scholarly journals Dysphagia as an Unusual Presentation of Myeloma

2018 ◽  
Vol 2018 ◽  
pp. 1-5
Author(s):  
A. Raissi ◽  
Z. Chahbi ◽  
M. Zyani ◽  
Y. Darouassi
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Plasma Cell ◽  
Rare Case ◽  
Unusual Presentation ◽  
Diagnosis And Management

Multiple myeloma is a plasma cell dyscrasis characterized by mature B cells proliferation in the bone marrow. In rare cases, the disease can present as an extramedullary location, making diagnosis and management more challenging. Here, we describe a rare case of tongue extramedullary myeloma and discuss diagnostic, prognostic, and therapeutic issues.

A Novel Role For Histone Deacetylase 11 (HDAC11) In Plasma Cell Differentation and Survival

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1907-1907
Author(s):  
Eva Sahakian ◽  
Jason B. Brayer ◽  
John Powers ◽  
Mark Meads ◽  
Allison Distler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Myeloma Cells ◽  
Peripheral Blood Plasma

Abstract The role of HDACs in cellular biology, initially limited to their effects upon histones, is now appreciated to encompass more complex regulatory functions that are dependent on their tissue expression, cellular compartment distribution, and the stage of cellular differentiation. Recently, our group has demonstrated that the newest member of the HDAC family of enzymes, HDAC11, is an important regulator of IL-10 gene expression in myeloid cells (Villagra A Nat Immunol. 2009). The role of this specific HDAC in B-cell development and differentiation is however unknown. To answer this question, we have utilized a HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allows the monitoring of the dynamic changes in HDAC11 gene expression/promoter activity in B-cells at different maturation stages (Heinz, N Nat. Rev. Neuroscience 2001). First, common lymphoid progenitors are devoid of HDAC11 transcriptional activation as indicated by eGFP expression. In the bone marrow, expression of eGFP moderately increases in Pro-B-cells and transitions to the Pre- and Immature B-cells respectively. Expression of eGFP doubles in the B-1 stage of differentiation in the periphery. Of note, examination of both the bone marrow and peripheral blood plasma cell compartment demonstrated increased expression of eGFP/HDAC11 mRNA at the steady-state. These results were confirmed in plasma cells isolated from normal human subjects in which HDAC11 mRNA expression was demonstrated. Strikingly, analysis of primary human multiple myeloma cells demonstrated a significantly higher HDAC11 mRNA expression in malignant cells as compared to normal plasma cells. Similar results were observed in 4/5 myeloma cell lines suggesting that perhaps HDAC11 expression might provide survival advantage to malignant plasma cells. Support to this hypothesis was further provided by studies in HDAC11KO mice in which we observed a 50% decrease in plasma cells in both the bone marrow and peripheral blood plasma cell compartments relative to wild-type mice. Taken together, we have unveiled a previously unknown role for HDAC11 in plasma cell differentiation and survival. The additional demonstration that HDAC11 is overexpressed in primary human myeloma cells provide the framework for specifically targeting this HDAC in multiple myeloma. Disclosures: Alsina: Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Baz:Celgene Corporation: Research Funding; Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding.

Generation of a Novel, Multi-Stage, Progressive, and Transplantable Model of Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 327-327
Author(s):  
Takashi Asai ◽  
Silvia Menendez ◽  
Delphine Ndiaye-Lobry ◽  
Anthony R Deblasio ◽  
Kazunori Murata ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Animal Model ◽  
B Cells ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Class Switch Recombination ◽  
Class Switch ◽  
Multi Stage ◽  
Plasma Cell Neoplasms

