Progression Of Monoclonal Gammopathy Research Articles

IgA monoclonal gammopathies are accompanied by higher total TGF-β1 levels than IgG or IgM monoclonal gammopathies.

The progression of monoclonal gammopathies is affected by a range of factors, including the microenvironment surrounding plasma cells. It is recognized that TGF-β1 plays a distinct role in stimulating IgA production. Hence, this study aims to investigate whether individuals with serum IgA monoclonal immunoglobulins (paraproteins) exhibit elevated total TGF-β1 levels compared to those with IgG or IgM paraproteins. To achieve this goal, individuals with a positive laboratory finding of monoclonal gammopathy were segregated according to the paraprotein class as well as according to the type of the light chain. Total TGF-β1 levels were assessed in blood serum samples containing IgG (n = 50), IgA (n = 46), and IgM (n = 31) paraproteins. Elevated level of TGF-β1 was confirmed in sera with IgA paraproteins (median 25.8 ng/mL; interquartile range IQR: 19.0-33.7) compared to those having IgG (median: 18.2 ng/mL; IQR: 14.3-22.1; p < 0.001) or IgM paraproteins (21.5 ng/mL; IQR: 15.0-27.4; p = 0.043). Also, a higher TGF-β1 level was detected in sera with IgMλ than those with IgMκ paraproteins (p = 0.043). This research affirms the role of TGF-β1 in the pathophysiology of IgA monoclonal gammopathies and the potential switch towards the IgA isotype, known for a less favourable prognosis.

Evaluation of Metabolic Profile in Monoclonal Gammopathy of Undetermined Significance and Asymptomatic Multiple Myeloma

Background: Multiple myeloma (MM) is an incurable, heterogeneous neoplasm of clonal plasma cells preceded by the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic multiple myeloma (AMM). Features of metabolic syndrome including obesity and diabetes mellitus (DM) have been linked to MM development and mortality. A study of serum metabolomics in patients with clinical MM revealed alterations in the citrate cycle, pyrimidine, purine, and amino acid metabolism (Chanukuppa V, et al, 2019). However, the role of dysregulated metabolism in progression of monoclonal gammopathy across the disease spectrum requires further investigation. We performed a pilot study to compare metabolic profiles in patients with MGUS and AMM. Methods: Clinical data and peripheral blood plasma samples were collected on 20 patients with non-immunoglobulin M MGUS and 20 patients with AMM. Global metabolomic studies by liquid chromatography (LC) tandem mass spectrometry (MS) were performed on plasma using a SCIEX TripleTOF 6600+ mass spectrometer. Each sample was run on Hypercarb and Reverse phase LC columns in both positive and negative MS modes. Standard targeted and untargeted metabolomic platforms were used with assessment of changing metabolites between the two groups in a one-to-one comparison. Correlation analysis and differential expression analysis were completed and top changing metabolites determined based on ranking of log fold change and p value cutoff (at least &amp;lt;0.05). Pathway enrichment data was generated with advanced data analysis. Results: Median age was 70 and 67 years in the MGUS and AMM groups, respectively. 65% of patients in the AMM group were male versus (vs) 40% in the MGUS group. Black individuals represented 15% of MGUS and 30% of AMM patients. Mean serum monoclonal (M) protein was higher in AMM patients (0.87 g/dL vs 0.28 g/dL, p=0.009); mean bone marrow clonal plasma cells in AMM was 17% (range 10-40%). Three AMM patients had high risk cytogenetics inclusive of chromosome 1 abnormalities. We observed that more individuals in the AMM group had a diagnosis of DM (35% vs 15%), were on hyperlipidemia (HLD) medications (80% vs 45%) and were on ≥3 hypertension (HTN) medications (35% vs 20%). Increasing weight and hemoglobin a1c values were seen with rise in serum M protein in the combined groups. For global metabolomics, 2,513 metabolites were annotated from targeted and untargeted peak curation and results underwent data normalization and standardization with exclusion of outliers from the data set. Using targeted data, Partial Least Squares-Discriminant Analysis showed separation of the MGUS and AMM groups (Figure 1). There were 8 significantly increased metabolites (dihydrouracil, quinate, melatonin, azelate, phosphonoacetate, malate, L-alanine, and lysine) and 9 significantly decreased metabolites (diethanolamine, xanthosine, nervonate, quinolinate, L-dopa, ethylmalonate, butanoate, carnosine, and thyroxine) in AMM when compared to MGUS. Pathway enrichment analysis revealed several pathways increased in AMM (Figure 2), including D-glutamine and D-glutamate metabolism and the citrate cycle. Pathways decreased in AMM included purine, pyrimidine, and glutathione metabolism. Conclusions: In our study, patients with AMM were more likely to demonstrate features of metabolic syndrome, including higher rate of DM and need for HTN and HLD medications. Additionally, a trend of higher weight and hemoglobin a1c values occurred as serum M protein increased. Global metabolomics identified unique metabolites that differed in AMM relative to MGUS patients. The unsaturated fatty acid nervonate, decreased in AMM in our study, was previously shown to have potential preventive effects on obesity-related metabolic disorders (Oda E, et al, 2005). Our findings in these precursor cohorts are concordant with prior serum metabolomics in MM showing alterations in amino acid metabolism including glutamine (Chanukuppa V, et al, 2019), with glutaminase inhibitors currently under study in relapsed/refractory MM (Bolzoni M, et al, 2016). Additional investigation of metabolic profile in larger groups across the spectrum of monoclonal gammopathy will help further elucidate the role of this dysregulated metabolism in myelomagenesis and could lead to preventative interventions targeting the associated metabolic syndrome earlier in disease course.

