Serum Free Light Chain Ratio Research Articles

Clinical characteristics and progression risk factors for patients with monoclonal gammopathy of undetermined significance

Objective: To analyze the clinical presentation and progression risk factors of patients with monoclonal gammopathy of undetermined significance (MGUS) in China. Methods: We retrospectively assessed the clinical features and disease progression of 1 037 patients with monoclonal gammopathy of undetermined significance between January 2004 and January 2022 at Peking Union Medical College Hospital. Results: A total of 1 037 patients were recruited in the study, including 636 males (63.6%) , with a median age of 58 (18-94) years. The median concentration of serum monoclonal protein was 2.7 (0-29.4) g/L. The monoclonal immunoglobulin type was IgG in 380 patients (59.7%) , IgA in 143 patients (22.5%) , IgM in 103 patients (16.2%) , IgD in 4 patients (0.6%) , and light chain in 6 patients (0.9%) . 171 patients (31.9%) had an abnormal serum-free light chain ratio (sFLCr) . According to the Mayo Clinic model for risk of progression, the proportion of patients in the low-risk, medium-low-risk, medium-high risk, and high-risk groups were 254 (59.5%) , 126 (29.5%) , 43 (10.1%) , and 4 (0.9%) , respectively. With a median follow-up of 47 (1-204) months, 34 of 795 patients (4.3%) had disease progression, and 22 (2.8%) died. The overall progression rate was 1.06 (0.99-1.13) /100 person-years. Patients with non-IgM MGUS have a markedly higher disease progression rate per 100 person-years than IgM-MGUS (2.87/100 person-years vs 0.99/100 person-years, P=0.002) . The disease progression rate per 100 person-years in non-IgM-MGUS patients of Mayo classification low-risk, medium-low risk and medium-high risk groups were 0.32 (0.25-0.39) /100 person-years, 1.82 (1.55-2.09) /100 person-years, and2.71 (1.93-3.49) /100 person-years, which had statistically difference (P=0.005) . Conclusion: In comparison to non-IgM-MGUS, IgM-MGUS has a greater risk of disease progression. The Mayo Clinic progression risk model applies to non-IgM-MGUS patients in China.

High prevalence of Wilms tumor 1 expression in multiple myeloma and plasmacytoma: A cohort of 142 Asian patients' samples.

Wilms tumor 1 (WT1) is a promising target antigen for cancer immunotherapy. However, WT1 protein expression and its clinical correlation in multiple myeloma (MM) patients are still limited. We, therefore, investigated WT1 expression in 142 bone marrow and plasmacytoma samples of MM patients at different stages of the disease by immunohistochemistry. The correlations between WT1 expression and clinical parameters or treatment outcomes were evaluated. The overall positive rate of WT1 expression was 91.5%; this high prevalence was found in both bone marrow and plasmacytoma samples, regardless of the disease status. Cytoplasmic WT1 expression was correlated with high serum free light chain ratio at presentation. However, no significant association between WT1 expression and treatment outcome was observed. This study confirms the high prevalence of WT1 expression in an Asian cohort of MM, encouraging the development of immunotherapy targeting WT1 in MM patients, particularly in those with extramedullary plasmacytoma or relapsed disease.

Serum Free Light Chain ratio: Utility as marker of residual disease in monoclonal gammopathies

Serum Free Light Chain ratio: Utility as marker of residual disease in monoclonal gammopathies

A prognostication system based on clinical parameters and [18F]-FDG PET/CT in patients with newly diagnosed multiple myeloma.

