Altered Plasma Cell Characteristics in Smoldering Myeloma and MGUS Patients with Preceding Immune-Related Conditions

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4006-4006
Author(s):  
Mary L Kwok ◽  
Neha Korde ◽  
Elisabet E. Manasanch ◽  
Aaron W. Flanders ◽  
Irina Maric ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Plasma Cell ◽  
Mayo Clinic ◽  
Plasma Cells ◽  
Risk Model ◽  
Autoimmune Disorder ◽  
Epidemiological Studies ◽  
Newly Diagnosed ◽  
Smoldering Myeloma

Abstract Abstract 4006 Background Emerging evidence from epidemiological studies suggests that immune-related conditions play a role in the causation of multiple myeloma (MM) precursor disease (smoldering myeloma, SMM; and monoclonal gammopathy of undetermined significance, MGUS) and is of clinical importance for the risk of developing MM. Recent guidelines emphasize tailored follow-up and the need for clinical trials for high-risk SMM. Aim of our study was to assess whether there is an altered biology in SMM/MGUS patients with preceding immune-related conditions. Methods From our ongoing prospective SMM/MGUS natural history study, we evaluated 85 SMM and 74 MGUS patients. Information on autoimmunity was identified at baseline. All patients underwent extensive clinical and molecular characterization. At baseline, all patients underwent bone marrow biopsy evaluation with immunohistochemistry and were assessed for expression patterns of adverse (CD56, CCND1, CD117) plasma cell biology, and applied risk-models based on serum immune markers and bone marrow characteristics. For the purpose of comparison, SMM/MGUS patients were compared to 29 patients newly diagnosed MM. Results Among enrolled SMM and MGUS patients, 10 (12%) and 12 (16%) had a preceding autoimmune disorder; 75 (88%) of SMM and 62 (84%) of MGUS patients did not have a preceding autoimmune disorder. In accordance with our previous findings, we found SMM/MGUS patients with (vs. without) preceding autoimmune disorders to have substantially lower rates of CD56 (p=0.004), CCND1 (p=0.02) and CD117 (p=0.11) expressing plasma cells. For SMM and MGUS patients with preceding autoimmunity, the proportion of CD56, CCND1 and CD117 positive plasma cells was virtually the same. Compared to newly diagnosed MM patients, MGUS or SMM patients with a preceding autoimmune disorder had significantly lower rates of CD56 (p=0.04) and CCND1 (p=0.06) expressing plasma cells; SMM patients without preceding autoimmunity were non-differential from newly diagnosed MM. For SMM patients without preceding autoimmunity newly diagnosed MM patients, the proportion of CD56, CCND1 and CD117 positive plasma cells was very similar. Using Mayo Clinic risk-model, none of the SMM patients with a preceding autoimmune disorder had high-risk features; in contrast, 3/75 (4%) of those without a preceding autoimmune disorder were high-risk SMM. Using Mayo-Clinic risk model, none of the MGUS patients were high-risk independent of autoimmune status. Conclusions Our prospective clinical study found SMM patients with preceding immune-related conditions to have less adverse biology, whereas SMM patients without preceding immune-related conditions to have characteristics similar to patients with MM, supportive of epidemiological studies suggesting the risk of developing MM is substantially lower in patients with preceding autoimmunity. Disclosures: No relevant conflicts of interest to declare.

Role of immune-related conditions in smoldering myeloma and MGUS.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8104-8104 ◽  
Author(s):  
Mary Kwok ◽  
Neha Korde ◽  
Elisabet E. Manasanch ◽  
Manisha Bhutani ◽  
Irina Maric ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Mayo Clinic ◽  
Plasma Cells ◽  
Risk Model ◽  
Expression Patterns ◽  
Autoimmune Disorder ◽  
Epidemiological Studies ◽  
Smoldering Myeloma

