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.

Serum Versus Urine Free Light Chains for Assessment of Monoclonal Gammopathies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5307-5307
Author(s):  
Montgomery Lobe ◽  
Donald Pasquale
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Medical Center ◽  
Statistical Significance ◽  
Serum Immunoglobulin ◽  
Light Chains ◽  
Total Serum ◽  
Free Light Chains ◽  
Monoclonal Gammopathies

Abstract Introduction Monoclonal gammopathies comprise a spectrum of disorders including Monoclonal Gammopathy of Undetermined Significant (MGUS), Smoldering Multiple Myeloma (SMM), and Active Multiple Myeloma (MM) characterized by production of monoclonal immunoglobulin heavy and/or light chains. Prior to availability of the FREELITE™ (Binding Site Ltd; Birmingham, UK) assay for measurement of immunoglobulin free light chains (FLC), laboratory monitoring of these disorders used predominantly SPEP, quantitation of immunoglobulin heavy chains (quantitative immunoglobulins), and 24 urine collection for total protein and UPEP to extrapolate production of immunoglobulin light chains. The FREELITE™ assay has up to 3-log increased sensitivity (1.5-3.0 mg/L) for detection of free light chains over standard electrophoresis (500-2,000 mg/L) and immunofixation (150-500 mg/L), and since its introduction, has been an integral tool in diagnosis and monitoring of monoclonal gammopathies. This assay detects more plasma cell disorders than SPEP, UPEP and IFE combined due to its higher sensitivity and ability to derive the ratio of affected to unaffected light chain. Measurement of urine FLC using FREELITE™ has not been integrated into standard practice due to presumed variability in FLC concentration due to changes in glomerular filtration, variability in tubular reabsorption of light chains, and lack of data regarding this use. In our practice, we routinely use random urine samples instead of 24 hour urine collections which are cumbersome and suffer from poor patient compliance. Methods: The study was approved by the Stratton VA Medical Center Institutional Review Board. As it has been our practice to obtain both random urine along with serum for FLC, we retrospectively reviewed patients diagnosed with monoclonal gammopathies and compared random urine free light chains measured by FREELITE™ to serum FLC and serum quantitative immunoglobulins. Data was analyzed for correlation using Pearson product moment correlation. P values of >0.05 were considered significant. Results: We identified 23 individuals, all male (consistent with VA population). Mean (±SD) age was 68±10 years at diagnosis, creatinine 1.3±0.5 mg/dl, and 9±6 pairs of data points per patient. Five (5) had MGUS, 5 SM, and 13 MM (2 light chain only). Results are illustrated in the Table. Normalization of urine results using concurrent serum and urine creatinine did not change the statistical significance of any of the results. Table. Correlation (p<0.05) between affected serum immunoglobulin, urine FLC, and serum FLC Serum Immunoglobulin Urine FLC Serum FLC #(%) of Patients YES YES no 2(10) YES no YES 6(29) YES YES YES 5(24) No no no 7(33) YES YES 11(48) Discussion While serum FLC is adequate in the majority of patients for monitoring monoclonal gammopathies, urine FLC correlates as well as serum FLC in about ½ of the patients. In addition, in a small number of individuals, urine FLC correlates with serum total serum immunoglobulin better than serum FLC. We feel that random urine FLC is useful for monitoring monoclonal gammopathies, and in a minority of instances, provides more accurate assessment of disease activity than serum. Disclosures No relevant conflicts of interest to declare.

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.

Improving Outcomes in Patients with Renal Failure Secondary to Multiple Myeloma: Results From ChAR2M2.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1875-1875
Author(s):  
Colin Hutchison ◽  
Parisa Airia ◽  
Mark Cook ◽  
Daniel Grima
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Side Effects ◽  
Light Chain ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Treatment Patterns ◽  
Free Light Chain ◽  
High Rate ◽  
Sustained Reduction

