Serum Pleiotrophin Is a New Multiple Myeloma Tumor Marker That Also Predicts Clinical Status.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3417-3417
Author(s):  
Howard S. Yeh ◽  
Haiming Chen ◽  
Steven J. Manyak ◽  
Regina A. Swift ◽  
Richard A. Campbell ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Marker ◽  
Plasma Cells ◽  
Clinical Status ◽  
Constitutive Expression ◽  
Disease Status ◽  
Heparin Binding ◽  
Serum Samples ◽  
Control Subjects

Abstract Pleiotrophin (PTN), an 18 kD heparin-binding protein, has been found to be expressed in some solid tumors whereas it has not been previously evaluated in hematologic malignancies. Constitutive expression of PTN promotes tumor expansion and may increase metastatic potential. This protein binds to syndecan-1 (CD138) and stimulates angiogenesis. Its role in multiple myeloma (MM), thus far, has not been evaluated. Recently, we showed that PTN was strongly expressed in MM cell lines and malignant plasma cells from fresh bone marrow samples but not in normal control bone marrow specimens. Since PTN has been shown to be elevated in the serum of some solid tumor patients, we determined whether PTN may be elevated in the serum of MM patients, and correlated these levels with the patients’ disease status. By using a highly sensitive and specific enzyme-liked immunosorbent assay (ELISA) for PTN, we tested 270 different serum samples [MM (n=194), MGUS (n=18) and age-matched healthy control subjects (n=58)]. Serum samples from MM patients were obtained at the time of diagnosis as well as during the course of their disease. Serum PTN levels were higher in MM patients than in the control subjects (median=1.44 ng/ml vs 0.42 ng/ml, p <0.0001). In addition, among patients with MGUS and smoldering myeloma, serum PTN was also higher than in the controls (median=1.14 ng/ml vs 0.42 ng/ml, p <0.0001) but lower than among patients with active MM (p <0.0001). Patients with untreated MM showed serum PTN levels similar to those patients who received prior treatment. Among previously treated patients, the group with progressive disease at the time of evaluating their PTN level had higher serum concentrations of this protein than patients with responsive or stable disease (median=1.73 ng/ml vs 1.16 ng/ml, p <0.0001). Evaluation of patients who had a change in disease status showed that the serum PTN level increased at the time of progression when compared with their baseline level (median=1.76 ng/ml vs 1.01 ng/ml, p=0.009). Conversely, patients who responded to anti-MM therapy exhibited significant decreases of PTN as compared with their pre-treatment PTN values (median=0.95 ng/ml vs 1.90 ng/ml, p=0.007). These results suggest that serum PTN may be a new tumor marker for MM, and monitoring of this protein may be useful to follow the responsiveness to therapy and disease status of MM patients. We are now undertaking studies to evaluate PTN as a prognostic marker in a large cohort of newly diagnosed MM patients.

Amphiregulin Is Produced by Myeloma Cells and Is Involved in Tumor-Environment Interactions in Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4306-4306
Author(s):  
Karène Mahtouk ◽  
Dirk Hose ◽  
Thierry Reme ◽  
John De Vos ◽  
Michel Jourdan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Growth Factors ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Erbb Receptors ◽  
Heparin Binding ◽  
Myeloma Cells ◽  
Heparin Binding Growth Factors ◽  
Egf Family

Abstract Multiple myeloma (MM) is characterized by the accumulation of clonal malignant plasma cells in the bone marrow. One of the hallmarks of plasma cells is the expression of the heparan-sulfate proteoglycan syndecan-1. In epithelial cells, syndecan-1 plays a major role as a coreceptor for heparin-binding growth factors and chemokines. This stresses that heparin-binding growth factors may play a major role in the biology of MM cells. Recently we have demonstrated that heparin-binding EGF-like growth factor (HB-EGF), one of the ten members of the Epidermal Growth Factor (EGF) family, is produced by the tumor microenvironment and is able to trigger myeloma cell growth. As amphiregulin (AREG) is another member of the EGF family that also binds heparan-sulphate chains, we investigated its role in MM. We looked for AREG expression on a panel of 7 normal plasmablastic cells (PPCs), 7 normal bone marrow plasma cells (BMPCs), purified MM cells from 65 patients and 20 myeloma cell lines (HMCLs), with Affymetrix U133A+B microarrays. We showed that primary MM cells overexpress AREG compared to normal BMPCs and PPCs. We then investigated the expression of the ErbB receptors with real-time RT-PCR. Myeloma cells variably expressed the 4 ErbB receptors. Normal BMPCs also expressed ErbB1 and ErbB2 unlike PPCs that did not express any ErbB receptors. We demonstrated that the high AREG expression by primary myeloma cells may have a dual effect. On the one hand, AREG stimulated IL-6 production and growth of bone-marrow stromal cells that highly express the AREG ErbB1 receptor. On the other hand, AREG could promote HMCL proliferation, suggesting that a functional autocrine loop involving AREG and ErbB receptors is involved in MM cell growth. Finally, we looked for the effect of ErbB inhibitors on MM cells of 14 patients cultured for 6 days together with their bone marrow environment. A pan-ErbB inhibitor (PD-169540, Pfizer) and an ErbB1-inhibitor (IRESSA, Astrazeneca) induced strong MM cell apoptosis in respectively 71% of patients (10 of 14) and 29% of patients (4 of 14). Of major interest, when PD169540 or IRESSA were combined with dexamethasone, they induced a dramatic myeloma cell death (respectively 92% and 69% inhibition of MM cell survival), while non-myeloma cells were unaffected. Thus ErbB activation is critical to trigger MM-cell survival in short-term culture. In conclusion, our findings provide evidence for a major role of AREG and HB-EGF in the biology of multiple myeloma and identify ErbB receptors as putative therapeutic targets. These data emphasize the interest of clinical evaluation of specific-ErbB-inhibitors in patients with MM, either used alone or in combination with dexamethasone.