8104 Background: Recent guidelines emphasize tailored follow-up and the need for clinical trials for high-risk smoldering myeloma (SMM). Emerging evidence from epidemiological studies suggests that immune-related conditions play a role in the causation of myeloma precursor disease (SMM and monoclonal gammopathy of undetermined significance; MGUS) and are of clinical importance for the risk of developing multiple myeloma. The aim of our study is to assess whether there is an altered biology in SMM/MGUS patients with preceding immune-related conditions. Methods: From our ongoing prospective SMM/MGUS natural history study, we evaluated 56 SMM and 60 MGUS patients. Information on autoimmunity was identified at baseline. All patients underwent extensive clinical and molecular characterization. At baseline, all patients underwent bone marrow biopsy evaluation using immunohistochemistry and multi-color flow cytometry of plasma cells. We assessed expression patterns of adverse plasma cell markers (CD56 and CD117), and applied risk models based on serum immune markers and bone marrow findings. Results: Among enrolled SMM and MGUS patients, 7 (12%) and 9 (15%) had a preceding autoimmune disorder. We found SMM patients with (vs. without) a preceding autoimmune disorder to have a substantially lower rate of CD56 (28% vs. 61%) and CD117 (28% vs. 61%) expressing plasma cells. When we compared the same markers in MGUS patients, CD56 and CD117 expression patterns were similar among patients with vs. without preceding autoimmunity (10% vs. 17%, and 50% vs. 48%). Using the Mayo Clinic risk model, none of the SMM patients with a preceding autoimmune disorder had high-risk features; in contrast, 3/41 (7%) of those without a preceding autoimmune disorder were high-risk SMM. Using the Mayo Clinic risk model, none of the MGUS patients were high-risk independent of autoimmune status. Conclusions: Our prospective clinical study found SMM patients with preceding immune-related conditions to have less adverse biology, supportive of epidemiological studies suggesting the risk of developing multiple myeloma is substantially lower in these patients.

scholarly journals Peripheral blood monoclonal plasma cells as a predictor of survival in patients with multiple myeloma [see comments]

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1780-1787 ◽  
Author(s):  
TE Witzig ◽  
MA Gertz ◽  
JA Lust ◽  
RA Kyle ◽  
WM O'Fallon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
High Risk ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Cell Labelling ◽  
Newly Diagnosed ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Beta 2 Microglobulin

Abstract The purpose of this study was to quantitate the number and labeling index of monoclonal plasma cells in the blood of patients with newly diagnosed multiple myeloma (MM) to learn if these values were independent prognostic factors for survival. Patients were candidates for this study if they had untreated myeloma requiring therapy, were evaluated at our institution between 1984 and 1993, and had a sample of blood analyzed with a sensitive immunofluorescence technique for monoclonal plasma cells and the blood B-cell labelling index (BLI). The % blood monoclonal plasma cells (%BPC) and the BLI were analyzed along with stage, marrow plasma cell LI, % marrow plasma cells, calcium, creatinine, albumin, beta-2-microglobulin, and C-reactive protein as univariate and multivariate factors for survival. Eighty percent of the 254 patients accrued to this study had monoclonal BPC detected. The median % BPC was 6% and 57% (144 of 254) of patients had a high number (> or = 4%). Patients with > or = 4% BPC had a median survival of 2.4 years vs 4.4 years for those with < 4% BPC (P < .001). The BLI was also prognostic (P = .008). In a multivariate analysis, the % BPC, age, albumin, stage, marrow plasma cell LI, and the BLI were independent factors for survival. The %BPC and the marrow plasma cell LI best separated the group into low, intermediate, and high risk myeloma with median survivals of 52, 35, and 26 months, respectively. Patients with high %BPC were less likely to have lytic bone disease from their MM (P = .002). The %BPC and the BLI are independent prognostic factors for survival and are useful in identifying patients as low, intermediate, and high risk. Clonal cells in the blood should be quantified in future clinical trials for myeloma.

Bone Marrow Immunophenotypic Analysis Allows the Identification of High Risk of Progression and Immune Condition-Related Monoclonal Gammopathy of Undetermined Significance.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2804-2804
Author(s):  
AndrÉs Jerez ◽  
Francisco Ortuño ◽  
María del Mar Osma ◽  
Ignacio Español ◽  
Ana Gonzalez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
High Risk ◽  
Plasma Cells ◽  
Plasma Cell Dyscrasia ◽  
Newly Diagnosed ◽  
Immune Disorders ◽  
Chronic Infections ◽  
Risk Of Progression ◽  
Bone Marrow Plasma

