scholarly journals Immunophenotyping in Multiple Myeloma and Others Monoclonal Gammopathies

10.5772/55938 ◽  
2013 ◽  
Author(s):  
Lucie Rihova ◽  
Karthick Raja Muthu Raja ◽  
Luiz Arthur Calheiros Leite ◽  
Pavla Vsianska ◽  
Roman Hajek
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathies

scholarly journals Iodine-based contrast media, multiple myeloma and monoclonal gammopathies: literature review and ESUR Contrast Media Safety Committee guidelines

2017 ◽  
Vol 28 (2) ◽  
pp. 683-691 ◽  
Author(s):  
Fulvio Stacul ◽  
◽  
Michele Bertolotto ◽  
Henrik S. Thomsen ◽  
Gabriele Pozzato ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Literature Review ◽  
Contrast Media ◽  
Monoclonal Gammopathies ◽  
Safety Committee

scholarly journals Characteristics of MGUS and Multiple Myeloma According to the Target of Monoclonal Immunoglobulins, Glucosylsphingosine, or Epstein-Barr Virus EBNA-1

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1254 ◽  
Author(s):  
Adrien Bosseboeuf ◽  
Nicolas Mennesson ◽  
Sophie Allain-Maillet ◽  
Anne Tallet ◽  
Eric Piver ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Epstein Barr Virus ◽  
Mild Form ◽  
Chronic Stimulation ◽  
Monoclonal Gammopathies ◽  
Barr Virus ◽  
Smoldering Multiple Myeloma ◽  
Monoclonal Immunoglobulins ◽  
Epstein Barr ◽  
Undetermined Significance

Chronic stimulation by infectious or self-antigens initiates subsets of monoclonal gammopathies of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM). Recently, glucosylsphingosine (GlcSph) was reported to be the target of one third of monoclonal immunoglobulins (Igs). In this study of 233 patients (137 MGUS, 6 SMM, 90 MM), we analyzed the GlcSph-reactivity of monoclonal Igs and non-clonal Igs. The presence of GlcSph-reactive Igs in serum was unexpectedly frequent, detected for 103/233 (44.2%) patients. However, GlcSph was targeted by the patient’s monoclonal Ig for only 37 patients (15.9%); for other patients (44 MGUS, 22 MM), the GlcSph-reactive Igs were non-clonal. Then, the characteristics of patients were examined: compared to MM with an Epstein-Barr virus EBNA-1-reactive monoclonal Ig, MM patients with a GlcSph-reactive monoclonal Ig had a mild presentation. The inflammation profiles of patients were similar except for moderately elevated levels of 4 cytokines for patients with GlcSph-reactive Igs. In summary, our study highlights the importance of analyzing clonal Igs separately from non-clonal Igs and shows that, if autoimmune responses to GlcSph are frequent in MGUS/SMM and MM, GlcSph presumably represents the initial pathogenic event for ~16% cases. Importantly, GlcSph-initiated MM appears to be a mild form of MM disease.

The Biologic and Analytic Variability of Serum Protein Electrophoresis M-Spike, Nephelometric Ig Quantitation, Serum FLC Quantitation, and Urine M-Spike in Monoclonal Gammopathies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1803-1803
Author(s):  
Melissa Snyder ◽  
Angela Dispenzieri ◽  
S.Vincent Rajkumar ◽  
Robert Kyle ◽  
Joanne Benson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Serum Protein ◽  
Protein Electrophoresis ◽  
Serum Protein Electrophoresis ◽  
Monoclonal Gammopathies ◽  
Number Of Patients ◽  
Measurable Disease ◽  
M Spike ◽  
Serial Samples ◽  
Serum And Urine