scholarly journals Pharmacodynamics of SEA-BCMA, a Nonfucosylated Antibody Targeting BCMA, in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1197-1197
Author(s):  
David Taft ◽  
Clark Henderson ◽  
Christine O'Day ◽  
Changpu Yu ◽  
Hong Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Receptor Binding ◽  
Plasma Cells ◽  
Binding Assay ◽  
Phase 1 ◽  
Receptor Occupancy ◽  
Publicly Traded ◽  
Serum Samples ◽  
Immune Effector

Abstract Patients with relapsed/triple class refractory (refractory to a proteasome inhibitor, immunomodulatory drug or anti-CD38 antibody) multiple myeloma (MM) have limited treatment options. Versatile therapies, such as unconjugated antibodies (Abs), that are well tolerated and can be combined with multiple modalities are critical for the MM treatment landscape. SEA-BCMA is an investigational, humanized, nonfucosylated IgG1 monoclonal Ab targeting B-cell maturation antigen (BCMA) on malignant plasma cells. Preclinical data show that SEA-BCMA blocks BCMA-mediated pro-survival and proliferative cell signaling and mediates antibody-dependent cellular phagocytosis and enhanced antibody-dependent cellular cytotoxicity via increased binding to activating Fc receptor, FcγRIIIa (Van Epps 2018). A phase 1, open-label, multicenter study to evaluate the safety, tolerability, and antitumor activity of SEA-BCMA in adults with relapsed or refractory MM (SGNBCMA-001; NCT03582033) is ongoing. To support maximal ligand blocking and immune effector engagement by SEA-BCMA, we investigated its binding and saturation pharmacodynamics (PD) in patients enrolled in dose escalation and currently recruiting dose expansion cohorts. Novel quantitative assays were developed to assess the BCMA target and the availability of SEA-BCMA in patients enrolled in the study. These assessments include: a liquid chromatography-mass spectrometry (LC-MS) soluble BCMA (sBCMA) assay, a BCMA receptor occupancy assay on malignant plasma cells in bone marrow aspirates, and a receptor binding assay to assess the direct binding and saturation capacity of SEA-BCMA in patients' serum samples and bone marrow aspirates to a BCMA-expressing cell in vitro. Results reported as median (min-max) values unless specified. At baseline, the median sBCMA level from patients enrolled in SGNBCMA-001 was 8.5(0.5-217.0) ng/mL. After the first dose of SEA-BCMA, a rapid and sustained increase in sBCMA was observed [32.0 (3.0-139.0) fold]. Mechanistically, because SEA-BCMA can bind to sBCMA, accumulation of sBCMA may occur due to formation of the sBCMA:SEA-BCMA complex, resulting in reduced clearance. Importantly, for patients at the dose selected for expansion (1600mg), the molar ratio of SEA-BCMA to sBCMA remained in excess (10:1-400:1), thereby overcoming the liabilities of this complex formation and supporting malignant plasma cell drug exposure. Results of a receptor binding assay using patients' serum samples also demonstrated a dose-dependent ability to saturate BCMA-expressing cells. Evaluation of receptor occupancy in patient bone marrow aspirates showed that at baseline, median unoccupied membrane BCMA (unbound by ligand) was 3,500(1,500-30,000) copies per cell with one excluded outlier that exhibited 270,000 copies per cell. On-treatment, unoccupied membrane BCMA reductions were observed ranging from 50% to 100% from baseline in majority of evaluable patients at the 1600mg dose. An on-treatment increase in total BCMA expression was also observed, which is being further investigated. Maximal ligand blocking and immune effector engagement is best achieved through saturation of a target receptor. Overall, these PD results provide insight into the saturation potential of plasma cell membrane BCMA by SEA-BCMA and informed the dose selection and schedule in expansion cohorts. Further evaluation of these relationships to patient response is ongoing as the Phase 1 study continues to enroll. Disclosures Taft: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Henderson: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. O'Day: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Yu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Li: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Van Epps: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company.