Abstract Abstract 2804 Poster Board II-780 Background: Monoclonal gammopathy of undetermined significance (MGUS) progresses to plasma cell dyscrasia, mainly multiple myeloma (MM), at a rate of approximately 1% per year. Moreover, recent studies have shown that MM is nearly always preceded by MGUS, encouraging investigators to find better predictors for MM development in order to implement strategies to prevent or delay progression. In addition, a high prevalence of MGUS has been noted in a series of patients with immune disorders or chronic infections. Multiparameter flow cytometry allows the identification and quantification of both monoclonal and polyclonal plasma cells. This study analyses the relationship between monoclonal and polyclonal bone marrow plasma cells (BMPC), studied by means of flow cytometry, and its association with either immune or infectious disorders, or the development of MM in newly diagnosed MGUS patients. Methods: We conducted a retrospective cohort study to analyse the prognostic value of the aberrant (CD38++ CD138+ CD19– CD45weak) to normal (CD38++ CD138+ CD19+ CD45+) phenotype bone marrow plasma cells ratio (A/N ratio) and another 13 variables at baseline for the development of a plasma cell dyscrasia. We also performed a cross-sectional study to evaluate the association of those variables at baseline with the presence of a chronic immune response disorder. In each patient, the following variables were examined: age, sex, hemoglobin, serum creatinine, serum calcium, B2-Microglobulin, type and size of the serum monoclonal component (MC), isotype of the MC immunoglobulin, presence of urine MC, quantification of serum immunoglobulin levels, erythrocyte sedimentation rate, BMPC percentage and presence of atypical plasma cells on light microscopy, and aberrant and normal phenotype BMPC percentages. The effect of variables on progression was calculated using a Cox proportional hazards regression model. To identify variables at baseline associated with immune or chronic infectious disorders. a series of univariate and multivariate analyses was fitted using a binary logistic regression strategy. Results: Between March 1997 and April 2008, flow cytometry analysis on bone-marrow samples was performed on 322 patients with newly diagnosed MGUS. Median patient age was 71 years (interquartile range (IQR) 63-78 years) with a slightly male predominance (51%). Median follow-up was 46 months (IQR 23-58 months). During the period of observation, in 23 (7.1%) patients a transformation was registered into: MM (n=22), and primary amyloidosis (n=1). A total of 24 (7.4%) patients had a diagnosis of autoimmune disorder, and 18 (5.6%) patients of a chronic infection. Multivariate analysis for progression to MM revealed an increased A/N ratio as the main independent prognostic variable. In addition, our study found a significant association between a reduced A/N ratio and the diagnosis of a chronic immune response related condition. Using receiver-operating characteristic analysis we created an A/N ratio range from 4 to 0.20. Values of 4 or higher define a group of MGUS patients at high risk of progression (OR, 10.7; 95% confidence interval 4.2-39), whereas A/N ratio values of 0.20 or lower are associated with immune disorders or chronic infections (OR, 20.9; 95% confidence interval 8.5-51.1). A total of 282 patients had an A/N ratio below 4, and 42 had values equal to or above the cut-off. Patients with an A/N ratio ≥ 4 had a cumulative probability of transformation of 35% at 5 years, compared with 3% for those with an A/N ratio < 4. Conclusions: Extreme values of the A/N ratio at diagnosis seem to be related with two different conditions: high risk MGUS, likely to progress to MM, and immune condition related MGUS. Our findings further support the routine use of phenotypic characterization of bone marrow plasma cells in patients with MGUS at diagnosis. Disclosures: No relevant conflicts of interest to declare.

Myelomatous Involvement Of The Central Nervous System: Mayo Clinic Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3119-3119 ◽  
Author(s):  
Jonas Paludo ◽  
Utkarsh Painuly ◽  
Shaji Kumar ◽  
Francis Buadi ◽  
Suzanne R Hayman ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
High Risk ◽  
Mayo Clinic ◽  
Plasma Cells ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Cns Involvement ◽  
Cns Disease ◽  
True Incidence

