Free Light Chain Ratio Research Articles

B-PRISM (Precision Intervention Smoldering Myeloma): A phase II trial of combination of daratumumab, bortezomib, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma.

8040 Background: Early therapeutic intervention with lenalidomide has shown to be effective in delaying progression in patients with high-risk smoldering multiple myeloma (HR-SMM) (Lonial J Clin Oncol 2020). Quadruplet regimen of daratumumab, bortezomib, lenalidomide and dexamethasone (D-RVD) has demonstrated significant activity in multiple myeloma, achieving high rates of minimal residual disease (MRD) negativity (Voorhees Blood 2020). Thus, we proposed to examine the activity and safety of D-RVD in patients with HR-SMM. Methods: This is a phase II single center, single-arm, open label study evaluating the combination of D-RVD in HR-SMM. Eligibility included high risk per Mayo 2018 “20-2-20” model and other previously established criteria including Mayo 2008 criteria, presence of immunoparesis, evolving type of SMM, and high risk FISH. Primary objective is rate of sustained MRD negativity at 2 years. Secondary objectives include PFS, response rates and safety. Treatment duration with modified D-RVD is for total of 2 years (24 cycles). Daratumumab is administered subcutaneously (SQ) per standard dose and schedule, bortezomib given weekly on days 1, 8, 15 for cycles 1-6 and then biweekly until completion of cycle 24. Lenalidomide is administered on days 1-21 and dexamethasone is administered weekly. All eligible patients will undergo stem cell collection after 6 cycles of therapy. Results: At the time of data cut off, 20 patients have been enrolled with a median follow up of 6 months. The median age is 58 years old (range 40-73). Sixteen out of 20 (80%) patients met high risk criteria per Mayo 2018 model with median plasmacytosis of 20%, median M protein value of 2.6 g/dl and median FLC ratio of 28.2. Seven patients had high-risk FISH: 5 with 1q duplication, 2 with t(4;14). Most common toxicities of any grade included neutropenia (65%), WBC decreased (55%) insomnia (50%), constipation (45%) and hypophosphatemia (45%). Most common grade 3 toxicities included neutropenia (15%), ALT increased (5%), thrombocytopenia (5%), hyperglycemia (5%), hypertension (5%), diarrhea (5%), syncope (5%). No patients discontinued therapy due to toxicity. The overall response rate is 90% with 40% PR, 25% VGPR and 25% CR. All patients have achieved at least a MR and 50% achieved VGPR or greater with responses deepening over time. No patients have progressed on treatment. MRD was evaluable in 16 patients and 8 patients have undergone MRD testing, with MRD negativity rate of 50% (4/8) and 25% (2/8) at thresholds of 10-5 and 10-6, respectively. Stem cells were successfully collected in all patients with mean stem cell yield of 5.78 x 106 CD34+/kg cells. Conclusions: D-RVD is well tolerated in patients with HR-SMM demonstrating significant early activity. Responses continue to deepen over time with patients achieving MRD negative disease. Clinical trial information: NCT04775550.

Inter-Laboratory Concordance of Cerebrospinal Fluid and Serum Kappa Free Light Chain Measurements.

The kappa index (K-Index), calculated by dividing the cerebrospinal fluid (CSF)/serum kappa free light chain (KFLC) ratio by the CSF/serum albumin ratio, is gaining increasing interest as a marker of intrathecal immunoglobulin synthesis. However, data on inter-laboratory agreement of these measures is lacking. The aim was to assess the concordance of CSF and serum KFLC measurements, and of K-index values, across different laboratories. KFLC and albumin of 15 paired CSF and serum samples were analyzed by eight participating laboratories. Four centers used Binding Site instruments and assays (B), three used Siemens instruments and assays (S), and one center used a Siemens instrument with a Binding Site assay (mixed). Absolute individual agreement was calculated using a two-way mixed effects intraclass correlation coefficient (ICC). Cohen’s kappa coefficient (k) was used to measure agreement on positive (≥5.8) K-index values. There was an excellent agreement in CSF KFLC measurements across all laboratories (ICC (95% confidence interval): 0.93 (0.87–0.97)) and of serum KFLC across B and S laboratories (ICC: 0.91 (0.73–0.97)), while ICC decreased (to 0.81 (0.53–0.93)) when including the mixed laboratory in the analysis. Concordance for a positive K-Index was substantial across all laboratories (k = 0.77) and within S laboratories (k = 0.71), and very good (k = 0.89) within B laboratories, meaning that patients rarely get discordant results on K-index positivity notwithstanding the testing in different laboratories and the use of different platforms/assays.

