Free Light Chain Testing Research Articles

Clinical significance of FLC tests in patients without other evidence of hematologic disorder

The clinical significance of an abnormal free light chain (FLC) test, performed due to unspecific complains in the absence of a known plasma cell dyscrasia (PCD) or lymphoproliferative disease (LPD), is not fully elucidated. We investigated the importance of an abnormal FLC ratio (FLC-R) in this setting. Patients registered in the Maccabi Healthcare Services database, tested for FLC during 2007–2023 without previously documented PCD/LPD or increased total protein (TP) level, were reviewed. Demographics, co-morbidities, and laboratory tests were recorded. FLC-R was defined as normal (0.26–1.65) or slightly (slAb 0.1–0.26/1.65–4), moderately (mAbn 0.1–0.05/4–8) and significantly abnormal (sigAb- < 0.05 or > 8). Factors associated with PCD/LPD and overall survival were identified. In total, 8,661 patients, 2,215 (25.6%) with abnormal FLC-R [2,090 (24.1%)-slAb, 65 (0.75%)-mAbn and 60 (0.7%)-sigAb], were analyzed. Almost none had anemia nor acute renal failure. 14% had concomitant increased immunoglobulins. Within a median follow-up of 52 months, 943 were diagnosed with PCD (816-MGUS, 127-MM/Amyloidosis/plasmacytoma) and 48 with LPD. Median time to PCD and LPD were 19 and 28 months. Multivariate analysis found slAb (HR = 1.8, CI95%:1.53–2.12, p < 0.001), mAbn (HR = 6.3, CI95%:4.16–9.53, p < 0.001), and sigAb FLC (HR = 10.4, CI95%:7.0–15.35, p < 0.001), to be associated with PCD/LPD diagnosis. Decreased IgG, increased IgA, and concomitant comorbidities predicted PCD, whereas increased IgM predicted LPD. Older age, male gender, anemia, decreased albumin, increased IgG and concomitant comorbidities, predicted shorter survival. Our large study emphasizes the independent clinical significance of abnormal FLC-R as a predictor of PCD/LPD diagnosis even in patients with normal TP level, promoting early detection of PCD/LPD.

The contribution of the free light chain test in cerebrospinal fluid in the diagnosis of multiple sclerosis

The contribution of the free light chain test in cerebrospinal fluid in the diagnosis of multiple sclerosis

Urine immunofixation electrophoresis and serum free light chain analyses benefit diagnosis of multiple myeloma in orthopedic patients with normal serum total proteins, creatinine, calcium, and hemoglobin.

A substantial number of patients with multiple myeloma (MM) who have bone destruction are initially admitted into the orthopedic service at the hospital. However, routine laboratory testing usually fails to identify these patients, thus delaying optimal therapy. Therefore, there is a clear medical need for early diagnosis of MM in these patients. Between 2019 and 2021, 42 patients receiving treatment for orthopedic conditions had normal hemoglobin (Hb), total protein (TP), albumin (ALB), creatinine (CREA), and blood calcium (Ca) levels before their surgical procedure(s) but were subsequently pathologically confirmed to have MM, based on their presenting orthopedic symptoms. During the same period, 52 patients with orthopedic conditions were pathologically excluded from the diagnosis of MM and were recruited into our control group. Serum free light chain (sFLC) testing was performed in 94 consecutive patients in the orthopedic service using Siemens N Latex FLC kits. The levels of Hb, TP, ALB, CREA, and Ca were also measured. All 42 patients with MM were divided into group A (n = 25: κ proliferation) and group B (n = 17: λ proliferation) by the pathology department. There were no significant differences in levels of Hb, TP, ALB, CREA, and Ca between group A and group B and the control group. However, the sFLC κ/λ ratio of group A and B was also significantly different from that of the control group (P < .001). The results of serum immunofixation electrophoresis (IFE) testing demonstrated negative results in 14 cases (58.3%) in group A and 4 cases (25.0%) in group B. Some patients with orthopedic conditions who do not have typical MM laboratory results, such as those with abnormal Hb, TP, ALB, CREA, and Ca levels before their operation(s), actually have MM. MM should be highly suspected in patients with unexplained bone lesions and with an abnormal sFLC κ/λ ratio. Further tissue or bone marrow biopsy is needed in these patients even if serum and urine IFE results are negative and light chain ratio is normal.