Abstract Background Limited data exist with respect to outcome and optimal therapeutic strategies in patients with central nervous system (CNS) involvement in multiple myeloma (MM). We present a single center experience of patients with myelomatous CNS involvement in newly diagnosed and relapsed / refractory MM. Methods Of 4060 patients with MM seen at Mayo Clinic, Rochester, MN between January, 1st 1998 and December, 31st 2012, 26 patients had identifiable CNS involvement confirmed by biopsy / presence of plasma cells in the cerebrospinal fluid (CSF) and/or identification of intraparenchymal or meningeal involvement by imaging (MRI/CT). Patients were risk stratified by mSMART (Mayo Stratification for Myeloma And Risk-adapted Therapy) criteria. Overall survival (OS) from diagnosis and the time of CNS involvement was calculated using the Kaplan-Meier method. Results Myelomatous CNS involvement occurred in 26 (0.6%) patients with MM of whom 3 were newly diagnosed. The median time to detection of CNS involvement was 24 months (range: 0-125) from diagnosis of MM. Median age at CNS myeloma diagnosis was 58 years (range 37-80) and 73% were male. Abnormally high LDH was observed in 11 out of 22 patients at the time of CNS involvement. Lumbar puncture was performed on 16 patients, 13 (81%) of whom had plasma cells in the CSF detected by cytology/flow-cytometry. Two patients, without evidence of plasma cells, had abnormally high CSF protein and 1 had normal CSF analysis. Of the 25 patients who underwent MRI, 16 (64%) had at least one of the following significant abnormalities; intraparenchymal disease (37%), leptomeningeal enhancement (68%) or direct extension of MM (31%). The neurological symptoms at or after diagnosis of CNS myeloma included headache (38%), cranial nerve palsy (38%), visual disturbance (38%), gait disturbance (35%), paresthesias (35%), limb weakness (31%), confusion (30%), nausea/vomiting (15%), dysarthria (12%), seizures (8%) and urinary incontinence (4%). Fluorescent in-situ hybridization (FISH n=7), cytogenetics (n=8) and/or plasma cell labeling index (PCLI n=12) were available in 18 patients prior to the diagnosis of CNS disease. Ten (56%) out of those 18 patients had high-risk features at least by one criterion. At the time of CNS involvement, six additional patients demonstrated high risk features [5 by PCLI (≥ 3%) and 1 by FISH]. Overall, 16 out of 26 (62%) patients were classified as high risk by mSMART criteria prior to or at the time of CNS involvement. Four (27%) out of 15 had a deletion p53 or monosomy 17 chromosomal abnormality. Median OS was 42 (95% CI, 19-55) months from the diagnosis of MM and 3 months (95% CI: 1-7.9) from the time of CNS involvement (Figure). OS of patients with high risk features was significantly worse (27 months) compared to standard risk disease (67 months, p=0.02) from diagnosis of MM. Eighteen patients received radiation therapy for CNS myeloma. Five of those patients also received intrathecal (MTX and ARA-C) therapy. One patient received intrathecal and systemic chemotherapy. Four patients did not receive any treatment. Novel agents, including bortezomib (23%), thalidomide (15%), and pomalidomide (4%) were administered to the patients post diagnosis of CNS disease. Six (23%) patients underwent autologous stem cell transplant post diagnosis of CNS disease with a median OS of 19 months (95% CI: 10-122 months) from the time of CNS involvement. Conclusion CNS involvement is a rare complication of MM that portends a poor survival outcome. It is likely that the rates in this study are an underestimate of the true incidence due the perceived futility of CNS directed therapy in this disease. Among those recognized, high-risk genetic and markers of increased proliferative activity, including deletion p53 / monosomy 17 and elevated PCLI (≥ 3%) appear to cluster in this cohort. Current therapeutic approaches are largely ineffective in managing this aggressive subset of myeloma patients. Disclosures: No relevant conflicts of interest to declare.

Rising Plasma Cell Proliferation By Ki67/CD138 Ratio at Relapse Is a Marker of High Risk Disease in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2991-2991
Author(s):  
Peter A. Forsberg ◽  
Tomer M Mark ◽  
Sujitha Yadlapati ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Overall Survival ◽  
High Risk ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Initial Therapy ◽  
First Line ◽  
High Risk Disease

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) for years but utilization remains limited. We recently developed a novel immunohistochemical (IHC) co-staining technique for CD138 and Ki67 expression to quantify plasma cells in active cycling. Previously presented results from newly diagnosed patients demonstrate that having an elevated ratio of plasma cells in active cycle by co-expression of CD138 and Ki67 (>5%) is associated with aggressive disease and poor outcomes including shorter overall survival (OS). The expansion of subclones with higher proliferative capacity following initial therapy may be an indicator of a higher risk relapse event and indicate poor prognosis. Here we assess MM patients (pts) with Ki67/CD138 co-staining on bone marrow samples both at diagnosis and relapse to assess the impact of changes in cell cycling ratio on outcomes with subsequent therapy and overall clinical course. Methods: A retrospective cohort study of pts with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital (WCMC/NYPH). For inclusion in the analysis, pts must have had bone marrow evaluation with double-staining for Ki67 and CD138 by immunohistochemistry both at diagnosis and relapse. Pts must have completed their first line and relapse treatments at WCMC/NYPH. The Ki67% was calculated as the ratio of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on alterations in Ki67% between diagnosis and relapse. Results: We identified 37 pts with bone marrow sampling that was evaluated for CD138 and Ki67 co-expression both at diagnosis and at the time of relapse. These pts had undergone a median of 2 lines of prior treatment at the time of relapse bone marrow biopsy (range 1-7). 19 pts were identified to have a rising Ki67% between diagnosis and relapse defined at a 5% or greater increase, the other 18 pts had stable or decreased Ki67%. Pts with a rising Ki67% at relapse had a shorter OS with a median of 72 months vs not reached (p=0.0069), Figure 1. Pts who had rising Ki67% at relapse had shorter progression free survival (PFS) on first line treatment with a median of 25 vs 47 months (p=0.036), Figure 2. Additionally pts with rising Ki67% had a trend towards shorter PFS with the treatment they received after relapse with median of 12.5 vs 3.5 months (p=0.09). Relapse regimens were most commonly carfilzomib (n=9), pomalidomide (5) or ixazomib (4) based. 37% of pts (7/19) with rising Ki67% achieved PR or better on relapsed treatment vs 67% (12/18) with stable Ki67%. Discussion: The presence of clonal evolution and selection of higher risk clones under therapeutic pressure in multiple myeloma is a key feature of disease progression. The ability to improve risk stratification at the time of relapse may help guide clinical decision making to best suit individual patient needs. We have identified rising plasma cell proliferation through quantification of Ki67/CD138 co-expression at relapse to be a useful marker of high risk disease evolution. This appears to help identify the emergence of higher risk clones which are ultimately responsible for treatment resistant disease. Patients with rising Ki67% were more likely than patients with stable Ki67% to have early relapses to initial therapy, were less likely to achieve responses to relapse regimens or to maintain their response and had shorter overall survival. Further evaluation is needed to identify if different approaches to patients with increasing proliferation may improve outcomes in these patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Mark: Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rossi:Calgene: Speakers Bureau. Pearse:Celegen: Consultancy. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Perry:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Niesvizky:Celgene: Consultancy, Speakers Bureau.

