Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma
Ibai Goicoechea, Noemi Puig, Maria-Teresa Cedena, Leire Burgos, Lourdes Cordón, María-Belén Vidriales, Juan Flores-Montero, Norma C Gutierrez, Maria-Jose Calasanz, Maria-Luisa Martin Ramos, David Lara-Astiaso, Amaia Vilas-Zornoza, Diego Alignani, Idoia Rodriguez, Sarai Sarvide, Daniel Alameda, Juan José Garcés, Sara Rodriguez, Vicente Fresquet, Jon Celay, Ramón Garcia-Sanz, Joaquin Martinez-Lopez, Albert Oriol, Rafael Rios, Jesus Martin-Sanchez, Rafael Martinez-Martinez, Josep Sarra, Miguel-Teodoro Hernandez, Javier de la Rubia, Isabel Krsnik, Jose-Maria Moraleda, Luis Palomera, Joan Bargay, Jose-Angel Martinez-Climent, Alberto Orfao, Laura Rosiñol, Maria-Victoria Mateos, Juan-José Lahuerta, Joan Blade, Jesús San Miguel, Bruno Paiva, Ibai Goicoechea, Noemi Puig, Maria-Teresa Cedena, Leire Burgos, Lourdes Cordón, María-Belén Vidriales, Juan Flores-Montero, Norma C Gutierrez, Maria-Jose Calasanz, Maria-Luisa Martin Ramos, David Lara-Astiaso, Amaia Vilas-Zornoza, Diego Alignani, Idoia Rodriguez, Sarai Sarvide, Daniel Alameda, Juan José Garcés, Sara Rodriguez, Vicente Fresquet, Jon Celay, Ramón Garcia-Sanz, Joaquin Martinez-Lopez, Albert Oriol, Rafael Rios, Jesus Martin-Sanchez, Rafael Martinez-Martinez, Josep Sarra, Miguel-Teodoro Hernandez, Javier de la Rubia, Isabel Krsnik, Jose-Maria Moraleda, Luis Palomera, Joan Bargay, Jose-Angel Martinez-Climent, Alberto Orfao, Laura Rosiñol, Maria-Victoria Mateos, Juan-José Lahuerta, Joan Blade, Jesús San Miguel, Bruno Paiva
Abstract
Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. 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 CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252.
© 2021 by The American Society of Hematology.
Source: PubMed