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

Cirino Botta, Diego Alignani, Sergio Matarraz, Sarai Sarvide, Bruno Paiva, Maria-Victoria Mateos, Cristina Moreno, Francisco Javier Gracia-Aznárez, Cirino Botta, Ibai Goicoechea, Rafael Valdes-Mas, Joan Blade, Maria-Teresa Cedena, José J. Perez, Ana-Isabel Teruel, Leire Burgos, Albert Oriol, Jesus F. San Miguel, Jesus F. San Miguel, Paula AguirreCatarina Maia, Gorka Alkorta, Alberto Orfao, Laura Rosiñol, Felipe De Arriba, Juan-Jose Lahuerta, Maria-Carmen Chillon, Felipe Prosper, Luis Palomera, Noemi Puig, Iria Vazquez, Norma C. Gutierrez, Ramon Garcia-Sanz, Maria-Jose Calasanz, Joan Blade, Joaquin Martinez-Lopez, Alberto Orfao, Juana Merino, Miguel T. Hernandez, Rafael Martinez, Marcos Gonzalez, Raquel De Paz

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


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 CD341 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 5.02) and overall survival (hazard ratio, 1.7; P 5.01). 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.
Original languageEnglish
Pages (from-to)2375-2387
Number of pages13
Publication statusPublished - 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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