Prognostic impact of cytogenetic evolution in multiple myeloma 483 transplant (auto -HSCT) 11 have significantly improved the prognosis of patients with MM. However, most cases of MM are still incurable.Recent studies using next -generation sequencing (NGS) approaches have provided evidence that MM is characterized by spatial and temporal genetic heterogeneity and is composed of multiple populations of genetically distinct subclones, which evolve over time following a pattern INTRODUCTION Multiple myeloma (MM) is the third most common hematologic malignancy in the European Union, with approximately 33 000 new cases and 20 000 deaths annually. 1 The introduction of novel agents, such as proteasome inhibitors (PIs), 2-4 immunomodulatory drugs (IMiDs), 5 -7 and anti -CD38 monoclonal antibodies 8 -10 along with high -dose melphalan followed by autologous hematopoietic stem cell
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.
Introducing substantial numbers of new drugs in treatment armamentarium for plasma cell mye loma (PCM) has improved the depth and duration of achieved responses as well as prolongation of overall survival. Although complete responses (CR) are significantly more common with novel therapies, a majority of patients still relapse. This may be due to small populations of clonal plasma cells persisting after treatment; the phenomenon known as minimal residual disease (MRD). The prognostic role of MRD in patients with CR has been confirmed by numerous clinical trials, and recently MRD assessment has become a routine tool for evaluating how effective the latest drugs and therapy protocols are. Furthermore, the updated response criteria of IMWG (International Mye loma Working Group) have included response categories based on MRD evaluation with modern techniques characterized by at least 10-5 sensitivity: i.e. next generation flow and next generation sequencing. In this paper, we discuss the current role of MRD in PCM, with particular emphasis on the methodology of assessing MRD by flow cytometry. In the opinion of the Polish Myeloma Consortium members, dissemination and standardization of MRD assessment in PCM may lead to improvement of PCM therapy in Poland.
Studies exploring the significance of minimal residual disease (MRD) in plasma cell myeloma (PCM) have proven its prognostic value, regardless of the type of administered treatment. In order to assess the current practice for evaluating MRD in Poland, we conducted a survey on the methods for assessing MRD and on the MRD testing time points at Polish hematological centres. Seven out of 15 institutions surveyed use of the flow cytometry (FC) method for MRD assessment. The FC-MRD assessment is performed uniformly only in those patients achieving complete remission (CR). However, the specific indications and assessment time points differed at the tested centres including: testing MRD only after autologous hematopoietic stem cell transplantation (auto-HSCT), after auto-HSCT and consolidation, after completion of first line chemotherapy or after obtaining CR in any line of treatment. The study also showed considerable heterogeneity in the FC-MRD methodology, which affects test sensitivity (from 10-3 to 10-5). None of the surveyed centres uses molecular techniques for MRD assessment. In 8 of the 15 institutions, patients are monitored by imaging techniques. Our survey may thus be useful for developing guidelines and standardization of MRD assessment in PCM in Poland.
Clonal evolution drives treatment failure in multiple myeloma (MM). Here, we used a custom 372-gene panel to track genetic changes occurring during MM progression at different stages of the disease. A tumor-only targeted next-generation DNA sequencing was performed on 69 samples sequentially collected from 30 MM patients. The MAPK/ERK pathway was mostly affected with KRAS mutated in 47% of patients. Acquisition and loss of mutations were observed in 63% and 37% of patients, respectively. Four different patterns of mutation evolution were found: branching-, mutation acquisition-, mutation loss- and a stable mutational pathway. Better response to anti-myeloma therapy was more frequently observed in patients who followed the mutation loss—compared to the mutation acquisition pathway. More than two-thirds of patients had druggable genes mutated (including cases of heavily pre-treated disease). Only 7% of patients had a stable copy number variants profile. Consequently, a redistribution in stages according to R-ISS between the first and paired samples (R-ISS″) was seen. The higher the R-ISS″, the higher the risk of MM progression and death. We provided new insights into the genetics of MM evolution, especially in heavily pre-treated patients. Additionally, we confirmed that redefining R-ISS at MM relapse is of high clinical value.
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