Treatment and Coaching Experience of Individuals with Relapsed/Refractory Multiple Myeloma: Qualitative Insights during Treatment with Isatuximab

Background: Understanding the treatment experience of patients (pts) with relapsed/refractory multiple myeloma (RRMM) is important to providing timely, appropriate supportive care. A multi-center trial (NCT05053607) is examining patient experience with isatuximab for treatment of RRMM, triangulating quantitative data from patient-reported outcomes (PRO) and wearable devices, along with qualitative data collected via individual interviews. Here we present outcomes from the qualitative data analysis, the aim of which was to describe experience with diagnosis and treatment, as well as the digital life coaching (DLC) intervention. Study Design and Methods: In a prospective, quasi-experimental study, 50 individuals aged ≥18 years are consented and enrolled in a 3-month DLC intervention. PROs are collected at baseline and up to once per month for 3 months in addition to physical activity data collected via wrist-worn activity tracker. Up to 10 participants were purposefully selected to participate in an individual interview of up to 1 hour at one time point between weeks 8-12 of study participation. Qualitative descriptive analysis was used to analyze study data and summarize key themes. Results: A total of 8 individuals participated in qualitative interviews (2 men and 6 women). One identified as African American, 1 as Hispanic, and 6 as White. The mean age of participants was 67.6 (R= 47-86); average time since diagnosis was 8.25 (R=1-15); and average lines of therapy was 4.25 (R= 3-8). Responses were organized into three themes, focused on experience with: diagnosis and prior lines of therapy; current isatuximab inclusive therapy; and DLC, with highlighted quotes represented in the Table. Participants self-reported the most common symptoms of prior lines of therapy were hair loss, gastrointestinal symptoms (e.g., nausea, reflux, upset stomach), and “steroid-related” symptoms of food cravings and insomnia. Previous lines of therapy were discontinued due to either treatment toxicity or disease progression; the most commonly reported treatment toxicities were blood clots, neuropathy, dizziness, and immunosuppression with associated infections or pneumonia. Related specifically to their isatuximab-treatment regimens, most participants reported feeling a “burst of energy” but few to no side effects at the end of treatment. Several commented on the time commitment of having to go to the cancer center for infusions. Most stated the frequency and duration is acceptable given the outcomes of treatment. Insights into the measures of success of treatment ranged from how individuals felt while receiving therapy, to what degree therapy interfered with their ability to participate in activities of daily living, and the effect of treatment on their RRMM status. Several participants specifically spoke by name to the response of their Kappa free light chain test results being significantly lower. When asked about what they found most supportive during treatment, knowledge was the most common response. They also reported family, having a plan, and spirituality/faith as helpful. Regarding their coaching experience on study all described it as “positive,” however, two reported that the content felt fundamental to them since they had been managing their diagnosis for several years. Benefits included having someone, particularly other than a family member, to speak to about their health, increased attention on healthy behaviors such as nutrition and exercise, and enhancing access to information and education about their diagnosis, treatment, and management. Conclusions: Qualitative interviews among individuals with RRMM provided insight into the challenges but also hope associated with chronic management of their condition. Treatment with isatuximab regimens was perceived as logistically manageable with few side effects. Though some individuals felt their long-term experience with MM made the coaching less impactful, coaching was generally perceived as a positive experience, with many individuals self-reporting benefits related to health behaviors and outcomes.

Cost-effectiveness of systematic screening and treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) in patients with heart failure with preserved ejection fraction (HFpEF) in United States

BackgroundTransthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure in clinical practice. 99mTc-pyrophosphate scintigraphy (PYP-scan) improves the accuracy of ATTR-CM detection, enabling timely initiation of tafamidis, a drug that slows the progression of ATTR-CM and lowers the risk of adverse cardiac events. PYP-scans, serum free light-chain (FLC) test and immunofixation electrophoresis (IFE) are critical components of a systematic screening. We assessed the cost-effectiveness of universal systematic screening (USS) compared to standard-of-care (SoC) selected clinical referrals for the systematic screening in patients aged 60 years or older with heart failure with preserved ejection fraction (HFpEF) and ventricular wall thickness of at least 12 mm. MethodsTwo screening strategies, USS versus SoC screening for ATTR-CM were compared in a model-based assessment. Treatment decisions were based upon the accuracy of each screening strategy, which was followed by Markov state transitions across New York Heart Association (NYHA) functional classes and death. Model inputs were identified from a literature review. We calculated lifetime cost in 2022 US dollars and quality adjusted life-years (QALYs) of each strategy. The primary outcome was the incremental cost-effectiveness ratio (ICER). ResultsThe USS was associated with a significant increase in lifetime costs ($124,380 vs. $70,412) and modest improvement in QALYs (4.42 QALYs vs 4.36 QALYs). The ICER for the USS was $919,509 per QALY gained. ICER was sensitive to the age at the time of ATTR-CM diagnosis, true prevalence rate of ATTR-CM, and daily cost of tafamidis. ConclusionsOwing to the high cost of treatment with tafamidis, USS along with PYP scan for ATTR-CM in older HFpEF patients with ventricular wall thickening is unlikely to become a cost-effective strategy at a liberal WTP threshold.