Informative value of whole-body magnetic resonance imaging with diffusion-weighted images for the detection of bone marrow infiltration in patients with multiple myeloma (literature review)

Magnetic resonance imaging (MRI) is increasingly being used to diagnose bone marrow lesions in patients with multiple myeloma (MM). Since 2014, the results of MRI have been included in the updated criteria of the International Myeloma Working Group. The presence of &gt;1 bone marrow lesion larger than or equal to 5 mm on MRI is considered sufficient for the diagnosis of symptomatic MM, requiring initiation of treatment. MRI assessment of bone marrow is also possible with functional sequences such as diffusion-weighted imaging (DWI), which provide additional information about the bone marrow. This article provides an overview of the possibilities of MRI with anatomical sequences and with DWI for diagnosing, monitoring and evaluating the response to treatment in patients with MM. In patients with monoclonal gammopathy of undetermined significance and smoldering myeloma, in some cases, pathological changes in the bone marrow can be detected by MRI. The presence of &gt;1 bone marrow lesion on MRI is a cut-off value as a prognostic factor for the progression of monoclonal gammopathy of undetermined significance or smoldering myeloma to symptomatic MM. In symptomatic MM, there are four patterns of bone marrow infiltration on MRI – focal, diffuse, “salt-and-pepper” infiltration, and combined diffuse and focal pattern, which have prognostic significance. Patients with diffuse pattern of infiltration on MRI had a 3-year overall survival of 35 % versus 92 % in patients with normal MRI bone marrow. During treatment of MM patients, residual bone marrow lesions are often identified on MRI. MRI residual bone marrow lesions increase the risk of MM relapse. In the group of patients who had residual bone marrow lesions on MRI on the 100th day after autologous hematopoietic stem cell transplant, 2-year progression-free survival was 50 % versus 89 % in patients without bone marrow lesions at the same time. The addition of DWI to the scan protocol helps to differentiate persistent focal bone marrow lesions that can lead to MM relapse after the treatment phase. Apparent diffusion coefficient is a quantitative indicator of DWI. MRI can serve as a valuable tool for assessing the treatment response in patients with MM.

Eight-Color Flow Cytometry Phenotypic Markers and Disease Progression in Monoclonal Gammopathy of Unknown Significance