Abstract Abstract 327 Multiple myeloma is characterized by the progressive expansion of monoclonal plasma cells in the bone marrow, which leads to the production of serum and/or urine monoclonal proteins and systemic complications including lytic bone lesions, renal abnormalities hypercalcemia, and infections. Although the treatment of multiple myeloma has vastly improved, multiple myeloma remains a generally incurable disease. Transgenic mouse models have been generated that develop plasma cell accumulations or myeloma, however these models are quite imperfect in mimicking the human disease. Quite serendipitously, we have generated a multi-stage, progressive, and transplantable mouse model of multiple myeloma, crossing a genetically modified mouse with aberrant class switch recombination with another modified mouse that has elevated DNA damage response signaling. We have reported that cells expressing the hypermorphic Rad50s allele show constitutive ATM activation, leading to cancer predisposition and aggressive hematopoietic failure in Rad50s/s mice. While deficiency of the transcription factor Mef/Elf4, which regulates the quiescence of hematopoietic stem/progenitor cells, can mitigate hematopoietic failure observed in Rad50s/s mice, we found that 70% of Mef−/−Rad50s/s mice more than 200 days old died from multiple myeloma, plasmacytoma, or plasma cell leukemia, confirmed by pathology, immunohistochemistry, flowcytometry (CD138/B220 profiles), and PCR analysis for VDJ recombination. Prior to the onset of the plasma cell neoplasms, the Mef−/−Rad50s/s mice show abnormal plasma cell accumulation in the peripheral blood and bone marrow, which worsens with age. As the mice age, they also develop progressive increases in g-globulin levels and decreases in serum albumin levels. Monoclonal protein peaks were frequently observed in the serum of mice older than 200 days, and in step with the progressive nature of these manifestations, anemia and lower bone mineral density becomes apparent as the mice further age. Overall, the median survival of the Mef−/−Rad50s/s mice is approximately 470 days. The plasma cell neoplasms derived from Mef−/−Rad50s/s mice can be transplanted into recipient mice and the onset of the transplanted disease is markedly accelerated, to approximately 4 weeks post transplantation. Thus, the transplanted neoplastic Mef−/−Rad50s/s plasma cells appear to be more aggressive than the original ones. Taken together, our findings suggest that the Mef−/−Rad50s/s animal model can recapitulate the spectrum and pace of human plasma cell neoplasms, including the progression from monoclonal gammopathy to multiple myeloma. Class switch recombination is facilitated in Mef−/−Rad50s/s B cells in vitro, compared with control, Mef−/−, and Rad50s/s B cells, thus the plasma cell neoplasms found in Mef−/−Rad50s/s mice may result from Rad50s-driven oncogenesis. This novel Mef−/−Rad50s/s myeloma animal model should be useful for the drug screening of novel anti-myeloma compounds, as well as defining the pathogenesis of multiple myeloma/plasma cell neoplasms. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Evidence for a bone marrow B cell transcribing malignant plasma cell VDJ joined to C mu sequence in immunoglobulin (IgG)- and IgA-secreting multiple myelomas.

1993 ◽  
Vol 178 (3) ◽  
pp. 1091-1096 ◽  
Author(s):  
P Corradini ◽  
M Boccadoro ◽  
C Voena ◽  
A Pileri
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Indirect Evidence ◽  
Specific Marker

Multiple myeloma is a B cell malignancy characterized by the expansion of plasma cells producing monoclonal immunoglobulins (Ig). It has been regarded as a tumor arising at the B, pre-B lymphocyte, or even stem cell level. Precursor cells are presumed to proliferate and differentiate giving rise to the plasma cell clonal expansion. Antigenic features and specific Ig gene rearrangement shared by B lymphocytes and myeloma cells have supported this hypothesis. However, the existence of such a precursor is based upon indirect evidence and is still an open question. During differentiation, B cells rearrange variable (V) regions of Ig heavy chain genes, providing a specific marker of clonality. Using an anchor polymerase chain reaction assay, these rearranged regions from five patients with multiple myeloma were cloned and sequenced. The switch of the Ig constant (C) region was used to define the B cell differentiation stage: V regions are linked to C mu genes in pre-B and B lymphocytes (pre-switch B cells), but to C gamma or C alpha in post-switch B lymphocytes and plasma cells (post-switch B cells). Analysis of bone marrow cells at diagnosis revealed the presence of pre-switch B cells bearing plasma cell V regions still joined to the C mu gene. These cells were not identified in peripheral blood, where tumor post-switch B cells were detected. These pre-switch B cells may be regarded as potential myeloma cell precursors.

scholarly journals A novel membrane antigen selectively expressed on terminally differentiated human B cells

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1922-1930 ◽  
Author(s):  
T Goto ◽  
SJ Kennel ◽  
M Abe ◽  
M Takishita ◽  
M Kosaka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Affinity Constant ◽  
Target Antigen ◽  
Specific Marker

