scholarly journals Liquid Biopsies in Multiple Myeloma

Liquid Biopsy ◽  
2019 ◽  
Author(s):  
David Vrabel ◽  
Adela Souckova ◽  
Lenka Sedlarikova ◽  
Sabina Sevcikova
Keyword(s):  
Multiple Myeloma ◽  
Liquid Biopsies

scholarly journals A Next Generation Liquid Biopsy Approach for Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-33
Author(s):  
Daniel Auclair ◽  
Mark Bustoros, MD ◽  
Carrie Cibulskis ◽  
Teni Dowdell ◽  
Svetlana Gavrilov ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Molecular Characterization ◽  
Liquid Biopsy ◽  
Clinical Care ◽  
Buffy Coat ◽  
Gene Panel ◽  
Clinical Grade ◽  
Liquid Biopsies ◽  
Validation Data ◽  
Gene Assay

Direct-to-Patient (DTP) Multiple Myeloma (MM) research studies have been launched recently, including PCROWD (NCT02269592), PROMISE (NCT03689595) and the MMRF CureCloud Research Initiative (NCT03657251), aimed at enrolling thousands of individuals from whom comprehensive molecular and immune analyses will be generated from blood specimens and the resulting data aggregated with the correlating clinical information. To support the molecular characterization of liquid biopsies for such DTP efforts, a set of myeloma-specific liquid biopsy approaches were developed. First, a hybrid selection panel was developed that detects somatic variants present in a patient's circulating-free DNA (cfDNA) in 70 commonly altered MM and Clonal Hematopoiesis of Indeterminate Potential (CHIP) genes. For this MM 70-Gene cfDNA Assay, samples are received as blood in a StreckTM tube designed for stabilization of cfDNA and DNA is extracted from buffy coat using magnetic bead-based chemistry. Deep coverage sequencing (80,000x depth) is performed and duplex BAM files generated with UMI alignment and error correction allowing for sensitive detection of clinically relevant variants. Technical validation data on healthy donor cfDNA mixes was generated using samples with a range of cfDNA inputs. This data determined that the assay is capable of achieving >90% sensitivity for detecting somatic events present at 1% variant allele frequency with a specificity of <0.2 false positives per megabase. Using a clinical cohort, we observed a strong correlation between Bone Marrow Aspirate (BMA) and cfDNA samples with the vast majority of variants previously detected in BMA also identified via the MM-70 Gene panel analysis. Interestingly, we also saw evidence of additional somatic variants identified in cfDNA previously undetected in BMA analysis. Because one the aims of this effort is to return results to treating physicians, a clinical-grade (CLIA) pipeline was established. For that CLIA pipeline, the variants reported are a subset of all the events detected by the MM 70-Gene Assay. The events detected in the assay are reviewed by experienced molecular pathologists at the Dana Farber Cancer Institute (DFCI) who have developed a customized reporting process. These reports utilize an internally-developed knowledgebase of variant/gene annotations that leverages the DFCI expertise in hematologic malignancies and myeloma specifically. The reports are then provided back through providers to the patient via the CureCloud system for their use in clinical care and trial identification. In order to complement the MM-70 Gene panel with copy number and translocation information, we have been exploring Circulating Multiple Myeloma Cells (CMMCs). Our current approach involves automated capture of CMMCs using ferrofluids coated with MM-selective and discriminating antibodies to immunomagnetically enrich circulating plasma cells. The highly enriched CMMCs fractions generated in such a fashion are then submitted for molecular characterization. At the submission date of this abstract, 163 patients have been fully enrolled into CureCloud from which results will be presented. In summary, we have developed a robust and very sensitive clinical-grade next-gen liquid biopsy sequencing platform allowing for minimally invasive monitoring of MM disease genomics that can be used to complement other more classical approaches and to help support our Direct-To-Patient Initiatives. Especially in this post-COVID19 era, such liquid biopsy-based approaches that avoid clinic visits for the patients and can be performed through at-home mobile phlebotomy are emerging as important new options. Disclosures Kim: LabCorp: Consultancy; Quanterix, Inc: Consultancy; PapGene, Inc: Consultancy. Ghobrial:AbbVie: Consultancy; GNS Healthcare: Consultancy; GlaxoSmithKline: Consultancy; Genentech: Consultancy; Noxxon Pharma: Consultancy; Novartis: Consultancy; Adaptive Biotechnologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Cellectar: Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

scholarly journals Characterization of Circulating and Bone Marrow Derived Exosomes in Multiple Myeloma Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3172-3172 ◽  
Author(s):  
Bruna Velosa Ferreira ◽  
Paulo Lucio ◽  
Manuel Neves ◽  
Antonio Parreira ◽  
Bruno Costa-Silva ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Poor Response ◽  
Staging System ◽  
Response To Treatment ◽  
Liquid Biopsies ◽  
Positive Correlation ◽  
Extramedullary Disease

