Lambda Free Light Chains Research Articles

Novel Assay for Quantification of Free Light Chain (FLC) Dimers in Serum of Patients with Plasma Cell Dyscrasias

Free light chains (FLCs) are a well-established biomarker of plasma cell dyscrasias. FLCs exist as monomers, dimers and oligomers. Lambda FLC is particularly prone to form dimers and oligomers. Under certain pathological conditions, FLC dimerization changes towards the increased dimer formation. For instance, high levels of FLC dimers were found in AL amyloidosis and multiple myeloma (MM) even when the total FLC concentrations were near the normal levels. Thus, FLC dimer quantification can be used as a tool to diagnose and monitor AL amyloidosis and MM. Here we report a novel assay to detect and quantify FLC dimers with mass spectrometry. To demonstrate the power of the assay, we quantified FLC dimers in LC-only MM serum samples and compared the results to the gold standard Freelite assay. FLC dimer quant assay relies on the detection and quantification of constant region dimeric peptides of lambda and kappa LCs in serum with targeted mass spectrometry. The serum sample is enzymatically digested under non-reducing condition for 1 hour, specific disulfide-bridged dimeric peptides are then separated by Evosep One liquid chromatography and analyzed with parallel reaction monitoring (PRM) on Orbitrap Exploris mass spectrometer. FLC dimers can be quantified relative to control serum samples and by absolute quant using stable isotope labelled (SIL) peptides resulting in mg/dL values. The identities of the peptides were confirmed by mass spectrometry analysis of synthetic dimeric peptides and recombinant FLCs. To determine the lower limit of quantification (LLoQ) the control pooled serum was spiked with the increasing amounts of recombinant FLC. The assay demonstrated exceptional linearity from 0.78 to 50 mg/dL of spiked FLC kappa or lambda (R 2=0.999 for both). The assay only requires 10 μL of serum without the need for a diagnostic sample and can be performed at any time point, as frequently as needed. FLC dimer quant assay was compared to Freelite assay for 17 newly diagnosed patients with LC-only MM. All patients underwent autologous stem cell transplant (ASCT) and had banked serum samples at diagnosis and day 100 post-ASCT. 15 patients (88%) reached CR at day 100 post-ASCT. 8 patients had lambda LC MM, while 9 patients had kappa LC MM. At diagnosis the median involved FLC was 250 mg/dL (range: 26.1 - 1440), while at day 100 post-ASCT the median involved FLC was 1.1 mg/dL (range 0 - 2.5). The FLC dimer quant results were reported as a ratio to control, whereby the FLC dimer amount in control pooled serum was set to 1. FLC dimers were detected at all time points in all patients. The median involved FLC dimer ratio to control at diagnosis was 23.3 (range: 4.5 - 445.7), while the median involved FLC dimer ratio to control at day 100 post-ASCT was 1.0 (range: 0.3 - 3.8). Strong correlation (R 2=0.993 for lambda and R 2=0.931 for kappa) was observed between FLC dimer and Freelite assays (Fig.1). To conclude, we developed a novel assay to measure FLC dimer with mass spectrometry. The assay demonstrated a good correlation to Freelite assay. This study establishes an FLC dimer assay as a promising diagnostic and monitoring tool in LC MM patients. Large clinical studies are needed to establish reference ranges for kappa and lambda dimers in healthy population and demonstrate clinical utility in other plasma cell dyscrasias.

Blood-Based Diagnostic Assay for λ Light Chain Amyloidosis through Quantification of an Amyloidogenicity-Indicating Neo-Epitope

Light chain amyloidosis (AL) is a rare, progressive, and often fatal protein misfolding disease. AL is caused by aberrant clonal plasma cell proliferation, where excess amounts of amyloidogenic monoclonal Free Light Chain (FLC) are produced, secreted into the circulation, misfolded and deposted as amyloid fibrils in various vital organs, such as the heart, kidney, liver, and nerves. The involed lambda (λ) FLC accounts for ~75% of all AL cases. Amyloidogenic FLCs (aFLCs) are believed to be the toxic species contributing to AL disease pathology. Specific quantification of aFLCs can provide critical guidance in clinical practice but has been hampered by the LCs sequence diversity as well as the lack of tests that are able to differentiate between circulating normal polyclonal FLCs and aFLCs. Contrary to non-amyloidogenic, aFLCs are kinetically and oftentimes thermodynamically unstable. aFLCs are prone to misfolding and formation of pathogenic conformations such as non-native structures, proteolytic fragments, soluble aggregates, and amyloid fibrils. We exploited such characteristics of aFLCs by applying limited proteolysis using Proteinase K, where less stable λ aFLC proteins readily yield a 23KDa fragment composed of the homodimeric LC constant domain (dLCCD) linked by a disulfide bond. Formation of the dLCCD fragment reveals a highly conserved, novel, cryptic epitope at the N-terminus of the fragment. We have generated monoclonal antibodies (mAbs) that explicitly bind to such novel epitope and developed immunoassays for the specific detection and sensitive quantification of λ aFLCs in biological samples. Western blot or Meso Scale Discovery (MSD) analyses were employed to detect and quantify dLCCD signal using the dLCCD mAbs on plasma samples from randomly selected, treatment naïve and λ-restricted cases with biopsy-proven AL amyloidosis before and after exposure to optimized proteolytic conditions. Tissue amyloid deposits of λ-type were confirmed in most AL cases. Informed consent for data and plasma sample collections were obtained from the Institutional Review Boards and in accordance with the Declaration of Helsinki. Multiple myeloma (MM) plasma samples of unknown LC restriction type, treatment or amyloid deposits status and normal volunteer control samples were purchased from BioIVT (USA). A set of representative results based on three runs are shown in Fig. 1. As little as 2 µL of biofluid was used for each assay. Upon limited proteolysis, dLCCD signal was detected in 32 of 35 AL plasmas, including two samples from patients with AL-associated IgM lymphoplasmacytic lymphoma (LPL). Of the three dLCCD negative AL samples, one presented with monoclonal IgAλ, and two cases were bi-clonal on serum immunofixation electrophoresis. dLCCD signal was not detected in 18 of 19 MM plasma samples. Similarly, dLCCD signal was undetectable in 23 normal plasmas. Overall, the dLCCD signals detected in AL plasmas were 10x-200x above that of normal control and most MM samples (Fig. 1). The low limit of quantification of the MSD assay was ~0.4 ng/dL (1.4 pM), with >500x dynamic range, enabling sensitive and robust quantification of λ aFLCs in biosamples. Analysis of Proteinase K recognition potential of the cleavage site of 389 λ LC sequences from the AL-Base, a database of amyloidogenic LC sequences (https://wwwapp.bumc.bu.edu/BEDAC_ALBase/) predicted that the dLCCD assay can detect λ aFLCs in up to 99% of λ AL patients, irrespective of the FLC sequences. This was confirmed with the 100% detection rate of the dLCCD signal in a validation cohort of 35 additional monoclonal λ-restricted AL samples. In summary, we have developed a quantitative blood-based immunoassay that is sensitive and highly specific for λ aFLC irrespective of the protein sequences. The preliminary data demonstrates the potential of our assay for AL diagnostics. Additional clinical applications for future exploration will include (i) monitoring and early detection of AL amyloidosis in plasma cell dyscrasias (monoclonal gammopathy of unknown significance, MM, and smoldering MM) and lymphoproliferative disorders, including LPL; and (ii) clinical management of patients with AL amyloidosis via the assessment and monitoring of minimal residual disease and therapeutic responses. The utility of the dLCCD assay in the quantification of λ aFLCs in bi-clonal AL cases warrants further investigation.