MO114: Incidence and Spectrum of Biopsy-Proven Dysproteinemic Kidney Diseases: A Single-Centre Experience

Abstract BACKGROUND AND AIMS We aimed to evaluate the incidence and clinical features of patients with biopsy-proven dysproteinemic kidney diseases (group 1), as well as spectrum of biopsy-proven kidney diseases of patients with monoclonal gammopathy (MG) or abnormal free light chain (FLC) ratio (group 2) at our institution. METHOD This was a single-centre retrospective study of all patients who had native kidney biopsies at the Singapore General Hospital between October 2015 and December 2021. Demographic, clinical, laboratory and histological data were retrieved from electronic medical records to identify patients with biopsy-proven dysproteinemic kidney diseases (group 1) and patients with positive MG and/or abnormal FLC (κ to λ) ratio who underwent kidney biopsy (group 2). Patients were considered to have MG if they tested positive on any of the following tests: serum protein electrophoresis, serum immunofixation, urine protein electrophoresis or urine immunofixation. Abnormal FLC ratio is defined as a ratio outside the range of 0.27–1.65 in patients with eGFR ≥60 mL/min/m2 or 0.37–3.10 in patients with eGFR <60 mL/min/m2. RESULTS Out of 1066 patients who underwent kidney biopsy between October 2015 and December 2021, 25 (2.3%) patients were diagnosed with dysproteinemic kidney diseases (group 1). The median age of the patients at diagnosis was 65.6 years (IQR 58.6, 68.2), and majority was male (17/25; 68.0%). Haematological diagnoses present in this cohort include multiple myeloma (5/25; 20.0%), chronic lymphocytic leukaemia (2/25; 8.0%), Waldenstrom's macroglobulinaemia (2/25; 8.0%) and mantle cell lymphoma (1/25; 4.0%). Two-thirds of the patients had acute kidney injury (AKI) at time of biopsy (17/25; 68.0%). All patients presented with proteinuria, and nephrotic syndrome was noted in approximately half of the patients (15/25; 60.0%). Hypocomplementemia was present in a third (7/21; 33.3%) of the patients who had complement levels performed prior to biopsy, with low C3 and low C3/C4 observed in 5 and 2 patients, respectively. The most common histological lesion is immunoglobulin-related amyloidosis (8/25; 32.0%), followed by proliferative glomerulonephritis with monoclonal immune deposits (PGNMID) (6/25; 24.0%) and light-chain cast nephropathy (4/25; 16.0%). Sixteen (64%) patients fulfilled criteria for monoclonal gammopathy of renal significance (MGRS). All patients with PGNMID had undetectable MG and normal FLC ratio at diagnosis. Among these 1066 patients who underwent kidney biopsy, 396 patients had serum/urine electrophoresis, serum/urine immunofixation and/or FLC performed prior to biopsy. A total of 44 (11.1%) patients with detectable MG and/or abnormal FLC ratio were identified (group 2), 5 of whom had previously known haematological conditions. Dysproteinemic kidney diseases were diagnosed in 14 (31.8%) patients. Amongst patients with non-dysproteinemic diagnosis, diabetic/hypertensive nephropathy was the most frequent (15/30; 50.0%). Majority of the remaining patients had a variety of glomerulonephritides and renal vasculitides (10/30; 33.3%), or tubulointerstitial diseases (2/30; 6.7%). In univariate analysis, non-diabetic status (P < .001), presence of AKI (P = .032) and abnormal FLC ratio (P = .005) increased the likelihood of diagnosing dysproteinemic kidney disease in this group of patients. CONCLUSION AKI and proteinuria are common in dysproteinemia kidney diseases. Non-diabetic status, presence of AKI and abnormal FLC ratio increased the likelihood of diagnosing dysproteinemic kidney disease.

Serum Free Light Chain Assay as a Prognostic Marker in Patients with Aggressive B-Cell Non-Hodgkin's Lymphoma: Impact on Survival Outcome.

T.M. AnoopBackground The role of serum free light chain (FLC) as a prognostic biomarker in lymphoproliferative diseases is being increasingly studied. In this study we present the 5-year survival outcome for patients with aggressive B-cell non-Hodgkin's lymphoma (NHL) and their relation to FLC and other known prognostic markers. Materials and Methods This is a prospective study conducted in patients diagnosed with aggressive B-cell NHL. Serum FLC level and ratio were estimated prior to initiation of treatment. Results A total of 100 patients were included in the study from December 2013 to December 2015 with a median age of 53 years. Thirty-eight patients (38%) had elevated FLC level of which 26% were polyclonal and 12% were monoclonal elevations. Abnormal FLC ratio was noted in 12% patients. Median follow-up duration of the study was 75 months. Five-year relapse-free survival (RFS) for the study population was 54.4%. Five-year RFS was 64.1% for early stage and 48.2% for advanced stage diseases ( p = 0.05). The RFS was significantly better in age less than 60 years (59.5% vs 43.8%, p < 0.001). Five-year overall survival (OS) was 61.3%. OS was significantly better in younger patients (73.6% vs 33.4%, p < 0.001), with International Prognosis Index score of 0 to 2 (87.4% vs 26.7%, p < 0.001). Patients with elevated FLC had inferior RFS (50% vs 71.4%, p = 0.04). Abnormal FLC ratio also strongly corresponded to inferior RFS (54.5% vs 66.2%, p = 0.001). OS was also significantly inferior in patients with abnormal FLC ratio (72.6% vs 63.6%, p = 0.001). Conclusion In patients with newly diagnosed aggressive B-cell NHL, elevated FLC levels and abnormal FLC ratio were significantly associated with inferior survival.

