High-dose sequential chemoradiotherapy in multiple myeloma: residual tumor cells are detectable in bone marrow and peripheral blood cell harvests and after autografting

Based on preliminary encouraging results in terms of response rate and survival, high-dose chemoradiotherapy has gained considerable interest in the treatment of patients with multiple myeloma (MM). We have evaluated the presence of residual myeloma cells in 15 of 18 patients enrolled in a high-dose sequential (HDS) chemoradiotherapy program followed by autografting. Our analysis has been performed both on bone marrow (BM) and peripheral blood (PB) cell harvests and after autografting. As it has been recently shown that B cells clonally related to malignant plasma cells are detectable in MM patients, we have developed a polymerase chain reaction (PCR)-based strategy to detect both residual B cells and plasma cells using clone-specific sequences derived from the rearrangement of Ig heavy chain (IgH) genes. The complementarity-determining regions (CDR) of IgH genes have been used to generate tumor-specific primers and probes. The constant (C) region usage defined the differentiation stage of residual myeloma cells. We report that plasma cells were detectable in PB and BM cell harvests and after transplantation in all assessable patients, irrespective of disease status. B cells were detectable in a consistent proportion of BM and PB samples at diagnosis, but only in one case at the time of PB and BM cell harvests. These cells became sometimes detectable after transplantation. Whether residual myeloma cells are clonogenic and contribute to relapse is currently unknown, and further investigations are required.

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Multiple Myeloma Cancer Stem Cell Animal Model.

Blood ◽

10.1182/blood.v114.22.1848.1848 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1848-1848

Author(s):

Christina C.N. Wu ◽

Daniel Jacob Goff ◽

Wenxue Ma ◽

Heather Leu ◽

Thomas A. Lane ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

B Cells ◽

Plasma Cells ◽

Memory B Cells ◽

The Self ◽

High Dose ◽

Self Renewal ◽

Immunomagnetic Bead

Abstract Abstract 1848 Poster Board I-874 Multiple myeloma (MM) is the second most common hematologic malignancy and characterized by clonal proliferation of CD138+ bone marrow plasma cells. Despite various treatment options few patients with MM have been cured. Furthermore, high relapse rates and recent evidence from xenogeneic transplantation models and primary MM marrow samples indicate that a rare population of cells or MM cancer stem cells (MM CSCs) within the marrow regenerates itself and may be responsible for drug resistance. These MM CSCs are phenotypically similar to memory B cells (CD138- CD34-CD19+) but differ in that they have the capacity to regenerate themselves or self-renewal. However, most of the reports on MM CSC animal models are established in NOD/SCID mice that require a larger number (1 – 10 × 106) of bead sorted cells for each animal. In addition, the latency of MM induction (4 – 6 months) in NOD/SCID mouse models and lack of in vivo tracking of the malignant clone preclude robust pre-clinical testing of novel therapeutic strategies that target MM CSC. Mononuclear cells were isolated from autologous mobilized peripheral blood of at least four primary MM patients after Ficoll gradient centrifugation followed by immunomagnetic bead depletion of CD34+ and CD138+ cells and/or further sorted using a FACSAria. The CD138-CD34- population was transduced with lentiviral luciferase GFP (GLF) and transplanted (10,000 to 106 cells per mouse) intrahepatically into neonatal RAG2-/- gamma chain-/- (RAG2-/-gc-/-) mice. Engraftment was compared to mice transplanted with either CD34+ or CD138+ cells. Mice were imaged with an in vivo imaging system (IVIS) to detect bioluminescent engraftment. Results showed that a relatively rare CD138- CD27+ population, resembling memory B cells (∼1.2%), persists in MM autografts and can engraft immunocompromised mice more rapidly and effectively than the CD138+ (Lin+) population of mature plasma cells. This data supports the persistence of CSCs despite high dose chemotherapy further underscoring the need for CSC targeted therapy. Bioluminescence was detected in live mice transplanted with as little as 60,000 cells of CD138- CD34- population and as soon as 4 weeks after transplantation. FACS analysis of these mice demonstrated successful engraftment with the presence of CD45+ and CD138+ population in bone marrow, spleen and liver and bioluminescence was also detected in the secondary transplantation of cells from MMCSC primary engraftment demonstrating the self-renewal capacity of this rare CD138- CD27+ population. Our results suggest that by utilizing a lentiviral GFP-luciferase system in a highly immunocompromised mouse strain fewer cells will be required to monitor MM engraftment and perhaps hasten disease development. Further studies to confirm the expression of selected IgG genes from myeloma cells and to characterize the self-renewal capacity with genes involved in developmental signaling such as sonic hedgehog and wnt pathways are underway. Disclosures: Goff: Coronado Biosciences: Research Funding.