Clinical Significance of a Slightly Abnormal FLC Levels/Ratio

The employment of Free Light Chain (FLC) test in the community is continuously expanding and incorporated into the assessments of unexplained tiredness or nonspecific complaints, even in the absence of clear suspicion of plasma cell dyscrasia (PCD). Consequently, there has been a growing occurrence of “incidental detection” of slightly abnormal FLC tests, in the absence of additional laboratory abnormalities, and data regarding the significance of this finding are limited. The current study aims to explore the clinical significance of an “incidental” finding of slightly increased FLC test in a cohort of seemingly “healthy” subjects, defining patients at risk of developing PCD or lymphoproliferative malignancy (LPM). This research employs a non-interventional retrospective cohort study design, utilizing data extracted from the electronic medical records of individuals insured in Maccabi Healthcare Services (MHS) tested for FLC in peripheral blood between 2007 and 2023. The index date is defined as the date of first FLC test, encompassing FLC-K, FLC-L, and FLC-R (FLC-K/FLC-L ratio) measurements. Inclusion criteria were age ≥ 18 years and registration in MHS ≥12 months(m) prior to and ≥6m after FLC testing. Patients diagnosed with MM/SMM/MGUS/NHL/AL ±6 months from the index date and those presenting with elevated total protein (TP) levels were excluded. Patient characteristics, including demographics, pre-existing co-morbidities, and laboratory tests, all performed at MHC laboratory on the index date, were recorded (table1). The index FLC results were categorized as normal if FLC-K/L/R were within normal limits, or abnormal if at least one of the FLC-K/L/R components was outside the normal range. FLC-R was divided into four categories: normal (0.26-1.65), slightly abnormal (SliAb) (0.1-0.26 / 1.65-4), abnormal (Ab) (0.05-0.1 / 4-8), and significantly abnormal (SigAb) (Ratio&amp;lt; 0.05 or &amp;gt;8). The follow-up period was up to 5 years from index test, and documentation of new events of PCD/LPM were captured (figure1). Factors predicting a higher risk to develop MGUS/MM/NHL in patients with normal TP and abnormal FLC were analyzed. 11,241 patients with no prior history of PCD/LPM underwent FLC tests. 8,942 patients, fulfilling the study criteria, were analyzed. 6,687had an “abnormal” FLC and 2,255 had a normal FLC result. The proportion of males and the median age in the abnormal FLC cohort were higher (50% vs 37%, p &amp;lt; 0.001; and 67 vs. 59 years, p &amp;lt; 0.001). Almost no patients had anemia, nor aRF, though, the proportions of both were higher in the abnormal cohort (7.4% vs 1.8% and 6.67% vs 0.9%, p&amp;lt;0.001, p&amp;lt;0.001, respectively). 1,153 patients presented with concomitant increase in Ig levels (IgG-464 (10.1%); IgA-205 (4.2%); IgM-484 (10.67%), and monoclonal protein was reported in 143 (2.14%). The index FLC-R was normal in 6,620 (74.1%), SliAb in 2,181 (24.4%), Ab in 68 (0.76%), and SigAb in 66 (0.74%). Within a median follow-up of 52 months, 1065 were diagnosed with PCD (965-MGUS; 96-MM, 4-plasmacytoma) and 92 were diagnosed with LPM. Median time to PCD/LPM was 22 months (range: 6-60); 21.5 (6-60) for the detection of MGUS, 23.5 (6-60) for MM, and 57 (6-60) for the detection of NHL. A multivariate Cox regression analysis confirmed FLC-R to be a significant predictor for PCD/LPM development (SliAb HR =1.47 (CI: 1.25-1.71, p&amp;lt; 0.001), Ab HR = 6.8 (CI: 4.65-9.44, p&amp;lt; 0.001), and SigAb HR= 7.61 (CI: 5.15-11.25, p&amp;lt; 0.001). In addition, age &amp;gt; 75 HR 1.83 (CI: 1.37-2.43, p &amp;lt; 0.001), elevate levels of both IgG (HR: 1.34, CI: 1.07-1.68, p=0.01, IgM (HR: 1.73, CI: 1.41-2.1, p&amp;lt;0.001), IgA (HR: 1.62, CI: 1.2-2.2, p=0.001), and osteoporosis ( HR of 1.36 (CI: 1.16-1.6, p &amp;lt; 0.001) were found to independently predict a higher risk for PCD/LPM. Concurrently, increased IgM level (HR: 3.2, CI: 1.8-5.7, p= 0&amp;lt;0.001) or a decreased IgM level (HR: 2.5, CI: 1.3-4.8, p=0.006) were associated with increased risk for LPM. Our retrospective cohort study emphasizes the independent clinical significance of elevated FLC levels and abnormal FLC-R in “healthy” individuals, being a “rough” predictor for PCD/LPM development, even in patients with no increase in their TP levels. This can be used as a simple risk assessment model that would incorporate all independent factors found to be associated with increased risk for PCD/LPM; thereby enabling physicians, especially in the community, to monitor their patients and promote an early detection, when required.

Retrospective analysis of serum free light chain reference intervals and risk for monoclonal gammopathy suggests different limits than those in international guidelines

ObjectivesRecent reference interval studies of the serum free light chain (FLC) test using contemporary instruments display divergence with the diagnostic range generally adopted as the international standard. In this study, we perform a retrospective reference interval analysis with risk predictions for monoclonal gammopathy. MethodsRetrospective laboratory and clinical data for 8,986 patients were included in the study. Reference intervals were generated against a set of inclusion/exclusion criteria for two time periods representing the use of different instruments. The presence of monoclonal gammopathy was established from diagnostic test interpretations and EHR diagnosis codes in the patient problem lists and medical history. ResultsThe 95% FLC ratio reference intervals were 0.76–2.38 for SPAPLUS®, and 0.68–1.82 for Optilite® instruments. These intervals varied considerably from the current diagnostic range of 0.26–1.65 and mapped approximately to the FLC ratios beyond which risk of monoclonal gammopathy substantially increased. ConclusionsThese findings corroborate recent reference interval studies and support recommendations for independent re-evaluation of intervals by institutions as well as an update of international guidelines.