Impact of light chain isotype on clinical features and outcomes in systemic AL amyloidosis

We performed a retrospective cohort study in AL amyloidosis to investigate the impact of light chain (LC) isotype on clinical features in 112 consecutive patients. Patients with kappa LC isotype had a significantly higher difference in free light chain (dFLC) (median, 61.5 vs. 21.6 mg/dL, p = .02) and involved/uninvolved FLC ratio (median, 63.5 vs. 10.6, p < .01) compared to lambda. Patients with lambda LC had a higher kidney involvement (64% vs. 38%, p = .02) but similar cardiac involvement rate (75% vs 72%; p = .81) as kappa. The hematologic ≥ VGPR rate after first-line therapy was similar (kappa [61%] vs lambda [68%]; p = .46). At a median follow-up of 43 months for surviving patients, the hazard ratio (kappa/lambda) for event-free survival (EFS) and overall survival (OS) was 0.76 (95% CI, 0.43–1.38; p = .37) and 0.49 (95% CI, 0.19–1.28; p = .14) respectively. Achievement of iFLC < 2 mg/dL and dFLC < 1 mg/dL was predictive of superior OS irrespective of LC isotype.

Body mass index associated with monoclonal gammopathy of undetermined significance (MGUS) progression in Olmsted County, Minnesota

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder that progresses to multiple myeloma (MM), or other plasma-cell or lymphoid disorders at a rate of 1%/year. We evaluate the contribution of body mass index (BMI) to MGUS progression beyond established clinical factors in a population-based study. We identified 594 MGUS through a population-based screening study in Olmsted County, Minnesota, between 1995 and 2003. Follow-up time was calculated from the date of MGUS to last follow-up, death, or progression to MM/another plasma-cell/lymphoid disorder. BMI (kg/m2 < 25/≥25) was measured close to screening date. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of BMI ≥ 25 versus BMI < 25 with MGUS progression and also evaluated the corresponding c-statistic and 95% CI to describe discrimination of the model for MGUS progression. Median follow-up was 10.5 years (range:0–25), while 465 patients died and 57 progressed and developed MM (N = 39), AL amyloidosis (N = 8), lymphoma (N = 5), or Waldenstrom-macroglobulinemia (N = 5). In univariate analyses, BMI ≥ 25 (HR = 2.14,CI:1.05–4.36, P = 0.04), non-IgG (HR = 2.84, CI:1.68–4.80, P = 0.0001), high monoclonal (M) protein (HR = 2.57, CI:1.50–4.42, P = 0.001), and abnormal free light chain ratio (FLCr) (HR = 3.39, CI:1.98–5.82, P < 0.0001) were associated with increased risk of MGUS progression, and were independently associated in a multivariable model (c-statistic = 0.75, CI:0.68–0.82). The BMI association was stronger among females (HR = 3.55, CI:1.06–11.9, P = 0.04) vs. males (HR = 1.39, CI:0.57–3.36, P = 0.47), although the interaction between BMI and sex was not significant (P = 0.15). In conclusion, high BMI is a prognostic factor for MGUS progression, independent of isotype, M protein, and FLCr. This association may be stronger among females.

Kidney Histopathologic Spectrum and Clinical Indicators Associated with MGRS.

Patients with monoclonal gammopathy and concomitant kidney diseases are frequently found in clinical practice. Some of them are diagnosed with monoclonal gammopathy of renal significance (MGRS) due to the presence of monoclonal Ig-related kidney injuries. This study aimed to investigate the histopathologic spectrum and clinical characteristics associated with MGRS in a large cohort of patients with monoclonal gammopathy and biopsy-proven kidney diseases from a single Chinese nephrology referral center. Patients who presented with monoclonal gammopathy (monoclonal spike on serum and/or urine immunofixation tests) and underwent kidney biopsy in the Peking University First Hospital from January 1, 1999 to December 31, 2020 were enrolled in this retrospective study. Patients with malignant hematologic diseases were excluded. Clinical and laboratory data were collected from the electronic medical record system. Comparisons of patients with and without MGRS and with and without amyloidosis were performed. The clinical characteristics associated with MGRS were identified using multivariable logistic regression. A total of 700 patients with monoclonal gammopathy and kidney biopsy were identified. Thirteen patients with repeat kidney biopsies were analyzed separately. For the remaining 687 patients with one kidney biopsy, 261 patients (38%) had MGRS lesions, and the rest (426 patients, 62%) had non-MGRS kidney diseases. Ig-related amyloidosis accounted for the most MGRS cases (n=164, 63%), followed by monoclonal Ig deposition disease (n=23, 9%) and thrombotic microangiopathy (n=22, 8%). In the non-MGRS group, membranous nephropathy was the most common diagnosis (n=171, 40%). In the multivariable logistic regression model, the presence of abnormal serum free light chain ratio, older age, and greater proteinuria were independently associated with MGRS. Monoclonal Ig amyloidosis is the leading cause of MGRS in Chinese patients with monoclonal gammopathy. The presence of abnormal free light chain ratio, older age, and greater proteinuria were associated with MGRS.