Abstract Abstract 1875 Poster Board I-900 Study purpose: To explore how free light chain (FLC) removal by high cut-off haemodialysis (HCO-HD) has been adopted into clinical practice for the management of renal failure secondary to multiple myeloma. Describing treatment patterns and the laboratory and clinical outcomes associated with its use. Methods: A chart audit of patients treated with FLC removal by HCO-HD, using the Gambro HCO 1100 dialyser, was performed in 16 dialysis centers across 9 countries. Patient demographics, treatment patterns and dialysis side-effects were recorded. In addition, the following outcomes were measured: dialysis independence and reductions in serum FLCs concentrations at 12 and 21 days. Results: Data for 66 patients was entered. Patients had an average age of 65.1 (SD×10.1); 42 of them (63.64%) were male and 24 (36.36%) were female. Sixteen (24%) presented with relapsing myeloma and 50 (76%) had de novo disease. On average, each patient received 13 HCO-HD sessions (SD×8). Forty-one patients became dialysis independent (62.12%), after an average of 12 sessions. Dialysis related side-effects were reported in 6% of all patients. Forty patients (60.61%) were reported to have a sustained reduction in serum FLC concentrations by day 12. By day 21 this had increased to forty-one (62.12%). Among the patients who achieved a sustained reduction in serum FLC concentrations, 28 (70%) had a decline in FLC levels of more than 50% by day 12 and 34 (82.93%) by day 21. Among patients who achieved sustained reduction of more than 50% in serum FLC concentrations by day 12, 75% became dialysis independent. In comparison only 53% of those with a reduction of less than 50% became dialysis independent (p×0.007). Furthermore, among patients who achieved sustained FLC reduction of greater than 75%, 81% became dialysis independent. The rate of dialysis independence was also significantly higher in patients with de novo disease compared with those with relapsing myeloma (64% versus 56%, p×0.04). Conclusion: Free light chain removal by HCO-HD was well tolerated and associated with a very high rate of dialysis independence in patients with renal failure secondary to multiple myeloma. Rates of renal recovery were greater in patients with de novo myeloma and those who achieved an early reduction in serum FLC concentrations. Disclosures: No relevant conflicts of interest to declare.

Efficacy of Lenalidomide-Based Regimens in Multiple Myeloma Complicated by Extramedullary Plasmacytomas at Relapse or Progression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4952-4952 ◽  
Author(s):  
Jose Manuel Calvo-Villas ◽  
Adrian Alegre ◽  
Ricarda García-Sánchez ◽  
Miguel T Hernández ◽  
Pilar Giraldo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Bone Lesions ◽  
Complete Disappearance ◽  
Toxicity Profile ◽  
Small Series ◽  
Extramedullary Plasmacytomas