This study aimed to assess prognosis of patients with newly diagnosed multiple myeloma (NDMM) by combining [18F]-FDG positron emission tomography (PET)/CT parameters and clinical indices. Clinical data and PET/CT parameters of 133 NDMM patients were retrospectively analyzed for associations between clinical indices and PET/CT parameters. Independent predictors of progression-free survival (PFS) and overall survival (OS) were determined. A new prognostic prediction system (NPPS) was constructed based on our findings. Prediction effectiveness was compared among the NPPS, International Staging System (ISS), Revised ISS (R-ISS), and R2-ISS. Prevalence of elevated β2-microglobulin, serum creatinine (sCr), serum calcium (sCa), and C-reactive protein concentrations was higher in patients with higher SUVmax (≥ 5.3). Prevalence of elevated sCa, sCr, and extramedullary disease (EMD) was higher in patients with a higher number of focal lesions (≥ 10). SUVmax, serum free-light chain (sFLC) ratio, and EMD were independent predictors of PFS and OS. The NPPS used SUVmax, sFLC ratio, and EMD could effectively predict OS and was more effective at prognostication than the ISS, R-ISS, and R2-ISS. [18F]-FDG PET/CT parameters play a significant role in predicting prognosis in NDMM patients. The NPPS based on SUVmax, sFLC ratio, and EMD outperformed the ISS, R-ISS, and R2-ISS in prognostication.

Patients with IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) or IgA with an M Band < 1.0 g/DL Have the Same Low Risk of Progression to Lymphoplasmacytic Neoplasm (LPN) As Those with IgG MGUS and an M-Band < 1.5 g/DL

Background Patients with MGUS can progress to LPN. Non-IgG subtype and the size of the M-band are known to correlate with the risk of progression. Consensus guidelines recommend that patients be monitored on an annual basis, but that IgG MGUS with an M-band < 1.5 g/dL, and a normal serum free light chain ratio is at low risk and can be managed with less intensive monitoring. There are limited data on the risk of progression to LPN in non-IgG MGUS with small M-bands. Methods Kaiser Permanente Northern California (KPNC) is a large integrated health care system serving more than 4 million members representative of Northern California residents. We identified a cohort of 3,303 KPNC health plan members who had at least one serum protein electrophoresis (SPEP) performed between January 1997 and December 2006 and extracted follow up data through December 2016. We excluded those with an M-Band > 3 g/dL, absence of a confirmatory immunofixation, or LPN before through 3 months after initial SPEP. The primary end point was progression to LPN, defined as multiple myeloma (MM), non-Hodgkin's lymphoma, or amyloidosis, and identified via an integrated tumor registry and, in the case of amyloidosis, by clinic diagnosis. Findings The median age of this cohort was 73 (IQR 63-80), 54.5% were male, and the ethnicity of this group was White 66.9%, Black 17.2%, Asian 6.7%, Hispanic 7.7%, and others 1.6%. Sixty six percent had an IgG gammopathy and 73% of gammopathies were < 1.0 g/dL. Overall, there were 2.1 (2.0-2.3) progressions per 100 patient years. The number of progressions per 100 patient years for an M-band < 1.0 g/dL, 1.0-1.5 g/dL, and 1.5-3.0 g/dL were 1.4 (1.2-1.6), 3.5(2.9-4.1), and 6.6 (5.5-7.7) respectively. As can be seen in the Figure, the cumulative risk of progression to LPN was clinically similar for patients with an IgG ≥ 1.5 g/dL and IgA ≥ 1.0 g/dL and considerably increased compared to those with an IgG gammopathy < 1.5 gm/dL, IgA gammopathy < 1.0 g/dL, or an IgM of any size. Discussion It has been estimated that there are several million individuals in the United States with MGUS. Following a patient with MGUS indefinitely is a financial burden and creates a substantial psychologic burden for the patient. Others have found that the effect of an MGUS diagnosis on quality of life is greater than a new diagnosis of symptomatic MM. Therefore, identifying additional categories of MGUS that could be assigned to a low-risk category could potentially diminish the burden and stress of ongoing monitoring. Limitations of our study are that, owing to the period from which our cohort was accrued, and the nature by which they were identified, free light chain levels were not obtained, bone marrow biopsies were done infrequently, and modern advanced imaging was not performed. In the modern era, many of our cohort would likely be identified with more advanced neoplasia such as smoldering or frank MM accounting for the higher rates of progression compared with other published reports. We found that during much of the period covered by our study, the clinical diagnosis of Waldenstrom's Macroglobulinemia was used in a non-discriminatory manner. We therefore limited our definition of progression only to those subjects developing frank malignancy that qualified for inclusion in our tumor registry rather than the less rigorously defined entity of "Waldenstrom's Macroglobulinemia.". This likely accounts for the lower risk of progression to LPN among our cohort with IgM gammopathy than has been described elsewhere. Conclusion Patients with either IgM MGUS of any size or IgA MGUS with an M-band < 1.0 g/dL have an equivalent clinical risk of progression as patients with an IgG MGUS < 1.0 g/dL and should potentially be assigned to a low-risk category to decrease the burden and stress of ongoing monitoring. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hypercalcemia: A Risk Factor for Early Disease Progression and Poor Survival in Cytogenetically Standard-Risk Multiple Myeloma