Gastrointestinal amyloidosis in a patient with smoldering multiple myeloma: A case report

BACKGROUNDSmoldering multiple myeloma (SMM) is an asymptomatic plasma cell proliferative disorder that can progress to multiple myeloma (MM). Amyloidosis (light chain) (AL) is the most common form of systemic amyloidosis. There are few reports of SMM coexisting with AL involving the digestive tract. CASE SUMMARYA 63-year-old woman presented with lower limb edema, abdominal distension, abdominal pain, and hematochezia. Gastroscopy showed gastric retention, gastric angler mucosal coarseness, hyperemia, and mild oozing of blood. Colonoscopy showed hyperemic and edematous mucosa of the distal ascending colon and sigmoid colon with the presence of multiple round and irregular ulcers, submucosal ecchymosis, and hematoma. Gastric and colonic tissue biopsy confirmed the diagnosis of AL by positive Congo red staining. MM was confirmed by bone marrow biopsy and immunohistochemistry. The patient had no hypercalcemia, renal dysfunction, anemia, bone lesions or biomarkers of malignancy defined as plasma cells > 60% in bone marrow. Additionally, no elevated serum free light chain ratio, or presence of bone marrow lesions by magnetic resonance imaging (SLiM criteria) were detected. The patient was finally diagnosed with SMM coexisting with AL. She received chemotherapy and was discharged when the symptoms were relieved. She is doing well at nearly five years of follow up.CONCLUSIONThis case highlights that high index of suspicion is required to diagnose gastrointestinal AL. It should be suspected in elderly patients with endoscopic findings of granular-appearing mucosa, ecchymosis, and submucosal hematoma. Timely diagnosis and appropriate therapy can help to improve the prognosis of these patients.

Detection of Plasma Cell Disorders by Mass Spectrometry: A Comprehensive Review of 19,523 Cases

ObjectivesTo verify the analytical performance of a new mass spectrometry–based method, termed MASS-FIX, when screening for plasma cell disorders in a routine clinical laboratory. Patients and MethodsResults from 19,523 unique patients tested for an M-protein between July 24, 2018, and March 6, 2020, by a combination serum protein electrophoresis (SPEP) and MASS-FIX were examined for consistency with pretest implementation performance. MASS-FIX’s ability to verify abnormal results from SPEP and free light chain measurements was then compared with that of immunofixation electrophoresis (IFE) using a separate cohort of 52,586 patients tested by SPEP/IFE during the same period. ResultsOverall, 62.4% of our cohort was negative for an M-protein. Importantly, 7.3% of all specimens had an M spike on SPEP (0.1 to 8.5 g/dL) and MASS-FIX detected an M-protein in all these samples. Of all samples, 30.3% had M-proteins that were detected by MASS-FIX but the SPEP finding was too small for quantification. Of the positive samples, 5.7% contained a therapeutic monoclonal antibody. Of the positive samples, 4.1% had an N-glycosylated light chain (biomarker of high-risk plasma cell disorders). MASS-FIX confirmed a higher percentage of SPEP abnormalities than IFE. MASS-FIX was slightly more sensitive than IFE when confirming an M-protein in samples with an abnormal free light chain ratio. MASS-FIX had a very low sample repeat rate (1.5%). MASS-FIX was highly automatable resulting in a higher number of samples/technologist/day than IFE (∼30% more). ConclusionOverall, MASS-FIX was successful in maintaining validation characteristics. MASS-FIX was more sensitive in confirming SPEP abnormalities when compared with IFE. Ability to detect therapeutic monoclonal antibodies and glycosylated light chains was distinctly advantageous.

47-Year-Old Woman With Bilateral Flank Pain

47-Year-Old Woman With Bilateral Flank Pain

Role of Serum Free Light Chain Assay in Relapsed/Refractory Multiple Myeloma. A Real-Life Unicentric Retrospective Study.

Simple SummaryAccording to the International Myeloma Working Group diagnostic criteria serum free light chain (sFLC) assay is recommended for disease monitoring in oligo-secretory and micromolecular multiple myeloma (MM). However, normo-secretory patients could suffer from oligo-secretory/micromolecular escape at disease relapse, making it difficult to monitor disease relapse with serum protein electrophoresis alone. The possibility of a simple and manageable biochemical exam able to predict either future treatment response at disease relapse or relapse type in the course of treatment could be of great aid. In this work, we retrospectively analyzed the occurrence of oligo-secretory/micromolecular escape at disease relapses and its impact on disease outcome. Moreover, we have retrospectively evaluated the role of sFLC ratio and involved sFLC at disease relapse in a historical real-life single-center cohort of MM patients that underwent at least three lines of treatment.Background: In the era of novel drugs a growing number of multiple myeloma (MM) patients are treated until disease progression. Serum free light chain (sFLC) assay is recommended for disease monitoring in oligo-secretory and micromolecular MM. Methods: In this real-life survey, a total of 130 relapsed/refractory MM patients treated at our center with at least three lines were investigated as a retrospective cohort. Results: The median age at diagnosis was 64 years and more than half of patients were male. A total of 24 patients (18%) had oligo-secretory/micromolecular disease at diagnosis. More than 20% of 106 normo-secretory patients had oligo-secretory/micromolecular escape. In order to evaluate potential role of sFLC assay before (“pre”) and after (“post”) every treatment line, involved serum free light chain values (iFLC) less than 138 mg/mL and serum free light chain ratios (FLCr) <25 were identified by using ROC curve analysis. The analysis of the entire cohort throughout four treatment lines demonstrated a statistically significant negative impact on progression-free survival (PFS) for both involved pre-sFLC and its ratio (respectively p = 0.0086 and p = 0.0065). Furthermore, both post-iFLC and post-FLCr greater than the pre-established values had a negative impact on PFS of the study cohort; respectively, p = 0.014 and p = 0.0079. Odds ratio analysis evidenced that patients with both involved post-sFLC greater than 138 mg/mL and post-FLCr above 25 at disease relapse had a higher probability of having clinical relapse (respectively p = 0.026 and p = 0.006). Conclusions: Alterations of sFLC values, namely iFLC and FLCr, both prior to treatment initiation and in the course of therapy at every treatment line, could be of aid in relapse evaluation and treatment outcome. We therefore suggest close periodical monitoring of sFLC assay, independently from secretory status.