Significance of the pee-value: relevance of 24-hour urine studies for patients with myeloma

International Myeloma Working Group (IMWG) response criteria require refrigerated 24-hour urine specimens for most patients. However, given that serum free light chain testing has been shown to outperform 24-hour urine immunofixation as a prognostic marker, the importance of maintaining urine testing options or requirements within each level of IMWG response criteria has not been investigated. We analyzed responses to induction therapy for all transplant-eligible patients with multiple myeloma at our institution over a 3-year period using traditional versus ‘urine-free’ IMWG response criteria (where references to urine were removed from the descriptions for every depth of response). Of 281 evaluable patients, responses changed for only 4% of patients (95% confidence interval 2–7%) using urine-free criteria. Our results call into question the continued requirement for 24-hour urine measurements as part of IMWG response assessments for all patients. Research into the prognostic performance of urine-free IMWG criteria is ongoing.

Use of Clinical Decision Support to Improve the Laboratory Evaluation of Monoclonal Gammopathies

There is considerable variation in ordering practices for the initial laboratory evaluation of monoclonal gammopathies (MGs) despite clear society guidelines to include serum free light chain (sFLC) testing. We assessed the ability of a clinical decision support (CDS) alert to improve guideline compliance and analyzed its clinical impact. We designed and deployed a targeted CDS alert to educate and prompt providers to order an sFLC assay when ordering serum protein electrophoresis (SPEP) testing. The alert was highly effective at increasing the co-ordering of SPEP and sFLC testing. Preimplementation, 62.8% of all SPEP evaluations included sFLC testing, while nearly 90% of evaluations included an sFLC assay postimplementation. In patients with no prior sFLC testing, analysis of sFLC orders prompted by the alert led to the determination that 28.9% (800/2,769) of these patients had an abnormal κ/λ ratio. In 452 of these patients, the sFLC assay provided the only laboratory evidence of a monoclonal protein. Moreover, within this population, there were numerous instances of new diagnoses of multiple myeloma and other MGs. The CDS alert increased compliance with society guidelines and improved the diagnostic evaluation of patients with suspected MGs.

"Customers Like You Also Ordered …".

Inappropriate laboratory test utilization is a significant challenge for clinical laboratories attempting to improve patient care while minimizing waste of resources.1 Overordering of tests is a high-priority target for laboratories due to external pressures to identify and prevent unnecessary health care expenses and phlebotomy. Fortunately, it is relatively easy for laboratories to measure the volumes of tests that have been performed and to monitor changes in volume in response to initiatives designed to reduce overuse. Underordering of tests, on the other hand, is a more formidable challenge. There are fewer economic incentives to recommend additional testing, and it is more difficult to predict an event that does not happen (ie, a test that should have been performed but was not, one that may have guided clinical decision-making to improve a patient’s care . . . if only it had been ordered at the right time). In this issue of AJCP, Pearson et al2 present a quality improvement initiative at a tertiary medical center designed to facilitate the laboratory evaluation of monoclonal gammopathies (MGs) by tackling an example of underordering: serum free light chain (sFLC) testing. Current expert guidelines recommend the use of sFLC in conjunction with serum protein electrophoresis (SPEP) testing for the initial screening and diagnosis of MGs due to the superior sensitivity and prognostic value of sFLC over SPEP alone.3 Unfortunately, sFLC testing is often not ordered when indicated. The reasons for this underordering are not known, but they may include lack of awareness by ordering providers or lack of adoption by clinical services of recently published guidelines.

Personalized Disease Monitoring in Pediatric Onset Multiple Sclerosis Using the Saliva Free Light Chain Test.

BackgroundDevelopment of new safe methods of monitoring disease activity in the pediatric onset multiple sclerosis (POMS) is a challenging task, especially when trying to refrain from frequent MRI usage. In our recent study, the saliva immunoglobulin free light chains (FLC) were suggested as biomarkers to discriminate between remission and active MS in adults.ObjectivesTo assess utility of saliva FLC measurements for monitoring disease activity in POMS.MethodsWe used semiquantitative Western blot analysis to detect immunoreactive FLC monomers and dimers and to calculate the intensity of their bands. Statistical tests included Firth logistic regression analysis suitable for small sample sizes, and Spearman’s non-parametric correlation.ResultsIn naive POMS patients, the saliva levels of FLC in relapse were significantly higher than those in remission. Significant correlation was found between FLC levels (monomers, dimers or both) and the load of enhanced lesions in MRI scans. FLC levels may be reduced under treatment, especially as result of corticosteroids therapy. Follow-up of individual patients showed the correspondence of changes in the FLC levels to MRI findings.ConclusionsOur results show the potential of the non-invasive saliva FLC test, as a new tool for monitoring the disease activity in POMS.