Introduction The advent of novel therapies over the last decade, including proteasome inhibitors, immunomodulators, and monoclonal antibodies, has drastically improved the outcomes in patients with Multiple Myeloma (MM). It is common in both clinical practice and design of clinical trials to risk stratify patients to determine poor-prognosis based on known high-risk cytogenetics and baseline health status. Despite efforts to unify and refine the definition of high-risk disease, significant heterogeneity exists within risk strata and the majority of MM patients do not harbor high-risk cytogenetics. Many patients with ostensibly standard-risk disease progress rapidly, exhibiting a clinical presentation that aligns more closely with high-risk disease biology. We retrospectively evaluated outcomes within an institutional database to determine whether variation in prognosis among patients with standard risk MM may be predicted by clinical and biochemical features that are measurable at the point of care. Methods This retrospective cohort study included patients diagnosed with MM at the Cleveland Clinic in Cleveland, OH between 1/1/2008 - 12/31/2015 who had relapsed or died prior to initiation of the study. Patients with conventional high-risk cytogenetic features including: del(17p), t(4;14), t(14,20) or t(14;16) by fluorescence in situ hybridization (FISH) were excluded. Multiple variables at diagnosis were included in the analysis: race, gender, age, serum calcium (Ca), B-2-microglobulin, albumin, kidney function, hemoglobin, involved: uninvolved serum free light chain ratio, lactate dehydrogenase (LDH), serum monoclonal (M) protein, International Staging System (ISS) stage, Eastern Cooperative Oncology Group (ECOG) score, and the presence of extramedullary disease. Hypercalcemia (HCa) was defined using 3 groups - Group 1: Ca <10.0, Group 2: 10.1 - 12.5, and Group 3: > 12.5 mg/dL. Time to event analysis was conducted using the Kaplan Meier method. The impact of clinical and biochemical features at presentation on PFS and OS was quantified using a Cox Proportional Hazard on a univariate and multivariate basis in order to determine risk factors for early relapse among this cohort of patients with standard-risk cytogenetics. Results A total of 264 NDMM patients were screened for high-risk cytogenetics and the 18 patients excluded. An additional 99 patients were excluded from our analysis due unavailable FISH data at diagnosis. Twenty-one patients did not have serum calcium levels available at the time of diagnosis and were excluded, resulting in a study population of 126. Among these patients, the median age was 61.5 years old, 77.6% (n=97) of patients were Caucasian, and 47.6% (n=60) were male. The median time to follow up was 5.2 (2.9-7.0) years. A total of 13.6% had extramedullary disease (n=17) and 25.4% had a frontline autologous stem cell transplant (ASCT) (n=32). Stratification was conducted utilizing ISS stage: 34.4% Stage 1 (n=42), 31.1% (n-38) Stage II, and 34.4% (n=42) and ECOG score: 34.4% (n=42) Score 1, 38% (n=38) Score 2, and 42% (n=34.4) Score 3. The three hypercalcemia groups were similar with regard to demographics, ECOG, and laboratory data; however, ISS stage (23%, 47%, and 73%, p=0.002) and serum creatinine (median 0.96, 1.4, and 2.3 mg/dL, p=0.001) were positively correlated with calcium level at time of diagnosis. There was a statistically significant difference in 2-year PFS among the HCa groups (54.4%, 36.1%, and 9.1%, p = 0.002 and p <0.001, respectively) (Figure 1). There was also a statistically significant difference in OS among the HCa groups (Median OS years/5-year OS: 6.1/65.3%, 4.5/46.9%, 2.4/9.1%, p=0.032 and p <0.001, respectively) as well (Figure 2). Differences in PFS and OS remained significant after adjusting for age, race, ISS stage, extramedullary disease, ECOG. and frontline ASCT. Conclusion Our results showed that serum calcium level predicted disease progression and survival in a large cohort of patients without high-risk cytogenetic features. Variation in outcomes among MM patients who do not harbor high risk cytogenetics has not been fully explained. These results may help to inform clinical decision making, refine current risk stratification models, and identify a subpopulation with the strata of standard risk for correlative studies to evaluate disease genomics and biology. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The role of serum-free light chain ratios in the prediction of poor prognosis in multiple myeloma patients: a systematic review and meta-analysis

