Multiple myeloma (MM) is the second most prevalent hematological malignancy, characterized by infiltration of the bone marrow by malignant plasma cells. Extramedullary disease (EMD) represents a more aggressive condition involving the migration of a subclone of plasma cells to paraskeletal or extraskeletal sites. Liquid biopsies could improve and speed diagnosis, as they can better capture the disease heterogeneity while lowering patients' discomfort due to minimal invasiveness. Recent studies have confirmed alterations in the proteome across various malignancies, suggesting specific changes in protein classes. In this study, we show that MALDI-TOF mass spectrometry fingerprinting of peripheral blood can differentiate between MM and primary EMD patients. We constructed a predictive model using a supervised learning method, partial least squares-discriminant analysis (PLS-DA) and evaluated its generalization performance on a test dataset. The outcome of this analysis is a method that predicts specifically primary EMD with high sensitivity (86.4%), accuracy (78.4%), and specificity (72.4%). Given the simplicity of this approach and its minimally invasive character, this method provides rapid identification of primary EMD and could prove helpful in clinical practice.

• Klíčová slova
• Extramedullary disease, Liquid biopsy, MALDI-TOF mass spectrometry, Machine learning, Multiple myeloma, Partial least squares-discriminant analysis, Principal component analysis,
• MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom * krev   diagnóza   MeSH
• nádorové biomarkery krev   MeSH
• senioři MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice metody   MeSH
• tekutá biopsie metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorové biomarkery MeSH

Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR = 2.4, p = 0.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. Conversely, we identified significantly upregulated EZH2 and CD70 as potential future therapeutic options. For the first time, we report on the tumor microenvironment of EMM, revealing CD8+ T cells and NK cells as predominant immune effector cells using single-cell sequencing. Finally, this is the first longitudinal study in EMM revealing the molecular changes from the time of diagnosis to EMM relapse.

• MeSH
• kostní dřeň patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom * genetika   patologie   MeSH
• mutace MeSH
• nádorové biomarkery genetika   MeSH
• nádorové mikroprostředí * genetika   MeSH
• prognóza MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorové biomarkery MeSH

In multiple myeloma (MM), malignant plasma cells infiltrate the bone marrow. In some cases, plasma cells migrate out of the bone marrow creating either para-skeletal plasmacytomas (PS) or infiltrating soft tissues as extramedullary plasmacytomas (EMD). The aim of this study was to define risk groups in newly diagnosed MM (NDMM) patients with PS and EMD plasmacytomas. In total, 523 NDMM patients with PS plasmacytomas and 196 NDMM patients with EMD plasmacytomas were diagnosed in the Czech Republic between 2004 and 2021 using modern imaging methods. Patients’ data were analyzed from the Registry of Monoclonal Gammopathies of the Czech Myeloma Group. In NDMM patients with PS plasmacytomas, we found a subgroup with <5% of bone-marrow plasma cells to have the best prognosis (mPFS: 58.3 months (95% CI: 33.0−NA); mOS: not reached). The subgroup with >5% of bone-marrow plasma cells and ≥3 plasmacytomas had the worst prognosis (mPFS: 19.3 months (95% CI: 13.4−28.8), p < 0.001; mOS: 27.9 months (95% CI: 19.3−67.8), p < 0.001). Our results show association between tumor burden and prognosis of NDMM patients with plasmacytomas. In the case of PS plasmacytomas, NDMM patients with low BM PC infiltration have an excellent prognosis.

• Klíčová slova
• multiple myeloma, plasmacytomas, risk factors, survival,
• Publikační typ
• časopisecké články MeSH