Pitfalls in Assessing Measurable Residual Disease in Plasma Cell Myeloma: a Comparison between Common Laboratory Tests.

Measurable residual disease (MRD) in plasma cell myeloma is one of the most important determinants for patients' outcome. Several laboratory tests exist to assess for the presence of MRD with variable accuracy. The aim of this study is to examine the sensitivity of immunofixation electrophoresis (IFE), serum free light chain (FLC), bone marrow immunohistochemistry (IHC), and multicolor flow cytometry (FC) and to address potential caveats of each test. Forty patients of plasma cell myeloma who were diagnosed with a positive MRD were retrospectively included in this study. The results of IFE and serum FLC at the time of bone marrow biopsy were collected. In all cases, malignant plasma cells constituted less than 5% of bone marrow cells. MRD was detected by FC in 38 cases (95%) and by IHC in 28 cases (70%). In 2 cases, residual malignant plasma cells appeared in the subcortical area which is difficult to aspirate, and thus they were detected by IHC but not by FC. Among the entire cohort, 38 patients (95%) had positive IFE at the time of bone marrow biopsy, while serum FLC abnormality was detected in 19 patients (48%) only. Both FC and IFE exhibited high sensitivity in detecting MRD in plasma cell myeloma with comparable results. IFE remains less invasive and less expensive than FC. Despite the lower sensitivity of bone marrow IHC staining, its diagnostic role is essential and can be superior to FC in a subset of cases, for which its routine examination is recommended. Serum FLC test provided the least sensitivity among all tests.

The Current Role of the Heavy/Light Chain Assay in the Diagnosis, Prognosis and Monitoring of Multiple Myeloma: An Evidence-Based Approach.

Despite tremendous progress being made in recent years, multiple myeloma (MM) remains a challenging disease. The laboratory plays a critical role in the overall management of patients. The diagnosis, prognosis, clinical monitoring and evaluation of the response are key moments in the clinical care process. Conventional laboratory methods have been and continue to be the basis of laboratory testing in monoclonal gammopathies, along with the serum free light chain test. However, more accurate methods are needed to achieve new and more stringent clinical goals. The heavy/light chain assay is a relatively new test which can overcome some of the limitations of the conventional methods for the evaluation of intact immunoglobulin MM patients. Here, we report an update of the evidence accumulated in recent years on this method regarding its use in MM.

Two Serum Free Light Chain Detection Systems in the Diagnosis of Multiple Myeloma

To investigate the comparability of the Freelite, Binding Site, Beckman and N Latex FLC, Siemens in the detection of serum free light chain (sFLC) . Fifty newly diagnosed multiple myeloma (MM) patients in Tianjin Institute of Blood Research from November 2019 to February 2020 were enrolled. The two systems (Freelite, Binding Site, Beckman and N Latex FLC, Siemens) were used to detect the sFLC of the samples. Outlier detection was performed by ESD method, methodological comparison and deviation assessment were performed by Passing-Bablok regression and Bland-Altman regression. Both the systems could quantitatively analyze free kappa light chain serum samples and free lambda light chain samples. Freelite, Binding Site, Beckman and N Latex FLC, Siemens free light chain test showed FLC-κ：36.5 (6.5, 194), 40.5 (6.94, 288), FLC-λ: 30.1 (4.3, 170.5), 35.1 (2.28, 526), rFLC (FLC-κ/ FLC-λ) : 0.82 (0.05, 43.25), 1.03 (0.03, 32.04), dFLC (｜FLC-κ- FLC-λ｜) : -5.8 (-161.97, 183.7), 1.1 (-505.1, 279.01), which existed no outliers. There were systematic differences, and the deviation level was not within the clinically acceptable range. Both the systems can meet the needs of clinical diagnosis and treatment, but there is a significant deviation between the two systems, the results are not comparable, and should be analyzed separately. In particular, the same system should be selected for monitoring the prognosis of MM.

Cardiac amyloidosis mimicking acute coronary syndrome: a case report and literature review.