Introduction: Flow cytometric immunophenotyping is considered an indispensable tool for the diagnosis, classification, and monitoring of plasma cell disorders. Herein, we seek to study the clinical significance of expression of phenotype markers in monoclonal gammopathy of unknown significance (MGUS).Methods: We identified a cohort of patients with a diagnosis of MGUS from the institutional myeloma database. Bone marrow (BM) aspirate assessment was performed using 8-color immunophenotypic next-generation flow cytometric (NGF) analysis with a minimum sensitivity of 10 -5 cells at the time of diagnosis or first visit to our institution. BM aspirate samples were immunophenotyped on a FACSCanto II flow cytometer using antibodies (BD) to delineate normal and abnormal plasma cells [CD138 (V-500), CD38 (FITC), CD19 (PE-Cy7), CD45 (V-450), CD27 (PercpCy5.5), CD81 (APC-H-7), CD56 (APC) and CD20 (PE)]. The sensitivity or the Limit of Detection (LOD) for this assay was validated to 20 cells in 2 ×10 6 events (0.001%), and the reproducibility or Lower Limit of Quantitation (LLOQ) is 50 cells in 2 ×10 6 events. Clinical and laboratory variables were also collected. Based on previously published data, expression (CD19, CD45, CD81), and lack of expression (CD56, CD27, CD20) of the above-mentioned surface antigens were analyzed. Additional variables such as IgA isotype, size of M-protein (≥15 g/L), and abnormal free light chain ratio(abnFLR) (defined as <0.1 or >10) were included in regression fitting models.Results: A total of 157 patients with MGUS were included in this analysis. The median age at diagnosis was 60 years (range 24- 84), 84 (53 %) patients were female and 25 (16%) were African American. Overall, IgG Kappa (75/148, 50%) was the most common isotype. Fluorescent-in-situ hybridization (FISH) data were available in 35 patients with t (4:14) and t (14;16) seen in 3 patients each. At a median follow-up of 18.15 years (quantiles 11.35, 33.62), 28 patients experienced disease progression (25 to MM, 2 to Waldenstrom macroglobulinemia, and 1 Smoldering myeloma). The median progression-free survival of this cohort was 17.3 years. Among these, occurrences of the bone lesion (8/28; 28.6%) were the most common pattern of disease progression to MM. This analysis showed lower odds of progression with the expression of CD27 (OR-0.39, 95% CI 0.15-0.99) (figure 1A). Disease progression was more common in patients with an abnormal plasma cell clone size ≥ of 3.1% at diagnosis (60% vs. 12.5%, p=0.0005). An abnormal plasma cell clone of ≥3.1% at diagnosis, was associated with increased odds of progression (OR-10.79, 95% CI 4.02-28.98) and a shorter PFS (12.5 years versus NR, p=0.01) (figure 1B). Serum M-spike ≥1.5 g/dL (OR-3.54;95% 1.30-9.62) and abnFLR (OR-2.30, 95% CI 1.00-5.32) were also associated with a higher odds of progression. However, in this population, the presence of IgA isotype did not increase the odds of MGUS progression. In a stepwise regression model, serum M-spike≥1.5 g/dL, abnFLR, and the lack of expression of CD27 were associated with the risk of disease progression.Conclusion: In addition to previously published risk factors, our cohort shows that the expression of CD27 antigen by eight-color flow cytometry confers a lower risk of disease progression of MGUS. This is consistent with our previous report that CD27 is progressively down-regulated in the transition from normal plasma cells (NPC) to MGUS to MM (Zhan et al, Blood 2006). Furthermore, we show that size of the myeloma clone (≥ 3.1% ) is a possible surrogate marker for disease progression in MGUS.Figure 1: 1A shows forest plot of odds ratios for flow cytometry markers, IgA isotype, size of M protein, abnFLR and plasma cell clone size. 1B shows the Kaplan Meier estimates of PFS for patients stratifies by plasma cell clone size. [Display omitted] DisclosuresMohan: Medical College of Wisconsin: Current Employment. Atrash: GSK: Research Funding; AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau.

Multiple Myeloma Cell-Derived Exosomes: Implications on Tumorigenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological disease that is still not curable. The bone marrow milieu, with cellular and non-cellular elements, participate in the creation of a pro-tumoral environment enhancing growth and survival of MM plasma cells. Exosomes are vesicles oscillating in dimension between 50 nm and 100 nm in size that can be released by various cells and contribute to the pathogenesis and progression of MM. Exosomes enclose proteins, cytokines, lipids, microRNAs, long noncoding RNAs, and circular RNAs able to regulate interactions between MM plasma cells and adjacent cells. Through exosomes, mesenchymal stem cells confer chemoresistance to MM cells, while myeloma cells promote angiogenesis, influence immune response, cause bone lesions, and have an impact on the outcome of MM patients. In this review, we analyze the role played by exosomes in the progression of monoclonal gammopathies and the effects on the proliferation of neoplastic plasma cells, and discuss the possible employment of exosomes as potential targets for the treatment of MM patients.

Abstract 895: Multi-trajectory models of multiple myeloma progression among patients with monoclonal gammopathy of undetermined significance

Abstract Background: Understanding the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma is needed to identify patients who would benefit from closer clinical surveillance. Given that two of the defining criteria of multiple myeloma are renal failure and anemia, we described the trajectories of creatinine and hemoglobin over time in patients with a diagnosis of MGUS. Methods: We analyzed data from 429 patients who were diagnosed with MGUS at a large provider group in central Massachusetts between 2007 and 2015 and were followed up through 2018. Patients diagnosed with MGUS were identified by a previously validated case-finding algorithm using health claims and electronic health record data. Group-based trajectory modeling was used to identify groups of patients with distinct laboratory value trajectories of creatinine (mg/dL) and hemoglobin (mg/dL). Results: The study sample was mostly non-Hispanic white (85.1%) with a mean age of 75 years at MGUS diagnosis. Three multi-trajectory groups were identified. Patients in Group 1 (54.3%) and Group 2 (43.1%) had increasing serum levels of creatinine and decreasing levels of hemoglobin over time, with group 2 having higher increments. Group 3 (2.6%) patients had increasing levels of creatinine and stable low levels of hemoglobin. Patients with MGUS in group 2 were older, less likely to have a prior cancer diagnosis, and had fewer comorbidities than other groups. Twenty-one patients (4.9%) developed multiple myeloma during the study period, with incidence proportions of 0.5%, 1.5%, and 1.6%, respectively for patients in groups 1, 2, and 3. Conclusion: The data suggest that certain subpopulations of patients with MGUS can be characterized by biomarker trajectories over time. Future research should further investigate how these trajectories may be related to risk of progression to multiple myeloma. Citation Format: Maira A. Castaneda Avila, Kate L. Lapane, Sharina Pearson, Jerry Gurwitz, Yanhua Zhou, Mara Epstein. Multi-trajectory models of multiple myeloma progression among patients with monoclonal gammopathy of undetermined significance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 895.

