Mutation landscape of multiple myeloma measurable residual disease: identification of targets for precision medicine.
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ABSTRACT:
SUBMITTER: Zatopkova M
PROVIDER: S-EPMC8791596 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
Publications
Mutation landscape of multiple myeloma measurable residual disease: identification of targets for precision medicine.
Zátopková Martina M Ševčíková Tereza T Fanfani Viola V Chyra Zuzana Z Říhová Lucie L Bezděková Renata R Žihala David D Growková Kateřina K Filipová Jana J Černá Lucie L Broskevičova Lucie L Kryukov Fedor F Minařík Jiří J Smejkalová Jana J Maisnar Vladimír V Harvanová Ĺubica Ĺ Pour Luděk L Jungova Alexandra A Popková Tereza T Bago Juli Rodriguez JR Anilkumar Sithara Anjana A Hrdinka Matouš M Jelínek Tomáš T Šimíček Michal M Stracquadanio Giovanni G Hájek Roman R
Blood advances 20220101 2
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Project description:The landscape of multiple myeloma (MM) has changed considerably in the past two decades regarding new treatments, insight into disease biology and innovation in the techniques available to assess measurable residual disease (MRD) as the most accurate method to evaluate treatment efficacy. The sensitivity and standardization achieved by these techniques together with unprecedented rates of complete remission (CR) induced by new regimens, raised enormous interest in MRD as a surrogate biomarker of patients' outcome and endpoint in clinical trials. By contrast, there is reluctance and general lack of consensus on how to use MRD outside clinical trials. Here, we discuss critical aspects related with the implementation of MRD in clinical practice.
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Project description:BackgroundRecent advances in therapeutic interventions have dramatically improved complete response rates in patients with multiple myeloma (MM). The ability to identify residual myeloma cells (e.g., measurable residual disease [MRD]) can provide valuable information pertaining to patient's depth of response to therapy and risk of relapse. Multiparametric flow cytometry is an excellent technique to monitor MRD and has been demonstrated to correlate with patient outcome post-treatment. To achieve the high sensitivity (one abnormal cell in 105 -106 cells) required for MRD evaluation, millions of cells have to be acquired and conventional immunophenotyping protocols are unable to attain these numbers, indicating the needs for alternative flow cytometric staining procedures. A bulk, "Pre-lysis" method is the consensus approach for staining large number of cells, requires two red blood cell lysis steps, and can adversely affect epitope density. In this study, we tested the "Pooled-tube" and "Dextran Sedimentation" staining procedures and correlated them with the "Pre-lysis" method as potential alternative approaches.MethodsA total of 22 bone marrow aspirates from patients with plasma cell (PC) dyscrasia were processed in parallel using the "Pre-lysis," "Pooled-tube," and "Dextran Sedimentation" techniques. Stain indices were calculated and compared to assess their impacts on staining performance for each antibody used in the consensus panel. The recovery of normal and abnormal PCs, mast cells, and B cell precursors was enumerated and compared after their counts were normalized using fluorescent beads. The limit of blank, limit of detection, and lower limit of quantification were established using serial dilution experiments.ResultsThe staining performances of CD19 PECy7, CD27 BV510, CD81 APCH7, and CD138 BV421 were improved using the "Pooled-tube" method when compared to "Pre-lysis." "Pre-lysis" was better at resolving CD56 using clone C5.9 but our results demonstrated similar improvement can also be achieved by "Pooled-tube" when alternative CD56 PE clones were used. "Dextran sedimentation" yielded similar staining results when compared to "Pre-lysis" for all the markers analyzed. The "Pooled-tube" method, when normalized to "Pre-lysis," recovered higher numbers of total PCs (1.2 ± 0.2 times higher; p = .049), normal PCs (1.4 ± 0.26; p = .007), mast cells (1.46 ± 0.27; p = .003), and B cell precursors (1.42 ± 0.3; p = .011), but not abnormal PCs (1.09 ± 0.2; p = .352). There was no evidence that the recovery of cells was different between "Pre-lysis" versus "Dextran Sedimentation." All three flow cytometric assays achieved a minimum sensitivity of 10-5 and approached that of 10-6 for detecting rare events.ConclusionBoth "Pooled-tube" and "Dextran Sedimentation" staining procedures were comparable to the "Pre-lysis" method and are suitable high sensitivity flow cytometric approaches that can be used to process bone marrow samples for MM MRD testing.
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Project description:We used a modified Delphi approach to establish areas of consensus and nonconsensus regarding the utility of determining measurable residual disease (MRD) to assess multiple myeloma (MM) treatment response, which may inform disease management and design of future clinical trials. This modified Delphi study incorporated 2 iterative rounds of surveys to evaluate the opinions of an expert panel of 61 practicing hematological oncologists from across 14 countries in Europe concerning the use of MRD testing in MM management. Survey 1 assessed experts' opinions on MRD testing in different clinical situations and associated challenges. Survey 2 focused on the lack of consensus areas identified in survey 1. Consensus to an individual question was defined a priori as 75% agreement or disagreement by the panel. From the 2 rounds of surveys, the experts reached consensus agreement that MRD testing should be performed in newly diagnosed or relapsed patients who achieved complete response (CR) or better after transplantation. In transplant-ineligible patients, experts recommended MRD testing in those who are ≤70 years old and in CR. If a patient was previously positive on positron-emission tomography and computed tomography (PET/CT), both MRD and PET/CT should be assessed at CR. MRD testing should be performed ≤6 months after transplantation and every 6-12 months in continuously treated patients in CR. There was no consensus on making treatment decisions based on MRD status. MRD testing is an important component of clinical management in MM. Additional data will further clarify the role of MRD in guiding treatment decisions.
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Project description:IntroductionRemarkable progress in molecular characterization methods has led to significant improvements in how we manage multiple myeloma (MM). The introduction of novel therapies has led to significant improvements in overall survival over the past 10 years. However, MM remains incurable and treatment choice is largely based on outdated risk-adaptive strategies that do not factor in improved treatment outcomes in the context of modern therapies.Areas coveredThis review discusses current risk-adaptive strategies in MM and the clinical application of proteomics in the monitoring of treatment response, disease progression, and minimal residual disease (MRD). We also discuss promising biomarkers of disease progression, treatment response, and chemoresistance. Finally, we will discuss an immunomics-based approach to monoclonal antibody (mAb), vaccine, and CAR-T cell development.Expert opinionIt is an exciting era in oncology with basic scientific knowledge translating in novel therapeutic approaches to improve patient outcomes. With the advent of effective immunotherapies and targeted therapies, it has become crucial to identify biomarkers to aid in the stratification of patients based on anticipated sensitivity to chemotherapy. As a paradigm of diseases highly dependent on protein homeostasis, multiple myeloma provides the perfect opportunity to investigate the use of proteomics to aid in precision medicine.
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