Plasma Cell Dyscrasias

2019 ◽  
pp. 33-38
Author(s):  
Kevin B. Hoover
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Trials ◽  
African Americans ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Organ Damage ◽  
Disease Staging ◽  
Plasma Cell Dyscrasias ◽  
Urine Testing

Chapter 76 discusses plasma cell dyscrasias, which are currently incurable diseases resulting from the proliferation of plasma cells and the secretion of immunoglobulins with associated anemia and end-organ damage. These diseases are more common in men than women and more common in African Americans than whites. Multiple myeloma is the most common of the plasma cell dyscrasias. Blood and urine testing, bone marrow biopsy, and radiography are the primary tests used for diagnosis. Radiographs are the standard tools in disease staging and monitoring with advanced imaging used primarily for evaluating symptomatic patients with negative radiographs and patients in clinical trials.

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 Myeloma Cell Associated Therapeutic Protein Discovery Using Single Cell RNA-Seq Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Lijun Yao ◽  
Reyka G Jayasinghe ◽  
Tianjiao Wang ◽  
Julie O'Neal ◽  
Ruiyang Liu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Surface ◽  
B Cell ◽  
Tumor Cells ◽  
Plasma Cell ◽  
Tissue Specificity ◽  
Plasma Cells ◽  
Expression Data ◽  
Intracellular Proteins

Multiple myeloma (MM) is a hematological cancer of the antibody-secreting plasma cells. Despite therapeutic advancements, MM remains incurable due to high incidence of drug-resistant relapse. In recent years, targeted immunotherapies, which take advantage of the immune system's cytotoxic defenses to specifically eliminate tumor cells expressing certain cell surface and intracellular proteins have shown promise in combating this and other B cell hematologic malignancies. A major limitation in the development of these therapies lies in the discovery of optimal candidate targets, which require both high expression in tumor cells as well as stringent tissue specificity. In an effort to identify potential myeloma-specific target antigens, we performed an unbiased search for genes with specific expression in plasma and/or B cells using single-cell RNA-sequencing (scRNAseq) of 53 bone marrow samples taken from 42 patients. By comparing >40K plasma cells to >97K immune cells across our cohort, we were able to identify a total of 181 plasma cell-associated genes, including 65 that encode cell-surface proteins and 116 encoding intracellular proteins. Of particular interest is that the plasma cells from each patient were shown to be transcriptionally distinct with unique sets of genes expressed defining each patient's malignant plasma cells. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to B-Cell receptor (BCR) signaling, protein transport, and endoplasmic reticulum (ER) stress, involving genes such as DERL3, HERPUD1, PDIA4, PDIA6, RRBP1, SSR3, SSR4, TXNDC5, and UBE2J1. To note, our strategy successfully captured several of the most promising MM therapeutic targets currently under pre-clinical and clinical trials, including TNFRSF17(BCMA), SLAMF7, and SDC1 (CD138). Among these, TNFRSF17 showed very high plasma cell expression, with concomitant sharp exclusion of other immune cell types. To ascertain tissue specificity of candidate genes outside of the bone marrow, we analyzed gene and protein expression data from the Genotype-Tissue Expression (GTEx) portal and Human Protein Atlas (HPA). We found further support for several candidates (incl. TNFRSF17,SLAMF7, TNFRSF13B (TACI), and TNFRSF13C) as being both exclusively and highly expressed in lymphoid tissues. While several surface candidates were not found to be lymphocyte-restricted at the protein level, they remain relevant considerations as secondary targets for bi-specific immunotherapy approaches currently under development. To further investigate potential combinatorial targeting, we examine sample-level patterns of candidate co-expression and mutually-exclusive expression using correlation analysis. As the majority of our detected plasma cell-specific genes encode intracellular proteins, we investigated the potential utility of these epitopes as therapeutic targets via MHC presentation. Highly expressed candidates include MZB1, SEC11C, HLA-DOB, POU2AF1, and EAF2. We analyzed protein sequences using NetMHC and NETMHCII to predict high-affinity peptides for common class-I and class-II HLA alleles. To correlate MHC allelic preference with candidate expression in our cohort, we performed HLA-typing for 29 samples using Optitype. To support our scRNAseq-driven findings, we cross-referenced gene expression data with 907 bulk RNA-sequencing samples, including 15 from internal studies and 892 from the Multiple Myeloma Research Foundation (MMRF), as well as bulk global proteomics data from 4 MM cell lines (TIB.U266, RPMI8226, OPM2, MM1ST) and 4 patients. We see consistent trends across both cohorts, with high positive correlation (Pearson R ranging between 0.60 and 0.99) for a majority of genes when comparing scRNA and bulk RNA expression in the same samples. Our experimental design and analysis strategies enabled the efficient discovery of myeloma-associated therapeutic target candidates. In conclusion, this study identified a set of promising myeloma CAR-T targets, providing novel treatment options for myeloma patients. Disclosures Goldsmith: Wugen Inc.: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals THE BONE MARROW ON STERNAL ASPIRATION IN MULTIPLE MYELOMA