An Analysis of M-protein in Plasma cell Dyscrasia Patients Identifies that IgG Lambda Subtype is More Commonly Associated with Normal Serum Free Light Chain (SFLC) Ratio.

The determination of monoclonal protein (M-protein) by SPE, IFE and SFLC assay is fundamental in the diagnosis of Plasma cell proliferative disorder (PCPD). In the present study, we seek to assess the diagnostic performance and concordance of these three techniques in un-treated PCPD patients. All new patients with dysproteinemia and/or suspected PCPD were included in this retrospective observational study. The baseline parameters were retrieved from electronic medical records. SPE was performed on gel electrophoresis system; monoclonal component was identified by IFE. SFLC assays were performed by nephelometry using a latex-enhanced immunoassay. Total 402 patients of PCPD were included (10.9% of MGUS/SMM and 89.1% of multiple myeloma). The combination of SPE + rSFLC (ratio of kappa/lambda light chain) and SPE + IFE + rSFLC was able to detect M-protein across all subgroups of patients. In 61 patients, rSFLC values were within normal range (54.5% of MGUS/SMM and 10.3% of MM) and was more commonly seen with IgG lambda M-protein (57.4% vs. all-others). The median dFLC value, among these patients, was higher for MM than MGUS/SMM patients (23.8 vs. 14.4mg/L, respectively). The combination of SPE and rSFLC can be reliably used to detect M-protein in PCPD patients. In a small subgroup of MM patients, despite the presence of an intact immunoglobulin (M-protein), the rSFLC is not abnormal. Historically, these patients should respond better to treatment. However, a further follow-up analysis with more number of such patients would be advantageous for better understanding.

The clinicopathological characteristics and outcomes of IgA nephropathy with predominant lambda or kappa light-chain deposition.

IgA nephropathy (IgAN) patients with monoclonal light-chain deposition may be at potential risk of hematological progression. However, whether the clinical characteristics of the patients with predominant lambda or kappa light-chain deposition were consistent with monoclonal light-chain deposition is limited to anecdotes. We retrospectively studied patients in whom immunofluorescence showed IgA-alone deposits (n = 617) between January 2016 and January 2020. We divided the patients into two groups, the predominant lambda or kappa light-chain deposition group and the control group. Predominant lambda or kappa light-chain deposition was defined as the deposition intensity of kappa or lambda being +- and the other deposition intensity being ≥ 2 + . Nineteen patients had predominant lambda or kappa light-chain deposition. The patients had a median age of 32years. The median proteinuria was 0.9g/day. The median eGFR was 79.8ml/min per 1.73m2. Two patients had a mildly abnormal FLC ratio, but serum immunofixation electrophoresis showed polyclonal immunoglobulin. Eighteen patients showed lambda light chain-dominated deposition. In electron microscopy, organized structures in dense deposits were not observed in all patients. Nine patients with proteinuria ≥ 1.0g/day received corticosteroids and immunosuppressants. The median follow-up time was 21months. The rate of proteinuria remission was 50%. The clinical and pathological characteristics and outcomes were not significantly different between the predominant lambda or kappa light-chain deposition group and the control group. The result for IgAN patients with predominant kappa/lambda light-chain deposition seemed to be the same as that of IgAN patients with light-chain codeposition. However, as this was a single-center study with a small size, further multicenter studies and long-term follow-up are needed to confirm our findings.

Monoclonal Proteinuria Predicts Progression Risk in Asymptomatic Multiple Myeloma with a Free Light Chain Ratio ≥100

Monoclonal Proteinuria Predicts Progression Risk in Asymptomatic Multiple Myeloma with a Free Light Chain Ratio ≥100

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

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

Factors Associated with Renal Impairment at Diagnosis in Multiple Myeloma with Survival Trends over Last Two Decades