Clonal Bone Marrow Plasma Cells Are Common in Patients with Vexas Syndrome

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder. Its prevalence increases with age, reaching 5.3% at 70 years and older. MGUS progression rate to multiple myeloma (MM) or lymphoplasmacytic malignancies is about 1% per year. Patients with autoimmune diseases are at increased risk for developing MGUS and MM. VEXAS ( vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome), an autoinflammatory disorder caused by somatic mutations in ubiquitin-activating enzyme, UBA1 gene, has been associated with plasma cell disorders, specifically MGUS, but the rate of progression is unknown. Cyclin D1, important in cell cycle progression, is regulated by ubiquitin-proteasome mediated degradation, and deregulated cyclin D1 degradation appears to be responsible for the increased levels of cyclin D1 in several cancers. We aim to assess marrow characteristics of plasma cell disorders (MGUS and MM) in VEXAS, and the impact of a defective UBA1 gene product on protein expression of cyclin D1. Methods We assessed 28 patients with VEXAS for the presence of plasma cell disorders, and studied the clinical and laboratory characteristics of those with clonal plasma cells (PC) in the marrow. Bone marrow biopsies and aspirates were evaluated by morphology, immunohistochemistry (IHC) dual staining CD138/cyclin D1, dual staining MUM-1/CD20), in situ hybridization (Kappa and Lambda light chains) and flow cytometry (FC) using antibodies for CD45, CD19, CD20, CD38, CD138, CD56, CD27, CD81, and cytoplasmic Kappa and Lambda immunoglobulins. Serum free kappa and lambda light chains, IgG, IgM, and IgA, and level of M paraprotein by serum protein electrophoresis with immunofixation were obtained. Fluorescent in situ hybridization (FISH) analysis for MM was performed in most patients with clonal PCs. Results Patients' characteristics are shown in Table 1. Eight out of 28 (28.6%) patients with VEXAS syndrome, all males, had clonal plasma cells in their bone marrows: 3 MGUS, and 5 MM (3 smoldering, SMM; 2 active MM). Median age at diagnosis of plasma cell disorder was 69.5 years (range 60-75). All patients had pathogenic UBA1 somatic mutations (5 M41T, 1 each with M41V, M41L, and splice). Clinically, monoclonal protein size was small, with no specific selection of the type of M protein. Strikingly, most (7/8) clonal plasma cells showed cyclin D1 expression by IHC (dual immunohistochemical stain cyclinD1/CD138 shows double-positive plasma cells; figure not shown), displaying nuclear immunoreactivity in 6 cases, and cytoplasmic immunoreactivity in 1 case. FC showed positive CD20 expression of clonal plasma cells in 4 cases, dim to negative CD19 expression in 4 cases, variable CD56 (positive in 3 cases, partial positive in 1 case, negative in 2 cases), dim to negative CD27 in 3 cases, dim to negative CD81 in 3 cases. FISH for MM revealed: t(11;14) in 4 cases, gain of 11q (CCND1) in 2 cases (in one case, CCND1 gain was present in addition to t(11;14); in the second case, CCND1 gain was associated with gains of 1q and 17p(TP53). The cyclin D1-negative MM case was negative for t(11;14) but had t(4;14). All cases with t(11;14) were positive for cyclin D1 by IHC (nuclear staining). The one MM case with negative nuclear staining for cyclin D1 but positive cytoplasmic staining, was negative for t(11;14) but had gain of 11q (CCND1).One patient evolved from SMM to active MM after 4 years. No evolution to MM was seen in patients with MGUS with median follow-up of 30 months. Conclusions Patients with VEXAS have a high prevalence of clonal plasma cell disorders. Clonal plasma cells in VEXAS patients are associated with t(11;14), and with nuclear cyclin D1 expression by IHC. Cytoplasmic cyclin D1 staining in the absence or weak nuclear staining was observed with CCND1 gain and absence of t(11;14). Cytoplasmic cyclin D1 expression may be related to lack of cyclin D1 protein degradation by a defective UBA1 gene product. Our results suggest that defective UBA1 and autoinflammation pose an increased risk for developing MGUS or multiple myeloma.

Lymphoplasmacytic Lymphoma: An Atypical Presentation with IgG Monoclonal Gammopathy

