IGFBP-7 correlated positively with TIMP-2 (R=0.31; p&amp;lt;0.001). In multiple linear regression, the negative correlation between urinary IGFBP-7 and eGFR was independent of other studied urinary markers of tubular injury. However, after adjustment for confounders (age, smoldering versus symptomatic MM, ISS, LDH, remission versus stable or progressive disease, and the concentrations of involved urine light chains), only urinary NGAL was independently associated with eGFR. Conclusion Urine TIMP-2 and IGFBP-7 may be useful in investigating tubular renal damage in patients with chronic kidney injury among patients with MM. This can lead to noninvasive biomarker-targeted diagnostic interventions and contribute to early beginning of treatment that may improve life expectancy quality of life in MM.