IntroductionMultiple myeloma (MM) is frequently accompanied by renal impairment (RI) in 30-40% patients at presentation (Dimopoulos et al, IMWG 2010). As per International Myeloma Working Group (IMWG), RI is defined as Creatinine clearance (CrCl) <40 mL/min. Patients with RI at diagnosis have inferior overall survival (OS), however, over the years their outcome has improved due to treatment with novel agents. We examined the baseline clinical characteristics, and outcomes in patients with a new diagnosis of multiple myeloma at our institution to identify factors associated with baseline RI and study prognostic trend over the last 2 decades.MethodsWe retrospectively reviewed records for MM patients with a new diagnosis of MM who were seen at Mayo Clinic, Rochester between 1/2004 and 12/2018. RI was defined as per IMWG criteria. Categorical variables were compared using chi-square test and continuous variables using Wilcoxon test. Overall Survival (OS) was estimated using Kaplan-Meier method and difference between groups was assessed using log-rank test.ResultsIn our cohort of 2702 patients, median age at diagnosis was 65 (range, 22-96) years and 61% were males. Number of patients with CrCl <15, 15-29, 30-59 and ≥60 ml/min at diagnosis was 176 (6.5%), 204 (7.6%), 685 (25.3%) and 1637 (61%) respectively.RI was present in 557 (21%) of patients at the time of presentation. On univariate analysis, factors significantly associated with RI at diagnosis were higher age, ECOG PS ≥2, hemoglobin< 10 g/dL, calcium >11 mg/dL , LDH >222 U/L, β-2-microglobulin >5.5 mg/L, free light chain ratio >100, uric acid >8 mg/dL, higher ISS stage and cytogenetics [gain 1q, t (14;20), absence of any trisomy] as shown in table 1. However, on multivariate analysis, only elevated serum calcium >11 g/dL (OR: 11.5; 95%CI:1.78-74.9; p=0.01) and free light chain ratio>100 (OR: 4.17; 95%CI:1.29-13.4; p=0.016) had significant association with RI.The RI group had inferior OS when compared to patients with no RI at diagnosis (4.5 years vs 7.7 years, p-value <0.001). However, use of novel agents was associated with improvement in OS in patients with RI (4.9 years vs 2.6 years; p=0.0001) (Figure 1).Looking at trends over time, the rate of RI at presentation had not changed. Over the last two decades, OS for the CrCl<30 group had significantly improved in the last 5-year period (3.8 years in 2004-2014 vs not reached for 2014-2018; p= 0.0064) as shown in figure 2.ConclusionIn our cohort of 2702 patient, frequency of RI at baseline was 21%, which corroborates with previous studies. Hypercalcemia and serum free light chain ratio were found to be independent factors associated with RI. RI at diagnosis is associated with inferior survival, however, use of novel agents in this population has led to improvement of patient outcomes. [Display omitted] DisclosuresKapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; GSK: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Kumar: Roche-Genentech: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Novartis: Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Bluebird Bio: Consultancy; Oncopeptides: Consultancy; Carsgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Characteristics and Outcomes of Non-Transplanted Patients with Newly Diagnosed Multiple Myeloma (NDMM) Initiating Treatment with Bortezomib, Lenalidomide, and Dexamethasone (VRd) As First-Line of Therapy

Introduction: In the US, bortezomib, lenalidomide, and dexamethasone (VRd) is one of the preferred treatment regimens in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) based on the results from the phase 3 Southwest Oncology Group (SWOG) S0777 study. Although the efficacy of VRd in transplant-ineligible or -deferred NDMM patients was demonstrated in SWOG S0777, clinical trials have strict eligibility criteria that may not translate to the real-world. There is limited real-world data on the characteristics and outcomes of non-transplanted patients with NDMM treated with VRd, especially in older, frail patients with comorbidities. This study aimed to address these knowledge gaps by evaluating the characteristics and outcomes of patients with NDMM who received VRd as first-line of therapy (LOT) in US oncology practice.Methods: This retrospective observational study included patients from the Flatiron Multiple Myeloma Core Registry who received VRd as first LOT between November 1, 2015 and February 28, 2021. The index date was defined as the first observed record of the VRd regimen. Non-transplanted patients were defined as those who did not receive a stem cell transplant (SCT) from the diagnosis date to the index date. Patients were excluded if they were <18 years of age on index date; were enrolled in a clinical trial; had other malignancies prior to the index date; had a diagnosis of amyloid light-chain amyloidosis prior to the index date; or had a SCT prior to index date. Demographics, clinical characteristics, and outcomes were assessed in the overall study cohort and among specific subgroups: older adults (≥75 years of age on index date); frail patients (frailty score ≥2, calculated using age on index date, Charlson Comorbidity Index during the pre-index period, and Eastern Cooperative Oncology Group performance status [ECOG PS] score on the closest date to the index date ≤90 days prior to and ≤7 days after the index date, patients with missing ECOG were not excluded); patients with high-risk cytogenetics, and patients with acute renal impairment ([RI], serum creatinine >2 mg/dL on the closest date to the index date or having diagnosis codes of ICD-9-CM 584.5-584.9, ICD-9-CM 586, ICD-10-CM N17.0-2, N17.8-9, and N19, measured ≤90 days prior to and ≤7 days after the index date). Duration of therapy was measured as the time between the index date and end of the LOT. Progression-free survival (PFS) was measured as time between the index date and disease progression or death, whichever occurred first. PFS did not account for treatment discontinuation for reasons other than progression or death. Disease progression was defined as a clinically meaningful increase in serum M-protein, urine M-protein, or the free light chain ratio according to the International Myeloma Working Group criteria. PFS was analyzed using the Kaplan-Meier method.Results: A total of 2342 eligible NDMM patients treated with VRd as first LOT were identified, with a median follow-up of 21.0 months. A majority of patients were ≥65 years (64.3%), with the mean (SD) age at index date being 67 (±10) years. Most patients were male (53.3%), had International Staging System [ISS] stage I/II (48.4%; 33% missing) and the ECOG PS score 0/1 (63.5%; 22% missing). Of the 2342 patients, 597 (25.5%) patients were categorized as older adults (≥75 years of age); 1122 (47.9%) as frail; 374 (16.0%) as patients with high-risk cytogenetics; and 250 (10.7%) as patients with RI. About 28% of the patients received a SCT within 1-year of the index date. The median duration of therapy was 5.6 months. The median PFS for the overall study group was 33.2 months. Median PFS was substantially shorter for patients who were ≥75 years of age (22.8 months), were frail (28.7 months), had high-risk cytogenetics (25.1 months), or had RI (25.1 months) (Figure).Conclusions: The majority of patients with NDMM treated with VRd in the real-world setting were aged ≥65 years, were ISS stage I or II, had an ECOG PS score of 0 or 1, and had standard-risk cytogenetics. Median PFS observed in the real-world setting was shorter than that observed in the SWOG S0777 clinical trial. Patients who were ≥75 years of age, were frail, had high-risk cytogenetics, or had RI demonstrated shorter median PFS than patients in the overall study population. Alternate treatment options with demonstrated efficacy in the older, frail, and transplant ineligible patients are available. [Display omitted] DisclosuresMedhekar: Janssen: Current Employment. Ran: Janssen Scientific Affairs, LLC: Current Employment. Fu: Janssen: Current Employment. Patel: Janssen: Current Employment. Kaila: Janssen Scientific Affairs, LLC: Current Employment. OffLabel Disclosure:Bortezomib, and lenalidomide are both FDA approved agents for treating multiple myeloma. The combination of bortezomib, lenalidomide, and dexamethasone is commonly used in clinical practice and is listed as a preferred regimen in NCCN guidelines.

