Standardization of flow cytometric minimal residual disease assessment in international clinical trials. A feasibility study from the European Myeloma Network

Bruinink, Davine Hofste op; Oliva, Stefania; Říhová, Lucie; Schmitz, Alexander; Gilestro, Milena; Marvelde, Jeroen te; Králová, Romana; Høholt, Helle; Broijl, Annemiek; Johnsen, Hans Erik; Boccadoro, Mario; Sonneveld, Pieter; Omedè, Paola; Velden, Vincent H.J. van der

doi:10.3324/haematol.2020.267831

Cited by 10 publications

(8 citation statements)

References 15 publications

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“…Undoubtedly, reliability of the highly sensitive cytometric MRD examination strictly depends on the experience and knowledge of the operator, and the reduction of subjectivity in data analysis is an important advantage. The result of our study supports the findings from previous studies including the assessment of comparability of MRD tests results between the European Myeloma Network (EMN) flow cytometry laboratories [41]. In that study, 20 BM samples were tested using the standardized EuroFlow protocol and full concordance of MRD results was seen in 95% cases.…”

Section: Discussionsupporting

confidence: 90%

Harmonization of Flow Cytometric Minimal Residual Disease Assessment in Multiple Myeloma in Centers of Polish Myeloma Consortium

et al. 2021

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Minimal residual disease (MRD) status is now considered as one of the most relevant prognostic factors in multiple myeloma (MM) while MRD negativity became an important endpoint in clinical trials. Here, we report the results of the first study evaluating the reproducibility of high-sensitivity flow cytometry MM MRD assessment in four laboratories in Poland. EuroFlow protocols for instrument setting standardization and sample preparation in MM MRD assessment were implemented in each laboratory. In the inter-laboratory reproducibility study, 12 bone marrow samples from MM patients were distributed and processed in participant laboratories. In the inter-operator concordance study, 13 raw data files from MM MRD measurements were analyzed by five independent operators. The inter-laboratory study showed high 95% overall concordance of results among laboratories. In the inter-operator study, 89% of MRD results reported were concordant, and the highest immunophenotype interpretation differences with regard to expression of CD27, CD45, CD81 were noticed. We confirmed the applicability and feasibility of the EuroFlow protocol as a highly sensitive method of MRD evaluation in MM. Results of our inter-center comparison study demonstrate that the standardization of MM MRD assessment protocols is highly desirable to improve quality and comparability of results within and between different clinical trials.

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Section: Discussionsupporting

confidence: 90%

Harmonization of Flow Cytometric Minimal Residual Disease Assessment in Multiple Myeloma in Centers of Polish Myeloma Consortium

et al. 2021

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“…Baseline CTC levels were determined by Next-Generation Flow (NGF; EuroFlow) in 297 patients with NDMM and by morphological assessment in 51 patients with pPCL. 40 , 41 …”

Section: Methodsmentioning

confidence: 99%

Identification of High-Risk Multiple Myeloma With a Plasma Cell Leukemia-Like Transcriptomic Profile

Bruinink

Kuiper

Duin

et al. 2022

JCO

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PURPOSE Primary plasma cell leukemia (pPCL) is an aggressive subtype of multiple myeloma, which is distinguished from newly diagnosed multiple myeloma (NDMM) on the basis of the presence of ≥ 20% circulating tumor cells (CTCs). A molecular marker for pPCL is currently lacking, which could help identify NDMM patients with high-risk PCL-like disease, despite not having been recognized as such clinically. METHODS A transcriptomic classifier for PCL-like disease was bioinformatically constructed and validated by leveraging information on baseline CTC levels, tumor burden, and tumor transcriptomics from 154 patients with NDMM included in the Cassiopeia or HO143 trials and 29 patients with pPCL from the EMN12/HO129 trial. Its prognostic value was assessed in an independent cohort of 2,139 patients with NDMM from the HOVON-65/GMMG-HD4, HOVON-87/NMSG-18, EMN02/HO95, MRC-IX, Total Therapy 2, Total Therapy 3, and MMRF CoMMpass studies. RESULTS High CTC levels were associated with the expression of 1,700 genes, independent of tumor burden (false discovery rate < 0.05). Of these, 54 genes were selected by leave-one-out cross-validation to construct a transcriptomic classifier representing PCL-like disease. This not only demonstrated a sensitivity of 93% to identify pPCL in the validation cohort but also classified 10% of NDMM tumors as PCL-like. PCL-like MM transcriptionally and cytogenetically resembled pPCL, but presented with significantly lower CTC levels and tumor burden. Multivariate analyses in NDMM confirmed the significant prognostic value of PCL-like status in the context of Revised International Staging System stage, age, and treatment, regarding both progression-free (hazard ratio, 1.64; 95% CI, 1.30 to 2.07) and overall survival (hazard ratio, 1.89; 95% CI, 1.42 to 2.50). CONCLUSION pPCL was identified on the basis of a specific tumor transcriptome, which was also present in patients with high-risk NDMM, despite not being clinically leukemic. Incorporating PCL-like status into current risk models in NDMM may improve prognostic accuracy.

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“…This may interfere with CD38 detection by flow cytometry for several months after the last antibody infusion, thus representing a diagnostic challenge [ 27 , 28 ]. To bypass this technical problem, it has been proposed to include alternative markers such as multi-epitope CD38, VS38c, CD319, CD200 or others in the panel for the identification of PCs [ 29 , 30 , 31 ]. All participants agreed on the need to specify in the report whether anti-CD38 treatment was performed, as well as whether markers other than CD38 and CD138 were used for PC identification.…”

Section: Discussionmentioning

confidence: 99%

Consensus for Flow Cytometry Clinical Report on Multiple Myeloma: A Multicenter Harmonization Process Merging Laboratory Experience and Clinical Needs

Cordone

Amodeo²,

Bellesi

et al. 2023

Cancers

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Flow cytometry is a highly sensitive and specific approach for discriminating between normal and clonal plasma cells in multiple myeloma. Uniform response criteria after treatment have been established by the International Myeloma Working Group and the EuroFlow Group; however, the way in which flow cytometry data are reported has suffered from no collaborative or multicentre efforts. This study, involving 8 expert laboratories and 12 clinical hematology units of the Lazio region in Italy, aims to produce a uniform and shared report among the various Centres. From the pre-analytical phase to sample processing, data acquisition, analysis, and evaluation of the potential limitations and pitfalls of the entire process, the study reaches a final conclusion shared by laboratories and clinicians according to the most updated principles and recommendations. The aim was to identify the necessary data to be included in the clinical report by using multiple-choice questionnaires at every single stage of the process. An agreement of more than 75% of the laboratories was considered mandatory for the data to be included in the report. By ensuring the operational autonomy of each laboratory, this study provides a clear report that limits subjective interpretations and highlights possible bias in the process, better supporting clinical decision-making.

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Standardization of flow cytometric minimal residual disease assessment in international clinical trials. A feasibility study from the European Myeloma Network

Cited by 10 publications

References 15 publications

Harmonization of Flow Cytometric Minimal Residual Disease Assessment in Multiple Myeloma in Centers of Polish Myeloma Consortium

Harmonization of Flow Cytometric Minimal Residual Disease Assessment in Multiple Myeloma in Centers of Polish Myeloma Consortium

Identification of High-Risk Multiple Myeloma With a Plasma Cell Leukemia-Like Transcriptomic Profile

Consensus for Flow Cytometry Clinical Report on Multiple Myeloma: A Multicenter Harmonization Process Merging Laboratory Experience and Clinical Needs

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