Abstract A monoclonal antibody (MoAb) that defines a novel terminal B-cell- restricted antigen, termed HM1.24, was developed against a human plasma cell line. The MoAb, designated anti-HM1.24, reacted with five different human myeloma cell lines, as well as with monoclonal neoplastic plasma cells obtained from the bone marrow or peripheral blood of patients with multiple myeloma or Waldenstrom's macroglobulinemia. The HM1.24 antigen was also expressed by mature Ig- secreting B cells (plasma cells and lymphoplasmacytoid cells) but not by other cells contained in the peripheral blood, bone marrow, liver, spleen, kidney, or heart of normal individuals or patients with non- plasma-cell-related malignancies. The anti-HM1.24 MoAb bound to human myeloma RPMI 8226 cells with an affinity constant of 9.2 x 10(8) M-1, indicating approximately 84,000 sites/cell. By immunoprecipitation assay under reducing conditions, this MoAb identified a membrane glycoprotein that had a molecular weight of 29 to 33 kD. Our studies indicate that the HM1.24-related protein represents a specific marker of late-stage B-cell maturation and potentially serves as a target antigen for the immunotherapy of multiple myeloma and related plasma cell dyscrasias.

Stridor: unusual presentation of multiple myeloma

2003 ◽  
Vol 117 (10) ◽  
pp. 829-831 ◽  
Author(s):  
David Sinclair ◽  
Adel Resouly ◽  
Anne Spedding
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Subglottic Stenosis ◽  
Unusual Presentation ◽  
Lytic Lesion ◽  
Cell Infiltrate ◽  
The Right ◽  
Bence Jones Proteinuria

We present a patient with multiple myeloma whose only presenting symptom was stridor caused by a subglottic stenosis. Biopsy suggested the presence of amyloid which prompted immunological investigations that showed hypogammaglobulinaemia and the presence of Bence Jones proteinuria at 0.93 g/24 hours. Further investigation demonstrated a 15 per cent plasma cell infiltrate into the bone marrow and a lytic lesion in the mid-shaft of the right femur. Chemotherapy and localized radiotherapy were commenced. This is a most unusual presentation of multiple myeloma and shows that immunoglobulin profiles should be properly investigated in such cases.

scholarly journals A novel membrane antigen selectively expressed on terminally differentiated human B cells

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1922-1930 ◽  
Author(s):  
T Goto ◽  
SJ Kennel ◽  
M Abe ◽  
M Takishita ◽  
M Kosaka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Affinity Constant ◽  
Target Antigen ◽  
Specific Marker

A monoclonal antibody (MoAb) that defines a novel terminal B-cell- restricted antigen, termed HM1.24, was developed against a human plasma cell line. The MoAb, designated anti-HM1.24, reacted with five different human myeloma cell lines, as well as with monoclonal neoplastic plasma cells obtained from the bone marrow or peripheral blood of patients with multiple myeloma or Waldenstrom's macroglobulinemia. The HM1.24 antigen was also expressed by mature Ig- secreting B cells (plasma cells and lymphoplasmacytoid cells) but not by other cells contained in the peripheral blood, bone marrow, liver, spleen, kidney, or heart of normal individuals or patients with non- plasma-cell-related malignancies. The anti-HM1.24 MoAb bound to human myeloma RPMI 8226 cells with an affinity constant of 9.2 x 10(8) M-1, indicating approximately 84,000 sites/cell. By immunoprecipitation assay under reducing conditions, this MoAb identified a membrane glycoprotein that had a molecular weight of 29 to 33 kD. Our studies indicate that the HM1.24-related protein represents a specific marker of late-stage B-cell maturation and potentially serves as a target antigen for the immunotherapy of multiple myeloma and related plasma cell dyscrasias.

scholarly journals Hematogones (medullar pro-B Cells) Are Present but Decreased in Active Multiple Myeloma and Are a Prognostic Factor in Treated Myeloma Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2006-2006
Author(s):  
Quentin Cabrera ◽  
Sylvain Chantepie ◽  
Jean-Baptiste Mear ◽  
Véronique Salaun ◽  
Edouard Cornet ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Multivariate Analysis ◽  
B Cells ◽  
Prognostic Factor ◽  
Partial Response ◽  
Plasma Cell ◽  
Disease Stage ◽  
Stage At Diagnosis ◽  
The Mean