Abstract Abstract 4952 Background Current clinical observations on extramedullary myeloma (EM) are based on small series of relapsed myeloma patients (pts) and, in this situation, results suggest that the disease course is often aggressive. Among novel therapies for extramedullary involvement, thalidomide has provided poor results and bortezomib is emerging as a possible useful drug. The role of lenalidomide for treatment of multiple myeloma (MM) with EM is still under investigation. Aim A multicenter retrospective study was performed by PETHEMA (Spanish Myeloma Group, Spain) to evaluate the response rate and toxicity profile of lenalidomide-based regimens in myeloma patients with extramedullary involvement at relapse or progression. All the cases were evaluated for response of MM and improvement of extramedullary plasmacytoma. Patients and Methods From October 2007 to March 2009, thirteen patients (median age 67 years; range 61–87; 7 females) treated with lenalidomide-containing regimens were recorded. Patients with bone disease without extramedullary manifestations were excluded. Response of MM was evaluated according to the new international criteria and the response of EM by measuring size changes by physical examination, CT scans and/or MR imaging. Adverse events were graded based on the WHO toxicity scale. The M-protein type was IgG in 7 cases, IgA in 5 and light chain in 1. The type of light chain was κ in 7 pts and l in 6. In eight patients the soft-tissue plasmacytomas may have developed from underlying bone lesions [(skull (n=2), rib cage (n=4) and paravertebral (n=2)], two patients had subcutaneous nodules and three had visceral involvement (liver (n=1), lung and kidney (n=1) and pleura (n=1). Multiple localizations were present in 4 pts (30.7%). Six cases (79.6%) received previous antimyeloma treatment for EM before lenalidomide therapy and the incidence of prior bone plasmacytomas was 61.5%. Median time from initial antimyeloma therapy to treatment with lenalidomide was 34 months (range 5 - 115). Median number of prior lines of chemotherapy regimens was 3 (range 1 – 4), including autologous stem cell transplantation in 2 pts, bortezomib-containing regimens in 12 (92.3%) and previous exposure to thalidomide in 1 patient. Ten pts received standard lenalidomide dose (25 mg/day every 4 weeks) plus dexamethasone (40 mg/d PO ranging from 1 to 12 doses/cycle) every 3-week; and three patients received lower doses of lenalidomide and/or different schedules. Involved-field radiotherapy was given in 2 cases. Thirty percent of patients required lenalidomide dose reduction, because of toxicity or intolerance. Results Median duration of lenalidomide treatment was 3.6 months (1 – 15). One case was not evaluable for response because of death from disease progression after one cycle. In nine out of twelve evaluable patients (75%), MM responded to lenalidomide regimens according to EBMT criteria. Three (25%) achieved complete response, five (41.6%) partial response and 1 (8.3%) minimal response. Median time to response was 63 days (range 37 – 180). Regarding EM, nine patients showed response in the size of extramedullary plasmacytomas. Seven (58.3%) achieved complete disappearance of EM and two pts reduction of the size. Response of EM was also achieved in 75% of pts previously exposed to bortezomib, and in 4/9 cases who received therapies for prior extramedullary involvement. Median follow-up period was 6.3 months (1 – 15.8). Median overall survival from the start of lenalidomide therapy was 4.7 months. At the time of analysis, seven patients were still on therapy, and ten (76.9%) were alive. Only one out of the 9 patients who had achieved a response has relapsed so far. Toxicity profile (grade 3/4) was: thrombocytopenia, 4 (30.7%); anemia, 2 (15.3%); neutropenia, 5 (46.4%); neutropenic fever, 1 (7.6%) and others, 3 (11.8%). No deep venous thrombosis (DVT) was reported. Thrombosis prophylaxis was used in most cases (92%) patients. Conclusions We report one of the first investigations specifically evaluating the activity of lenalidomide on EM. Lenalidomide-containing regimens could be an alternative promising approach to achieve clinical response in heavily treated MM patients with extramedullary disease. The duration of response and the best regimen or combination are at present unknown. These preliminary observations require further analysis and longer follow-up. 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.

Bortezomib with Dexamethasone in Newly Diagnosed Patients with Primary Systemic Light Chain Amyloidosis or Multiple Myeloma-Associated AL Amyloidosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5036-5036 ◽  
Author(s):  
Beihui Huang ◽  
Juan Li ◽  
Junru Liu ◽  
Dong Zheng ◽  
Mei Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Hematologic Response ◽  
Best Response ◽  
Organ Response

Abstract Abstract 5036 Objective: To assess the efficacy and tolerability of bortezomib with dexamethasone for patients with primary systemic light chain (AL) amyloidosis or multiple myeloma-associated AL amyloidosis. Methods: Twelve newly diagnosed patients with primary systemic AL amyloidosis and six patient with multiple myeloma-associated AL amyloidosis were treated with a combination of bortezomib (1. 3 mg/m2 d1, 4, 8, 11) and dexamethasone (20 mg d1–4). Results: Sixteen patients was evaluable. 12/16 had a hematologic response and 6/16 (37. 5%) a hematologic complete response. Median cycles to response was 1 cycle and median cycles to best response was 2 cycles. In patients with primary AL amyloidosis, 8/10 (80. 0%) had a hematologic response and 5/10 (50. 0%) a hematologic complete response. In patients with myeloma-associated AL amyloidosis, 7/10 (70. 0%) had a hematologic response and 1/6 (16. 7%) a hematologic complete response. Twelve patients (75. 0%) had a response in at least one affected organ, in which 7 in patients with primary AL amyloidosis and 5 in myeloma-associated AL amyloidosis. Person correlation between hematologic response and organ response was 0. 667 (p=0. 005). Fatigue, diarrhea and infection were the most frequent side effects. Three patients developed herpes zoster and had to stop chemotherapy. Conclusions: VD produces rapid and high hematological responses in the majority of patients with newly diagnosed AL regardless of primary or associated with myeloma. It is well tolerated with few side effects. This treatment may be a valid option as first-line treatment for newly diagnosed patients with primary systemic AL amyloidosis and multiple myeloma-associated AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