“Ideal” PTH in ESA-Resistant Anemia

Background: Anemia is a nearly universal complication of End Stage Renal Disease (ESRD). Erythropoiesis-stimulating agents (ESAs) have greatly decreased transfusion dependence in the anemia of ESRD. In some cases, ESAs are not effective, indicating ESA-resistance. ESA-resistant anemia is not well characterized and can be difficult to manage. Among the most frequent causes of ESA-resistant anemia is secondary hyperparathyroidism (SHP), which can induce bone marrow remodeling and fibrosis. Treatment protocols in SHP are centered on goal calcium, phosphorus and parathyroid hormone (PTH) levels and not the biologic consequences of high PTH. The hematologic insults secondary to SHP are rarely addressed. Instead, it is common to simply increase ESA dosing, rather than address the cause of ESA-resistance. In this retrospective review, we describe a cohort of patients with ESRD and SHP and highlight in detail one patient with reversible bone marrow changes and transfusion-dependent anemia, as well as descriptive and laboratory findings of bone marrow changes in patients with anemia and ESRD referred to our center.Methods: Using the EMR, the patient's data including demographics, progress notes, laboratory values, and bone marrow findings were extracted. Subsequently, the EMR was interrogated to reveal all patients with anemia and ESRD, who had undergone a bone marrow biopsy at out center over a ten year period from 2010 to 2020, revealing 64 patients. Data including demographics, laboratory values, bone marrow findings, and medications were extracted. Data was presented descriptively.Results: A 67-year-old male with ESRD secondary to hypertension and type 2 diabetes was referred to our Hematology clinic for anemia of ESRD. He was receiving Epoetin 20,000 IU three times weekly but was still transfusion-dependent to maintain a hemoglobin of 6.3 g/dL, with a concomitant PTH of 400.5 pg/mL. Calcium and phosphorus were normal and thus his SHP was not aggressively managed. Bone marrow biopsy revealed focal areas of bone marrow remodeling and reticulin fibrosis. Fluorescence in situ hybridization studies for myelodysplastic syndrome were negative, as were thyroid studies, serum protein electrophoresis, and free light chain ratio. In conjunction with his nephrologist, treatment of his SHP was optimized. His initial regimen was calcitriol 0.25 mcg once daily and calcium acetate 667 mg three times daily. Subsequently, cinacalcet 30 mg twice daily was added and calcium acetate was replaced with sevelamer 1600 mg three times daily. Following these changes, his hemoglobin remained stable in the range of 8-9 g/dL. He was no longer transfusion-dependent, despite only a modest reduction in PTH to 311.2 pg/mL. Repeat bone marrow biopsy revealed no bone marrow remodeling or reticulin fibrosis. Bone marrow findings for all patients referred to our clinic with ESRD and anemia are summarized in Table 1. The range of PTH for patients with bony remodeling was 183-16161.9 pg/mL versus 90.8-3283 pg/mL for those without bony remodeling. The range of PTH for patients with fibrotic changes was 183-2487 pg/mL versus 90.8-16161.9 pg/mL for those without fibrotic changes. ESA dosing varied among the patients.Conclusion: SHP is an increasingly identifiable cause of ESA-resistant anemia, as demonstrated by the reversal of transfusion dependence in our patient once SHP was more adequately treated. The degree of reversible ESA-resistant anemia and transfusion dependence in the setting of a PTH elevation to 400.5 in this case is surprising. The great variability in PTH levels of patients both with and without bone marrow changes presented here indicates the relationship between SHP and anemia is intricate. A single target level for the whole dialysis population is not appropriate; neither is targeting only and the same goal calcium, phosphorus, and PTH levels for the whole dialysis population either. Based on the findings of our institutional cohort, we suggest that it is justified to deviate from “on-size-fits-all” protocols and attempt a trial of aggressive management of SHP in patients with difficult to manage ESA-resistant anemia with what is considered only modest PTH elevation. [Display omitted] DisclosuresMoe: Allena Pharmaceutical: Consultancy; Janssen: Consultancy; Alnylum: Consultancy; DIcerna: Consultancy; Tricida: Consultancy.