Abstract BACKGROUND Hematogones (HG) are normal bone marrow B-cells precursors, characterized on Multiparameter Flow Cytometry (MFC) study by CD19 expression, progressive loss of CD10 and CD34, acquisition of CD45 and CD20. HG level is lowered by age or medullar tumoral infiltration, but is higher (>5%) after chemotherapy, Hematopoietic Stem Cell Transplantation (HSCT) or viral infection. An HG level >0.01% in first complete remission in Acute Myeloid Leukemia (AML) patients is associated with a better Overall Survival (OS) and Progression Free Survival (PFS). Further correlations have been made between HG level and good evolutions in AML patients or HSCT recipients. Although Multiple Myeloma (MM) is a mature B-cell malignancy, no clinical study has focused on HG in MM patients. Furthermore, there is no data on prognostic impact of HG in treated MM patients. However, HG study could be of prime interest for medullar micro-environment evaluation which is not assessed by routine prognostic factors. AIM Our primary objective was to establish the presence and level of HG in the bone marrow of patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), Smoldering Myeloma (SM) or active MM (aMM), and to analyze correlations with clinical characteristics. Our secondary objective was to determine a prognostic correlation between HG level at diagnosis and PFS or OS in aMM patients. METHODS In this monocentric prospective observational study conducted between March 2011 and January 2014, we analyzed all bone marrow samples sent to the MFC lab in our center of CHU de Caen, France. Samples were routinely obtained by bone marrow aspirations at diagnosis for MGUS or MM patients. Medullar cells were analyzed by 4-color MFC, using a CD20-FITc/CD19-PE/CD45-PerCp/CD10-APC panel for HG detection. HG level was calculated over all nuclear medullar cells, samples with less than 100.000 cells were excluded, and sensitivity was 1/104 cells. All biological data were recorded at diagnosis. The median follow-up was 16 months. All statistical analysis, including multivariate analysis, were performed with two-sided 95% confidence intervals. RESULTS A total of 90 patients have been included: 25 MGUS (27%), 12 SM (13%) and 53 aMM (58%). The mean age at diagnosis was respectively 63, 68 and 67 y (35-90), and mean β2-µglobulinemia (β2) was 2.5, 5 and 6.3 mg/l respectively. HG were detected in more than 90% of cases. The mean HG level was significantly higher in MGUS (2.86%, median 2%, p=0.006) or in SM (1.95%, median 1.5%, p=0.019) than in aMM (1.10% median 0.5%) (Figure 1). HG level at diagnosis was inversely correlated with age, plasma cell infiltration, hypoalbuminemia, or β2 (mean HG=2% if β2≤3.5 mg/l, and 0.8% if β2>5 mg/l). HG level was higher in patients with hemoglobin levels ≥10 g/dL (2.8% vs 0.7%, p=0.015). There were no correlations between HG level at diagnosis and white blood cells count, gender, renal insufficiency, plasma cell phenotype nor monoclonal component subtype. In the subgroup of 53 aMM patients, 22% were ISS1, 29% were ISS2 and 49% ISS3. Mean HG levels were 2.1%, 0.8% and 0.85% respectively (p=0.008 between ISS1 vs ISS2+3). All patients but one received a triple regimen chemotherapy including Bortezomib. Patients with HG level >0.5% at diagnosis (median of the group) had a longer median PFS (29.8 vs 13.5 months, n=26 and 27, p=0.002, cf. Figure 2) and a better OS (85% alive vs 60% at 20 months, median not reached, p=0.02). In multivariate analysis, a cut-off of 0.5% of HG at diagnosis was a prognostic factor for PFS in aMM patients (p=0.03, IC=0.14-0.9), with age (p=0.041, IC=1.0-1.09) but not ISS subgroup (p=0.6). Furthermore, patients who achieved Very Good Partial Response (VGPR) or more had higher HG level at diagnosis than patients who achieved Partial Response or less (IC=1.08-6.07, p=0.015). CONCLUSION HG are present in MM patients. The HG level is decreased in MM patients as compared to MGUS, and is inversely correlated with the disease biomarkers or activity. An HG level >0.5% at diagnosis is a good prognostic factor in treated MM patients, and may reflect bone marrow micro-environment condition. Figure 1. HG level and disease stage at diagnosis. Figure 1. HG level and disease stage at diagnosis. Figure 2. PFS of aMM patients sort by HG at diagnosis. Figure 2. PFS of aMM patients sort by HG at diagnosis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Deficient Drug Transporter Function of Bone Marrow–Localized and Leukemic Plasma Cells in Multiple Myeloma

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3751-3759 ◽  
Author(s):  
Linda M. Pilarski ◽  
Agnieszka J. Szczepek ◽  
Andrew R. Belch
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Plasma Cell ◽  
Drug Transport ◽  
Plasma Cells ◽  
Phenotypic Expression ◽  
Treatment Strategies ◽  
Cell Stage