Not All Polyps Are Created Equal: Multiple Myeloma in the Gut

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5602-5602
Author(s):  
Divya Akella ◽  
Fnu Aparna ◽  
Marijeta Pekez ◽  
Nirmala S. Nathan ◽  
Hemchand Ramberan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Light Chain ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Correct Diagnosis ◽  
Colonic Polyps ◽  
Immunohistochemical Analysis ◽  
Recurrent Bleeding ◽  
Dexamethasone Therapy

Abstract Background: Multiple myeloma is a neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin usually restricted to the bone marrow. Recent literature confirms increased extramedullary involvement of skin, liver and lymph nodes but gastrointestinal multiple myelomas remain rare. Case: We report a case of 57-year-old female with a past medical history of progressive multiple myeloma IgA lambda on elotuzumab, lenalidomide and dexamethasone therapy, who presented with generalized weakness and black stools for approximately one week. Initial laboratory work demonstrated a hemoglobin of 6.7 grams per deciliter and heme positive stools consistent with anemia secondary to presumed gastrointestinal blood losses. Esophagogastroduodenoscopy (EGD) was unremarkable. Colonoscopy revealed 6 colonic polyps scattered throughout the distal transverse, cecal and descending colon which were excised and sent for pathology. Pathology of the polyps showed plasma cell myeloma with anaplastic features. Immunohistochemistry demonstrated cells that were positive for CD-138 and negative for keratin staining, confirming plasma cell origin. Furthermore analysis was positive for lambda light chain, but negative for kappa light chain. The patient was managed with packed red cell transfusion with no further evidence of recurrent bleeding. Conclusion: Gastrointestinal multiple myeloma are rare, but as our case demonstrates, they must be considered in the differential diagnosis of patients with gastrointestinal bleeding, particularly those with multiple myeloma. The endoscopic appearance of multiple myeloma polyps may be similar to other more common conditions, making pathological and immunohistochemical analysis of biopsies essential for making a correct diagnosis. Disclosures No relevant conflicts of interest to declare.

Hevylite™ Assays Detect a Hidden Immunoparesis Associated with Adverse Biology in Myeloma Precursor Disease: A Prospective Clinical Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5065-5065
Author(s):  
Rene Costello ◽  
Karina Espana ◽  
Neha Korde ◽  
Mary Kwok ◽  
Adriana Zingone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prospective Study ◽  
Heavy Chain ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Prospective Clinical Study ◽  
Biological Features ◽  
Increased Risk ◽  
M Spike

Abstract Abstract 5065 Recent studies have found immunoparesis (suppression of an uninvolved heavy-chain immunoglobulin (Ig) isotype; e.g. low quantitative IgA and/or IgM levels in a patient with an IgG M-spike) to be an independent risk factor for transformation from smoldering multiple myeloma (SMM) to multiple myeloma (MM). About 70–80% of SMM patients have evidence of immunoparesis. Among remaining 20–30% of SMM patients without immunoparesis, it is currently unknown whether there could be a hidden immunoparesis, reflected in suppression of the uninvolved light chain counter part of the same heavy-chain Ig isotype (e.g. IgG kappa in a patient with an IgG lambda M-spike), which in turn may be associated with adverse biology. A total of 50 SMM patients were enrolled in the first analysis of this prospective study (target: 124 SMM patients). At baseline, a bone marrow core biopsy/aspirate was conducted, and comprehensive immunohistochemistry and flow cytometry analyses were done to confirm the diagnosis and to generate risk profile data for individual patients. For each patient we obtained peripheral blood at baseline. Using serum, we performed the following clinical analyses: serum protein electrophoresis (SPEP); immunofixation electrophoresis (IFE); serum free light chains (sFLC); and quantitative Ig levels for IgG, IgA, and IgM. Using the Hevylite™ assay on a SPAplus (Specialty Protein Analyzer) platform, for each patient, we measured the heavy-light chain (HLC) protein pairs for the complete pair of the patient's heavy-chain Ig isotype (e.g. IgG kappa and IgG lambda for a patient with an IgG M-spike). Consistent with the literature; overall, we found 32/50 (64%) SMM patients to have immunoparesis of an uninvolved heavy-chain Ig isotype; 31 (97%) of these patients also had suppression of the uninvolved HLC counterpart. Among remaining SMM patients without immunoparesis of an uninvolved heavy-chain Ig isotype, using the Hevylite™ assay we found 8/18 (44%) to have a hidden immunoparesis of the uninvolved HLC counterpart. Compared to SMM patients without any type of Ig suppression, adverse biological features were profound in patients with a hidden immunoparesis of the uninvolved HLC counterpart. For example, the FLC-ratios were more skewed (mean: 14.2 vs. 2.5), the distribution of abnormal/normal plasma cells was more pronounced (90.1% vs. 80.3%), the concentration of the M-spike was higher (1.4 g/dL vs. 1.0 g/dL), and the plasma cell percentage in the bone marrow was higher (15.1% vs. 11.9%). In conclusion, using the Hevylite™ assay we identified, for the first time, among SMM patients without immunoparesis, a hidden immunoparesis of the uninvolved HLC counterpart, associated with adverse biological features. Our ongoing prospective study will evaluate whether immunoparesis of the uninvolved HLC counterpart is associated with an increased risk of progression to MM. Disclosures: No relevant conflicts of interest to declare.