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

Blood ◽

10.1182/blood.v122.21.1907.1907 ◽

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.

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

Blood ◽

10.1182/blood.v84.6.1922.1922 ◽

1994 ◽

Vol 84 (6) ◽

pp. 1922-1930 ◽

Cited By ~ 142

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.

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

Blood ◽

10.1182/blood.v84.6.1922.bloodjournal8461922 ◽

1994 ◽

Vol 84 (6) ◽

pp. 1922-1930 ◽

Cited By ~ 1

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.

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Non-Invasive Liquid Biopsy to Quantify and Molecularly Characterize Circulating Multiple Myeloma Cells in the Assessment of Precursor Disease Pathology

Blood ◽

10.1182/blood-2021-150622 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 78-78

Author(s):

Ankit K. Dutta ◽

Elizabeth D. Lightbody ◽

Ziao Lin ◽

Jean-Baptiste Alberge ◽

Romanos Sklavenitis-Pistofidis ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Molecular Characterization ◽

Peripheral Blood ◽

Plasma Cells ◽

Whole Genome ◽

Myeloma Cells ◽

Molecular Analyses ◽

Non Invasive

Abstract Introduction: Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by the abnormal growth of clonal plasma cells in the bone marrow (BM). In most cases MM develops from early, asymptomatic disease stages known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Despite effective new therapies, most MM patients inevitably relapse and require further treatment, highlighting the need for better early detection methods for precursor patients and targeted interventions to prevent early disease from progressing. The initial diagnosis of MGUS/SMM remains an incidental process following the identification of increased clonal immunoglobulin in the blood. BM biopsy is the gold standard for diagnosis and monitoring of MM progression, but is intrusive, painful, and comes with possible secondary complications for patients. Consequently, repeated assessment is not a feasible option for MGUS and SMM patients who are asymptomatic. Here we tested the utility of circulating multiple myeloma cells (CMMCs) from non-invasive blood biopsy to accompany BM as a method to monitor disease development, by enumerating CMMCs from MGUS/SMM patients. Methods: Peripheral blood from 185 precursor patients (75 MGUS and 110 SMM) from the Dana-Farber Cancer Institute observational PCROWD study (IRB #14-174) was collected in CellRescue TM Preservative Tubes and processed on the CellSearch CellTracks Autoprep system using the CMMC assay kit using 4mL of blood. This assay employs the enrichment of CMMCs through the immunophenotype of CD138 +CD45 -19 -, and leukocyte exclusion based on CD45 +CD19 +. Nucleated cells were identified using DAPI staining. The CellTracks Analyzer II fluorescence microscope system was subsequently used to scan captured CMMC cartridges, with software allowing the automated scoring and enumeration of CMMCs. Additional molecular analyses were carried out on SMM patients. Briefly, minipools of CMMCs were sorted by DEPArray and underwent whole genome amplification using Ampli1 kit, PCR-free library construction, quantification and low pass whole genome sequencing (~0.5x) on the Illumina HiSeq2500. To assess whether molecular analyses can be performed to detect hyperdiploidy as a genomic biomarker of MM disease, ichorCNA analyses was performed to determine copy number variant (CNV) events and infer tumour fraction. Results: CMMCs were detected in 27% of MGUS patients collected, with a median count of 2 CMMCs (range 0 to 1328). Comparably, CMMCs were detected in 57% of SMM patients, with a median enumeration of 13 CMMCs (range 0 to 43836). Enumeration of CMMCs illustrated a correlation with clinical measure of disease including the International Myeloma Working Group 2/20/20 risk stratification model. A higher CMMC count was associated with increasing risk group based on the 3-risk factor model, with a median of 5, 29 and 59 CMMCs detected at low, intermediate, and high-risk SMM groups, respectively. CMMC counts were significantly increased at intermediate (P = 5.0 x 10 -4) and high-risk stages (P = 3.7 x 10 -3) compared to low-risk. While enumeration provides a correlative measure of CMMCs that may be of tumor origin, downstream molecular characterization can confirm MM-associated genetic alterations. At the precursor stages, a low tumour burden is evident clinically, thus both normal and malignant plasma cells are present. Therefore, to determine the concordance between bone marrow and peripheral blood CMMCs, we performed genomic analyses to identify arm level gain or loss events. Molecular analyses of CMMCs was carried out in patients who had matched BM and clinical fluorescent in situ hybridization (FISH) results. We showed that CMMCs can capture 100% of clinically annotated BM FISH CNV events. Furthermore, CMMC samples identified additional yield, with further CNVs identified that were not observed by FISH. In cases that did not have BM biopsy results, sequencing of CMMCs revealed the existence of genetic aberrations. Conclusion: Our results demonstrate clinical correlation and molecular characterization of CMMCs from MGUS/SMM patients. This study provides a foundation for non-invasive detection, enumeration and genomic interrogation of rare CMMCs from the peripheral blood of MGUS/SMM, illustrating the clinical potential of using liquid biopsies for monitoring and managing disease in the precursor setting of MM. Disclosures Getz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