A Paracrine Circuit Regulates Vascular Endothelial Growth Factor Production By Bone Marrow Plasma Cells in Patients with POEMS Syndrome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1757-1757
Author(s):  
Chen Wang ◽  
Qian-qian Cai ◽  
Xin-xin Cao ◽  
Dao-bin Zhou ◽  
Jian Li
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Serum Levels ◽  
Poems Syndrome ◽  
Newly Diagnosed ◽  
Bone Marrow Biopsies ◽  
Fluorescent Intensity ◽  
Bone Marrow Plasma ◽  
Endothelial Growth Factor

Abstract Background : POEMS syndrome is a rare paraneoplastic disorder, characterized by polyneuropathy, organomegaly, osteosclerosis and extravascular volume overload, due to an underlying plasma cell dyscrasia. Vascular endothelial growth factor (VEGF), a potent angiogenic cytokine that can increase vascular permeability, plays a critical role in its pathogenesis. Despite extensive VEGF studies concerning its role in disease diagnosis, monitoring and response assessment, little is known about its cellular source and mechanisms governing the production of VEGF in POEMS patients. Methods and Materials : Patients with POEMS syndrome, 62 newly diagnosed and 46 of them after lenalidomide-dexamethasone (LenDex) treatment, admitted to Peking Union Medical College Hospital between February 2014 and April 2015, were included in the current study. Clinical information, serum and bone marrow samples were collected with the Institutional approval. Serum levels of VEGF were measured by ELISA. VEGF levels in bone marrow plasma cells were quantified via real-time quantitative PCR and multiparameter flow cytometry, respectively. In addition, the phenotype, clonality and intracellular interleukin-6 (IL-6) expression of bone marrow plasma cells were also analyzed by flow cytometry. Furthermore, immunohistochemical staining was performed to study the plasma cell distribution, clonality and expression of VEGF, IL-6 and hypoxia-inducible factor-1α (HIF-1α) in bone marrow biopsies. Statistical analyses were conducted using SPSS 22, and a p < 0.05 was considered as significant. Results : Serum levels of VEGF were dramatically elevated in patients with newly diagnosed POEMS syndrome (median 5958 pg/mL), significantly higher than both disease and healthy controls (p < 0.001), and can be used as a diagnostic marker (area under curve 0.988, p < 0.001). A cut-off value of 2000 pg/mL had a specificity of 97.7% with a sensitivity of 91.9% in support of the diagnosis. After treatment, VEGF levels decreased gradually (6-cycle after LenDex, median 1184 pg/mL, p < 0.001; 12-cycle after LenDex, median 832 pg/mL, p < 0.001). Bone marrow plasma cells showed remarkable VEGF expression, validated in both mRNA and protein levels, which also decreased in response to LenDex therapy. More importantly, a statistically linear correlation was observed between serum and bone marrow plasma cell VEGF levels (newly diagnosed patients, rho = 0.33, p = 0.01; post-therapeutic patients, rho = 0.53, p < 0.001), supporting that bone marrow plasma cells were the source of circulating VEGF. Intriguingly, immunophenotying revealed that bone marrow plasma cells were polyclonal in most newly diagnosed cases. Monoclonal population, co-existing with polyclonal plasma cells, was observed only in 11 patients (18%). Further analyses showed that the relative amounts of these two populations were similar (41% vs. 59%) and they also had comparable intracellular VEGF expression (mean fluorescent intensity, 2009 vs. 2367, p = 0.594). However, monoclonal plasma cells had significantly higher intracellular IL-6 expression (mean fluorescent intensity, 1635 vs. 865, p = 0.006). In 46 newly diagnosed cases with bone marrow biopsies available, immunohistochemical staining was performed, and plasma cells were typically distributed in a scattered manner, with focal aggregates observed in 21 cases (46%). Intracellular κ and λ light chain staining demonstrated that the background scattered plasma cells were polyclonal, while both monoclonal and polyclonal fractions were observed in the focal area, which showed similar nuclear and intracellular staining of HIF-1α and VEGF, respectively. In contrast, IL-6 was mainly expressed in λ-restricted plasma cells. Conclusion : Bone marrow plasma cells are the potential source of VEGF production in patients with POEMS syndrome. Monoclonal plasma cells, aggregates focally in the bone marrow, may secret IL-6 to stimulate polyclonal plasma cells proliferation, and consequent VEGF production in a paracrine circuit. Disclosures Off Label Use: Lenalidomide for POEMS syndrome.