Introduction Lymphocytic lymphoma (LPL) is a rare type of low-grade mature B-cell non-Hodgkin lymphoma, characterized by a monoclonal population of B lymphocytes, lymphoplasmacytic cells, and plasma cells. In around 95% of LPL cases, the serum immunoglobulin M (IgM) paraprotein is increased, which is correlated to Waldenstrom's Macroglobulinemia (WM), a clinicopathological disease. Only around 5% of LPL cases are associated with the serum paraproteins immunoglobulin G (IgG) or immunoglobulin A (IgA), or light chains alone, or are not linked to a paraprotein. Non-IgM LPLs have a wide range of clinical and pathological features, and MYD88 L265P mutations can occur, though at a lower frequency than WM. Hence, MYD88 testing is advised for prospective therapeutic purposes. Case Presentation A 69-year-old male was referred to a hematologist for uncontrolled epistaxis and periorbital edema. On initial workup, he had high total protein, elevated globulin, hypoalbuminemia, anemia, and proteinuria. Further investigation revealed a high IgG level with low IgM, IgA, and complement levels. Serum Protein Electrophoresis (SPEP): Increased total protein, decreased alpha two and beta globulins with a large monoclonal protein peak migrating in the gamma region, which accounts for 4.77 g/dl of the total 5.38g/dl gamma. Elevated Kappa Quantitative Free Light Chains of 355.39 (3.30 - 19.40mg/L), Decreased Lambda Quantitative Free Light Chains of 1.51 (5.71 - 26.30mg/L), Elevated Kappa Lambda Free Light Chains Ratio of 235.36 (0.26 - 1.65). Serum ImmunoFixation Electrophoresis demonstrated IgG-type kappa monoclonal protein with an additional faint band in IgG kappa. X-Ray skeletal survey showed a possible small lytic area in the inferior aspect of the C2 vertebral body, prompting him to have a cervical spine MRI which revealed no lytic lesions but an 18 mm vertebral body hemangioma inside T2. Molecular testing was positive for MYD88 Mutation c.794T>C (p. L265P) and negative for CXCR4 mutation. Plasma cell myeloma prognostic panel and chromosome analysis were normal. Flow cytometry of bone marrow aspirate showed a kappa light chain restricted plasma cell population (1.6% of total cells) with the following immunophenotype: positive for CD138, CD38, CD45, and negative for CD19, CD20, CD56, CD 117, and lambda light chains. The B-cell population showed kappa light chain restriction with the following immunophenotype: positive for CD19, CD20, and kappa light chains and negative for CD5, CD10, CD11c, CD23, and lambda light chains (Image 2). PET-CT of the whole body was negative for the extension of the disease. Transfusion with the two least incompatible PRBCs had little effect. However, plasmapheresis significantly improved his hemoglobin level by less than 7g/dl. A bone marrow biopsy revealed he had LPL with IgG Monoclonal Gammopathy (Image 1). He received one cycle of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone), followed by seven cycles of KCD (Carfilzomib, Cyclophosphamide, Dexamethasone) and Rituximab. The patient was diagnosed with low-grade B cell lymphoma with plasmocytic differentiation/lymphoplasmacytic lymphoma, with MYD88 mutation c.794T>C (p. L265P) positivity and CXCR4 mutation negativity. After plasmapheresis, the IgG level dropped to 1958. Follow-up SPEP revealed decreased alpha2 and beta globulins, decreased free lambda light chains, and increased K/L ratio. The patient was treated with Acalabrutinib, and his anemia, epistaxis, and coagulopathy resolved. Repeat PET-CT scan revealed no evidence of illness progression. Discussion LPL is not always linked with IgM monoclonal gammopathy; it can also be associated with IgG or IgA monoclonal gammopathy, light chains alone, or no monoclonal paraprotein. Non-IgM LPL has a high prevalence of extramedullary involvement, a lower rate of MYD88 mutation, and few hyper viscosity symptoms. The MYD88 mutation does not allow WM and Non-IgM LPL to be distinguished from other lymphoproliferative disorders with similar clinical and immunophenotypic features. The case described is unique as the patient has high levels of IgG (11,200) at presentation. In contrast to our patient, who has LPL with IgG Monoclonal gammopathy, approximately 95 percent of LPL patients have IgM Monoclonal gammopathy, which corresponds with WM. As a result, clinicians should be on the lookout for LPL that lacks an IgM Monoclonal Paraprotein.

SAT210 A Case Of Recurrent Metastatic Parathyroid Cancer Complicated By Multiple Brown Tumors

Abstract Disclosure: A. Elmaaz: None. E. Bustamante: None. M. Batra: None. Introduction: Parathyroid cancer is a rare malignancy with about 25 % incidence of metastasis. Brown tumors are benign bone lesions caused by excessive bone turnover which are rarely associated with parathyroid carcinoma. Here, we present a case of recurrent metastatic parathyroid cancer complicated by multiple brown tumors. Case Presentation: A 63-year-old male presented with back pain, generalized weakness, and significant weight loss. Laboratory findings showed hypercalcemia 14.4 mg/dl, Alkaline phosphatase 253 U/L, and phosphorus 2.3 mg/dl. He was admitted to the hospital for hypercalcemia workup. MRI spine showed a heterogeneous mass arising from the left thyroid lobe and conglomerate lymph node, along with extensive metastatic sclerotic lytic lesions throughout the spine. MRI brain revealed multiple metastatic lesions in the skull base, facial bones, and the right angle of the mandible. Further workup revealed normal PSA, normal serum levels of free lambda and kappa light chains, and normal urine and serum protein electrophoresis. PTH levels, 2435.1 (8.7-77.1) pg/ml, and PTH-rP levels <1.1 pmol/l were noted. Ultrasound-guided FNA of the thyroid mass showed solid growth of malignant parathyroid cells strongly stained for PTH. Biopsy of the body of the T12 vertebra and mandibular lesions showed giant cell lesions of the bone with fibrous dysplasia, consistent with brown tumors. IV hydration, calcitonin, cinacalcet, and IV zoledronic acid started, followed by left hemithyroidectomy and left inferior parathyroidectomy. Surgical pathology was positive for parathyroid carcinoma invading the thyroid gland. His calcium and PTH levels post-surgery significantly improved. A few months later, the patient presented again with hypercalcemia and high levels of PTH. Sestamibi parathyroid scan showed no evidence of parathyroid adenoma. Because of enlarging left neck mass, confirmed by MRI neck, he then underwent excision of the left subcutaneous cervical lesion involving the left sternomastoid muscle. Surgical pathology was consistent with parathyroid carcinoma involving soft tissue. His calcium and PTH levels improved on subsequent follow-up visits. Conclusion: Parathyroid carcinoma is not a common cause of hypercalcemia. Though a rare entity, parathyroid cancer should be considered in the differentials of hypercalcemia and extremely high levels of PTH. Metastasis either locally or remotely should not be overlooked. Brown tumors could mimic bone metastasis and giant cell tumors; therefore, the clinical presentation is important for the diagnosis. Presentation: Saturday, June 17, 2023

Extracorporeal light-chain elimination in myeloma with simple medium cutoff membrane hemodialysis: a retrospective cohort study.