Abstract Abstract 1803 Poster Board I-829 Background Plasma cell proliferative disorders are monitored by a variety of methods. Serum protein electrophoresis (SPEP) and/or urine PEP M-spike quantitation are commonly assessed in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) to determine disease progression, response, or relapse. Serum immunoglobin (Ig) concentrations can be quantitated when the M-spike is large or if the migration is obscured within the SPEP beta fraction. Serum FLC quantitation provides a rapid indicator of response, will detect the rare occurrence of FLC escape, and will allow disease monitoring in the absence of a measurable serum or urine M-spike. The International Myeloma Working Group (IMWG) has recommended that the serum and urine M-spike should be used to monitor disease, and that FLC quantitation should be used only if there is no measurable disease by electrophoresis and if the monoclonal FLC concentration is greater than 10 mg/dL in the context of an abnormal FLC K/L ratio. We have studied serial samples in clinically stable patients in order to assess the total variability (analytic and biologic) of these assays and to confirm the IMWG recent recommendations. Methods Serial data from stable MGUS patients (n=35) were identified by the availability of all 3 serum test results (M-spike, Ig, FLC) in at least 4 serial samples that were obtained 9 months to 5 years apart and whose serum M-spikes varied by less than 25%. For MM (n=60) and SMM (n=48) the samples were within 9-15 months and serum M-spikes varied by less than 0.5 g/dL. Among the 60 MM, 48 SMM, and 35 MGUS patients, there were 23, 41, and 18 patients with measurable disease by serum M-spike (i.e. M-spike >1 g/dL); 19, 10, and 10 patients with an evaluable FLC (i.e. monoclonal FLC > 10 mg/dL and an abnormal FLC ratio); and 5, 5, and 1 patient with an evaluable urine (i.e. M-spike > 200mg/24 hr). The FLC data was analyzed as the involved FLC concentration (iFLC), the difference between the involved and uninvolved FLC concentration (dFLC), and the FLC K/L ratio (rFLC). The coefficients of variability (CV) were determined for each methodology in each patient sample set, and the average CVs were determined. Igs were quantitated by immunonephelometry using a Siemens BNII and Siemens reagent sets; kappa and lambda FLC were quantitated using a Siemens BNII and Freelite reagent sets from The Binding Site; M-spikes were quantitated using Helena SPIFE SPE and reagent sets. Results The CVs for the Ig quantitation, SPEP M-spike, FLC quantitation, and urine M-spike in each of the patient groups are listed in the table: Our laboratory's interassay analytic CV for replicate samples are 4-5% for Ig quantitation, 6-8% for SPEP M-spikes, 6-7% for FLC quantitation, and 5-7% for urine M-spikes. The analytic CVs of the methods are similar, but the total (analytic + biologic) CVs are very different. The samples have been selected by restricting the variability of serum M-spike values; when we apply the same criteria to the IgG quantitation, the IgG total CV comes closer to the serum M-spike CVs. The remaining differences, however, may be due to biologic variability contributed by polyclonal Ig. The total CV for iFLC is similar to the urine M-spike CV and suggests a previously unrecognized large biologic CV for serum FLC. The iFLC and dFLC CVs were comparable but were smaller than the rFLC CV. Conclusion The variability of the serum and urine M-spike, Ig, and FLC measurements confirm the IMWG recommendations for patient monitoring. If a patient has a measurable M-spike >1 g/dL, then the serum M-spike should be followed. If there is no measurable disease, then the iFLC can be monitored, provided that the rFLC is abnormal and the iFLC concentration is >10 mg/dL. Although the number of patients with evaluable urine M-spikes in this study is small, larger studies may confirm the utility of serum FLC compared to urine M-spike for monitoring patients with monoclonal gammopathies. Disclosures No relevant conflicts of interest to declare.

High Frequency of Monoclonal Immunoglobulins Exhibiting Natural Autoantibody-Like Activity in Patients with Multiple Myeloma and Waldenström Macroglobulinemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2893-2893
Author(s):  
Peggy Lymberi ◽  
Evangelos Terpos ◽  
Aikaterini Hatzioannou ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
Apostolos Balafas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Carbonic Anhydrase ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Significant Proportion ◽  
Similar Proportion ◽  
Antibody Activity ◽  
Monoclonal Gammopathies ◽  
High Incidence ◽  
Monoclonal Immunoglobulins