Abstract Although chemotherapy effectively reduces the plasma cell burden in multiple myeloma (MM), the disease recurs. MM includes circulating and bone marrow (BM) localized components. A large majority of circulating CD11b+ MM B cells (81%) express an IgH VDJ rearrangement identical to that of autologous BM plasma cells. Unlike plasma cells, these monoclonal circulating B cells exhibit dye and drug transport activity before and throughout chemotherapy. Drug resistance was measured as the ability to export the fluorescent dye Rhodamine123 (Rh123) or the drug adriamycin, using flow cytometry. The role of P-glycoprotein 170 (P-gp), the multidrug transporter, was defined by cyclosporin A (CsA)-sensitive dye export. Only 8% to 11% of BM-localized plasma cells exported dye with the majority retaining dye, identified as bright staining. Circulating leukemic plasma cells were also unable to export dye and remained Rh123bright. However, 53% of circulating clonotypic MM B cells exhibited CsA-sensitive dye export. BM plasma cells taken before or after initiation of first line chemotherapy were equally unable to export dye. Thus in myeloma, differentiation to the plasma cell stage is accompanied by a loss of P-gp function, although P-gp phenotypic expression is retained. In contrast, for monoclonal gammopathy of undetermined significance (MGUS), 54% of BM-localized plasma cells exported dye, comparable to the 53% of circulating MGUS B cells that also exported dye, suggesting that the apparent defect in P-gp function is unique to myeloma plasma cells. Virtually all BM plasma cells in MM retained the drug adriamycin, consistent with their initial drug sensitivity in vivo, in contrast to circulating MM B cells, or to T cells in BM or blood. Thus, circulating B cells appear to be the predominant drug resistant component of the MM B-lineage hierarchy. This report suggests that successful therapeutic strategies will be those that target circulating B cells. Chemosensitization methods involving inhibition of P-gp are likely to improve depletion of these cells by compromising their ability to exclude drug. This work suggests that circulating clonotypic B cells should be monitored in clinical trials to confirm their depletion and the overall efficacy of novel treatment strategies.

scholarly journals Multiple myeloma: circulating lymphocytes that express plasma cell antigens

Blood ◽  
1984 ◽  
Vol 64 (2) ◽  
pp. 352-356
Author(s):  
GJ Ruiz-Arguelles ◽  
JA Katzmann ◽  
PR Greipp ◽  
NJ Gonchoroff ◽  
JP Garton ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Peripheral Blood Lymphocytes ◽  
Tumor Burden ◽  
B Cell Differentiation ◽  
Blood Lymphocytes ◽  
Bone Marrow Plasma

The bone marrow and peripheral blood of 14 patients with multiple myeloma were studied with murine monoclonal antibodies that identify antigens on plasma cells (R1–3 and OKT10). Peripheral blood lymphocytes expressing plasma cell antigens were found in six cases. Five of these cases expressed the same antigens that were present on the plasma cells in the bone marrow. Patients that showed such peripheral blood involvement were found to have a larger tumor burden and higher bone marrow plasma cell proliferative activity. In some patients, antigens normally found at earlier stages of B cell differentiation (B1, B2, and J5) were expressed by peripheral blood lymphocytes and/or bone marrow plasma cells.

scholarly journals B cells suppress medullary granulopoiesis by an extracellular glycosylation-dependent mechanism

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Eric E Irons ◽  
Melissa M Lee-Sundlov ◽  
Yuqi Zhu ◽  
Sriram Neelamegham ◽  
Karin M Hoffmeister ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Progenitor Cell ◽  
Hematopoietic Progenitors ◽  
Myeloma Cells ◽  
Human B Cells ◽  
Extrinsic Cues ◽  
Bone Marrow Niches ◽  
Dependent Mechanism

The immune response relies on the integration of cell-intrinsic processes with cell-extrinsic cues. During infection, B cells vacate the marrow during emergency granulopoiesis but return upon restoration of homeostasis. Here we report a novel glycosylation-mediated crosstalk between marrow B cells and hematopoietic progenitors. Human B cells secrete active ST6GAL1 sialyltransferase that remodels progenitor cell surface glycans to suppress granulopoiesis. In mouse models, ST6GAL1 from B cells alters the sialylation profile of bone marrow populations, and mature IgD+ B cells were enriched in sialylated bone marrow niches. In clinical multiple myeloma, ST6GAL1 abundance in the multiple myeloma cells negatively correlated with neutrophil abundance. These observations highlight not only the ability of medullary B cells to influence blood cell production, but also the disruption to normal granulopoiesis by excessive ST6GAL1 in malignancy.

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