Blood ◽  
1948 ◽  
Vol 3 (9) ◽  
pp. 987-1018 ◽  
Author(s):  
EDWIN D. BAYRD
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Multinucleated Cells ◽  
Cytoplasmic Bodies ◽  
Plasma Cell Type ◽  
Well Differentiated ◽  
Diagnostic Pitfalls

Abstract Generalizing, it can be said that the pathologic cells seen in smears of the bone marrow in multiple myeloma resemble the plasma cell and vary from the very anaplastic and immature cell to the well-differentiated and almost characteristic plasma cell. The feature which the "myeloma" cell shares with the plasma cell is the abundant, granular, basophilic cytoplasm which tends to be fragile and undergo the same degenerative changes in each; namely, the formation of Russell bodies and vacuolization. Fairly frequently a perinuclear clear area or Hof is present and the nucleus tends to be eccentrically placed. Cytoplasmic extensions or pseudopodia may also be seen in either case, but they occur more often and more dramatically in instances of multiple myeloma. Multinucleated cells are commonly seen. In addition, myeloma-plasma cells will often have a large clear nucleolus and a leptochromatic nucleus and will exhibit a tendency to the formation of isolated areas of condensed chromatin. Cytoplasmic extrusions, free cytoplasmic bodies, occasionally complete with Russell bodies and vacuoles are almost universally present. All cases were of the plasma cell type; there was no exception. In these cases, the myeloma-plasma cell constituted from 2.5 to 96 per cent of the leukocytic elements present. The opinion was expressed that all so-called types of multiple myeloma are merely variations in differentiation of this same cell. It was noted that anaplasia, hypernucleation and lack of plasma cell predominance in certain cases were diagnostic pitfalls. Additional evidence was adduced to confirm the reticulo-endothelial origin of the myeloma-plasma cell. It was further observed that certain prognostically valuable information could be gleaned from a careful review of the cytologic characteristics in these cases.

Serum Free Light Chain Ratio in Distinguishing Smoldering Multiple Myeloma From Active Multiple Myeloma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3948-3948
Author(s):  
Jeremy T Larsen ◽  
Shaji Kumar ◽  
S. Vincent Rajkumar
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Predictive Value ◽  
Plasma Cells ◽  
Organ Damage ◽  
End Organ Damage ◽  
Cut Point ◽  
Smoldering Multiple Myeloma ◽  
Bone Marrow Plasma