Abstract Abstract 2893 Serum monoclonal immunoglobulins (M-Igs) of patients with monoclonal gammopathies are known to possess antibody activity against autoantigens, bacterial antigens and haptens, but their incidence is controversial. So far, high incidence of autoantibodies (autoAb) have been demonstrated against actin, Ro/SS-A and La/SS-B for M-Igs of all three classes (IgG, IgA, IgM) and against Fc fragment of IgG and the Ii group exclusively for IgM M-Ig. Other less frequent antiboby specificities of M-Igs include anti-myosin, anti-tubulin, anti-thyroglobulin and anti-DNA. M-Igs with anti-actin activity were found to express polyreactivity, which is a property of natural autoAbs (NAbs). NAbs are germ-line encoded, occur in all species, circulate in low concentrations and belong to all Ig classes. NAbs play important immunoregulatory role and anti-F(ab')2 reactivity is crucial for the establishment of the idiotypic network. The aim of this study was to investigate the frequency of human M-Igs that exhibit NAb-like activity in patients with monoclonal gammopathies and to explore possible correlations with their clinical features. Thus, 151 M-Igs (124 of IgG class: 71IgG-kappa/53 IgG-lambda and 27 of IgA class: 16 IgA-kappa/11 IgA-lambda) from patients with symptomatic multiple myeloma (MM; n=136), asymptomatic MM (n=8) or MGUS (n=7) and 50 M-Igs from patients with Waldenström Macroglobulinemia (WM) or IgM-MGUS (43 IgM-kappa and 7 IgM-lambda), without any autoimmune diseases, were studied by an in-house ELISA for polyreactivity against six autoantigens (native DNA, actin, tubulin, myosin, carbonic anhydrase, thyroglobulin) and the non-self hapten TriNitroPhenyl (TNP). Sera were also tested for antibody activity against F(ab')2 fragment of human polyclonal IgGs. Most of these antigens are known targets of NAbs. Sera were first screened with enzyme-coupled human heavy chain antibodies (anti-G, anti-M and anti-A), and reactivity–with the exception of anti-F(ab')2–was further attributed to the M-Ig using enzyme-coupled light chain antibodies (anti-kappa and anti-lambda). A significant proportion (18.2%: 35/192 evaluated patients) of pathological sera exhibited anti-F(ab')2 activity (27 from IgG-MM, 3 from IgA-MM and 5 from WM patients). Among the total M-Igs tested, 9.5% (18/189) recognised actin, 8.7% (17/194) carbonic anhydrase, 4.6% (9/194) thyroglobulin, 3.7% (7/186) TNP, 3.5% (7/196) tubulin, 2.5% (5/193) myosin and 1.5% (3/188) DNA. M-Igs reacting with actin, carbonic anhydrase, tubulin, myosin and TNP were found to belong to all three Ig classes (IgG, IgA, and IgM). Among the IgG M-Igs tested, the most frequent reactivity was that for thyroglobulin (7.6%), while among the IgA and IgM M-Igs the highest incidence observed was for actin and carbonic anhydrase (23%, 23% and 16.6%, 15.2%, respectively). Positive IgM and IgG M-Ig had either kappa or lambda light chain in a similar proportion, while positive IgA were mostly IgA-lambda (16/18). A high percentage of positive M-Igs from MM and WM patients were polyreactive (46%), i.e., reacted with at least two panel antigens. Polyreactivity was a prominent characteristic of IgA (6/6) and IgM (9/13) but not of IgG (6/36) M-Ig. Most frequent polyreactivity profile was that for actin, carbonic anhydrase and TNP. There was no significant correlation of immune-related features of symptomatic WM (immune cytopenias, cold agglutinin disease, cryoglobulinemia) or of MM characteristics (ISS, CRAB, LDH, plasma cell infiltration) with any of the detected M-Ig specificities or their NAb-like profile. In conclusion, we report for the first time anti-carbonic anhydrase and anti-TNP activity of the M-Igs from patients with monoclonal gammopathies. We also report high incidence of anti- F(ab')2 activity in the sera of these patients as well as of polyreactive M-Igs. Our findings suggest that the M-Igs with NAb activity might reflect the expansion of a clone normally producing a NAb. To-date, it has been assumed that a naive B-cell is first driven to clonal expansion by antigenic stimulation and that subsequently, an oncogenic stimulus results in malignant transformation. Assuming that certain malignant monoclonal gammopathies arise from the proliferation of a clone normally producing a NAb which recognise F(ab')2 and hence is probably involved in the regulation of the NAbs network, it may also be postulated that this may result in deregulation of this network. Disclosures: No relevant conflicts of interest to declare.