miRNA in Serum and Bone Marrow Plasma Cells From Multiple Myeloma Patients.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2921-2921
Author(s):  
Andrew Stiff ◽  
Alberto Rocci ◽  
Craig C. Hofmeister ◽  
Paola Omedè ◽  
Susan Geyer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Immunoglobulin M ◽  
Differentially Expressed ◽  
Healthy Controls ◽  
Circulating Mirnas ◽  
Serum Samples ◽  
Screening Analysis

Abstract Abstract 2921 Background: Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the aberrant expansion of clonal plasma cells (PCs) within the bone marrow. Malignant PCs produce intact or partial monoclonal immunoglobulin (M protein) and cause organ damage. More than 20,000 new cases of multiple myeloma (MM) are diagnosed every year in the US with approximately 10,700 deaths occurring. The pathogenesis of MM is still largely unclear, but several reports suggest that interaction of tumor cells with the bone marrow microenvironment and microRNAs (miRNAs) deregulation may play a role in the etiology and progression of MM. miRNAs are small non-coding RNAs capable of regulating protein expression by binding to mRNA, and have been implicated in the development of MM. First identified inside cells, miRNAs can also be detected in body fluids, including serum and plasma, and may be a valid biomarker. Few studies have investigated the agreement between circulating miRNAs and intracellular myeloma PC miRNAs at diagnosis. Methods: Using Nano-String nCounter technology we first performed a screening analysis on serum samples obtained from MM patients and healthy controls. We identified a candidate set of miRNAs differentially expressed in the serum of MM patients. The levels of these miRNA markers were validated by RT-PCR in both serum and bone marrow PCs from the same cohort. Agreement of the quantitative miRNA marker levels between sample types was evaluated using intraclass correlation coefficients (ICC) (both for normalized and log2 measures). Results: Thirty-nine MM patients (21 male, 18 female) with a median age of 72 years (range: 65 – 83) were included in the analysis. Most were ISS stage I or II (59% vs. 41% ISS stage III) and 39% were high risk according to FISH abnormalities – 21% of patients carried del17p, 24% t(4;14) and 5% t(14;16). Medians and ranges for lab markers were as follows: hemoglobin 10.0 g/dl (7.2 to 15.1), beta2-microglobulin 5.18 ug/ml (1.38 – 12.1), creatinine 0.94 mg/dl (0.65 – 2.49), CRP = 1.6 mg/dl (0.02 – 116.0). Nine age-matched healthy controls were also used for the analysis. After the screening analysis, the following miRNAs were differentially expressed between healthy subjects and MM patients in serum samples: miR-92a, miR-451, miR-19b, miR-21, miR-16, miR-25, miR-30a, and miR-126. There was no significant agreement or correlation between serum and myeloma cell samples using either untransformed as well as log2measures (all p>0.40) (Table 1). Conclusion: Our preliminary results suggest a difference between circulating miRNAs in myeloma patients from controls. This indicates that future studies are needed to better define the role of miRNAs in the peripheral blood as a prognostic and even diagnostic biomarker in myeloma. From our preliminary data it also appears that circulating miRNAs are not simply secreted into the peripheral blood by myeloma PCs as it seems that circulating miRNAs do not reflect those of myeloma PCs. Differential expression could be determined by other cells that can release and or modify their miRNA expression in response to MM. Ongoing studies are examining the origin and function of miRNAs in the peripheral blood. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
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.

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

Blood ◽  
1995 ◽  
Vol 85 (6) ◽  
pp. 1596-1602 ◽  
Author(s):  
P Corradini ◽  
C Voena ◽  
M Astolfi ◽  
M Ladetto ◽  
C Tarella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Disease Status ◽  
Residual Tumor ◽  
High Dose ◽  
Myeloma Cells ◽  
Igh Genes

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.

Bone disease as the first manifestation of systemic AL-amyloidosis

2020 ◽  
Vol 92 (7) ◽  
pp. 85-89
Author(s):  
L. P. Mendeleeva ◽  
I. G. Rekhtina ◽  
A. M. Kovrigina ◽  
I. E. Kostina ◽  
V. A. Khyshova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Plasma Cells ◽  
Interventricular Septum ◽  
Bone Destruction ◽  
Amyloid Deposition ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

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