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Biological and clinical significance of dysplastic hematopoiesis in patients with newly diagnosed multiple myeloma

Autores: Da Silva Maia, Catarina Alexandra; Puig, N. ; Cedena, M. T.; Goicoechea Oroz, Ibai; Valdes-Mas, R.; Vázquez Urio, Iria; Chillon, M. C. ; Aguirre, P.; Sarvide Plano, Sarai; Gracia Aznárez, Francisco Javier; Alkorta Aranburu, Gorka; Calasanz Abinzano, María José; Garcia-Sanz, R. ; Gonzalez, M.; Gutierrez, N. C.; Martinez-Lopez, J.; Perez, J. J.; Merino Roncal, Juana María; Moreno Parado, Cristina; Burgos Rodríguez, Leire; Alignani, Diego Oscar; Botta, C. ; Prosper Cardoso, Felipe; Matarraz, S. ; Orfao, A.; Oriol, A. ; Teruel, A. I. ; de Paz, R. D.; de Arriba, F.; Hernandez, M. T.; Palomera, L.; Martinez, R. ; Rosinol, L. ; Mateos, M. V. ; Lahuerta, J. J.; Blade, J.; San Miguel Izquierdo, Jesús; Paiva, Bruno (Autor de correspondencia)
Título de la revista: BLOOD
ISSN: 0006-4971
Volumen: 135
Número: 26
Páginas: 2375 - 2387
Fecha de publicación: 2020
Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell-targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC.