Defining New Reference Intervals for Serum Free Light Chains in Individuals with Reduced Kidney Function: Results of the Population- Based on Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) Study

Background: In addition to serum protein electrophoresis (SPEP) and serum immunofixation (IFE), measurement of serum free light chains (FLC) has become the hallmark for detection, prognostication, and monitoring of monoclonal gammopathies. However, serum FLC levels are heavily dependent on kidney function due to discrepancy in the rate of kidney clearance of the FLC. As chronic kidney disease (CKD) is common in the general population, it is possible that a large number of individuals have false FLC results. A kidney reference interval (eGFR < 60) has previously been published based on small numers (N=688) for serum FLC ratio (0.37-3.10) instead of the standard reference interval (0.26-1.65), but no kidney reference exists for kappa (3.3-19.4mg/L) or lambda (5.7-26.3mg/L). The aim of this study was to define and improve the reference interval for individuals with various degree of decreased kidney function and assess its effect on prevalence of light chain monoclonal gammopathy of undetermined significance (LC-MGUS) among CKD patients. Methods: A total of 80,759 participants of the Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM) study were included. Participants were screened by SPEP and IFE as well as by serum FLC assay (Freelite®). Serum creatinine (SCr) value closest to the time of screening was used to calculate (CKD-EPI) eGFR. Participants with M-protein, eGFR >60 mL/min/1.73 m2, missing SCr measurements or more than 1 year from the SCr measurement to the iStopMM screening were excluded. Correlation was assessed graphically and using the Spearman correlation coefficient. A nonparametric bootstrapping method was used to calculate the 95% CI. Partitioning was determined based on the proportion of subgroups (sex, age, eGFR) outside the whole group reference interval (<0.9% or >4.1%). However, intervals were not partitioned if subgroups included few participants and/or if deemed more applicable and reasonable for clinical practice. LC-MGUS was defined as FLC ratio outside the reference interval and raised FLC level without evidence of monoclonal heavy chain on SPEP or IFE or end-organ damage attributed to the plasma cell proliferative disorder. Results: Of 75,422 individuals who were screened, 6,503 (12%) participants had eGFR < 60 mL/min/1.73 m2, without evidence of monoclonality on SPEP or IFE and were analysed further. The median (IQR) kappa level was 21.7 (16.6-29.4) mg/L, lambda level 19.0 mg/L (14.8-25.0) and FLC ratio 1.16 (0.97-1.39). Serum FLC levels increased with decreasing eGFR: serum free kappa (ρ= -0.44, p < 0.001), lambda (ρ= -0.39, p < 0.001), and FLC ratio (ρ= -0.15, p < 0.001). Using current reference intervals, 60% and 21% of persons had values outside the normal range for kappa and lambda, respectively. The FLC ratio was outside the standard reference interval in 9% and outside the kidney reference interval in 0.6% of participants. Based on these findings, we established new reference intervals for FLC and FLC ratio (Table). Participants on dialysis (N=26) had significantly higher median (IQR) serum free kappa 29.3 mg/L (26.1-57.6, p = 0.01) and lambda 25.1 mg/L (19.5-52.6, p = 0.01) than participants with eGFR 30-59, but no significant difference compared to participants with eGFR < 30 (p = 0.57). The FLC ratio in participants on dialysis was 1.22 (0.96-1.37), which was similar to participants with eGFR 45-59 (p = 0.63) and 30-44 (p = 0.34). Participants on dialysis had significantly lower FLC ratio than participants with eGFR < 30, or 1.31 (1.10-1.57, p = 0.02). Utilising our novel reference intervals, the crude prevalence of LC-MGUS in all participants with eGFR < 60 was 75 (1.2%), with no difference between participants with eGFR of 45-59, 30-44 and < 30, respectively. When the crude rate of LC-MGUS was compared to a rate based on previous reference intervals, the crude rate of both kappa and lambda LC-MGUS increased in participants with eGFR 45-59, eGFR 30-44 and eGFR < 30 (p<0.001). Conclusion: Current reference intervals for serum FLC and FLC ratio are inaccurate for patients with decreased kidney function. Here we propose new reference intervals for serum FLC and FLC ratio for use in patients with CKD which also seem to be accurate in patients on dialysis. Implementing these novel reference intervals is likely to increase the sensitivity and specificity of the analyses and lead to a more accurate diagnosis of monoclonal gammopathy in individuals with kidney dysfunction. Figure 1 Figure 1. Disclosures Kampanis: The Binding Site: Current Employment. Hultcrantz: Intellisphere LLC: Consultancy; Curio Science LLC: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Daiichi Sankyo: Research Funding. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services . Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Amgen: Honoraria; Janssen: Honoraria; Celgene: Research Funding; Janssen: Other: IDMC; Takeda: Other: IDMC; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

Extracorporeal light chains removal – What role does this play in 2020?

Multiple Myeloma (MM) is characterized by a neoplastic proliferation of plasma cell clones producing monoclonal immunoglobulin. Manifestations of the disease are heterogenous and include dialysis­‑requiring acute kidney injury (AKI) caused mainly by cast nephropathy (CN). It is known that early and rapid decrease in serum free light chains (sFLC) levels is particularly important for renal recovery, which has led to a renewed interest in extracorporeal methods of removal of sFLC. In this review we will discuss the management of light chain CN focusing on extracorporeal light chains removal modalities and their indication.

Real world analysis of high-cut-off (HCO) hemodialysis with bortezomib-based backbone therapy in patients with multiple myeloma and acute kidney injury

Background In patients with multiple myeloma (MM) free light chain-induced cast nephropathy is a serious complication associated with poor survival. High-cut-off (HCO) hemodialysis can reduce the amount of serum free light chains (sFLC), but data on its impact on clinical outcome is limited and contradictory. To gain further insights we collected real world data from two major myeloma and nephrology centers in Austria and the Czech Republic. Methods Sixty-one patients with MM and acute kidney injury, who were treated between 2011 and 2019 with HCO hemodialysis and bortezomib-based MM therapy, were analyzed. Results The median number of HCO hemodialysis sessions was 11 (range 1–42). Median glomerular filtration rate at diagnosis was 7 ± 4.2 ml/min/1.73m2. sFLC after the first HCO hemodialysis decreased by 66.5% and by 89.2% at day 18. At 3 and 6 months, 26 (42.6%) and 30 (49.2%) of patients became dialysis-independent. Conclusion The widely used strategy combining HCO hemodialysis and bortezomib-based antimyeloma treatment is dissatisfactory for half of the patients undergoing it and clearly in need of improvement.

Serum and Urine Protein Electrophoresis and Serum-Free Light Chain Assays in the Diagnosis and Monitoring of Monoclonal Gammopathies

Background Laboratory methods for diagnosis and monitoring of monoclonal gammopathies have evolved to include serum and urine protein electrophoresis, immunofixation electrophoresis, capillary zone electrophoresis, and immunosubtraction, serum-free light chain assay, mass spectrometry, and newly described QUIET. Content This review presents a critical appraisal of the test methods and reporting practices for the findings generated by the tests for monoclonal gammopathies. Recommendations for desirable practices to optimize test selection and provide value-added reports are presented. The shortcomings of the serum-free light chain assay are highlighted, and new assays for measuring monoclonal serum free light chains are addressed. Summary The various assays for screening, diagnosis, and monitoring of monoclonal gammopathies should be used in an algorithmic approach to avoid unnecessary testing. Reporting of the test results should be tailored to the clinical context of each individual patient to add value. Caution is urged in the interpretation of results of serum-free light chain assay, kappa/lambda ratio, and myeloma defining conditions. The distortions in serum-free light chain assay and development of oligoclonal bands in patients‘ status post hematopoietic stem cell transplants is emphasized and the need to note the location of original monoclonal Ig is stressed. The need for developing criteria that consider the differences in the biology of kappa and lambda light chain associated lesions is stressed. A new method of measuring monoclonal serum-free light chains is introduced. Reference is also made to a newly defined entity of light chain predominant intact immunoglobulin monoclonal gammopathy. The utility of urine testing in the diagnosis and monitoring of light chain only lesions is emphasized.

Comparison of lambda and kappa light-chain cardiac amyloidosis in Polish patients diagnosed in cardiology department

Background Lambda (λ) and kappa (κ) types of light-chain amyloidosis (AL amyloidosis) are believed to have a similar prognosis. Data on the comparison of these two types of cardiac amyloidosis is scanty. Objectives The aim of the study was to investigate wether lambda light-chain cardiac amyloidosis indicates worse prognosis than the kappa variety. Methods The initial analysis covered all consecutive pts with cardiac AL amyloidosis diagnosed in the cardiology department from August 2011 to August 2019. Diagnosis was confirmed by increased serum free light-chains and positive tissue biopsy. Amyloid type was identified using immunohistochemical reactions. Blood pressure and heart rate (HR) were measured on admission. The difference between involved and uninvolved serum free light chains (dFLC), NT-proBNP, high-sensitivity troponin T (hs-TnT), creatinine, potassium, albumin and total protein were measured. During echocardiography, tissue Doppler imaging was used to assess early lateral (e' lat) and septal mitral annulus velocities and longitudinal myocardial velocities of ventricles. Standard parameters were measured. The presence of pleural effusion was assessed in chest X-ray. Results Sixty-four pts were diagnosed with AL amyloidosis. Four pts were excluded from the final analysis due to ambiguous amyloid typing. Median (interquartile range, IQR) age was 61 (52–67) yrs. Median (IQR) dFLC was 19.9 (5.5–50.6) mg/dL. Median NT-proBNP and hs-TnT concentrations were 4948 (2251–10206) pg/ml and 77 (39–139) ng/l, respectively. Forty-four pts had a λ type AL amyloidosis (73.3%). There were significant differences (p<0.05) between the λ and the κ groups in regard to: HR (80 vs. 73.5 BPM), systolic blood pressure (102 vs. 117 mmHg), serum creatinine (88 vs. 116 umol/L) and potassium (4.4 vs. 4.9 mmol/L), e' lat (5 vs. 7.5 cm/sec), left ventricular end-diastolic diameter (LVEDD, 42 vs. 46 mm), right ventricular end-diastolic diameter (RVEDD, 35 vs. 40 mm) and right ventricular wall thickness (8 vs. 6 mm). Pleural and pericardial effusions were more frequent in the λ group (59% vs. 19% and 80% vs. 44%, respectively) according to Fisher's exact test (p<0.05). Median (IQR) survivals for the λ and the κ groups were 3 (2–9) and 16 (5.5–22) months, respectively (p=0.03). The Kaplan-Meier curves analysis showed a trend towards worse survival of the λ group (Log rank test, p=0.08). Conclusions Cardiologists should be aware that lambda light-chain cardiac amyloidosis may indicate shorter survival than the kappa variety, although kappa AL amyloidosis may be associated with worse kidney function. Further research would be worth considering. Kaplan-Meier curves, Time (months) Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Institute of Cardiology