Estimating Selection Bias in Previous Monoclonal Gammopathy of Undetermined Significance Research - the Importance of Screening: Results from the Population-Based Screening Study Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM)

IntroductionMonoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder preceding multiple myeloma and related disorders, present in 4.2% of the population over the age of 50. Although usually asymptomatic, MGUS has been associated with various health-related problems, including thrombosis, infections, fractures, neuropathy, and death. Because MGUS is asymptomatic, its diagnosis is typically incidental, during clinical workup for unrelated medical issues, and therefore most individuals remain undiagnosed. Consequently, MGUS cohorts in past studies may have suffered from more comorbidities than the actual population with MGUS. This might have introduced selection bias in previous studies on MGUS, which extent has not been studied in a systematic way. Therefore, previously reported associations between MGUS and various medical issues might not be as profound as formerly observed. The aim of this study was to compare characteristics of incidentally diagnosed MGUS versus MGUS diagnosed by systematic screening, with particular focus on demographics, comorbidities, and MGUS-related factors.MethodsThe study is based on the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. iStopMM is a population-based screening study for MGUS and a randomized controlled trial of follow-up strategies that has included 54% (n = 80,759) of the Icelandic population above 40 years of age. In total, 75,422 participants were screened for MGUS by serum protein electrophoresis (SPEP) and free light chain (FLC) assay. Information on which individuals had incidentally diagnosed MGUS (clinical MGUS) prior to participation in iStopMM were gathered from the Icelandic cancer registry and laboratory results from Landspítali University Hospital and Læknasetrið, the only laboratories in Iceland that perform SPEP. M-protein concentration, MGUS isotype and FLC ratio were obtained from the original screening samples. Comorbidity data was acquired from two high-quality national registries: Hospital Discharge Register and Register of Primary Health Care Contacts, with >95% completeness and accuracy. MGUS diagnosed by screening was further classified into MGUS with or without M-proteins (light-chain MGUS). Those with clinical MGUS were used as the reference group in all analyses. Since all individuals with clinical MGUS had M-proteins, individuals with light-chain MGUS were excluded from this study. T-test and chi-square test were used for demographic comparison; linear regression adjusting for sex and age for continuous variables, and logistic regression adjusting for sex and age for comparison of categorical variables, regarding MGUS-related factors and comorbidities.ResultsThe study cohort consisted of 3,300 individuals who had MGUS with M-proteins; 224 individuals with clinical MGUS and 3,076 with screened MGUS. The clinical MGUS group was significantly older (p <0.01), more likely to live in the capital area of Iceland (p 0.02), and had a 0.14 g/dL higher mean M-protein concentration (95% confidence interval [95% CI] 0.10-0.19 g/dL, p <0.001) than those with screened MGUS. Individuals with clinical MGUS were also 1.73 times more likely to have a comorbidity (odds ratio [OR] 1.73, 95% CI 1.14-2.72, p 0.01) than those with screened MGUS, reflected in a significantly higher mean number of comorbidities (2.79 vs. 2.09, p <0.001). Finally, clinical MGUS were significantly more likely to have arrhythmias (OR 1.45, p 0.05), chronic kidney diseases (OR 2.42, p <0.001), endocrine diseases (OR 1.82, p <0.001), heart failure (OR 2.60, p <0.001), neurological diseases (OR 3.07, p <0.001) or rheumatological diseases (OR 3.25, p <0.001).DiscussionIn this large population-based study including 75,000 screened individuals, we found clinical MGUS cases to be older, more likely to live in Iceland's capital area, and have a higher M-protein concentration than those found to have MGUS while screened on the iStopMM study. Individuals with clinical MGUS also had a higher number of underlying comorbidities and were 1.5-3.3 times more likely to suffer from arrhythmias, chronic kidney diseases, endocrine disorders, heart failure, neurological diseases, and rheumatological diseases. Our findings highlight the importance of screening studies to evaluate the true epidemiological and biological implications of MGUS and suggest selection bias in prior studies. [Display omitted] DisclosuresKampanis: The Binding Site: Current Employment. Hultcrantz: Daiichi Sankyo: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Amgen: Research Funding; Intellisphere LLC: Consultancy. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services . Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Honoraria; Janssen: Other: IDMC; Takeda: Other: IDMC; Janssen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

Changing Patterns of Symptomatic Myeloma after the Implementation of the 2014 IMWG Diagnostic Criteria and Reduced Early Mortality

Changing Patterns of Symptomatic Myeloma after the Implementation of the 2014 IMWG Diagnostic Criteria and Reduced Early Mortality