We determined the efficacy of free light chain (FLC) removal by regular dialysis equipment (high-flux filtration) with medium cutoff (MCO) membrane hemodialysis (HD) as an adjuvant treatment to standard chemotherapy for patients with acute kidney injury complicating multiple myeloma (MM) and its impact on further dialysis dependency. Sixty patients with acute dialysis-dependent renal failure secondary to MM were treated with MCO-HD (55 patients) or HCO (high cutoff)-HD (5 patients) as a control. FLC serum concentration, total protein, immunoglobulins, and LDH were measured throughout the dialysis therapy. The kidney function of the patients was followed up for 1 year. The median age was 69 years; 25 female and 35 male patients were enrolled. HD significantly reduced FLC kappa levels in the MCO/HCO group by 58%/84% (MCO/HCO group; p < 0.05) and FLC lambda by 39%/33% (MCO/HCO group; p < 0.05). Single HD data (MCO) showed a relative reduction of 70% in kappa and 37% in lambda FLC concentration, as expected by the different sizes of the light chains. Renal function improved significantly and continuously from starting creatinine 5.7/3.8 mg/dl (MCO/HCO group) before HD to 1.4/2.0 mg/dl (MCO/HCO group; p < 0.001) after 1 year. No significant alteration of total protein, immunoglobulins, and LDH concentrations by HD (HCO and MCO group) was observed. After 1 year, 37 of 60 patients were alive and 34 of them were off dialysis. FLC elimination with MCO-HD is effective, technically easy, and less cost-intensive as compared with HCO-HD. Kidney function recovery in MM patients is achievable.

Freelite and Kloneus assays in free light chain measurements in patients with renal impairment

BackgroundSerum free light chain (FLC) quantification is a diagnostic criterion for monoclonal gammopathy and its values in patients with renal impairment are different from those in healthy subjects. The aim of this study was to evaluate Freelite and Kloneus assays in these patients. MethodsIn this retrospective study, serum samples from 226 patients with chronic kidney disease (CKD) of stages 2–5 were measured with a Freelite assay on the Optilite system and with a Kloneus assay on the AU5800 system and compared with controls without renal impairment. ResultsBoth kappa FLC (K-FLC) and lambda FLC (L-FLC) concentrations increased with Kloneus and Freelite assays with each increment in CKD stage. In patients with CKD, Kloneus detected lower concentrations of K-FLC (median: 20.4 mg/L; 95% range: 9.8–57.2) than Freelite (median: 36.5 mg/L; 95% range: 16.5–137.7) and higher concentrations of L-FLC (median: 32.2 mg/L; 95% range: 14.4–96.7) than Freelite (median: 25.4 mg/L; 95% range: 11.9–86.0). This resulted in significantly different kappa/lambda ratios (K/L-FLC) in patients with CKD for the two tests. The Freelite K/L-FLC in the CKD group (median: 1.50; min–max: 0.66–3.45) was significantly increased compared with healthy controls, and the Kloneus K/L-FLC in the CKD group (median: 0.63; 95 % min–max: 0.34–1.01) was slightly lower. ConclusionsThese findings demonstrate that Freelite and Kloneus assays provide higher but not parallel values when FLCs are measured in patients with CKD, so an increase in K/L-FLC was observed in the case of Freelite, and we found a slight decrease in the case of Kloneus.

#5130 THE EXPERIENCE OF SELECTIVE PLASMA EXCHANGE THERAPY IN PATIENTS WITH MULTIPLE MYELOMA

Abstract Background and Aims High concentrations of free light chains (FLCs) in multiple myeloma lead to cast-nephropathy and obstructive acute renal failure in 18-56% of patients. The aim of this research is to estimate the efficiency of extracorporeal free light chains of immunoglobulin elimination under this pathological condition during plasma exchange therapy using selective filters. Method Selective plasma exchange therapy (SEPET) was carried out in 11 patients with multiple myeloma. The patients were 61 [47-69] years old. Paraproteinemia level at primary examination varied from 1.6 to 78.8 g/liter. All patients exhibited proteinuria of 0.56 to 12.7 g/day, Bence Jones protein excretion (from 0.4 to 11.2 g/day) was detected in 9 cases. Blood creatinine levels ranged from 272 μmol/L to 534 μmol/L. None of the patients required renal replacement therapy. FLCs levels above 500 mg/L, irrespective of azotemia level, served as an indication for starting the procedure. All patients received VMP induction chemotherapy after sessions of selective plasma exchange therapy. SEPET was carried out on a “Multifiltrate” (Fresenius) hemodialysis machine in hemofiltration mode. «Evaclio 2C20» plasmafilter (Japan) was used. Patients underwent one procedures of SEPET in a dose of 3 volumes of circulating plasma. Blood flow velocity during varied from 40 to 60 ml/min, the duration of each procedure was 5-6 hours. Plasma substitution was performed with «Prismasol K4» solution - 10.0 L and albumin solution 20%-400 ml. Regulated clotting by nonfractionated heparin was calculated individually from the APTT values. No early or delayed complications of extracorporeal hemocorrection were recorded. FLCs, creatinine levels, and coagulogram results of patients were examined before and after the procedure. Results Analysis of serum FLC values before treatment showed a significant increase of κ- or λ-FLC levels, significantly surpassing normal values: 3-21.5 mg/liter κ-FLC and 5-27 mg/liter λ-FLC, with κ/λ-FLC proportion of 0.25-1.65. The primary levels of involved FLC medians in the group were 472 [312;44700] mg/L for κ-FLC and 163 [ 473; 24673] mg/L for λ-FLC, κ/λ-FLC proportions were 2.89. Through the membrane of the plasma filter “Evaclio 2C20” are sieved and removed substances with a molecular weight less than the molecular weight of albumin (65 kD). Kappa FLCs circulate as monomers of 22 kDa but may assemble into dimers of 45 kDa, particularly lambda FLCs. There is a partial loss of albumin. High molecular weight substances do not pass through this membrane. During SEPET the κ-FLC level in the plasmafiltrate was 272 mg/L, the λ-FLC level was 94 mg/L. After SEPET median serum κ-FLC was 231 mg/L, median serum λ-FLC was 96 mg/L. Compared with baseline data, serum FLC levels decreased after 24 hours, so that median serum κ-FLC was 281 mg/L, median serum λ-FLC was 101 mg/L. Clinical tolerance of extracorporeal detoxification was satisfactory and hemodynamically stable in all patients; and there were no were traumas of blood elements or decrease of serum albumin. Renal function recovered in 3 patients in the course of therapy, improved in 5 patients with renal insufficiency, and remained unchanged in 3 patients. Conclusion The Selective plasma exchange therapy directly removes FLCs excess from circulating blood. Rapid reduction of FLCs level in the course of selective extracorporeal elimination can prevent the development of irreversible renal failure and make it possible to carry out adequate antitumor therapy.