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Bone Morphogenic Protein 6: A Prognostic Factor Expressed by Normal Plasma Cells and Multiple Myeloma Cells Inhibiting Their Proliferation and Angiogenesis Induction

Blood ◽

10.1182/blood.v112.11.2701.2701 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2701-2701

Author(s):

Anja Seckinger ◽

Tobias Meißner ◽

Jérôme Moreaux ◽

Hartmut Goldschmidt ◽

Axel Benner ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Cell Lines ◽

Plasma Cells ◽

Myeloma Cell ◽

High Dose Chemotherapy ◽

High Dose ◽

Myeloma Cells

Abstract BACKGROUND: Pathogenesis of multiple myeloma is partly attributed to an aberrant expression of proliferation-, pro-angiogenic and bone-metabolism modifying factors by malignant plasma-cells. AIM. Given the long and variable time-span from first diagnosis of early-stage plasma-cell dyscrasias to overt myeloma and the low proliferation rate of malignant plasma-cells, we hypothesize these to concomitantly express a novel class of anti-proliferative factors of potential prognostic relevance. Here, bone morphogenic proteins (BMPs) represent possible candidates, as they inhibit proliferation, stimulate bone formation, and have an impact on the survival of cancer patients. PATIENTS AND METHODS. We assessed expression of BMPs and its receptors by Affymetrix DNA-microarrays (n=434) including CD138-purified primary myeloma-cell-samples, normal bone-marrow plasma-cell-samples, polyclonal plasmoblasts-samples, human myeloma-cell-lines (HMCL), and whole bone-marrow. Presence and differential gene expression was determined by PANP-algorithm and empirical Bayes statistics. Event-free (EFS) and overall survival (OAS) were investigated for the 168 patients undergoing high-dose chemotherapy (HM-group) using Cox’s proportional hazard model. Findings were validated using the same strategy on an independent group of 345 patients from the Arkansas-group. For validation, quantitative real-time PCR and flow cytometry were performed. In vitro induction of angiogenesis was assessed using the AngioKit-assay. Effect of BMP6 on proliferation of HMCL was assessed by 3H-thymidine uptake. RESULTS. BMP6 is the only BMP expressed by normal- (13/14 samples) and malignant plasma-cells (228/233 samples). It is significantly lower expressed in proliferating non-malignant plasmablastic cells and human myeloma cell-lines. In vitro, BMP6 significantly inhibits proliferation of myeloma-cell-lines with an IC50 ranged from 0.08–2.15μg/ml, survival of primary myeloma-cells, and in vitro tubule formation down to the level of the negative control. High BMP6-expression in malignant plasma cells delineates significantly superior overall-survival for patients undergoing high-dose chemotherapy in both independent series of patients (n=168, P=.02 and n=345, P=.03, respectively, see below). CONCLUSION. With BMP6 we report for the first time the autocrine expression of a prognostically relevant anti-angiogenic and anti-proliferative factor and its receptors by normal and malignant plasma-cells. Figure Figure