A bottom-up proteomic approach in bone marrow plasma cells of newly diagnosed multiple myeloma patients

2020 ◽  
Vol 17 ◽  
Author(s):  
Beycan Ayhan ◽  
Seçil Karahisar Turan ◽  
N. Pınar Barkan ◽  
Klara Dalva ◽  
Meral Beksaç ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Marginal Zone ◽  
Plasma Cells ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Cell Content ◽  
Peptide Mass ◽  
Proteomic Approach

Background: Multiple myeloma (MM) is characterized by infiltration of bone marrow (BM) with clonal malignant plasma cells. The percentage of plasma cells in the BM is required for both diagnosis and prognosis. Objective: Intracellular protein screening and quantitative proteomic analysis was performed in myeloma plasma cells with an aim to compare expressions between low (0-9%), intermediate (10-20%) and high (>20%) plasma cell infiltration groups. Methods: BM aspiration samples were collected from newly diagnosed untreated patients with MM. The samples were pooled into three groups according to the plasma cell content (PCC) in the BM: group 1 (0-9%), group 2 (10-20%) and group 3 (>20%). Protein profiles were obtained and proteins were identified by peptide mass fingerprinting analysis. Results: Differentially expressed proteins were detected between all groups. The identified proteins are Endoplasmin, Calreticulin, Protein Disulfide-isomerase, Marginal zone B and B1 cell specific protein/pERp1, Actin cytoplasmic 1, Myeloblastin, Thioredoxin domain-containing protein 5, Ig kappa chain C region, Apoptosis regulator B-cell lymphoma 2 and Peroxiredoxin- 4. Conclusion: Proteins involved in cell proliferation, apoptosis, redox homeostasis and unfolded protein disposal through endoplasmic reticulum-associated degradation machinery has been found to be correlated to PCC. Our results confirm earlier reports in regards to the potential effects of identified proteins in the major signaling pathways that lead to cancer. Moreover, this study reveals a novel association between PCC levels and MM. It further highlights the roles of Marginal zone B and B1 cell specific proteins in MM, which could be used as candidate biomarkers in future studies.

scholarly journals High and Low Tumor Infiltration Affect the Differences Among the Detection of Plasma Cells Evaluated in Bone Marrow By Flow Cytometry, Aspirate and Biopsy(Grupo Interdisciplinario de Mieloma Multiple, Hospital Universitario Fundacion Santa Fe, Colombia)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5604-5604
Author(s):  
Diego Martinez ◽  
Maria Valencia ◽  
Juan Pablo Mayorga ◽  
Andres Melo ◽  
Carlos Saavedra ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Bone Marrow Involvement ◽  
Tumor Infiltration ◽  
Newly Diagnosed ◽  
Santa Fe ◽  
Plasma Cell Neoplasms ◽  
The Mean