Abstract Abstract 3948 Background: Smoldering multiple myeloma (SMM) is an asymptomatic precursor disease of multiple myeloma, and is defined by excess bone marrow plasma cells and monoclonal protein without evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions [CRAB]). The identification of SMM patients with more aggressive underlying disease remains a challenge. We hypothesize that SMM is a clinical entity comprised of both premalignant, high-risk MGUS and early multiple myeloma in transition to malignant disease, which may be differentiated with the use of the serum FLC (FLC) ratio. Methods: This was a retrospective analysis of 586 patients with newly diagnosed SMM from 1970–2010 with available stored serum samples around the time of diagnosis to be utilized for quantification of FLC ratios. SMM was defined by the International Myeloma Working Group 2003 definition; serum M-protein ≥ 3 g/dL and/or ≥ 10% bone marrow plasma cells with no evidence of CRAB features. The immunoglobulin FLC assay (Binding Site, U.K.) was used for testing. The FLC ratio was calculated as κ/λ (reference range 0.26–1.65). The involved/uninvolved FLC ratio was recorded to simplify the reporting of data. Receiver Operating Characteristics (ROC) curves were created to assess the ability of the FLC ratio to discriminate patients who progressed to symptomatic multiple myeloma (MM) in the first 2 years or at any point during follow-up versus patients without evidence of progression. Patients with less than 24 months follow-up without progression were censored. The optimal diagnostic cut-point for FLC involved/uninvolved ratio to identify patients with progressive disease from the ROC curve was >88.6 (equivalent to <0.011 or >88.6). For ease of clinical application, the optimal value for involved/uninvolved FLC ratio was rounded to >100. Time to progression (TTP) from date of the initial FLC to active MM was calculated using Kaplan-Meier analysis and compared to patients with a high (>100) and low (<100) involved/uninvolved FLC ratio at time of SMM diagnosis. TTP within 24 months of the initial FLC was also calculated. Results: During the study period, 54% of patients progressed to active MM. On ROC analysis, a cut-point of >100 corresponded to a sensitivity of 25% (95% CI, 20.5–30.4) and specificity of 99.3% (97.3–99.9), with positive likelihood (+LR) ratio of 33.9 (38.1–41.0), negative likelihood ratio (−LR) of 0.75 (0.2–3.0), positive predictive value (PPV) of 97.6 (91.5–99.7) and negative predictive value of 53.0 (48.5–57.4). Using the ROC to assess progression to MM within 24 months (Figure 1), sensitivity was 29.6% (23.5–36.4), specificity 94.5% (91.7–96.5), +LR 5.36 (4.3–6.6), -LR 0.75 (0.5–1.1), PPV 85.8 (77.7–91.8), and NPV 54.3 (49.8–58.9). Median TTP to active MM in the FLC >100 group was 15 months (9–17) versus 52 months (44–60) in the FLC <100 group (p <.0001) [Figure 2]. In the FLC ratio >100 group, progression at 1 year was 47%, 76% at 2 years, and 90% at 3 years. Only 25% of the FLC <100 patients had progressed at 2 years. The most common progression event was bone disease (42%), followed by anemia (26%), renal impairment (23%), and hypercalcemia (5%). Conclusion: Elevation of the FLC ratio >100 (or <0.01) is highly specific for the future development of active MM, with 76% of these patients developing end-organ damage requiring therapy within 2 years. Risk of transformation to MM in the FLC <100 group was similar to previously reported rates of 10% per year for the first 5 years. Development of an FLC ratio >100 is associated with increasing disease burden and in this study behaved in a malignant fashion rather than a precursor state. The FLC is a simple and useful predictor of progression to MM in SMM, and patients with FLC ratios of <0.01 or >100 within the first 2 years of SMM diagnosis should be monitored especially closely. Future studies are needed to determine optimum cutoffs for FLC ratio to where a change in definition of MM could be considered. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Biological Significance and Prognostic Value of Cytogenetics in 160 Patients with Multiple Myeloma: Predictivity of 13 and/or 14 Monosomies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4735-4735
Author(s):  
Jolanda Donatella Vincelli ◽  
Antonio Scopelliti ◽  
Angela Violi ◽  
Corrado Mammi' ◽  
Maria Grazia D'Errigo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Diagnostic Criteria ◽  
Plasma Cell ◽  
Bone Disease ◽  
Molecular Classification ◽  
Organ Damage ◽  
Disease Biology ◽  
Risk Of Progression