No Recurrent Mutation of SF3B1, U2AF1 and SRSF2 Spliceosomal Gene in Multiple Myeloma but Polymorphisms of These Genes Are Associated with the Prediction of Worse Prognosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3958-3958
Author(s):  
Trang Nguyen Thi Dai ◽  
Hye-Ran Kim ◽  
Min-Gu Kang ◽  
Stephanie J. Won ◽  
Hwan-Young Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Bone Lesion ◽  
Disease Free Survival ◽  
Free Light Chain ◽  
Immunoglobulin Level ◽  
Exon 2 ◽  
Number Of Patients

Abstract Abstract 3958 Background: Recently, a striking example of the effects on acquired somatic mutations in splicing factors such as SF3B1, U2AF1, and SRSF2 has been described. The sequencing of the DNA from abnormal blood cells from patients with several types of leukemia such as AML, CLL, CMML, pre-leukemic syndromes, and MDS, has shown that a high proportion of these cases are associated with somatic mutations in spliceosomal proteins. Also, evidence of cancer-specific alternative splicing and oncogenic somatic mutations in spliceosome subunits has been steadily growing. However, there is not much research regarding aberrant splicing pathways in Multiple myeloma (MM) patients. Therefore, we tried to investigate the presence and prognostic implication of mutation of the SF3B1 and U2AF1 protein in these patients in South Korea. Materials and Methods: We examined a cohort of 87 MM patients and 100 healthy controls for somatic mutations in SF3B1, U2AF1 and SRSF2 by using direct sequencing method. The medical records were reviewed for age, sex, plasma cell percentage, serum M protein, immunoglobulin level, free light chain ratio, calcium, creatinine, hemoglobin, bone lesion, albumin, beta 2 microglobulin, lactate dehydrogenase, treatment outcome, and so on. The collected data was analyzed by SPSS for Windows version 18.0. We performed Pearson's chi-square tests, one way ANOVA analysis, and Student t-test. Survival rates of myeloma patients according to the result of SF3B1, U2AF1 and SRSF2 sequencing were analyzed using Kaplan-Meier log-rank test. Results: Our 87 MM patients showed no mutation including known recurrent ones in SF3B1, U2AF1 and SRSF2 genes. However, the patients displayed 39198T>T/C polymorphism (70.1%) in exon 18 of SF3B1, 8345T>T/G polymorphism (13.8%) in exon 2 of U2AF1 and 5399C/T polymorphism (100%) in exon 1 of SRSF2. In the entire cohort, the number of patients with no polymorphism, one polymorphism, two polymorphisms and three polymorphisms was counted up to 0%, 24.1%, 67.8% and 8.0%, respectively. The T/C polymorphism at position 39198 of SF3B1 exon 18 and the T/G polymorphism at position 8345 of U2AF1 exon 2 were analyzed by allele-specific PCR using normal control. Results in 100 normal controls, polymorphism of SF3B1 exon 18 was taken into account of 82.0%, the remaining is non polymorphism while U2AF1 exon 2 showed 10.0% polymorphism and 90.0% non polymorphism. Sex (p=0.048) and free light chain ratio (p=0.002) showed significant results according to polymorphism status while other clinical characteristics were not associated. The patient with polymorphisms in both SF3B1 and U2AF1 had worse overall survival (P=0.042) and disease-free survival (P<0.01), compared to patients without polymorphism. Conclusion: Our results show no recurrent SF3B1, U2AF1 and SRSF2 mutations in MM patients rather polymorphisms in SF3B1 and U2AF1 gene were significantly implicated in the prediction of poor prognosis. Disclosures: No relevant conflicts of interest to declare.