Cancer/Testis Antigens MAGE-C1/CT7 and MAGE-C2/CT10 Are Expressed in 90% of Multiple Myeloma Samples and Can Be Explored in Combined Immunotherapy for This Malignancy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4974-4974
Author(s):  
Fabricio de Carvalho ◽  
Veruska Lia ◽  
Fook Alves ◽  
Walter Moisés ◽  
Tobias Braga ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune Responses ◽  
Plasma Cell ◽  
Conflicts Of Interest ◽  
Staging System ◽  
Cytotoxic T Cell ◽  
Malignant Neoplasms ◽  
Rt Pcr ◽  
Monoclonal Gammopathies ◽  
International Staging System

Abstract Abstract 4974 Background: Multiple Myeloma (MM) is a malignant proliferation of B-cells with plasma cell differentiation. Vaccines formulated with antigens associated with myeloma cells can instruct the immune system to eliminate malignant cells. Can/Testis Antigens (CTAs) tumor-associated antigens are identified in several human malignant neoplasms and in normal testis, fetal ovary and trophoblast cells. MAGE CTA genes are recognized by CTL (cytotoxic T cell) and are strictly tumor-specific. MAGE-C1/CT7 and MAGE-C2/CT10 are highly immunogenic and both CTAs have been previously shown in various human tumors, suggesting its potential role to evoke both humoral and cellular immune responses. Objective: We evaluated MAGE-C1/CT7 and MAGE-C2/CT10 expression in bone marrow (BM) aspirates collected from patients with MM, solitary plasmacytomas, MGUS (monoclonal gammopathy of undetermined significance) and normal controls to evaluate potential combination of CTA genes for immunotherapy in this disease by RT-PCR (reverse transcription-polymerase chain reaction). Material and Methods: BM aspirates from 20 MM patients [30% ISS (International Staging System) stage 1–2 and 70% stage 3], five solitary plasmacytomas, four MGUS and five normal BM aspirates. RNA was prepared from total BM aspirates using TRIzol, followed by synthesis of cDNA with SuperScript III, according to the manufacturer's instructions. MAGE-C1/CT7 and MAGE-C2/CT10 were analyzed by RT-PCR and 2% agarose gel electrophoresis and visualized by Sybr Safe. Results: MAGE-C1/CT7 was positive in 75% (15/20) and MAGE-C2/CT-10 in 70% (14/20) of MM cases. In 11 out of 20 MM cases (55%), both CTAs were positive and in 18 out of 20 samples (90%) the expression of at least one of the genes could be detected by RT-PCR. In the other monoclonal gammopathies (solitary plasmacytomas and MGUS), MAGE-C1/CT7 and MAGE-C2/CT10 were expressed in at least one of the analyzed cases. All BM aspirates collected from healthy donors were negative for both CTAs evaluated, showing restricted expression of these genes in monoclonal gammopathies. Considering the International Staging System (ISS), the data show that expression of both CTA genes were widely expressed in MM samples studied, independently on the stage of disease. Conclusions: These findings suggest that both MAGE-C1/CT7 and MAGE-C2/C10 CTA genes can have a biological role in MM distinct clinical phases and maybe contribute to malignant plasma cell development. The high frequency found in MM patients suggests that the subfamily of MAGE-C has a role on the development of myeloma. Although the function of these genes is still poorly understood, several studies have shown that MAGE-C1/CT7 and MAGE-C2/CT10 genes are able to elicit spontaneous immune responses; therefore they can be considered potential targets for cell therapy in this incurable disease. Disclosures: No relevant conflicts of interest to declare.