Abstract Until recently, MM was defined using strict clinical pathological criteria that required evidence of specific end-organ damage (CRAB) attributable to the underlying clonal plasma cell disorder. In the case of absence of end-organ damage, patients with clonal plasma cell proliferation were diagnosed either with monoclonal gammopathy of undetermined significance (MGUS) or with smoldering multiple myeloma (SMM). Further, on one hand there have been on-going revisions of the diagnostic criteria for MM and SMM, on the other there have also been revisions of the molecular classification of these disorders; namely, staging and risk. These revisions regarding both the diagnostic criteria and the molecular classification of these disorders are very important because recent advances in understanding these disorders have led to significant progress in the treatment of MM and SMM, in our understanding of disease biology, and in prognostic evaluation for cancer patients. The Revised International Staging System (RISS) combines elements of tumor burden (ISS) and disease biology (presence of high-risk cytogenetic abnormalities or elevated lactate dehydrogenase level) to create a unified prognostic index that helps in clinical care, comparing clinical trial data. The RISS will be of importance in the clinic in terms of counseling patients regarding prognosis, as well as in clinical trials to compare outcomes across clinical trials. The initial cytogenetic classification of SMM also has implications for prognosis as patients with t(4;14) translocation, 17p deletion, and 1q amplification have a higher risk of progression from SMM to MM. Although patients with trisomies are considered to have a better prognosis when diagnosed with MM, they have a higher risk of progression from SMM to MM compared to patients with t(11;14). It is possible that trisomic MM manifests earlier with more obvious bone disease, producing in essence a lead-time bias. Thus, the time from SMM to MM is shortened while the time from MM to death appears longer. There are several molecular subtypes of MM, associated with several unique differences in disease presentation and prognosis. For example, trisomic MM appears to respond particularly well to lenalidomide-based therapy, while t(4;14) MM requires bortezomib-based induction and maintenance for good outcome. In terms of clinical presentation, t(4;14) MM appears to have a lower propensity for bone disease at diagnosis, while t(14;16) MM is often associated with high levels of serum free light chains (FLC) and a higher risk of acute renal failure at diagnosis. Disease biology in MM is best reflected based on the molecular subtype of the disease and the presence or absence of specific cytogenetic abnormalities. The abnormalities such as t(4;14), t(14;16), t(14;20), gain(1q), del(1p), and del(17p) influence disease course, response to therapy, and prognosis in MM. In our center we evaluated the cytogenetics data at the onset of the disease, after 1st line therapy, after transplantation and during maintenance therapy to analyze any changes in the cytogenetic panel and additional anomalies and if all this is correlated with the characteristics of the disease, patient, and risk predictor. In particular, we evaluated 160 patients and analyzed the clinical evolution in patients in which monosomies 13 and/or 14 were present, currently not classifiable in prognostic terms. The significance of these monosomies was evaluated based on the various stages of the disease and the type of therapy administered. Disclosures No relevant conflicts of interest to declare.

scholarly journals Salmonella SiiE prevents an efficient humoral immune memory by interfering with IgG+ plasma cell persistence in the bone marrow

2019 ◽  
Vol 116 (15) ◽  
pp. 7425-7430 ◽  
Author(s):  
Christian Männe ◽  
Akiko Takaya ◽  
Yuzuru Yamasaki ◽  
Mathias Mursell ◽  
Shintaro Hojyo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Autoimmune Diseases ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Therapeutic Option ◽  
Immune Memory ◽  
Humoral Immune ◽  
Serum Igg ◽  
Specific Igg