BackgroundCardiac amyloidosis, a progressive cardiac disease, results from the accumulation of undegraded proteinaceous substrates in the extracellular matrix of the heart. It may present as acute coronary syndrome (ACS); therefore, a clear distinction remains challenging in clinical practice. We describe a case of cardiac amyloidosis mimicking ACS.Case summaryA 72-year-old man experienced chest discomfort for 2 days. He gradually developed dyspnoea during the preceding month. Electrocardiogram (ECG) showed sinus rhythm with right bundle branch block and low voltage. Echocardiography revealed concentric left ventricular thickening, biatrial dilation, and preserved ejection fraction with predominantly left ventricular basal hypokinesis. Serial testing of the cardiac biomarkers showed persistently increased high-sensitive cardiac troponin T levels and normal serum creatine kinase myocardial band levels. He was diagnosed with ACS with haemodynamic stability. However, coronary angiography demonstrated non-obstructive coronary arteries. Furthermore, significant macroglossia and periorbital purpura were noticed. Laboratory investigations revealed elevated serum immunoglobulin free light chain (FLC) kappa and lambda levels with an increased FLC ratio. Histological analysis of the biopsied abdominal skin confirmed amyloidosis.DiscussionCardiac amyloidosis often presents as restrictive cardiomyopathy. The usual symptoms include dyspnoea and peripheral oedema. Chest pain may manifest rarely, leading to misdiagnosis as coronary artery disease. Some findings suggestive of cardiac amyloidosis include clinical signs such as amyloid deposits, dyspnoea, low ECG voltage, and basal-predominant hypokinesis with relative apical sparing in echocardiography. Serum FLC test and abdominal skin biopsy can confirm the diagnosis of amyloidosis when a myocardial biopsy is not feasible.

P1114HA-130 HEMOPERFUSION CARTRIDGE IN THE TREATMENT OF CAST NEPHROPATHY IN A 58-YEAR-OLD MALE WITH MULTIPLE MYELOMA: A CASE REPORT

Abstract Background and Aims Multiple myeloma is a plasma cell neoplasm that results in the production of monoclonal immunoglobulin. Renal failure is a common complication of multiple myeloma, occurring in approximately one-half of patients on initial presentation and is associated with increased mortality. Cast nephropathy in particular, is considered to be one of the major mechanisms of renal failure in multiple myeloma, and is characterized by precipitation of free light chains in the distal nephron, leading to intratubular obstruction, inflammation and fibrosis. Recent studies have demonstrated the use of extracorporeal methods such as plasmapheresis and high-cutoff membrane dialysis as an adjunctive therapy to chemotherapy in the management of cast nephropathy, however currently there are no existing guidelines in the use of extracorporeal therapies in the management of complications of multiple myeloma. Hemoperfusion is an extracorporeal treatment technique which utilizes adsorption in the removal of specific toxins. The HA 130 cartridge in particular has a resin pore size distribution of 500Da- 40 KDa and is able to remove molecules at 5-30kDa. In this case report we describe the use of HA 130 hemoperfusion cartridge in the treatment of cast nephropathy in Multiple Myeloma. Method A 58-year-old male, diabetic, non-hypertensive came in for 5-day history of generalized body weakness, associated with myalgia, lumbar pain and undocumented fever, with 1-day history of loose stools and vomiting. Upon admission blood tests done revealed anemia with a hemoglobin of 7.8g/dl, creatinine of 9.97mg/dL and potassium of 5.5mmol/L. He was diagnosed with acute renal failure and underwent hemodialysis on the second hospital day. On workup he had lytic bone lesions in the spine, pelvis and cranium on CT scan and x-ray. Serum Protein Electrophoresis (SPEP) and Serum Free Light Chain (sFLC) tests showed a monoclonal gammopathy. Serum beta 2 microglobulin was elevated at 12,618ng/ml. Free kappa and lambda light chains were also elevated at 19,250mg/L and 25.7mg/L, respectively. Bone marrow biopsy was done, with findings of markedly hypercellular marrow with 80% plasma cells confirming the diagnosis of Multiple Myeloma. Combined hemodialysis with hemoperfusion were done using HA 130 filter and hi flux dialyzer for 2.5 hours then hemodialysis for three times a week. Patient was also started on chemotherapy using Bortezomib with Dexamethasone for 2 cycles. Results Patient had a total of 14 sessions of combined hemoperfusion with hemodialysis. On repeat free kappa light chains decreased to 212.5mg/L. Patient was maintained on hemodialysis three times a week and was discharged after 55 hospital days. Outpatient hemodialysis was continued three times a week, and after 2 weeks, patient showed signs of renal recovery with a repeat creatinine of 2.1mg/dL. Four weeks after discharge, patient was independent of hemodialysis with a repeat creatinine of 1.3mg/dL. Conclusion This report highlights the use of hemoperfusion using HA 130 cartridge in combination with chemotherapy using Bortezomib in reducing free light chain levels in a 58-year-old male that developed renal failure secondary to cast nephropathy. Patient was able to achieve reduction in free light chain levels, improvement in renal function and eventually independence from hemodialysis four weeks after the last hemoperfusion treatment. Further studies using a randomized control trial on the use of hemoperfusion in directly reducing serum free light chain levels is recommended. The value of hemoperfusion on the rate of independence from hemodialysis, as well as survival rates among patients with renal failure secondary to multiple myeloma may also be worth investigating using larger studies.