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Malignant Plasma Cells Responsible for Multiple Myeloma Relapse Are Detectable and Survive Nine Days After High Dose Melphalan: Highlight of An Optimal Therapeutic Window ?

Blood ◽

10.1182/blood.v118.21.131.131 ◽

2011 ◽

Vol 118 (21) ◽

pp. 131-131

Author(s):

Anouk Caraux ◽

Laure Vincent ◽

Jerome Moreaux ◽

Guilhem Requirand ◽

Caroline Bret ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Stem Cell ◽

Growth Factor ◽

Plasma Cells ◽

Therapeutic Window ◽

High Dose ◽

Myeloma Cells ◽

Time Points ◽

High Dose Melphalan

Abstract Abstract 131 Background and Objectives: Multiple myeloma (MM) is still an incurable plasma cell dyscrasia. In an attempt to further improve MM patients' outcome, we have characterized malignant plasma cells resistant to treatments as well as their cellular and molecular environment. The aim is to highlight interactions that could be targeted at optimal time points of the treatment schedule. Methods: Twenty-four newly diagnosed MM patients treated in first line by bortezomib and dexamethasone induction followed by high dose melphalan (HDM) and autologous stem cell transplantation were included. Tumor and normal plasma cell were detected and counted in peripheral blood and bone marrow using 7-color multiparameter flow cytometry at different time points of treatment: at the end of induction, 9 days, 3 months and 6 months after high dose melphalan and autologous stem cell reinjection. The sensitivity of detection reached was 10−5. The cellular content of the leukapheresis product was also analyzed after thawing before being reinjected. Plasma cells were characterized in terms of tumor markers (CD200, CD56, CD117, CD27, CD19, CD45), proliferation status (KI67) and expression of CCR2 chemokine receptor. Using multiplex technique, we also evaluated the medullary cytokine / chemokine environment (Interleukin-1b (IL-1b), IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, Epidermal Growth Factor (EGF), eotaxin, Fibroblast Growth Factor-basic (FGF-b), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), G-CSF, Hepatocyte Growth Factor (HGF), Interferon-a (IFN-a), IFN-g, Inducible Protein 10 (IP-10, CXCL10), Monocyte Chemotactic Protein-1 (MCP-1, CCL2), Monokine Induced by IFN-g, Regulated on Activation Normally T-cell Expressed and Secreted (RANTES, CCL5), Tumor Necrosis Factor a (TNF- a), and Vascular Endothelial Growth Factor (VEGF) at the end of induction, 9 days and 3 months post HDM. IGF1, IL21, BAFF and APRIL were measured by Elisa. Results: Two thirds of the 24 patients had detectable tumor plasma cells after induction treatment and in all these patients, tumor plasma cells (median 5.9 cells/ mm3, range 0.1–76.9 cells/mm3) as well as normal plasma cells (median 3.3 cells/mm3, range 0.4–32.2 cells/mm3) could be detected 9 days after HDM treatment in an aplastic bone marrow (median cell count 400 cells/mm3). Nine days post HDM, a burst of cytokines / chemokines was detected in bone marrow plasma which could prompt survival, growth and homing of tumor plasma cells. CCL2 chemokine (chemokine C-C motif ligand 2) which is a chemotactant and survival factor for myeloma cells was the only cytokine / chemokine differentially expressed in immuno-phenotypic complete response patients compared to patients with persistent tumor plasma cells, with a concentration 2.1 times higher in the last ones. In parallel, preliminary data show an enrichment in CCR2 positive tumor plasma cells 9 days after HDM, CCR2 being the receptor for CCL2. This interaction could be a clinically significant target to get rid of minimal residual disease. Conclusions: In conclusion, we show that the early post intensification (HDM) period could be an interesting therapeutic window to target resistant myeloma cells and their interactions with the pro-survival micro-environment. The CCL2-CCR2 interaction could be of particular interest, an anti CCR2 antibody already being in clinical development in rheumatoid arthritis (Van Driel et al. 2008). Disclosures: No relevant conflicts of interest to declare.