Serum IgG, which is mainly generated from IgG-secreting plasma cells in the bone marrow (BM), protects our body against various pathogens. We show here that the protein SiiE of Salmonella is both required and sufficient to prevent an efficient humoral immune memory against the pathogen by selectively reducing the number of IgG-secreting plasma cells in the BM. Attenuated SiiE-deficient Salmonella induces high and lasting titers of specific and protective Salmonella-specific IgG and qualifies as an efficient vaccine against Salmonella. A SiiE-derived peptide with homology to laminin β1 is sufficient to ablate IgG-secreting plasma cells from the BM, identifying laminin β1 as a component of niches for IgG-secreting plasma cells in the BM, and furthermore, qualifies it as a unique therapeutic option to selectively ablate IgG-secreting plasma cells in autoimmune diseases and multiple myeloma.

The Natural History of Smoldering (Asymptomatic) Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3396-3396 ◽  
Author(s):  
Robert Kyle ◽  
Ellen Remstein ◽  
Terry Therneau ◽  
Angela Dispenzieri ◽  
Paul Kurtin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Plasma Cells ◽  
M Protein ◽  
Cell Content ◽  
Bone Marrow Plasma ◽  
M Spike

Abstract Smoldering multiple myeloma (SMM) is characterized by a serum M protein ≥ 3g/dL and/or 10% or more of plasma cells in the bone marrow. However, the definition is not standardized, and it is not known whether both serum M protein levels and bone marrow plasma cell counts are necessary for diagnosis or if one parameter is sufficient. We reviewed the medical records and bone marrows of all patients from Mayo Clinic seen within 30 days of recognition of an IgG or IgA M protein ≥ 3g/dL or a bone marrow containing ≥ 10% plasma cells from 1970 to 1995. This allows for a minimum potential follow-up of 10 years. Patients with end-organ damage at baseline from plasma cell proliferation, including active multiple myeloma (MM) and primary amyloidosis (AL) and those who had received chemotherapy were excluded. A differential of the bone marrow aspirate coupled with the bone marrow biopsy morphology and immunohistochemistry using antibodies directed against CD138, MUM-1 and Cyclin D1 were evaluated in every case in order to estimate the plasma cell content. In all, 301 patients fulfilled either of the criteria for SMM. Their median age was 64 years and only 3% were less than 40 years of age; 60% were male. The median hemoglobin value was 12.9 g/dL; 7% were less than 10 g/dL, but the anemia was unrelated to plasma cell proliferation. IgG accounted for 75%, IgA 22%, and biclonal proteins were found in 3%. The serum light-chain was κ in 67% and λ in 33%. The median serum M spike was 2.9 g/dL; 11% were at least 4.0 g/dL. Uninvolved serum immunoglobulins were reduced in 81%; only 1 immunoglobulin was reduced in 31% and both were decreased in 50%. The urine contained a monoclonal κ protein in 36% and λ in 18% and 46% were negative. The median size of the urine M spike was 0.04 g/24h; only 5 (3%) were &gt; 1 g/24h. The median bone marrow plasma cell content was 15 – 19%; 10% had less than 10% plasma cells, while 10% had at least 50% plasma cells in the bone marrow. Cyclin D-1 was expressed in 17%. Patients were categorized into 3 groups: Group 1, serum M protein ≥ 3g/dL and bone marrow containing ≥ 10% plasma cells (n= 113, 38%); Group 2, bone marrow plasma cells ≥ 10% but serum M protein &lt; 3g/dL (n= 158, 52%); Group 3, serum M protein ≥ 3g/dL but bone marrow plasma cells &lt; 10% (n= 30, 10%). During 2,204 cumulative years of follow-up 85% died (median follow-up of those still living 10.8 years), 155 (51%) developed MM, while 7 (2%) developed AL. The overall rate of progression at 10 years was 62%; median time to progression was 5.5 yrs. The median time to progression was 2.4, 9.2, and 19 years in groups 1, 2, and 3 respectively; correspondingly at 10 years, progression occurred in 76%, 59%, and 32% respectively. Significant risk factors for progression with univariate analysis were serum M spike ≥ 4g/dL (p &lt; 0.001), presence of IgA (p = 0.003), presence of urine light chain (p = 0.006), presence of λ urinary light chain (p = 0.002), bone marrow plasma cells ≥ 20% (p &lt; 0.001) and reduction of uninvolved immunoglobulins (p &lt; 0.001). The hemoglobin value, gender, serum albumin, and expression of cyclin D-1 were not of prognostic importance. On multivariate analysis, the percentage of bone marrow plasma cells was the only significant factor predicting progression to MM or AL.