#3709 KIDNEY IMPAIRMENT AT DIAGNOSIS IN MULTIPLE MYELOMA: THE NEPHROLOGIST PERSPECTIVE

Abstract Background and Aims Kidney impairment (KI) at multiple myeloma (MM) diagnosis ranges between 20 and 50% and is associated with high mortality. Therefore, an important percentage of the newly diagnosed cases of MM come from nephrologists. We aimed to evaluate the new cases of MM with KI diagnosed in our nephrology tertiary care center for presentation features, initial treatment, and survival. Method We performed a unicentric retrospective study on 89 consecutive patients newly diagnosed with MM (median age 66 years, 38% male) between 2015-2020. Patients were followed until death or end of study (September 2022), whichever came first. Results The most common MM type was free light chain (FLC) only (55%) followed by IgG (30%), IgA (14%) and IgM (1%). Kappa FLC was more frequent than lambda FLC (53 vs 47%); the median FLC level was 1760 (IQR 450, 7373) mg/L, and the median marrow plasmocytosis was 30 (IQR 15, 60) %. Among the 89 patients, 81% presented with acute kidney injury, 12% with chronic kidney disease, 5% with isolated proteinuia and 2% with nephrotic syndrome. Baseline median serum creatinine and eGFR were 5 mg/dL and 9 mL/min, respectively. Median proteinuria was 3.3 (IQR 1.3, 6) g/g with median albuminuria of 0.27 (IQR 0.11, 0.66) g/g. More than one third (34%) of the studied patients needed hemodialysis (HD) at diagnosis, and 50% progressed to renal replacement therapy by the end of the follow up period (CKD5D). The most frequent clinical features at presentation were asthenia (75%), followed by bone pain (51%), orthostatic hypotension (14%), peripheral neuropathy (10%), edema (10%) and dyspnea (6%). Arterial hypertension (71%), systemic atherosclerosis (58%), ischemic heart disease (44%) and diabetes mellitus (12%) were the most frequent recorded comorbidities. Treatment with dexamethasone was started by the nephrologist in 74% of the patients at a median dose of 128 (IQR 96, 160) mg, afterwards the patients were reffered to hematology for a bortezomib based regime. During the follow up period 58 (65%) patients died; they had higher serum creatinine (5.8 vs 2.5 mg/dL, p 0.02), needed HD at diagnosis more often (41 vs 20%, p 0.01), had lower serum albumin (3.7 vs 4.4 g/dL, p 0.001), higher LDH (236 vs 201 U/L, p 0.01) and increased inflammation (C-reactive protein: 14 vs 3 mg/L, p 0.001). In univariate logistic regression, the risk factors at diagnosis associated with mortality were increased age (OR 1.07, 95%CI1.03-1.12), atherosclerotic burden (OR 5.51, 95%CI 2.13-14.22), low serum albumin (OR 0.28, 95%CI 0.13-0.63), inflammation (OR 1.05, 95%CI 1.01-1.09), increased LDH (OR 1.01, 95%CI 1.00-1.02) and the need for HD at diagnosis (OR 2.94, 95%CI 1.04-8.26). However, in multivariate analysis only low serum albumin (OR 0.22, 95%CI 0.05-0.90) and the need for HD at diagnosis (OR 10.64, 95%CI 1.71-66.14) were significantly associated with mortality. Conclusion Patients with MM and kidney impairment at diagnosis are more frequent kappa FLC, present most often as AKI, around one third of them require HD at diagnosis, and half of them progress to CKD5D. Therefore, these patients are a distinct group of MM with a high mortality rate (&amp;gt;60% at five years) who need interdisciplinary care.

#6658 ORAL HEALTH STATUS IN DIABETIC AND NON-DIABETIC PATIENTS ON MAINTENANCE HEMODIALYSIS TREATMENT

Abstract Background and Aims Uremic toxins and inflammation influence the oral health in patients on maintenance hemodialysis treatment. The presence of diabetes additionally aggravates the oral status. Aims: To compare the oral health status in diabetic and non-diabetic patients on different dialysis modality treatment. Method Observational, cross-section, monocentric study was conducted in 72 hemodialysis (HD) patients divided into two groups regarding the presence of Diabetes mellitus (DM). Patients were routinely designed to hemodialysis or hemodiafiltration (HDF) during the previous year of HD treatment. Demographic characteristics as patients age, dialysis vintage, laboratory inflammatory markers as C-reactive protein (CRP), albumin and Interleukin 6 (IL-6) were measured at the start of the study. Also, uremic small and middle molecules as blood urea nitrogen (BUN), creatinine, β2-microglobilin (β2M), myoglobin, albumin, free light chains kappa (FLC-k), and free light chains lambda (FLC-λ) were analyzed. Patients were examined by a dentist specialist scoring the oral hygiene index (OHI) by Greene Vermillion as good, fair and poor. Presence of tooth fillings and extractions, caries, hyperkeratosis, periodontal disease, erosions, ulceration, erythema, pigmentations, saburral tonque and uremic fetor were notified. Gingival hyperplasia (GH) was scored (1-3) with 3 for worst score and the tooth color was scored 1-3, signing 1-yellow, 2-gray, 3-white. Data was presented as mean and standard deviation for continuous and percentages for nominal values. X squared Fisher exact and Mann-Whitney test were used for statistical analysis. P&amp;lt;0.05 was considered as significant. Results The patients from group 1 - with DM (N=26) didn't differ from the non-diabetic group (N= 46) in respect of gender, age and dialysis modality but had significantly shorter dialysis vintage (48.68 ± 37.45 vs. 88.13 ± 63.29, P = .02, respectively). From the inflammatory markers only Il-6 was significantly higher in diabetics (P = .03). All the analyzed uremic toxins – small and middle molecules also didn't differ between the two groups. Diabetic patients were at 3 fold risk for manifestation of fissure, 4 fold risk for pigmentations and 7 fold risk for erythema (OR 3.58; CI:1.017-12.380, p= 0.003; OR 4.12; CI:0.684-22.870; p= 0.02, OR 4.84; CI:1.343-17.498, p= 0.000), (OR 7.25; CI:1.123-46.880, p= 0.000), respectively. GH was more likely to be present in diabetic patients (35%, 54%, 11% vs 83%, 15, 0%, p= 0.000, respectively). The presence of hyperkeratosis, periodontal disease erosions, caries, extractions, tooth fillings and the tooth colour didn't differ between the groups. Diabetics were found with higher percentage of bad oral hygiene index (38% vs 20%), but the overall comparison of OHI showed no significant difference. Conclusion Oral health is significantly deteriorated in dialysis patients, especially in those with inflammation. Diabetic patients are at higher risk of developing changes in the oral health status.