ABSTRACT Background The association between the serum free light chain (sFLC) ratio and the prognosis of multiple myeloma (MM) patients is controversial. Aim The purpose of this study is to explore the relationship between the sFLC ratio and the prognosis of MM patients through meta-analysis. Methods Online public databases were searched to find relevant studies. The retrieval time is limited from the establishment of the database to July 2021. The overall survival (OS) and progression-free survival (PFS) rates were compared. The results were described using hazard ratio (HR) and a 95% confidence interval (CI). Qualitative studies were also included. Results A total of 9 studies involving 2864 participants were included. A pooled analysis based on four studies including newly-diagnosed MM patients, demonstrated that an abnormal sFLC ratio was associated with poor outcomes of OS (HR = 1.82, 95% CI: 1.15–2.90) and PFS (HR = 1.87, 95% CI: 1.20–2.90). Three qualitative studies showed that an abnormal sFLC ratio was related with poor outcomes of OS (studies all included newly diagnosed MM patients) and PFS (two studies included newly-diagnosed MM patients and one study included non-newly-diagnosed MM patients). Two studies stated that the sFLC ratio is not associated with OS (both studies included non-newly-diagnosed MM patients) and one study reported that the sFLC ratio is not associated with PFS (study included non-newly-diagnosed MM patients). Conclusion sFLC ratio could be used to predict adverse outcomes in newly-diagnosed MM patients, but is not suitable for non-newly-diagnosed MM patients.

Circulating Tumor and Immune Cells for Minimally Invasive Risk Stratification of Smoldering Multiple Myeloma.

Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under- and overtreatment. We hypothesized that replacing bone marrow (BM) plasma cells (PC) for circulating tumor cells (CTC), and adding immune biomarkers in peripheral blood (PB) for the identification of patients at risk of progression due to lost immune surveillance, could improve the International Myeloma Working Group 20/2/20 model. We report the outcomes of 150 patients with SMM enrolled in the iMMunocell study, in which serial assessment of tumor and immune cells in PB was performed every 6 months for a period of 3 years since enrollment. Patients with >0.015% versus ≤0.015% CTCs at baseline had a median time-to-progression of 17 months versus not reached (HR, 4.9; P<0.001). Presence of >20% BM PCs had no prognostic value in a multivariate analysis that included serum free light-chain ratio >20, >2 g/dL M-protein, and >0.015% CTCs. The 20/2/20 and 20/2/0.015 models yielded similar risk stratification (C-index of 0.76 and 0.78). The combination of the 20/2/0.015 model with an immune risk score based on the percentages of SLAN+ and SLAN- nonclassical monocytes, CD69+HLADR+ cytotoxic NK cells, and CD4+CXCR3+ stem central memory T cells, allowed patient' stratification into low, intermediate-low, intermediate-high, and high-risk disease with 0%, 20%, 39%, and 73% rates of progression at 2 years. This study showed that CTCs outperform BM PCs for assessing tumor burden. Additional analysis in larger series are needed to define a consensus cutoff of CTCs for minimally invasive stratification of SMM.

P-170: Evaluating serum free light chain ratio as a biomarker for multiple myeloma

P-170: Evaluating serum free light chain ratio as a biomarker for multiple myeloma

Serum Free Light-Chain Ratio at Diagnosis Is Associated with Early Renal Damage in Multiple Myeloma: A Case Series Real-World Study.