Multiple Myeloma Presenting as Pulmonary, Gastric and Epidural Extramedullary Plasmacytomas: Synchronous Presentation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5050-5050
Author(s):  
Maged Khalil ◽  
Candice Ruby ◽  
Zili He ◽  
Shetra Sivamurthy ◽  
Steier Williams ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Extramedullary Plasmacytoma ◽  
Significant Past Medical History ◽  
Upper Airways ◽  
Response To Chemotherapy ◽  
Gastric Mass ◽  
Extramedullary Plasmacytomas

Abstract Plasma cell tumors are lymphoid neoplastic proliferations of B cells that may be classified as multiple myeloma (MM), solitary bone plasmacytoma (SBP) and extramedullary plasmacytoma (EMP). The extramedullary plasmacytoma account for 1–2% of the total number of plasma-cell growths of which 80 % are originated on the head and neck and upper airways. Males are more frequently affected at sixth-seventh decade. Herein we are presenting a case of 51 years old male with synchronous multiple extramedullary plasmacytomas involving lung, stomach and spine, Presentation of a case 51 years old black male from St. Lucia with no significant past medical history, presented to the local hospital in St. Lucia with hematemesis. Endoscopy was performed and a growth in the stomach was found. He came to the US for treatment. When seen in our hospital, patient complained of black tarry stool, severe right sided chest pain radiating to the back, generalized body aches, fatigue and 10 Lbs. weight loss within the last 2 months Physical examination: revealed tenderness on the right side of chest and back, and decreased breath sound on the righ upper lobe, otherwise unremarkable Work up including CT scan of the chest/abdomen /pelvis showed an irregular right apical mass posteriorly with destruction of the adjacent second and third ribs posteriorly and in T2 and T3 vertebrae, diffuse lytic lesions involving the spines, sacrum, ribs and sternum. There was also a large irregular soft tissue mass the posterior aspect of the fundus of the stomach. Liver, spleen and lymph nodes were normal. Laboratory studies showed WBCs 9.8, Hg 6.9, Platlets 218, BUN 71, Cr. 5.2, Ca 13.4, albumin 3.4, B2 microglobulin 7.5, TP 11.4, LDH 1063, LFT’s all normal, Cea 00 ng/ml, AFP 6.0 ng/ml, Ca19-9 9.4 U/ml, PSA.97 ng/ml, iron study, folate, B12 all within normal range, serum protein electropheresis and immunofixation showed monoclonal spike in the Gamma region 53.8% (IgG Kappa and IgA Kappa), IgG 10917 mg/dl, IgA 85 mg/dl, IgM 16 mg/dl, urine protien elctrophersis showed 88 mg/dl M-spike in beta region, 24 hours urine was 2400 mg/24 h Bone marrow biopsy showed extensive infiltration with poorly differentiated plasma cells, flow cytometry consistent with plasma cell neoplasm, cytogenetics and FISH did not show any evidence of chromosome 13 deletion or trisomy 11. Gastric mass biopsy and lung mass biopsy showed plasma cells similar to the bone marrow infiltrate consistent with plasmacytoma. Diagnosis of multiple myeloma and multiple extramedullary plasmacytomas were made. Plasmaphersis was started because of worsening renal function despite aggressive hydration. Kidney function and calcium level normalized after 5 sessions of Plasmaphersis. Chemotherapy with Doxil, Vincrestine and dexamethasone (DVd) was started. Because of the persistent drop in hemoglobin from gastric mass bleeding, Radiation therapy to the gastric area was given (2300 cGy in 4 weeks) While on treatment he developed severe bilateral lower extremities weakness, MRI showed 8 cm epidural mass at the T8 level, the field of radiation was increased to include the new lesion along with Decadron. He developed severe oral mucositis, esophagitis pancytopenia, continue to bleed from the gastric mass, and finally developed an overwhelming VRE sepsis and shock. He was transferred to MICU and expired despite aggressive supportive care. Conclusion: MM can present as multiple extramedullary plasmacytomas. The response to chemotherapy is very poor The prognosis is very poor,