#6648 LONG TERM EFFECT OF MEDIUM CUT-OFF DIALYZER ON MIDDLE UREMIC TOXINS

Abstract Background and Aims Better removal capacities for middle and large middle molecules in hemodialysis was achieved in (HD) treatment with the new medium cut-off (MCO) membranes. The aim of this study was to evaluate the long term removal efficacy of Theranova® in standard HD in comparison with standard high-flux HD. Method 11 patients were assigned to high flux and 11 to MCO membranes in 12-months observational study. Each patient was assessed every three months from T0 with high-flux dialyzers, T1 to T5 with MCO at first, third, sixth, nineth and twelfth month by measuring pre- and post-HD samples of β2-microglobilin (β2M), myoglobin, albumin, free light chains kappa (FLC-k), and free light chains lambda (FLC-λ). The cumulative change from as RR from T0 to T5 was defined as long term outcome. Results The data showed a higher average removal rate (RR) for all the uremic toxins with Theranova® dialyzers for β2M, myoglobin, FLC-k, and FLC-λ (66.1, 53.2, 59.2.5, and 60.9%, respectively) compared to high flux (57.1, 10.8, 29.9 and 37.4%, respectively). The analyses on the cumulative RR from T0 to T5 found significant decrement of β2M, myoglobin, FLC-λ in MCO vs high flux group where those values significantly raised (14.9 vs −6.1, p = 0.043; 27.7 vs −7.8, p = 0.001; 21.9 vs −4.2, p = 0.017, respectively). The FLC-k showed borderline significantly better removal with MCO (17.8 vs 8.4. p = 0.067). The distribution of patients with 12 month middle molecules reduction was much better in the MCO group. Albumin retention was better in MCO group and did not change between T0 and T5 (p = 0.824). Conclusion Compared to high-flux membranes, MCO membranes show greater permeability for middle molecules and albumin stability in long-term report. Their use in HD standard setting is effective and safe.

#6348 HFR USING A HIGH-FLUX DIALYZER (SUPRA-H) AS NEW EFFECTIVE ALTERNATIVE TO ON-LINE HEMODIAFILTRATION: A SINGLE SESSION ANALYSIS

Abstract Background and Aims Hemodiafiltration with regeneration of the ultrafiltrate (HFR) is a highly biocompatible dialysis technique that combines convection, diffusion, and adsorption. SUPRA-H is a new HFR system which uses a high-flux dialyzer in the diffusive stage to improve large uremic toxin removal. The aim of our study was to compare the toxin removal of the SUPRA-H system with high-volume online-hemodiafiltration (OL-HDF). Method In an open, randomized, cross-over, single-center, controlled study, 16 adult chronic hemodialysis patients were treated with SUPRA-H or OL-HDF. Hemodialysis sessions were delivered with Flexya dialysis monitor (Medtronic) in the middle-week session, lasting four hours. OL-HDF session was performed in post-dilution mode with the same high-flux dialyzer (Phylter HF17G, Medtronic) as that used in the diffusive stage of the SUPRA-H system. All other dialysis parameters were kept constant in both study arms. The reduction rate (RR) of urea, creatinine, phosphate, β2-microglobulin (β2mglob), kappa (κFLC) and lambda (λFLC) free light chains, interleukin-6 (IL-6) p-Cresyl sulfate, indoxyl sulfate and albumin, was intraindividually compared for the two dialysis types with linear mixed models. Results Whereas urea RR was significantly lower, SUPRA-H had significantly higher RR for κFLC (Median: 58.63%, IQR: 49.91-70.24) than those obtained with OL-HDF (Median: 51.97%, IQR: 37.12-62.71); p = 0.03). The RRs for the other large and protein-bound uremic toxins tended to be higher with the SUPRA-H system (Figure 1). There were no significant differences in the RRs for creatinine, phosphate, IL-6, and albumin. Conclusion The new HFR system SUPRA-H, appears to be a potential technologic step ahead in terms of improved large molecule removal for dialysis patients, and might contribute to a more adequate dialysis therapy.

#5076 MONOCLONAL GAMMOPATHY IN C3 GLOMERULOPATHY: DOES THE BUCKET STOP THERE?

Abstract Background and Aims C3 glomerulopathy (C3G) is a rare diagnosis, characterized by dysregulation of the alternative pathway of complement, classically presenting in children and young adults. Recently, it has been reported the association between the production of a monoclonal protein and the development of C3G, affecting a larger age span. Method We report the case of a 53-year-old male patient, that attended the emergency department due to persistent holocranial headache. He was an IV drug abuser with a history of treated Hepatitis C infection and free lambda light chain monoclonal protein, being studied by the Haematology Department. On admission, he was hypertensive (187/98 mmHg), and labs showed an acute on chronic kidney disease (serum creatinine 2.35 mg/dL from a basal of 1.5 mg/dL) with an active urinary sediment (38 erythrocytes/field, with dysmorphia), a urinary protein/creatinine ratio of 626 mg/g, and C3 consumption (0.52 g/L). The patient was admitted, and a kidney biopsy was performed. Results Further lab results confirmed a serum IgG Lambda monoclonal protein. Autoantibodies screening (ANCAs, ANAs, Anti-GBM), ASLO and Rheumatoid Factor were negative. Cryoglobulinemia was detected, and the cryoprecipitate's immunofixation revealed monoclonal proteins IgG Lambda and IgM Kappa. HCV viral load was negative. Bone marrow biopsy revealed a small population (&amp;lt; 3%) of plasma cells with Lambda light chain restriction. Kidney biopsy's light microscopy showed increased mesangial matrix and cells, endocapillary hypercellularity, and some glomeruli with lobulated appearance. Five out of 15 glomeruli presented fibrocellular crescents. Immunofluorescence showed C3 dominant staining on capillary walls and in the mesangium, with absent IgG and light chain deposits. A presumptive diagnosis of C3 glomerulopathy was made and the patient was empirically started on corticosteroids (3 pulses of intravenous methylprednisolone, followed by oral prednisolone 1mg/Kg/day), which was followed by paraprotein-directed chemotherapy with bortezomib, cyclophosphamide and dexamethasone (VCD). The patient is currently on the third VCD cycle, presenting both renal and haematological responses: recovery of serum creatinine to basal levels (1.54 mg/dL), resolution of haematuria and proteinuria, normalisation of C3 levels. Serum immunofixation is currently negative for monoclonal protein, with normal serum immunoglobulin levels. Electron microscopy revealed electron-dense deposits in the mesangium, and mesangium-capillary transition, supporting the diagnosis of C3 glomerulonephritis. Genetic testing of complement-related genes revealed a rare missense variation of unknown significance (c.4855A&amp;gt;C) on the C3 gene, that has been previously reported in association with C3 glomerulopathy and atypical Haemolytic-Uremic syndrome. Conclusion This case represents a monoclonal gammopathy associated-C3 glomerulonephritis with a favourable response to paraprotein-directed chemotherapy. Although the association between monoclonal gammopathy and C3G rests on epidemiologic findings, experimental evidence suggests that several monoclonal proteins have complement dysregulation features, which may enhance alternate complement pathway activation. Our patient's response is in line with observational data that have shown improved renal outcomes in patients who achieve a haematological response following clone-directed chemotherapy, which further supports the role of monoclonal gammopathy in C3G pathogenesis [1]. Interestingly, the genetic variation identified in our patient might have provided a favourable genetic background for the development of C3G, which is thought to rely upon a complex interaction of triggering events, such as a monoclonal gammopathy, and underlying complement abnormalities, such as genetic variants in complement genes.