Evaluation Of Immunoglobulin Variations (Clonal Changes) In Symptomatic Multiple Myeloma (MM) Patients’ Course

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3173-3173
Author(s):  
Eftychia Nikolaou ◽  
Panayiotis Panayiotidis ◽  
Katerina Sarris ◽  
Dimitrios Maltezas ◽  
Efstathios Koulieris ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Median Number ◽  
Immunoglobulin M ◽  
Rank Test ◽  
Clinical Relapse ◽  
Cell Competition ◽  
Number Of Treatment

Abstract Changes in the production of monoclonal intact immunoglobulin (M-Ig) or of serum free light chains (sFLC) during symptomatic MM patients’ relapse eventually reflect molecular myeloma cells changes and / or reveal clonal cell competition. We aimed to study changes in Ig production (CIg) in symptomatic MM patients and to evaluate related frequency and corresponding specific disease characteristics. Patients and Methods 232 symptomatic MM patients with available follow-up sFLC measurements, were retrospectively studied. Light chain escape (LCE) was defined as sFLC increase with stable or falling M-Ig concentrations, M-Ig escape (MCE) as decreasing sFLC with increasing M-Ig, de-differentiation (DD) as clinical relapse with normal or decreased M-Ig and sFLC and Clonal Domination (CD) as normalization of formerly increased IgG, IgA or FLC in relapsing patients presenting increase of another component. Survival was calculated from diagnosis or from CIg date to last follow-up or death, survival curves were plotted by Kaplan-Meyer Method and assessed by the log-rank test. Results There were 94 women and 128 men, median aged 66 years; 29%, 42%, 29% and 22%, 30%, 48% were in Durie-Salmon and ISS stages I, II, III and 1, 2, 3 respectively. MM type was IgG MM in 59%, IgA in 21%, light chain only in 17%, IgD in 2% and non-secretory in1%. Median survival of the whole cohort was 46,4 months. CIg was observed in 39 patients (17%), consisting in LCE in 15 patients (6%), MCE in 7 (3%), DD in 5 (2%) and CD in 10 (4%); two additional patients (1 IgD and 1 LC) transiently produced another monoclonal component that was IgG in both cases, while in stringent complete remission. In CD patients, the dominated clone was IgG in 9 out of 10 patients, while the dominating one was LC in 8 and IgA in 2. LCE and MCE were more frequent in IgG patients. The median number of treatment lines received prior CIg was 5 for LCE, 4 for MCE, 2 for DD and 1 for CD. LCE and MCE patients had all received novel agents and/or ASCT. The median time from CIg to last follow-up or death was 2,6 months (2,2-3) for LCE, 3,3 months (2,2-4,4) for MCE, 6,3 months (1,1-11,6) for DD and 31,1 months (23,6-38,6) for CD. Patients presenting LCE, MCE and DD had a considerably shorter survival after CIg compared to patients presenting CD (p=0,0002). However because CIg was usually a late event in the course of the disease the overall survival of CIg patients was 60,6 months. In conclusion, LCE, MCE and DD are late events in the course of MM, mainly observed in patients whose previous treatments included with novel drugs. They reflect a very aggressive disease behavior with shortened survival thereafter, probably due to the emergence of a new resistant clone. CD was mainly observed in patients secreting low IgG levels and FLCs, and possibly reflect IgG clone remission in biclonal patients, given that thereafter, the disease behaves as a usual multiple myeloma, secreting however the other clone. Disclosures: No relevant conflicts of interest to declare.

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