Autoimmune disease is associated with a lower risk of progression in monoclonal gammopathy of undetermined significance

We conducted a population-based study including 19303 individuals diagnosed with MGUS in Sweden from 1985 to 2013, with the aim to determine whether a prior history of autoimmune disease, a well-described risk factor for MGUS is a risk factor for progression of MGUS to multiple myeloma (MM) or lymphoproliferative diseases (LPs). Using the nationwide Swedish Patient registry, we identified MGUS cases with versus without an autoimmune disease present at the time of MGUS diagnosis and estimated their risk of progression. A total of 5612 (29.1%) MGUS cases had preceding autoimmune diseases. Using Cox proportional hazards models, we found the risk of progression from MGUS to MM (HR=0.83, 95% CI 0.73-0.94) and LPs (HR=0.84, 95% CI 0.75-0.94) to be significantly lower in MGUS cases with prior autoimmune disease (compared to MGUS cases without). In this large population-based study, a history of autoimmune disease was associated with a reduced risk of progression from MGUS to MM/other LPs. Potential underlying reason is that MGUS caused by chronic antigen stimulation is biologically less likely to undergo the genetic events that trigger progression. Our results may have implications in clinical counseling for patients with MGUS and underlying autoimmune disease.

MM-106: The Role of Some Markers in the Progression of Monoclonal Gammopathy of Undetermined Significance Among Residents of Gomel Region of Belarus

Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is a pre-stage of multiple myeloma (MM) with a risk of transformation of 1% per year. Malignant cells, interacting with the BMM, acquire resistance to apoptosis, leading to the progression of the disease. Materials and methods: Our study presents the results of a study of the CD138 immunohistochemical marker in plasma BM cells, CD56, CD200, CD40, and CD95 immunophenotypic markers in MGUS patients, and studied the relationship with disease progression. The study included 114 MGUS patients observed in Gomel (Belarus) in 2017-2019. The average age was 60.5 years; females prevailed (77%). The pathological protein was IgG (45.5%). Results were assessed after 3 years of observation. The signs of progression include the appearance of any one of the CRAB-criteria. Results: Signs of progression during the observation period were detected in 22% of MGUS patients. Of this group, 35.3% of patients had an immunohistochemical marker CD138 + 10% (25.2%), progression criteria were identified in 64.7% of cases. Of the general group, CD95 20% and CD95 10% in an immunohistochemical study of bone marrow (p=0.0001) and CD95 Conclusions: Our study has shown that the combination of signs in MGUS patients of CD138 + cells >10% IHC, exceeding levels of CD56 > 20%, CD40 > 20%, and CD95

Metabolomic and Lipidomic Profiling of Bone Marrow Plasma Differentiates Patients with Monoclonal Gammopathy of Undetermined Significance from Multiple Myeloma

Oncogenic drivers of progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) such as c-MYC have downstream effects on intracellular metabolic pathways of clonal plasma cells (PCs). Thus, extracellular environments such as the bone marrow (BM) plasma likely have unique metabolite profiles that differ from patients with MGUS compared to MM. This study utilized an untargeted metabolite and targeted complex lipid profiling of BM plasma to identify significant differences in the relative metabolite levels between patients with MGUS and MM from an exploratory cohort. This was followed by verification of some of the metabolite differences of interest by targeted quantification of the metabolites using isotopic internal standards in the exploratory cohort as well as an independent validation cohort. Significant differences were noted in the amino acid profiles such as decreased branch chain amino acids (BCAAs) and increased catabolism of tryptophan to the active kynurenine metabolite 3-hydroxy-kynurenine between patients with MGUS and MM. A decrease in the total levels of complex lipids such as phosphatidylethanolamines (PE), lactosylceramides (LCER) and phosphatidylinositols (PI) were also detected in the BM plasma samples from MM compared to MGUS patients. Thus, metabolite and complex lipid profiling of the BM plasma identifies differences in levels of metabolites and lipids between patients with MGUS and MM. This may provide insight into the possible differences of the intracellular metabolic pathways of their clonal PCs.

