Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard and high risk myeloma
Ibai Goicoechea 1 , Noemi Puig 2 , María-Teresa Cedena 3 , Leire Burgos 4 , Lourdes Cordón 5 , Maria Belen Vidriales 2 , Juan Flores-Montero 6 , Norma Gutierrez 7 , Maria Jose Calasanz 8 , Maria-Luisa Martin Ramos 9 , David Lara-Astiaso 10 , Amaia Vilas-Zornoza 11 , Diego Alignani 12 , Idoia Rodriguez 13 , Sarai Sarvide 14 , Daniel Alameda 15 , Juan José Garcés Garcés 16 , Sara Rodríguez 17 , Vicente Jose Fresquet 18 , Jon Celay 19 , Ramon Garcia-Sanz 20 , Joaquin Martinez-Lopez 21 , Albert Oriol 22 , Rafael Rios 23 , Jesús Martín Sánchez 24 , Rafael Martinez 25 , Josep Sarra 26 , Miguel-Teodoro Hernandez 27 , Javier de la Rubia 28 , Isabel Krsnik 29 , Jose M Moraleda 30 , Luis Palomera 31 , Joan Bargay 32 , Jose Angel Martinez-Climent 33 , Alberto Orfao 34 , Laura Rosiñol 35 , Maria-Victoria Mateos 36 , Juan-José Lahuerta 37 , Joan Bladé 38 , Jesús San Miguel 4 , Bruno Paiva 15
Patients with multiple myeloma (MM) carrying high-risk cytogenetic abnormalities (CA) have inferior outcome despite achieving similar complete response (CR) rates when compared to cases with standard-risk CA.
This questions the legitimacy of CR as treatment endpoint for high-risk MM, and represents a biological conundrum regarding the nature of tumor reservoirs persisting after therapy in patients with standard- and high-risk CA.
Here, we used next-generation flow (NGF) to evaluate measurable residual disease (MRD) in MM patients with standard- (N=300) vs high-risk CA (N=90) enrolled in the PETHEMA/GEM2012MENOS65 trial (NCT01916252), and to identify mechanisms determining MRD resistance in both patient subgroups (N=40). The 36-month progression-free and overall survival rates were higher than 90% in patients with undetectable MRD, with no significant differences (P≥0.202) between cases having standard- vs high-risk CA. Persistent MRD resulted in median progression-free survival of approximately three and two years in patients with standard- and high-risk CA, respectively (P<0.001).
Further use of NGF to isolate MRD followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CA, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying lost or acquired genetic abnormalities driving MRD resistance.
Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and ROS-mediated MRD resistance in high-risk MM.
Our study supports undetectable MRD as treatment endpoint for MM patients with high-risk CA and proposes characterizing MRD clones to understand and overcome MRD resistance.
CITA DEL ARTÍCULO Blood . 2020 Jul 21;blood.2020006731.doi: 10.1182/blood.2020006731