Abstract Background In plasma cell neoplasms, the percentage of plasma cells in bone marrow (PPCBM) is important for diagnosis and assessment of the treatment. This quantification is performed using bone marrow multiparameter flow cytometry (FC), aspirate smears (BMA) and biopsy. Differences among the percentage of infiltration detected by these techniques have been reported, which can be related to a heterogeneous pattern of infiltration of multiple myeloma (MM) or sample quality. However, a simultaneous evaluation of these three techniques has not been reported nor their ability to detect bone marrow involvement with high or low infiltration, associated with different stages of this disease. Purpose The aim of this study was to compare the results of PPCBM obtained by FC, BMA, and biopsy with CD138 immunohistochemistry (BMB) in different stages of the disease with high and low infiltration, and the ability of these techniques to correctly classify the disease. Methods Pathological studies of patients referred to Hospital Fundación Santa Fe, Colombia were reviewed between January 2015 and June 2018. The selection of patients was based on both, a diagnosis of plasma cell neoplasms, classified according to the International Myeloma Working Group criteria and the simultaneous use of FC by FACSCanto II flow cytometer (Infinicyt 2.0 software program), wright-stained aspirate smears and biopsy with CD138 immunohistochemistry in the detection. Descriptive analysis was performed and PPCBM was expressed as the mean± standard error of the mean (SEM). The Kruskal-Wallis test was used to compare the mean of PPCBM among the three methods. Lineal regression and Spearman´s coefficient were used to correlate the variables. Statistical association was considered significant for p values <0.05. Results A total of 130 patients with plasma cells neoplasms were included in this study, 57 with newly diagnosed MM (N), 58 following therapy MM (F) and 15 MGUS patients. In the N patients, the mean of infiltration was 12.3% ±1.8, 30.3% ±3.4 and 52.2% ±3.74 detected by FC, BMA and BMB, respectively. The PPCBM detected by this three analysis were significantly different (p<0.001). In F patients, the mean of infiltration was 0.37% ±0.05, 1.88 % ±0.16 and 2.61% ±0.21 while in MGUS-patients was 0.49% ±0.09, 2.067 % ±0.37 and 2.4% ±0.28 detected by FC, BMA and BMB, respectively. For F and MGUS patients, significant statistic differences between BMB and BMA versus FC (p<0.01) were observed, but not between BMB and BMA (Figure 1). In the comparative analysis of the three methods in all patients, the highest infiltration was always detected by BMB, followed by BMA and finally by FC (p<0.01) (Figure 2). Linear regression established that for each 1% of infiltration detected by FC or BMA, the BMB identified 2.11% and 1.4% of infiltration, respectively (Figure 2). However, each univariate model only explained 55% and 67% of the observed results. Notably, there was a high correlation among these three techniques (Spearman´s coefficient > 0.8). Finally, given that there are important PPCBM such as ≥10 that allows establishing the diagnosis of MM or ≥60%, considered an MM definitive event, we found that 21% and 52% of cases assessed by BMA and FC had PPCBM <10%, but all of them were reclassified as MM with BMB. None case had PCBM <10% using BMB. Finally, among all cases diagnosed as MM, there were identified 26 by FC and 35 cases by BMA with a PCBM percentage between 10 and 59%, of which 84% and 54% respectively had ≥60% of involvement detected by BMB Conclusion In the comparison of the PCBM was observed a high linear correlation between MFC, BMA, and BMB, although we found a differential behavior of these methods, depending on the level of tumor infiltration. High percentages of infiltration, such as newly diagnosed MM patients, the BMB detected significantly more PPCBM than the others two methods (1.7 to 4-fold compared to BMA and FC). This supports the systematic incorporation of BMB into the analysis of patients with suspected MM for allowing a proper classification of disease. With low percentages of infiltration, such as MGUS and following therapy patients, the difference of PPCBM between BMA and BMB was not significant. Although, FC detected the lowest percentage of infiltration, it known its high specificity to discriminate tumor and normal plasma cells, being in one of the most important analysis to monitor minimal residual. Disclosures No relevant conflicts of interest to declare.

Pretreatment Plasma Cell Proteasome Levels Predict Responses To Treatment With Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Followed By Lenalidomide Extended Dosing (CRd-R) In Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1905-1905
Author(s):  
Irina Maric ◽  
Olga Simakova ◽  
Neha Korde ◽  
Adriana Zingone ◽  
Rene Costello ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Partial Response ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Single Agent ◽  
Newly Diagnosed ◽  
Proteasome Subunit ◽  
Flow Cytometric ◽  
Best Responses