Dosage des chaînes légères libres : indications et méthodes

Serum free light chains (sFLC) assay is an important marker in plasma cell dyscrasia. It is thus recommended for the diagnosis of monoclonal gammopathy, together with serum protein electrophoresis and immunofixation. sFLC assay has also a prognostic value and is a criterion for treatment response and relapse of some monoclonal gammopathies. Three assays are currently available in France, the gold standard being the Freelite® assay, the two others requiring further validation. These three assays are not interchangeable during patient's follow-up. The Freelite® assay is integrated in the myeloma diagnostic criteria from the International Myeloma Working Group 2014, and has a higher sensitivity than Bence Jones protein test for diagnosis, treatment response and follow-up of light chain myeloma. The Freelite® assay is the main marker of therapeutic response in light chain amyloidosis and allows to stratify the risk for progression in monoclonal gammopathy of undetermined significance. Some studies have also shown its value in diagnosis of multiple sclerosis and in screening for monoclonal gammopathy in the cases of acute renal failure. The Freelite® assay is then currently essential in myeloma or amyloidosis, and could be soon extended to the management of autoimmune diseases.

Risk of Progression in Monoclonal Gammopathy of Undetermined Significance (MGUS): Results from a Population-Based Screening Study

BackgroundMonoclonal gammopathy of undetermined significance (MGUS) is a precursor condition to multiple myeloma and other lymphoproliferative disorders. In individuals with MGUS, the average risk of progression to a lymphoproliferative disorder has been estimated to be 1% per year, however, most previous studies have been performed on clinically established cohorts and very few have been population-based. A high monoclonal (M)-protein concentration, non-isotype IgG, and skewed free light chain (FLC) ratio are routinely taken into account when assessing risk for progression. Other risk factors have also been identified, such as low serum albumin.MethodsThe cohort under study consisted of 299 individuals, 158 men and 141 women, with MGUS, identified through screening the participants of the population-based, longitudinal AGES-Reykjavik Study using serum protein electrophoresis and FLC assessment. The median age was 78 years (range 67-93 years). The outcome was first incidence of lymphoproliferative disorder, denoting multiple myeloma, lymphoma, amyloidosis, lymphocytic leukemia, plasmacytoma, and Waldenström’s macroglubulinemia. Information on outcomes was supplemented by cross-linkage to national registries, and median follow-up time was 8.8 years. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of lymphoproliferative disorders. Results were adjusted for serum albumin in categories (below 35 g/L, 35-40 g/L, or above 40 g/L), M-protein concentration (above or below 15 g/L), FLC ratio, levels of free light chains, use of statins, smoking status, renal function in categories, and M-protein isotype. The multivariate model was reduced in a step-wise manner to a final model with only significant covariates.ResultsDuring follow-up, 26 of 299 individuals with MGUS proceeded to develop a lymphoproliferative disorder, representing a cumulative risk of 8.7% and an annual risk of 1.0%. MM occurred in 17 of 218 individuals with non-IgM MGUS, representing a cumulative risk of 7.8% and an annual risk of 0.9%.In multivariate analysis, the final model contained serum albumin, M-protein concentration, and isotype A versus all other isotypes. Low serum albumin (HR = 6.3, 95% CI 1.0-40.6 for <35 g/L, and HR = 3.9, 95% CI 1.1-14.2 for 35-40 g/L), high M-protein concentration (HR = 4.1, 95% CI 1.2-14.0), and isotype A (HR = 5.8, 95% CI 1.6-21.0) were significantly associated with risk of progression.In a similar model for progression to multiple myeloma only, low serum albumin, high M-protein concentration, and isotype A were also significantly associated with risk of progression, although the impact of low serum albumin was greater (HR = 33.1, 95% CI 2.4-462.2 for <35 g/L, HR = 10.97, 95% CI 1.4-88.3 for 35-40).When assigning a risk score for progression where 1 point each was assigned for isotype IgA, serum albumin <35 g/L, and M-protein concentration >15 g/L, the HRs for individuals with 1 point was 3.9 (95% CI 1.6-9.9), and for 2 points 10.02 (95% CI 2.3-43.3). No individual had 3 points. For Kaplan-Meier estimates from risk scores, see Figure.Summary and conclusionsIn this large, population-based screening study, we found an annual risk of progression from MGUS to lymphoproliferative disease of 1%. Low serum albumin, high M-protein concentration, and M-protein isotype A were all independent risk factors for progression. Our results are in line with results from previous studies where a low serum albumin at MGUS diagnosis also has been associated with shorter survival and/or malignant transformation. Results from our study contradict previous studies that have pointed to skewed FLC ratio as an important risk factor for progression; in our study, a skewed FLC ratio was not significantly associated with risk of progression when adjusted for other covariates. The findings in our study suggest that serum albumin is important to take into account when assessing the risk of progression for individuals with MGUS. [Display omitted] DisclosuresKorde:Medscape: Honoraria. Landgren:Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Medscape Myeloma Program: Honoraria; BMS: Honoraria; Celgene: Honoraria, Research Funding.

