Publicaciones científicas

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

16-abr-2020 | Revista: Blood

Maia CADS (1), Puig N (2), Cedena MT (3), Goicoechea I (3), Valdés-Mas R (4), Vazquez I (5), Chillon MC (6), Aguirre P (1), Sarvide S (7), Gracia-Aznárez FJ (1), Alkorta-Aranburu G (1), Calasanz MJ (8), Garcia-Sanz R (6), González M (9), Gutierrez N (10), Martinez-Lopez J (3), Perez JJ (9), Merino J (8), Moreno C (8), Burgos L (8), Alignani D (11), Botta C (8), Prosper F (8), Matarraz S (12), Orfao A (13), Oriol A (14), Teruel AI (15), de Paz R (16), de Arriba F (17), Hernandez Garcia MT (18), Palomera L (19), Martinez R (20), Rosiñol L 21, Mateos MV (22), Lahuerta JJ (3), Bladé J (23), San Miguel J (8), Paiva B (24).

(1) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/00369 and CB16/12/00489, Pamplona, Pamplona, Spain.
(2) Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), CIBER-ONC number CB16/12/00233 Salamanca, Spain.
(3) CIBER-ONC number CB16/12/00369, Madrid, Spain.
(4) DREAMgenics, Oviedo, Spain.
(5) Universidad de Navarra, Pamplona, Spain.
(6) Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), CIBER-ONC number CB16/12/00233 Salamanca, Spain.
(7) Centro de Investigacion Medica Aplicada, Pamplona, Spain.
(8) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/00369 and CB16/12/00489, Pamplona, Spain.
(9) Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), CIBER-ONC number CB16/12/00233 Salamanca, Spain.
(10) Instituto de Investigacion Biomedica de Salamanca,CIBER-ONC number CB16/12/00233 Salamanca (IBSAL),, Spain.
(11) Clinica Universidad de Navarra,Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/00369 and CB16/12/00489, Pamplona, Spain.
(12) Cytometry Service (NUCLEUS), and IBSAL. Cancer Research Center (IBMCC, University of Salamanca-CSIC), Salamanca, Spain.
(13) Cancer Research Center (IBMCC-CSIC/USAL-IBSAL); Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca (USAL), CIBER-ONC number CB16/12/00400 Salamanca, Sri Lanka.
(14) Institut Català d'Oncologia i Institut Josep Carreras, Badalona, Spain.
(15) Hospital Clínico Universitario de Valencia.
(16) Hospital Universitario La Paz, San sebastian de los Reyes, Spain.
(17) Instituto Murciano de Investigación Biosanitaria (IMIB), Spain.
(18) Hospital Universitario de Canarias, La Laguna. Tenerife, Spain.
(19) Hospital Clínico, Zaragoza, Spain.
(20) Hospital Clinico San Carlos, Madrid, Spain.
(21) Hospital Clínic, Institut d'investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
(22) CIBER-ONC number CB16/12/00233 Salamanca, Spain.
(23) Hospital Clínic i Provincial, Institut de Investicacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
(24) Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/00369 and CB16/12/00489, Pamplona, Spain.


Risk of developing myelodysplastic syndromes (MDS) is significantly increased in both multiple myeloma (MM) and MGUS, suggesting that 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 presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 MM patients enrolled in the PETHEMA/GEM2012MENOS65 trial (NCT01916252), and investigated the clinical significance of monocytic MDS-PA in a larger series of 1,252 patients enrolled in four PETHEMA/GEM protocols.

At diagnosis, 33/285 (11.6%) cases displayed MDS-PA. Bulk- and single-cell targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients unveiled clonal hematopoiesis in 13/26 (50%) cases with MDS-PA versus 9/41 (22%) 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 86/285 patients, and showed that in most cases (69/86, 80%) MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively.

Noteworthy, MDS-associated mutations unfrequently emerged after high-dose therapy. Based on MFC profiling, we found that patients with MDS-PA have altered hematopoiesis and Treg distribution in the tumor microenvironment. Importantly, presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematological toxicity and was independently associated with inferior progression-free (HR:1.5, P=.02) and overall survival (HR:1.7, P=.01).

This study unveils the biological and clinical significance of dysplastic hematopoiesis in newly-diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC.

CITA DEL ARTÍCULO  Blood. 2020 Apr 16. pii: blood.2019003382. doi: 10.1182/blood.2019003382.