The serum free light-chain (FLC) ratio is a sensitive tool for the differential diagnosis of plasma cell disorders and is biomarker of multiple myeloma (MM) progression from premalignant conditions. Here, we investigate the potential role of FLC ratio at diagnosis in identifying early renal damage in MM patients and other correlations with clinical, laboratory, and molecular findings. A total of 34 MM patients who had undergone autologous stem cell transplantation were included in this retrospective case series study, and FLC quantification was performed with nephelometric assays. In our study, sFLC ratio was significantly associated with light-chain MM and β-2 microglobulin levels, likely indicating a high disease burden at diagnosis, especially in patients without heavy chain M-protein at serum electrophoresis. Moreover, the sFLC ratio was inversely correlated with glomerular filtration rate, possibly identifying early renal damage in MM patients. Our preliminary results confirm the importance of early sFLC evaluation, especially in patients with the light-chain MM type and low disease burden, to minimize the risk of late renal failure.

S177: EVALUATING SERUM FREE LIGHT CHAIN RATIO AS A BIOMARKER FOR MULTIPLE MYELOMA

Background: In 2014, the definition of multiple myeloma (MM) was updated to include serum free light chain (FLC) ratio ≥100 as a myeloma defining biomarker, based on retrospective data indicating a 2-year progression rate of 80% and a median time to progression (TTP) of 12 months associated with this marker. As a result, patients previously diagnosed as smoldering MM (SMM), were considered to have MM requiring treatment if they had a FLC ratio ≥100. However, two recent studies have reported lower 2-year progression rates, 30-44%, and a longer median TTP of 40 months in patients with FLC ratio ≥100, raising concern about the FLC criteria. Aims: To assess the risk of progression in patients with SMM and a FLC ratio ≥100. Methods: We performed a retrospective analysis of patients diagnosed with SMM at Memorial Sloan Kettering Cancer Center between January 2000 and December 2017. Diagnosis of SMM and progression to active MM requiring therapy was defined according to the International Myeloma Working Group (IMWG) criteria at the time of diagnosis. Kaplan-Meier method was used to assess TTP and generate survival curves, with log-rank test for comparison between groups. Results: A total of 438 patients were included in the study, with a median follow-up time of 52 months. While all patients with FLC ≥100 (n=66) had elevated involved FLC levels, 35 (53%) had an involved FLC concentration >100 mg/L. Per current diagnostic criteria, we only included patients with an involved FLC concentration >100 mg/L in the FLC ratio ≥100 group and found a median TTP of 31 months (95% confidence interval [CI] 16-59 months) and a 2-year progression rate of 49% (CI 28-63%). In a sensitivity analysis including all 66 cases with FLC ratio ≥100 (independent of involved FLC concentration), we found the median TTP to be 41 months (CI 30-72 months), compared to 101 months for those with a FLC ratio <100 (CI 78-127 months; p<0.0001). Furthermore, the risk of progression within 2 years was 35% (CI 22-46%) compared to 18% (CI 14-23%; p<0.0001) for those with a FLC ratio <100. Of note, 22 patients with a FLC ratio ≥100 were monitored expectantly for >4 years, among whom 12 patients had involved FLC levels >100 mg/L. Ten patients (7 with involved FLC level >100 mg/L) were followed over a period ranging from 4 to 8.5 years before eventually progressing, and 12 patients (5 with an involved FLC level >100 mg/L) were followed between 4 and 8 years and did not progress during the study period. Image:Summary/Conclusion: While FLC ratio ≥100 is associated with a high risk of progression in patients with SMM, it does not infer an imminent risk of progression, defined by the IMWG as median TTP of 12 months and 2-year progression rate of at least 80%. On the contrary, select patients with FLC ratio ≥100 can be followed for many years without progressing and some may never progress despite long-term follow-up. These findings suggest that in patients where FLC ratio ≥100 is the only myeloma-defining event, other high-risk features as well as the evolution of FLCs over time should be considered in the decision to start a patient on treatment.

Evaluating serum-free light chain ratio as a biomarker for multiple myeloma.

