RESUMO
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-ISSâ³) was seen. The higher the R-ISSâ³, 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.
RESUMO
INTRODUCTION: Prognosis of patients with newly diagnosed multiple myeloma (MM), a third most common hematological cancer, is dependent on baseline cytogenetics. However, little is known about the prognostic significance of cytogenetic evolution (CE) at the time between the diagnosis and relapse of MM. OBJECTIVES: Here, we retrospectively analyzed the prognostic impact of CE detected in a routine interphase fluorescence in situ hybridization (FISH) test in a cohort of patients with MM. PATIENTS AND METHODS: Among 650 patients evaluated with the FISH MM panel at our center between 2014 and 2019, we identified 29 individuals with MM who had been tested twice, at the time of diagnosis and relapse. Cytogenetic evolution was defined as the acquisition or loss of at least 1 cytogenetic abnormality at relapse (FISH2) compared with the baseline test result (FISH1). RESULTS: Cytogenetic evolution was seen in 14 patients (48%), whereas 15 had stable cytogenetics. Acquired chromosome 17p deletion (del[17p]) was the most common type of CE, found in 7 patients (24%). In univariable analysis, stable cytogenetics predicted longer overall survival (median not reached vs 3.8 years; hazard ratio [HR], 0.15; P = 0.04; median followup of 3.1 years) and longer overall survival after FISH2 (median not reached vs 0.8 years; HR, 0.13; P = 0.002; median followup of 0.6 years). In multivariable analysis, acquired del(17p) predicted shorter progressionfree survival and the overall survival after FISH2 (HR, 9.3 and 18.8; P = 0.005 and P = 0.004, respectively). CONCLUSIONS: Presence of CE and, particularly, the acquisition of new del(17p) at relapse, negatively affect the outcome of MM. Therefore, reevaluation of FISH at MM relapse should be included in routine clinical practice.