Abstract Background Carfilzomib (Cz) is an irreversible proteasome inhibitor with potent anti-myeloma effects resulting in deep clinical responses and durable remissions in the majority of patients. In our two-stage phase II trial of 45 newly diagnosed multiple myeloma (MM) patients using carfilzomib (Cz), lenalidomide (Ln), and dexamethasone (Dx) combination therapy followed by 2 years of Ln maintenance, best responses after a median of 9 completed cycles (range 2-20), included 17-stringent-(s)-complete response-(CR)/1-CR/6-near-(n)-CR (63%), 10-very good partial response (VGPR) (26%), 3-partial response (PR) (8%), and 1-stable disease (SD) (3%) (reported in a separate abstract). In this pre-planned correlative sub-study based on our ongoing clinical CRd trial for newly diagnosed MM patients, we conducted a prospective flow cytometric study designed to characterize pretreatment levels of proteasomes and aggresomes in plasma cells in relation to response to therapy. Methods Bone marrow aspirates were collected at baseline and C1D2 (single agent Cz exposed). Permeabilized CD138 and CD38 positive plasma cells were tested using anti-19S proteasome subunit antibodies (Abcam, Cambridge, UK). In parallel, cells were labeled with ProteoStat Aggresome Detection Reagent (Enzo Life Sciences, Farmingdale, NY). Multicolor flow cytometric acquisition and analysis was performed using BD FACS CANTO and DIVA software. Data was expressed as mean fluorescence intensity (MFI) ratio using isotype-matched controls. Patients’ best responses to therapy after minimum of 4 cycles were correlated to the acquired proteasome and aggresome data. Statistical analysis was performed using DataPrism software. Statistical significance was considered as p-value <0.05. Results Total of 21 patients were assessed: 14 achieved CR (CR group), 4-VGPR, 2-PR and 1-SD (non-CR group). The median plasma cell 19S MFI ratio in the CR group was 20.21 (range 5.21-84.27), and in the non-CR group 6.19 (range 2.88-11.68), p<0.005. The percent of plasma cells in bone marrow aspirates was not statistically significantly different between two groups. 45% of non-CR patients had plasma cell 19S MFI ratio of less than 5, while 65% of CR patients had plasma cell 19S MFI ratio of over 12. After single agent Cz treatment (C1D2) plasma cell 19S proteasome MFI ratio in the CR group decreased in 90% of patients, while aggresome MFI ratio increased compared to baseline. Conversely, in the non-CR group, C1D2 plasma cell 19S MFI ratio increased in 80% of patients, while aggresome MFI ratio remained unchanged or decreased compared to baseline. Conclusions We found the pretreatment florescence intensity (MFI) ratio of 19S proteasome subunit in plasma cells to be significantly higher in MM patients who obtained CR (versus non-CR) when treated with CRd treatment. None of the patients with pretreatment 19S MFI ratio of less than 5 achieved CR; conversely, all patients with pretreatment 19S MFI ratio of over 12 achieved CR. After a single dose of carfilzomib, 90% of CR patients had decreased 19S MFI and increased aggresomes MFI ratio, while 80% of non-CR patients showed opposite changes: increased 19S MFI and unchanged/decreased aggresomes MFI ratio. We conclude that pretreatment plasma cell proteasome levels predict response to the CRd treatment in newly diagnosed MM patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Peripheral blood monoclonal plasma cells as a predictor of survival in patients with multiple myeloma [see comments]

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1780-1787 ◽  
Author(s):  
TE Witzig ◽  
MA Gertz ◽  
JA Lust ◽  
RA Kyle ◽  
WM O'Fallon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
High Risk ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Cell Labelling ◽  
Newly Diagnosed ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Beta 2 Microglobulin

The purpose of this study was to quantitate the number and labeling index of monoclonal plasma cells in the blood of patients with newly diagnosed multiple myeloma (MM) to learn if these values were independent prognostic factors for survival. Patients were candidates for this study if they had untreated myeloma requiring therapy, were evaluated at our institution between 1984 and 1993, and had a sample of blood analyzed with a sensitive immunofluorescence technique for monoclonal plasma cells and the blood B-cell labelling index (BLI). The % blood monoclonal plasma cells (%BPC) and the BLI were analyzed along with stage, marrow plasma cell LI, % marrow plasma cells, calcium, creatinine, albumin, beta-2-microglobulin, and C-reactive protein as univariate and multivariate factors for survival. Eighty percent of the 254 patients accrued to this study had monoclonal BPC detected. The median % BPC was 6% and 57% (144 of 254) of patients had a high number (> or = 4%). Patients with > or = 4% BPC had a median survival of 2.4 years vs 4.4 years for those with < 4% BPC (P < .001). The BLI was also prognostic (P = .008). In a multivariate analysis, the % BPC, age, albumin, stage, marrow plasma cell LI, and the BLI were independent factors for survival. The %BPC and the marrow plasma cell LI best separated the group into low, intermediate, and high risk myeloma with median survivals of 52, 35, and 26 months, respectively. Patients with high %BPC were less likely to have lytic bone disease from their MM (P = .002). The %BPC and the BLI are independent prognostic factors for survival and are useful in identifying patients as low, intermediate, and high risk. Clonal cells in the blood should be quantified in future clinical trials for myeloma.

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