Angiogenesis in Multiple Myeloma (MM): Angiogenic Switch or Reflexion of Plasma Cell Number? A Gene Expression Based Survey in Primary Myeloma Cells and the Bone Marrow Microenvironment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3405-3405
Author(s):  
Dirk Hose ◽  
John DeVos ◽  
Christiane Heiß ◽  
Jean-Francois Rossi ◽  
Angela Rösen-Wolff ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Empirical Bayes ◽  
Plasma Cells ◽  
De Novo ◽  
Cell Number ◽  
Bone Marrow Microenvironment ◽  
Myeloma Cells ◽  
Angiogenic Switch

Abstract BACKGROUND. Angiogenesis is a hallmark of active multiple myeloma. However, two etiologic hypotheses have been proposed: an angiogenic switch (i.e. differential or de novo expression of pro/antiangiogenic genes in MM), and, alternatively an effect of increased plasma cell number. AIM of this study was to investigate the angiogenic signature of multiple myeloma cells (MMC), normal bone marrow plasma cells (BMPC), the bone marrow microenvironment (BMME) and cellular subfractions therein. PATIENTS AND METHODS. 128 newly diagnosed MM-patients (65 training (TG) / 63 independent validation group (VG)) and 14 normal donors (ND) were included. Bone marrow aspirates were CD138-purified by activated magnetic cell sorting. Whole bone marrow (n=49) and FACSAria sorted subfractions thereof (n=5) were investigated. RNA was in-vitro transcribed and hybridised to Affymetrix HG U133 A+B GeneChip (TG) and HG U133 2.0 plus arrays (VG). Expression data were gcrma-normalised and the empirical Bayes algorithm used. p-Values were adjusted using the Benjamini-Hochberg method (Bioconductor). iFISH was performed on purified MM-cells using probesets for chromosomes 1q21, 9q34, 11q23, 11q13, 13q14, 15q22, 17p13, 19q13, 22q11 and the translocations t(4;14) and t(11;14). HGF expression was verified by real time RT-PCR and western blotting. Based on Medline review, we established a list of 89 pro- and 56 antiangiogenic genes and investigated their expression according to the stage of disease: BMPC vs. MGUS, SD stage I (asymptomatic myeloma) vs. SD stage II/III (symptomatic myeloma requiring therapy). RESULTS. BMPC express pro- (e.g. VEGFA) and antiangiogenic genes (e.g. TIMP2). Only one pro-angiogenic gene (hepatocyte growth factor, HGF) is significantly overexpressed in MMC compared to BMPC. HGF has previously been linked with myeloma progression and induction of angiogenesis. Six antiangiogenic genes (TIMP2, SERPINF1, COL18A1, PF4, THBS1, CXCL14) are downregulated in MMC compared with BMPC. Compared to healthy donors, the BMME of MM shows a significant downregulation of PLAU (urokinase, antiangiogenic) and upregulation of TNF(proangiogenic). CONCLUSION. Upregulation of HGF-expression, downregulation of TIMP2, SERPINF1, COLA18A1, PF4, THBS1 and CXCL14 expression in MMC as well as downregulation of PLAU and upregulation of TNFα in the BMME seem to indicate an “angiogenic switch”. However, given the relatively low number of differentially expressed genes (7/145) and the expression of angiogenic genes by BMPC, an effect caused by an increasing number of plasma cells might be evenly important.