Abstract Background: Multiple myeloma (MM) is characterized by clinical and biological heterogeneity, translating to variable outcome. High International Staging System (ISS), high risk cytogenetics, elevated LDH, poor response to novel drugs or extramedullary-disease (EMD) are associated to poor prognosis. Exosomes (EXO) are extra vesicular particles implicated in intercellular communication. Exosomal cargo has recently been studied as prognostic factors in cancer. MM-EXO may act as biomarkers of disease aggressiveness and potentially be used for better stratification of high risk disease in the clinical setting as liquid biopsies. Aims: To characterize peripheral blood (PB) and bone marrow aspirates (BM) EXO in MM and MGUS patients versus healthy donors (HD) and to analyze its potential use as a prognostic biomarker. Methods: EXO were isolated from PB and BM samples by ultracentrifugation. EXO protein quantity (EXOcargo) was determined by the ratio between total quantity of proteins and the total number of exosomes. Comparisons among groups of patients (MM, MGUS) and HD were made regarding EXO total protein cargo (PB and BM). Results: MM patients revealed 5x times higher EXOcargo in PB (ug/EXO) when compared to MGUS patients (p=0.007, n=15 MM and n=8 MGUS); MM median 2.34 (1.08-6.5) ug/EXO versus MGUS median 0.51 (0.29-1.04) ug/EXO. There was no differences regarding the EXOcargo between the MGUS and HD (n=6, HD median 0.88 (0.57-1.83)ug/EXO). In BM, MM EXOcargo was also higher than in MGUS: MM 2.09 (0.49-3.85)ug/EXO versus MGUS 0.53 (0.21-0.831)ug/EXO. Analyzing the patients with higher EXOcargo, we found that patients with EMD (n=4) are among the ones with higher circulating exosomal protein cargo (median 5.76 (4.36-7.95). A positive correlation in EXOcargo between PB and BM in MM and MGUS (Spearman r=0.85; p< 0.0001) was found. We also studied circulating EXOcargo at response evaluation (T2) compared to EXOcargo before MM treatment (T1): patients with deeper response had significant lower EXOcargo (CR T2 median 0.85 (0.65-1.35) p<0,05); patients in VGPR (T2 median 1.52 (0.86-2.34) p=0.36) PR (T2 median 2.68 (2.03-3.33) p=0.94) and progression (T2 median 2.22 (1.0-2.46) p=0.58). Conclusion: 1-The positive correlation of the exosomal protein cargo in PB and BM samples may be a reflection of the BM compartment and potentially supports the use of EXO as liquid biopsies for biomarkers of BM disease, in a less invasive method. 2-MM patients have higher circulating exosomal protein cargo in PB when compared to MGUS patients and HD. 3- Patients with extramedullary disease and more aggressive forms of multiple myeloma have a higher exosomal cargo in the PB and this might be related to different biological features of the disease. The longitudinal evaluation in 2 different time-points suggests a correlation between EXO protein cargo and response to treatment, to be confirmed in a larger cohort. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Liquid biopsies for multiple myeloma in a time of precision medicine

2020 ◽  
Vol 98 (4) ◽  
pp. 513-525 ◽  
Author(s):  
Bruna Ferreira ◽  
Joana Caetano ◽  
Filipa Barahona ◽  
Raquel Lopes ◽  
Emilie Carneiro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Precision Medicine ◽  
Liquid Biopsies

Proteasome inhibitors as therapeutics

2005 ◽  
Vol 41 ◽  
pp. 205-218
Author(s):  
Constantine S. Mitsiades ◽  
Nicholas Mitsiades ◽  
Teru Hideshima ◽  
Paul G. Richardson ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Drug Class ◽  
Proteasome Inhibitors ◽  
Cell Cycle Regulators ◽  
Current State ◽  
Intracellular Mechanism ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Hodgkin's Lymphomas ◽  
Clinical Research Data

The ubiquitin–proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

Bone sialoprotein mRNA and protein expression in human multiple myeloma cell lines and patients

2000 ◽  
Vol 111 (4) ◽  
pp. 1118-1121 ◽  
Author(s):  
A. Bellahcene ◽  
I. Van Riet ◽  
C. de Greef ◽  
N. Antoine ◽  
M. F. Young ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Expression ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Bone Sialoprotein ◽  
Multiple Myeloma Cell ◽  
Human Multiple Myeloma ◽  
Mrna And Protein Expression

Continuous low-dose dexamethasone in relapsed or refractory multiple myeloma

2000 ◽  
Vol 111 (1) ◽  
pp. 381-381 ◽  
Author(s):  
C. W. Tiplady ◽  
G. P. Summerfield
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
Refractory Multiple Myeloma

Controversies surrounding the clonogenic origin of multiple myeloma

2000 ◽  
Vol 110 (1) ◽  
pp. 240-241 ◽  
Author(s):  
Faith E. Davies ◽  
Andrew C. Rawstron ◽  
Roger G. Owen ◽  
Gareth J. Morgan
Keyword(s):  
Multiple Myeloma

Sturge-Weber syndrome and multiple myeloma

1969 ◽  
Vol 100 (4) ◽  
pp. 488b-488
Author(s):  
H. O. Curth
Keyword(s):  
Multiple Myeloma ◽  
Weber Syndrome ◽  
Sturge Weber Syndrome
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