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

AbstractThe importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138+ cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138+ cells. Gln-free incubation or treatment with the glutaminolytic enzyme l-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138+ cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.

Dysregulation Of Cyclin D1 Or Activation Of KRAS Accelerate The Development Of Monoclonal Gammopathy and Cooperate To Cause Its Progression

We have previously proposed the dysregulation of the D type cyclins by chromosome translocations to the IgH locus or by not fully characterized mechanisms in hyperdyploid patients as a unifying genetic event in the pathogenesis of Monoclonal Gammopathy of Uncertain Significance (MGUS) and multiple myeloma (MM). However, no experimental data are available to evaluate the direct consequences of cyclin Ds overexpression in plasma cells. Similarly, activating mutations of KRAS have been identified in 15% of MM patients, but never in MGUS, and have been proposed to contribute to the progression of MGUS to MM, but this hypothesis has never been experimentally validated. We evaluated the contribution of CyclinD1 and KRAS to the development and progression of monoclonal gammopathy (MG) that develops spontaneously in C57BL/6 mice. We aged a cohort of EuCCND1 mice, and lslKRASV12 mice crossed to three different CRE expressing mice: IgG1CRE, CD19CRE or Vk* CRE (KRAS/CRE). A cohort of Vk* MYC mice, Vk* MYC x EuCCND1 (MYC/CD1) and triple transgenic mice (CD1/KRAS/CRE) was also analyzed. Mice were bled every 10 weeks beginning at 30 weeks, and the presence of MG was evaluated by serum protein electrophoresis. The median Time To M-Spike (mTTS) detection was 97 weeks in C57Bl/6, 63w in EuCCND1, 54w in KRAS/CRE, 54w in Vk* MYC, 38w in CD1/KRAS/CRE and 36w in MYC/CD1 mice. This indicates that acceleration of the development of MG occurs in all these strain of mice. However, we noticed that the spontaneous MG in C57BL/6 wt, EuCCND1 or KRAS/CRE rarely progresses (as determined by detection of a M-spike >7 g/L), while in the other mouse strains it frequently progresses, with a mTTS >7 g/L around 65w. A clear progression of MGUS to MM was observed only in Vk* MYC mice, and was further accelerated in MYC/CD1 mice, which are characterized by extra-medullary disease and shorter overall survival.In conclusion, these data support our hypothesis that Cyclin Ds dysregulation in plasma cells is the initial transformation step leading to MGUS. Further oncogenic events, like activating mutations of KRAS are required to expand the monoclonal plasma cells. Among the oncogenes examined MYC provides the greatest acceleration of the MG in wildtype and EuCCND1 mice, and results in a disease with the malignant features of MM.▪ Disclosures:No relevant conflicts of interest to declare.

Corrigendum

British Journal of HaematologyVolume 148, Issue 3 p. 491-491 Free Access Corrigendum This article corrects the following: UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M-proteins and the management of monoclonal gammopathy of undetermined significance (MGUS) Jenny Bird, Judith Behrens, Jan Westin, Ingemar Turesson, Mark Drayson, Robert Beetham, Shirley D’Sa, Richard Soutar, Anders Waage, Nina Gulbrandsen, Henrik Gregersen, Eric Low, , Volume 147Issue 1British Journal of Haematology pages: 22-42 First Published online: August 10, 2009 First published: 11 January 2010 https://doi.org/10.1111/j.1365-2141.2009.08048.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat In Bird et al (2009), the normal range for the FLC ratio of Table IX should read 0·26–1·65 and not 0·26–0·65 as stated. The corrected Table IX appears below: Table IX. Proposed risk stratification model. Risk Group No. patients Relative risk 95% CI 20 year risk of progression % 20 year risk accounting for death % Low risk (serum M-protein <15 g/dl, IgG subtype, normal FLC ratio (normal range 0·26–1·65) 449 1 5 2 Low-intermediate risk (any 1 factor abnormal) 420 5·4 21 10 High-intermediate risk (any 2 factors abnormal) 226 10·1 37 18 High risk (all 3 factors abnormal) 53 20·8 58 27 This research was originally published in Blood. Rajkumar, S.V., Kyle, R.A., Therneau, T.M., Melton, L.J. III, Bradwell, A.R., Clark, R.J., Larson, D.R., Plevak, M.F., Dispenzieri, A. & Katzmann, J.A. (2005) Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood, 106, 812–817. © American Society of Hematology. Reference Bird, J., Behrens, J., Westin, J., Turesson, I., Drayson, M., Beetham, R., D’Sa, S., Soutar, R., Waage, A., Gulbrandsen, N., Gregersen, H. & Low, E., Writing group: On behalf of the Haemato-oncology Task Force of the British Committee for Standards in Haematology, UK Myeloma Forum and Nordic Myeloma Study Group (2009) UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M-proteins and the management of monoclonal gammopathy of undetermined significance (MGUS). British Journal of Haematology, 147, 22– 42. Volume148, Issue3February 2010Pages 491-491 ReferencesRelatedInformation