Single Arm, Prospective, Open-Label Phase II Trial to Evaluate the Efficacy of Isatuximab in Patients with Monoclonal Gammopathy of Renal Significance

Background: Monoclonal gammopathy of renal significance (MGRS) is a monoclonal B cell disorder, not meeting the definition of lymphoma or myeloma, that produces monoclonal proteins which deposit in the kidneys. Permanent renal damage can occur either as a consequence of direct deposition of toxic proteins or by an induced inflammatory response. Due to the low burden of the plasma cell clone, patients do not otherwise qualify for potentially toxic anti-plasma cell treatments and treatment is generally based on consensus opinion. To date there are no clinical trials exploring treatment options. Isatuximab is a chimeric mouse/human IgG1k monoclonal antibody which targets CD38 on both malignant and normal plasma cells and exhibits it antitumor effects primarily by antibody-dependent cellular toxicity. Isatuximab has recently been shown to be an active drug in the treatment of multiple myeloma, with improvements seen in hematologic and renal markers, and has been shown to have manageable toxicity. Given the efficacy of isatuximab in multiple myeloma, we propose a trial evaluating isatuximab monotherapy to treat the small plasma cell clone in MGRS with the hopes of maximizing response and minimizing toxicity. Study Design and Methods: The primary objective of this study is to evaluate efficacy of isatuximab monotherapy in patients with MGRS in order to establish a standard of care treatment for patients with this disease. Adult patients with proteinuria of at least 1 gram in 24 hours and a histopathological diagnosis of MGRS on renal biopsy in the last 24 months will be eligible for the trial. Patients will be excluded if their estimated GFR is below 30 mL/min, they have multiple myeloma, high risk smoldering myeloma, other B cell neoplasm meeting criteria for treatment, concurrent diabetic nephropathy, or require dialysis. Patients will be screened for B cell disorders with bone marrow biopsy and aspirate, serum protein electrophoresis (SPEP) with immunofixation (IFE), 24-hour urine protein electrophoresis (UPEP), free light chain (FLC) testing and screening PET/CT at time of enrollment. Enrolled patients will be administered isatuximab 20 mg/kg IV weekly for 4 weeks and then will receive the same dose every 2 weeks thereafter for a total of 6 months. Patients may be continued on treatment following completion of the 6 months at the discretion of the provider. To reduce the risk of infusion related reactions, patients will receive premedications with corticosteroids, diphenhydramine, H2 blockade and acetaminophen at least 60 minutes prior to infusion. Patients will have repeat SPEP + IFE, 24-hour UPEP + IFE and FLC testing every 4 weeks. There will be an optional repeat kidney biopsy 9-12 months following treatment initiation to assess pathologic response in the kidneys. Statistical Methods: The study will be comprised of 20 patients being treated with isatuximab over a span of 24-30 months. Ten patients will be initiated on the therapy for a period of 6 months. Interim analysis will be done after these patients have completed all the treatment cycles. If 4 out of 10 patients show response in form of improved/stable renal function, the study will proceed to include next 10 patients. If &gt;50% of the first group of 10 patients show doubling of creatinine while on therapy, that would be considered as an indication to discontinue the therapy and the study due to drug toxicity. Endpoints: The primary endpoint will be efficacy as measured by renal response and hematologic response. Renal response will be measured by assessing the amount of proteinuria in a 24 hour urine sample. A sustained reduction in proteinuria by 30% from the patient's baseline amount of proteinuria with stable renal function (serum eGFR within 20% of baseline) will be considered a positive renal response. Hematologic response will be quantified per the 2016 International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma. An important secondary endpoint will be safety and will be analyzed from all patients who receive any study drug. Adverse events will be characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Other endpoints include time to dialysis and rate of minimal residual disease (MRD) negativity. Disclosures Lentzsch: Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents &amp; Royalties: 11-1F4mAb as anti-amyloid strategy. Bhutani:Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Our trial will be evaluating the efficacy of targeting CD38 on plasma cells with isatuximab in patients with monoclonal gammopathy of renal significance (MGRS). We will evaluate the effects of this drug on 24 hour proteinuria and hematologic response.

Rationalization of Bence Jones protein analysis based on a serum algorithm including free light chain testing

The aim of the present study was to develop and clinically validate a high-throughput assay for serum IgA and IgG antibodies against transglutaminase-2 (TG2) and to determine appropriate assay cut-offs for large-scale population screening for celiac disease.An automated method was developed using dual label time-resolved fluorometry on the AutoDELFIA platform. Individuals (n = 1920) from the general population were screened. Subjects with serum anti-TG2 concentrations above a preliminary cut-off (>0.3 mg*/L anti-TG2 IgA or >0.5 mg*/L anti-TG2 IgG) were offered endoscopic examination and biopsy. A diagnosis of celiac disease was given if villous atrophy (Marsh grade 3) was found.The assay had a limit of quantification of 0.25 mg*/L (anti-TG2 IgA) and 0.60 mg*/L (anti-TG2 IgG) with imprecision (CV) < 16% and <18% respectively. A total of 66 individuals were above the preliminary cut-off, and 56 underwent endoscopy. Of these, 26 were diagnosed with celiac disease. Sixty-eight percent of subjects with anti-TG2 IgA ≥ 0.7 mg*/L or anti-TG2 IgG ≥ 1.0 mg*/L had biopsy-proven celiac disease, and utilization of these higher cut-offs identified 96% of biopsy-positive patients. At the time of endoscopy, all individuals with anti-TG2 IgA > 2.0 mg*/L had celiac disease, and this cut-off identified 88% of newly diagnosed celiac patients. Eight percent (2/26) of the newly diagnosed patients had primarily anti-TG2 IgG.In this study we developed and clinically validated a robust and automated assay suitable for celiac disease screening in the general population.