Plasma Circulating Proteasomes As Biomarkers Along Natural History Of Asymptomatic Monoclonal Gammopathies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3133-3133 ◽  
Author(s):  
Carlos Fernández de Larrea ◽  
Adriana Zingone ◽  
Elisabet E. Manasanch ◽  
Neha Korde ◽  
Peter Wu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Mayo Clinic ◽  
M Protein ◽  
Current Time ◽  
Monoclonal Gammopathies ◽  
Chymotrypsin Activity ◽  
Healthy Donors

Abstract Background Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic plasma cell dyscrasias with a heterogeneous probability to progress to symptomatic multiple myeloma (MM). Reliable markers for progression to MM are vital to advance the understanding of myeloma precursor disease and for the development of intervention trials designed to delay/prevent MM. The Mayo Clinic and Spanish PETHEMA have proposed models to stratify patient risk based on clinical parameters. At the current time, no molecular biomarkers have been established to determine risk of transformation. Based on the fact that MM tumor cells are highly sensitive to proteasome inhibition and that circulating proteasomes (cProt) have been detected in the blood of MM patients, we conducted a prospective clinical study designed to characterize patterns of cProt in peripheral blood from MGUS, SMM and MM patients. Patients and Methods Ninety two patients diagnosed with asymptomatic monoclonal gammopathies (39 MGUS and 53 SMM; median age 63 years; 46M/47F) were studied. This group was compared to normal sera from healthy donors (n=6) and untreated patients with recent diagnosed MM (n=38). Initial baseline demographics, clinical and laboratory data were collected. MGUS patients were classified according to Mayo Clinic risk score (M-protein, monoclonal isotype and serum FLC), while SMM could be stratified according to PETHEMA (malignant bone marrow plasma cell (BMPC) percentage and immunoparesis) and Mayo system (BMPC infiltration, serum M-protein and serum FLC). Plasma and bone marrow supernatant samples were collected at diagnosis and frozen to -80ºC. In 58 MGUS and SMM cases, sequential plasma samples at 6 months and 1 year were also analyzed. Chymotrypsin-like, caspase-like, and trypsin-like activities from cProt were assayed by continuously monitoring the production of 7-amino-4-methylcoumarin (AMC) from fluorogenic peptides by plasma. Briefly, samples were activated with SDS (for chymotrypsin-like and caspase-like) or 10% Tween-20 (for trypsin-like). The reaction wells contained 30 μL assay buffer (25 mmol/L HEPES), 10 μL activated sample, and 10 μL of the prospective fluorogenic peptide-AMC substrate. To measure the fluorescence release of free AMC with time, the SpectraMax M5 (Molecular Devices) instrument was used with a read interval of 1 min during 30 min at 37ºC. All samples were performed by triplicate. Enzymatic activities were quantified (pmol AMC/s/mL plasma) by generating a standard curve of AMC. Results MGUS patients had zero (38.5%), one (41%) or two risk factors (20.5%) according to the Mayo Clinic model. In contrast, 49% of the patients with SMM were classified as high-risk according to the PETHEMA model, versus 69.8% with 2 or 3 risk factors in the Mayo Clinic model. Chymotrypsin activity levels in plasma were statistically correlated with serum M-protein concentration and total IgG concentration (p<0.001). Chymotrypsin-like activity was differentially expressed in plasma across the different groups of patients (p=0.009; Figure 1). Particularly, SMM and MM showed higher levels than healthy controls and MGUS patients. In SMM, patients with highest-risk of transformation showed a higher levels of this chymotrypsin-like activity than the other groups (p=0.02). When only IgG SMM and MGUS patients were considered, a correlation with immunoparesis (reduction of IgM and IgA), BMPC infiltration, relative lower hemoglobin levels and higher FLC ratio (p<0.05) was observed. Caspase-like activity was also associated with diagnosis, showing higher levels in symptomatic and SMM patients than healthy donors and MGUS (p=0.016) (Figure 2) and correlated with IgG and serum M-protein (p=0.01 and p=0.006). In contrast, trypsin-like levels were negatively correlated along the spectrum of tumoral mass in the four groups (p=0.004) (Figure 3). Bone marrow supernatant chymotrypsin activity was higher in symptomatic MM than MGUS patients (p=0.004), with a trend for caspase. Conclusion Chymotrypsin-and caspase-like activity of circulating proteasome in asymptomatic gammopathies is related to tumoral mass and immunoparesis degree. MGUS patients are close to healthy individuals, with SMM not so different than symptomatic patients. Prognostic significance of these findings after longer follow-up is warranted. Disclosures: No relevant conflicts of interest to declare.

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