Curcumin for the prevention of progression in monoclonal gammopathy of undetermined significance: A word of caution

A recent pilot study found that curcumin, in certain patients with monoclonal gammopathy of undetermined significance (MGUS), decreases the paraprotein load and the urinary N-telopeptide of type 1 collagen bone turnover marker. While this result is encouraging, the easy availability of the food component turmeric, containing curcumin, may lead to intake by MGUS patients without medical supervision. Curcumin is generally considered safe. Nevertheless, it is known that curcumin inhibits interleukin-12 production in dendritic cells, thereby dampening the Th1 response. It is also well established that Th1 cells are protective against invading pathogens and tumors. The present study describes a case in which bronchitis developed upon turmeric intake for gastrointestinal complaints. While one case does not provide proof of curcumin toxicity, a thorough literature overview suggests that turmeric may have an immunosuppressive effect, notably in patients with a compromised immune system. A warning against the use of turmeric or curcumin without medical supervision in immunocompromised patients seems therefore very opportune. Patients with MGUS, in whom the levels of non-affected immunoglobulins are reduced, should be carefully monitored for toxicity when curcumin is administered.

Prevention of Progression in Monoclonal Gammopathy of Undetermined Significance

Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma. Because myeloma is an incurable malignancy, strategies to delay or prevent progression in high-risk patients are of considerable importance.

New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells

Monoclonal gammopathy of uncertain significance (MGUS) and smoldering multiple myeloma (SMM) are plasma cell disorders with a risk of progression of approximately 1% and 10% per year, respectively. We have previously shown that the proportion of bone marrow (BM) aberrant plasma cells (aPCs) within the BMPC compartment (aPC/BMPC) as assessed by flow cytometry (FC) contributes to differential diagnosis between MGUS and multiple myloma (MM). The goal of the present study was to investigate this parameter as a marker for risk of progression in MGUS (n = 407) and SMM (n = 93). Patients with a marked predominance of aPCs/BMPC (> or = 95%) at diagnosis displayed a significantly higher risk of progression both in MGUS and SMM (P< .001). Multivariate analysis for progression-free survival (PFS) selected the percentage aPC/BMPC (> or = 95%) as the most important independent variable, together with DNA aneuploidy and immunoparesis, for MGUS and SMM, respectively. Using these independent variables, we have identified 3 risk categories in MGUS (PFS at 5 years of 2%, 10%, and 46%, respectively; P< .001) and SMM patients (PFS at 5 years of 4%, 46%, and 72%, respectively; P < .001). Our results show that multiparameter FC evaluation of BMPC at diagnosis is a valuable tool that could help to individualize the follow-up strategy for MGUS and SMM patients.

Detection of four lymphotropic herpesviruses in Hungarian Patients with multiple myeloma and lymphoma

It has been suggested that human herpesvirus 8 (HHV-8), also known as KSHV (Kaposi's sarcoma-associated human herpesvirus), might possess a promoting effect in the development and progression of monoclonal gammopathies. In this study, the presence of Epstein-Barr virus (EBV), human cytomegalovirus (CMV), human herpesvirus 6 (HHV-6) and human herpesvirus 8 (HHV-8) were tested in patients with multiple myeloma (MM) using both serologic and nucleic acid amplification techniques. The transient reactivation or continuous presence of EBV, CMV, HHV-6 and HHV-8 could be detected in, respectively, 36, eight, 13 and 29 of 69 MM patients; nine, one, four and six of 16 monoclonal gammopathy of unknown significance patients; and seven, four, zero and five of 10 Waldenström's macroglobulinemia patients. The total number of MM patients was 95. HHV-8 PCR-positivity was significantly more frequent in the MM group than in the control group of patients with non-Hodgkin's lymphoma (NHL). However, serologic testing did not reveal significant differences between the two patient groups. The number of MM patients with concomitant herpesvirus infections as detected by PCR was as follows: 15 double, seven triple and two quadruple virus nucleic acid positive. In 13/95 MM patients, the simultaneous presence of acute EBV infection and HHV-8 PCR-positivity was detected compared with none of the control group (P=0.009). These results indicate that in addition to HHV-8, the transitional reactivation of EBV may also play a role in the pathogenesis of MM.

Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance

AbstractWe hypothesized that the presence of monoclonal free kappa or lambda immunoglobulin light chains in monoclonal gammopathy of undetermined significance (MGU225), as detected by the serum free light chain (FLC) assay increases the risk of progression to malignancy. Of 1384 patients with MGUS from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 1148. At a median follow-up of 15 years, malignant progression had occurred in 87 (7.6%) patients. An abnormal FLC ratio (kappa-lambda ratio < 0.26 or > 1.65) was detected in 379 (33%) patients. The risk of progression in patients with an abnormal FLC ratio was significantly higher compared with patients with a normal ratio (hazard ratio, 3.5; 95% confidence interval [CI], 2.3-5.5; P < .001) and was independent of the size and type of the serum monoclonal (M) protein. Patients with an abnormal serum FLC ratio, non–immunoglobulin G (non-IgG) MGUS, and a high serum M protein level (≥ 15 g/L) had a risk of progression at 20 years of 58% (high-risk MGUS) versus 37% with any 2 of these risk factors (high-intermediate risk), 21% with one risk factor (low-intermediate risk), and 5% when none of the risk factors were present (low risk).

Presence of an Abnormal Serum Free Light Ratio Is an Independent Risk Factor for Progression in Monoclonal Gammopathy of Undetermined Significance (MGUS).

Background: Monoclonal gammopathy of undetermined significance (MGUS) affects 3% of persons age 50 yrs or greater. Reliable predictors of progression of MGUS to myeloma or related malignancy are needed. We hypothesized that the presence of monoclonal unbound (free) kappa or lambda immunoglobulin light chains in MGUS, as detected by an abnormal serum kappa/lambda free light chain (FLC) ratio would indicate clonal evolution in the neoplastic plasma cell and increase risk of progression to malignancy.Methods: Patients (pts) from Southeastern Minnesota with MGUS seen at the Mayo Clinic from Jan 1, 1960 through Dec 31, 1994 who had baseline serum samples collected and stored at the time MGUS was first recognized were studied. Free kappa and lambda chains were measured using the serum FLC assay (FREELITETM, The Binding Site Ltd).Results: Of 1384 pts with MGUS during the defined time period, baseline serum samples obtained within 30 days of diagnosis of MGUS were available in 1148 pts. At a median follow-up of 15 yrs, malignant progression has occurred in 87 (7.6%) pts: myeloma (53 pts), IgM lymphoma (17), primary amyloidosis (6), macroglobulinemia (6), chronic lymphocytic leukemia (3) and plasmacytoma (2). An abnormal kappa/lamda FLC ratio (kappa/lambda ratio <0.26 or >1.65) indicating presence of monoclonal FLC was detected in 379 (33%) pts. In a Cox proportional hazards model, the risk of progression in pts with an abnormal kappa/lamda FLC ratio was significantly higher (hazard ratio 3.5, 95% CI 2.3–5.5; p<0.001) compared to pts with a normal ratio. After adjusting for the size of the serum monoclonal (M) protein by multivariate analysis, the hazard ratio was only slightly reduced to 2.8, p<0.001. The risk of progression to myeloma or related malignancy at 10 years was 17% with an abnormal kappa/lambda FLC ratio versus 5% with a normal ratio; corresponding rates at 20 years were 35%, and 13%, respectively. MGUS pts with both an abnormal serum FLC ratio and high serum M protein had a risk of progression at 20 years of 46% (high-risk), versus 26% with one of two risk factors (intermediate-risk) and 7% with no risk factors (low-risk) (Table). The true life-time (28 year) risk of myeloma or related malignancy in the low-risk group was only 5.3% when other competing causes of death were taken into account.Conclusions: Presence of monoclonal FLC in the serum as detected by an abnormal kappa/lamda FLC ratio is a major independent risk factor for progression of MGUS to myeloma or a related malignancy. The new risk-stratification identifies a low-risk subset with a remarkably small life-time risk of progression, a finding of significant importance for the management of MGUS.Risk-stratification of MGUS using the size of the serum M spike and free light chain ratioRisk GroupNo. of patientsHazard ratioAbsolute risk of progression at 20 yearsLow-risk (Serum M protein <1.5 gm/dL and normal FLC ratio [0.26–1.65])60617%Intermediate-risk (Either risk factor present)3733.526%High-risk (Serum M protein >/=1.5 gm/dL and abnormal FLC ratio [<0.26 or >1.65])1696.846%