The force awakens, but questions remain: The future of MGUS.

The force awakens, but questions remain: The future of MGUS.

Determination of sensitivities and specificities of cerebrospinal fluid free light chains to diagnose multiple sclerosis- a multicentric case-control study.

CSF free light chains help diagnose multiple sclerosis, but no data is available on the Asian population. Our objective was to study the diagnostic utility of CSF free light chains for diagnosing multiple sclerosis in Indian patients. Prospective multicentric case-control study. Cases included those who were tested for oligoclonal bands and fulfilled the modified McDonald criteria 2017 for multiple sclerosis and clinically isolated syndromes. Those tested for oligoclonal bands (OCB) but with other diagnoses- inflammatory and non-inflammatory were included as controls. Clinical details were collected from electronic medical records. CSF and serum kappa and lambda free light chains were measured, apart from oligoclonal bands, immunoglobulin, and albumin in paired serum and CSF samples. There were 70 patients (31 cases and 39 controls). The mean age was 43.41(SD 16.073) years, and 43(61.4%) were females. CSF kappa showed highest specificity 97.4%, at a cut off 2.06mg/L (sensitivity 71%) and highest sensitivity 90.3%, at a cut off 0.47mg/L (specificity 79.5%). Best balance of sensitivity and specificity for CSF kappa was seen at a cut-off of ≥ 0.63mg/L {sensitivity 87·1 (CI - 70.17-96.37), and specificity 87·18 (CI -72.57-95.70)}. The ratio of Kappa/lambda showed highest specificity of 100%(similar to OCB) with a sensitivity of 71% at a cut off of 1.72. The ratio of sum of kappa and lambda light chains, and Qalb (∑CSF FLC/Qalb), showed the highest specificity (94.87%)among the blood brain barrier corrected ratios. This study showed that the diagnostic utility of CSF kappa was comparable to OCB to diagnose multiple sclerosis in sensitivity, but not specificity, so can be a screening test before testing for OCB in our population.

Non-invasive monitoring associated with B lymphoma cells in post-transplant lymphoproliferative disorder (PTLD) patients: Systematic review.

One of the most severe side effects of solid-organ transplantation is posttransplant lymphoproliferative disease (PTLD). People with human immunodeficiency virus infection (HIV), an immunosuppressive disease comparable to HIV, have a higher chance of developing lymphoma when their peripheral blood contains elevated levels of the immunoglobulins kappa and lambda free light chains (FLCs). This systematic review's objective was to monitor associated B lymphoma cells in PTLD patients. In order to find relevant studies published between 1/1/2000 and 1/9/2022, two independent researchers conducted searches (MT, AJ). A literature search of English language publications was conducted using MEDLINE through PubMed, EMBASETM through Ovid, the Cochrane Library, and Trip. In addition to Magiran and SID, we searched KoreaMed and LILACS for literature published in other languages. sFLC or PTLD, transplant, or Electrophoresis are terms used in the search strategy. A total of 174 studies were selected. After analyzing their correspondence with the required criteria, a final review of five studies was conducted. The manuscript presents current findings on the potential benefits of the clinical applicability of sFLCs in PTLD. While the preliminary results appear promising, the only consistent result is that early-onset PTLD is predicted within the first two years after transplant, a biomarker that could be used to diagnose the condition. Therefore, PTLD has been predicted by using the sFLCs. There have been contradictory results to date. Future research could include assessing the quantity of sFLCs and their quality in transplant recipients. In addition to PTLD and complications after transplantation, sFLCs may provide insight into other diseases. To confirm the validity of sFLCs, more studies are needed.

The Clinical Significance of Serum Free Light Chains in Bladder Cancer.

This research aimed to assess the clinical usefulness of serum kappa (κ) and lambda (λ) free light chains (FLCs) in patients with bladder cancer (BC). One hundred samples were collected and analysed from healthy volunteers (C) and bladder cancer patients. Cancer patients were divided into two subgroups: low-grade (LG) and high-grade cancer (HG). Concentrations of FLCs, CEA, CA19-9, creatinine and urea were measured per manufacturers' guidelines. The concentrations of κ and λ FLCs and CEA were significantly higher in BC patients in comparison to the control group. Moreover, the concentrations of κ and λ FLCs and CEA were significantly higher in both low-grade as well as high-grade cancer in comparison to the controls. The levels of κ and λ FLCs differed between tumour grades, with patients presenting higher concentrations in high-grade compared to low-grade cancer. In the total study group, κFLC correlated with λFLC, the κ:λ ratio, CRP, CEA, CA19-9, creatinine and urea. There was also a correlation between λFLC and κFLC, CRP, CEA, creatinine and urea. The λFLC showed a higher ability (sensitivity and PPV) to detect bladder cancer in comparison to κFLC and CEA. In addition, λFLC had a higher ability to exclude BC (specificity and NPV) than κFLC and CEA. λFLC also showed the highest accuracy in the detection of bladder cancer. In conclusion, the revealed differences in the concentrations of both κ and λ FLCs suggest their potential participation in bladder cancer development. Increased concentrations of free light chains in bladder cancer patients and the association with the tumour grade suggest that κ and λ FLC measurements may be useful in the diagnosis and prognosis of bladder cancer. This is the first research that evaluates the concentration of FLCs in bladder cancer, so further studies are necessary to confirm their usefulness as tumour markers of this malignancy.