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Exomic microRNA Profiling of Bone Marrow Aspirate Plasma and Comparison with mRNA Profiles Used in the Clinical Management of Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.5681.5681 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5681-5681

Author(s):

Ryan K Van Laar ◽

Rachel Flinchum ◽

Brown Nathan ◽

Joseph Ramsey ◽

John Shaughnessy ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Peripheral Blood ◽

Bone Marrow Aspirate ◽

Plasma Cells ◽

Molecular Subtype ◽

Gene Expression Signature ◽

Disease Status ◽

Hematologic Malignancies ◽

Microrna Profiling

Abstract Exosome-mediated processes are increasingly being implicated in the pathobiology of many forms of solid tumors and hematologic malignancies. In the case of blood cancers, an oncogenic role for exosomes has been demonstrated for multiple myeloma (MM). An increased understanding of the abundance and disease association of extra-cellular microRNAs in particular, may lead to opportinities to improve early detection and management of MM and precursor conditions. We performed microRNA profiling of cell-free bone marrow aspirate plasma on a series of 100 patients with diagnoses of MGUS, active multiple myeloma or relapsed multiple myeloma. The microRNA profiles were compared between disease status groups and also individually with each patient’s routine MyPRS results (ie. GEP70 high/low risk and molecular subtype gene signatures), generated from their malignant CD138+ plasma cells1. MicroRNAs with patterns of expression associated with these clinically validated genomic (mRNA) signatures were investigated to determine if they (i) were known regulators of the genes used in MyPRS and (ii) in a cross-validated analysis, were able to predict the patients MyPRS risk group and molecular subtype. An additional series of paired peripheral blood and bone marrow aspirates (isolated CD138+ plasma cells) were also microRNA and MyPRS profiled, to further investigate the role and potential clinical utility of extracellular microRNAs in multiple myeloma. Results will be presented which describe the abundance of individual microRNA's in realtion to disease status, including microRNA's previously linked to the regulation of mRNA's contained in the GEP70 signature. The ability to predict MGUS progression risk or active myeloma prognosis using molecular signatures in peripheral blood may increase access to, and adoption of, genomic technologies in the diagnosis and management of these related conditions. Reference: [1] van Laar R, Flinchum R, Brown N, et al. Translating a gene expression signature for multiple myeloma prognosis into a robust high-throughput assay for clinical use. BMC Medical Genomics. 2014;7(1):25. Disclosures Van Laar: Signal Genetics: Employment, Equity Ownership. Flinchum:Signal Genetics: Employment. Nathan:Signal Genetics: Employment. Ramsey:Signal Genetics: Employment. Shaughnessy:Signal Genetics: Consultancy.

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Multiple myeloma: circulating lymphocytes that express plasma cell antigens

Blood ◽

10.1182/blood.v64.2.352.bloodjournal642352 ◽

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.

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

eLife ◽

10.7554/elife.47328 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 1

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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