Inhibition of Interleukin-6 Signaling with CNTO 328 Sensitizes Plasma Cell Dyscrasias to the Effects of Melphalan in Association with Suppression of Signaling through Protein Kinase B/Akt.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1836-1836
Author(s):  
Sally A. Hunsucker ◽  
Valeria Magarotto ◽  
Jairo A. Matthews ◽  
Michael Wang ◽  
Veerabhadran Baladandayuthapani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Kinase ◽  
Cell Lines ◽  
Plasma Cell ◽  
Stromal Cells ◽  
Plasma Cells ◽  
Protein Kinase B ◽  
Myeloma Cell ◽  
Ortho Biotech ◽  
Plasma Cell Dyscrasias

Abstract Abstract 1836 Poster Board I-862 Background: The neutralizing anti-interleukin (IL)-6 monoclonal antibody (MAb) CNTO 328 acts in an additive to synergistic manner to enhance the activity of bortezomib and dexamethasone against models of multiple myeloma by suppressing several IL-6-induced anti-apoptotic signaling pathways. We therefore sought to evaluate the possibility that blockade of IL-6 signaling could also augment the activity of melphalan, and to determine the potential mechanisms underlying this interaction. Methods: A panel of myeloma cell lines was studied both in suspension and with bone marrow stromal cells to evaluate the activity of CNTO 328 with and without melphalan. The CNTO 328 + melphalan combination was also tested in primary cells from patients with a variety of plasma cell dyscrasias. Results: Treatment of IL-6-dependent KAS-6/1, INA-6, and ANBL-6 myeloma cell lines with CNTO 328 + melphalan reduced plasma cell viability in an additive-to-synergistic manner compared to melphalan with a control MAb. Isobologram analysis demonstrated that the combination was synergistic in KAS-6/1 cells regardless of the sequence of drug treatment (combination indices (CIs) from 0.275-0.607), although the strongest synergy was seen with CNTO 328 pretreatment (CIs from 0.275-0.493). These anti-proliferative effects were accompanied by an enhanced activation of drug-specific apoptosis, and this increased cell death was not rescued by the trophic effects of co-culture of plasma cells with the human-derived stromal cell line HS-5. CNTO 328 increased melphalan-mediated induction of both extrinsic, caspase-8-mediated apoptosis, as well as intrinsic, caspase-9-mediated death, which converged to produce increased levels of caspase-3 activity. Apoptosis was enhanced in part by CNTO 328-stimulated cleavage of Bid to tBid, and alterations in the phosphorylation status of BimEL, as well as increased conversion of Bak and, to a lesser extent, of Bax, to their active forms. Neutralization of IL-6 by CNTO 328 also suppressed signaling through the protein kinase B/Akt pathway, as evidenced by decreased levels of phospho-Akt, and decreased activation of several downstream Akt targets, including p70 S6 kinase and 4E-BP1. Importantly, CNTO 328 + melphalan showed enhanced anti-proliferative effects compared to melphalan and a control MAb against primary CD138+ plasma cells derived from patients with multiple myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis, while demonstrating less toxicity to stromal cells. The enhanced effect of the CNTO 328 + melphalan combination was statistically significant compared to either drug alone (p<0.05) in CD138+ cells isolated from patients who had not received prior melphalan therapy. Conclusions: These studies provide a rationale for translation of CNTO 328 into the clinic in combination with melphalan-based therapies, including either high dose therapy in transplant-eligible patients, or standard dose melphalan-containing induction regimens in transplant-ineligible patients, such as with the combination of bortezomib, melphalan, and prednisone. Disclosures: Voorhees: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Xie:Centocor Ortho Biotech Inc.: Employment. Cornfeld:Centocor Ortho Biotech Inc.: Employment. Nemeth:Centocor Ortho Biotech Inc.: Employment.

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