POEMS syndrome associated with vitiligo (P13-8.007)

<h3>Objective:</h3> To report a case of POEMS syndrome with vitiligo. This is the second case to be reported and the first in an Afro-American patient. <h3>Background:</h3> POEMS syndrome is a rare plasma-cell disorder with multisystem involvement, characterized by the acronym composing its name: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein (M-protein), and Skin changes. Major criteria include mandatory polyneuropathy and monoclonal plasma cell proliferative disorder in addition to Castleman’s disease, sclerotic bone lesions, or elevated vascular endothelial growth factor (VEGF). Minor criteria, still helpful for diagnosis, include organomegaly, endocrinopathy, papilledema, thrombosis, and skin changes, the most common being hyperpigmentation. <h3>Design/Methods:</h3> Case Presentation <h3>Results:</h3> A 50-year-old Afro-American male presented with 3 years of ascending stocking-glove pattern numbness and skin discoloration in his feet. Other positive history included anhidrosis, heat intolerance and erectile dysfunction suggestive of dysautonomia. Medical history included hypoparathyroidism and idiopathic cirrhosis. He did not have history of alcohol overuse, diabetes, or glucose intolerance. Examination revealed confluent hypopigmented macules in feet, vibratory sensation impairments up to knees, absent temperature sensation in feet, and abnormal Romberg test and tandem gait. Remainder of the neurological examination was normal. Laboratory tests were significant for elevated free kappa and lambda light chains, plasma VEGF levels twice over normal range, and an IgA monoclonal band on serum protein electrophoresis. Other relevant laboratory findings included PTH-independent hypercalcemia and alkaline phosphatase elevation. Radiographs of hands, elbows, shoulders, and knees disclosed non-sclerotic lytic lesions. Nerve conduction studies were consistent with a sensorimotor axonal polyneuropathy. The patient met diagnostic criteria for POEMS syndrome. Autologous stem cell transplantation was recommended but the patient declined. His vitiligo, neuropathy, and monoclonal gammopathy remain stable under surveillance at 4 years without pharmacotherapy. <h3>Conclusions:</h3> POEMS syndrome should be suspected in any patient with new onset of vitiligo in the presence of an underlying polyneuropathy and a monoclonal plasma cell proliferative disorder. <b>Disclosure:</b> Dr. Landman has nothing to disclose. Dr. Escobar-Montealegre has nothing to disclose. Dr. Singh has nothing to disclose. Dr. Morales has nothing to disclose. Dr. Rossi has nothing to disclose.

Validation of ELISA assays for the calculation of FLC indices for the diagnosis of intrathecal immunoglobulin synthesis.

Define the cutoff thresholds of the Kappa (K) and Lambda (L) free light chains (FLC) indices for the detection of intrathecal immunoglobulin synthesis (IIS) using the new K and L FLC ELISA from SEBIA. The reference technique, which is not readily standardized between laboratories, is based on the demonstration of oligoclonal banding (OCB) in cerebrospinal fluid (CSF) which is absent in serum. For the past 6 years, we have also routinely calculated the K FLC index using The Binding Site (TBS) reagents on an Optilite instrument, an approach increasingly used as an alternative and/or a complement to electrophoretic analysis. We analyzed 391 serum/CSF pairs divided into three groups. The first group were cases without OCB and with normal albumin CSF/serum ratio (n=174). The second group were cases with specific OCB (n=73). The last group included patients with increased albumin CSF/sera ratio without OCB (n=142). Analysis of the first group determined that the cutoffs for detection of IIS are respectively 2.55 and 1.02 forthe K FLC and L FLC indices. Of the 73 cases with IIS, only2 had a K FLC index below this threshold (sensitivity of 97.26%), while 16 out of 73 cases (78.08%) and 13 out of 72 cases (81.94%) had an IgG and L FLC index below the cutoffs, respectively. Additionally, we illustrate equivalent performances for prediction of the presence of OCB between SEBIA and TBS methods. Sebia K FLC and L FLC assays are adequate alternative methods for the diagnosis of IIS.

Abstract 6480: Mortality in patients with monoclonal gammopathy of undetermined significance: an analysis of National Health and Nutrition Examination Survey

Abstract Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder with an annual risk of ~1% of progression to more advanced diseases, including multiple myeloma (MM). Few studies reported mortality risk in patients with MGUS, among which the diagnosis of MGUS was typically incidental due to unrelated symptoms or laboratory abnormalities. This study aims to compare the survival of MGUS patients with the U.S. general population using a nationally representative screening-based survey. Methods: Data were obtained from the third National Health and Nutrition Examination Survey (NHANES III) 1988-1994 and continuous NHANES 1999-2004, with follow-up all-cause mortality data through December 31, 2019. Participants were screened for MGUS by protein electrophoresis, immunofixation, and kappa and lambda free light chain assays in serum. Multivariable Cox-proportional regressions were performed, adjusting for demographic characteristics (age, gender, race/ethnicity, education, income, body mass index [BMI]), health behaviors (smoking, physical activity), baseline medical conditions (hypertension, diabetes, osteoporosis, myocardial infarction, stroke, congestive heart failure, coronary heart disease, peripheral vascular disease [PVD], arthritis, liver diseases, chronic obstructive pulmonary disease, renal diseases, cancer), and survey year. We also tested the interaction between race/ethnicity and MGUS diagnosis in the fully adjusted model. The NHANES complex sampling design was accounted for in all analyses to obtain population estimates. Results: The prevalence of MGUS among the U.S. population aged 50 years or older was 2.5% in 1988-1994 (sample size n=6,557; population size N=56,136,480) and 2.3% in 1999-2004 (n=5,847; N=68,835,295). MGUS patients were older and more likely to have PVD (13.1% vs. 7.7%, p = 0.03). No evidence was found showing a difference in gender distribution, education, income, BMI, and other comorbidities between the two populations. In NHANES 1999-2004, MGUS was associated with an increased risk of death (Hazard ratios [HR] 1.20, 95% CI: 1.02-1.41, p = 0.03) compared to the general population. NHANES III also showed a trend toward increased risk of mortality (HR 1.15, 95% CI: 0.89-1.48, p = 0.27). No interaction between race/ethnicity and MGUS diagnosis was found. It was notable that PVD was associated with an increased risk of death (HR 1.67, 95% CI: 1.43-1.94, p &amp;lt; 0.001). Conclusion: In the large cohort of NHANES participants, MGUS was associated with an increased risk of mortality. MGUS is typically viewed as a “benign” condition that has the potential to progress to cancer. These findings suggest that there may be alternate health implications to a diagnosis of MGUS. Future studies should focus on the causes of death in this population and the role of MGUS. Citation Format: Mengmeng Ji, John Huber, Mei Wang, Yi-Hsuan Shih, Yao-Chi Yu, Lawrence Liu, Theodore Thomas, Martin W. Schoen, Kristen M. Sanfilippo, Graham A. Colditz, Shi-Yi Wang, Su-Hsin Chang. Mortality in patients with monoclonal gammopathy of undetermined significance: an analysis of National Health and Nutrition Examination Survey [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6480.