8047 Background: In 2014, the definition of multiple myeloma was updated to include serum free light chain (FLC) ratio ≥100 as a myeloma defining biomarker, based on retrospective data indicating a 2-year progression rate of 80% and a median time to progression (TTP) of 12 months associated with this marker. However, two recent studies have reported lower 2-year progression rates, 30-44%, and longer median TTP of 40 months in patients with FLC ratio ≥100. Because of the disparity in risk prediction by FLC ratio across studies, we were motivated to assess the risk of progression in patients with SMM and a FLC ratio ≥100. Methods: We performed a retrospective analysis of patients diagnosed with SMM at Memorial Sloan Kettering Cancer Center between January 2000 and December 2017. Diagnosis of SMM and progression to MM was defined according to the International Myeloma Working Group (IMWG) criteria at the time of diagnosis. Kaplan-Meier method was used to assess TTP and generate survival curves, with log-rank test for comparison between groups. Results: A total of 438 patients were included in the study, with a median follow-up time of 52 months. While all patients with a FLC ratio ≥100 (n = 66) had elevated involved FLC levels, 35 (53%) had an involved FLC concentration &gt; 100 mg/L. Per current diagnostic criteria, we only included patients with an involved FLC concentration &gt; 100 mg/L in the FLC ratio ≥100 group, and found a median TTP of 31 months (95% confidence interval [CI] 16-59 months) and a 2-year progression rate of 49% (CI 28-63%). In a sensitivity analysis including all 66 cases with FLC ratio ≥100 (independent of involved FLC concentration), we found the median TTP to be 41 months (CI 30-72 months), compared to 101 months for those with a FLC ratio &lt; 100 (CI 78-127 months; p &lt; 0.0001). The risk of progression within 2 years was 35% (CI 22-46%) compared to 18% (CI 14-23%; p &lt; 0.0001). Of note, 22 patients with a FLC ratio ≥100 were monitored expectantly for &gt; 4 years, among whom 12 patients had an involved FLC level &gt; 100 mg/L. Ten patients (7 with involved FLC level &gt; 100 mg/L) were followed over a period ranging from 4 to 8.5 years before eventually progressing, and 12 patients (5 with involved FLC level &gt; 100 mg/L) were followed between 4 and 8 years and did not progress during the study period. Conclusions: While FLC ratio ≥100 is associated with a high risk of progression in patients with SMM, it does not infer an imminent risk of progression, defined by the IMWG as median TTP of 12 months and 2-year progression rate of at least 80%. On the contrary, select patients with FLC ratio ≥100 can be followed for many years without progressing and some may never progress despite long-term follow-up. These findings suggest that in patients where FLC ratio ≥100 is the only myeloma-defining event, other high-risk features as well as the evolution of FLCs over time should be considered in the decision to start a patient on treatment.

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.

Spinal MRI-Based Radiomics Analysis to Predict Treatment Response in Multiple Myeloma.

The aim of this study was to explore the clinical utility of spinal magnetic resonance imaging-based radiomics to predict treatment response (TR) in patients with multiple myeloma (MM). A total of 123 MM patients (85 in the training cohort and 38 in the test cohort) with complete response (CR) (n = 40) or non-CR (n = 83) were retrospectively enrolled in the study. Key feature selection and data dimension reduction were performed using the least absolute shrinkage and selection operator regression. A nomogram was built by combining radiomic signatures and independent clinical risk factors. The prediction performance of the nomogram was assessed using the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis. Treatment response was assessed by determining the serum and urinary levels of M-proteins, serum-free light chain ratio, and the percentage of bone marrow plasma cells. Thirteen features were selected to build a radiomic signature. The International Staging System (ISS) stage was selected as an independent clinical factor. The radiomic signature and nomogram showed better calibration and higher discriminatory capacity (AUC of 0.929 and 0.917 for the radiomics and nomogram in the training cohort, respectively, and 0.862 and 0.874 for the radiomics and nomogram in the test cohort, respectively) than the clinical model (AUC of 0.661 and 0.674 in the training and test cohort, respectively). Decision curve analysis confirmed the clinical utility of the radiomics model. Nomograms incorporating a magnetic resonance imaging-based radiomic signature and ISS stage help predict the response to chemotherapy for MM and can be useful in clinical decision-making.

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.

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.

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.