Light Chain Escape in Multiple Myeloma

Light Chain Escape in Multiple Myeloma

Clinical Characteristics and Outcome of Patients with Wild-Type Transthyretin and AL Cardiac Amyloidosis Confirmed By Mass Spectrometry

INTRODUCTIONCardiac involvement is common in both wild-type transthyretin (wATTR) and AL amyloidosis and these entities can have overlapping clinical features (Banypersad et al, JAHA 2012). Accurate diagnosis is vital given differences in spectrum of disease, management, and prognosis. We examined the presenting clinical features and survival outcome of patients diagnosed with cardiac wATTR and AL amyloidosis confirmed by mass spectrometry.MATERIALS & METHODS: Patients diagnosed between January 2014 and September 2017 with biopsy proven wATTR or AL amyloidosis and cardiac involvement by consensus criteria (Gertz et al, Amyloid 2010) were included. Mass spectrometry testing was performed at the Mayo Clinic Laboratories to confirm amyloid subtype in all cases. Patient records were retrospectively reviewed to identify clinical characteristics as well as details regarding treatment and survival. RESULTSForty-three patients were identified (wATTR n=27, AL n=16) with site of biopsy: 41 cardiac (95%); 1 gastric (2%); 1 skin (2%). Two (13%) patients with AL amyloid had coexisting multiple myeloma. Thirty-five (81%) patients were male, with a strong male predominance in wATTR patients (100% vs 50% for AL patients, p=<0.01). Median age at diagnosis was 73 years (range 45-86), with a trend towards older age in wATTR patients (median 75 vs 62 years for AL patients, p=0.09). No difference was seen in presenting NYHA class or levels of troponin and ntProBNP between amyloid subtypes. BNP trended towards higher values in AL patients (median 514 vs 249 ng/L for wATTR, p=0.09). wATTR amyloid patients had lower median presenting left ventricular ejection fraction (43 vs 53%, p=0.05). Two (7%) patients with wATTR amyloid had an M-protein on SPEP compared to 7 (44%) with AL amyloid. Only 2 patients with AL amyloid had M-protein greater than 5 g/L while both wATTR patients had less than 5 g/L. In those with serum free light chain testing available (wATTR n=24, AL n=16), median lambda light chain level was higher in AL patients (176.0 vs 16.9 mg/L for wtATTR, p=<0.01). No difference was seen in kappa light chains (16.5 vs 23.8 mg/L for wATTR, p=0.60), though the only patient with kappa AL amyloid had kappa light chains significantly elevated at 1640 mg/L. The kappa/lambda ratio was abnormal in 15% of wATTR patients (all kappa predominant) compared to 100% in AL amyloid patients (94% lambda predominant) (p=<0.01). The median difference between involved and uninvolved light chain (dFLC) was 22 mg/L for wtATTR patients compared to 249 mg/L for AL patients. In patients with bone marrow biopsy results available (AL n=15, wATTR n=7), bone marrow plasma cell percentage was higher in patients with AL amyloid (median 7% vs 2%, p=0.01). No monoclonal plasma cells were seen on bone marrow in wATTR patients by immunophenotype. Treatment for patients with AL amyloid wasbortezomib, cyclophosphamide, and dexamethasone (VCD) in 11 (69%); VCD followed by melphalan 200 mg/m2 autologous transplantation in 1 (6%); melphalan/dexamethasone in 1 (6%); no treatment in 2 (13%); unknown in 1 (6%). In evaluable patients, hematologic response rate was 54% (complete response n=4, very good partial response n=2, partial response n=1, no response n=6). With a median follow-up of 1.8 years for surviving patients, 1 year overall survival (OS) was 76% for the entire cohort. Patients with AL amyloidosis had significantly poorer 1 year OS (41% vs 92% for wATTR patients, p=<0.01). Patients with NYHA class 3-4 had significantly worse 1 year OS (54% vs 96% for those 1-2, p=<0.01), and this held true for both AL and wATTR patients. In AL patients, revised Mayo stage (Kumar et al, JCO 2012) of III-IV predicted for poor 1 year OS (19% vs 75% for stages I-II, p=0.03), as did not achieving complete response to primary treatment (1 year OS 33% vs 67% for CR patients, p=0.06).DISCUSSION & CONCLUSIONS: Male sex, older age, and lower LVEF were more common in patients with wATTR compared to AL amyloidosis. Higher levels of BNP, larger dFLC with lambda predilection, and higher bone marrow plasma cell percentage were more common in AL amyloid patients. Overall survival was significantly worse for patients with AL amyloidosis, particularly those with high NHYA class, advanced revised Mayo stage, and suboptimal response to primary therapy. These results highlight the importance of accurate amyloid sub-typing in patients with suspected cardiac amyloidosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.