Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma
Por:
Goicoechea I, Puig N, Cedena MT, Burgos L, Cordón L, Vidriales MB, Flores-Montero J, Gutierrez N, Calasanz MJ, Martin Ramos ML, Lara-Astiaso D, Vilas-Zornoza A, Alignani D, Rodriguez I, Sarvide S, Alameda D, Garcés JJG, Rodríguez S, Fresquet VJ, Celay J, Garcia-Sanz R, Martinez-Lopez J, Oriol A, Rios R, Martín Sánchez J, Martinez R, Sarra J, Hernandez MT, de la Rubia J, Krsnik I, Moraleda JM, Palomera L, Bargay J, Martinez-Climent JA, Orfao A, Rosiñol L, Mateos MV, Lahuerta JJ, Bladé J, San Miguel J and Paiva B
Publicada:
7 ene 2021
Ahead of Print:
21 jul 2020
Resumen:
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 similar to 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.
Filiaciones:
Goicoechea I:
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
Puig N:
Hospital Universitario de Salamanca, Salamanca, Spain
Cedena MT:
Hospital Universitario 12 de Octubre
Burgos L:
Universidad de Navarra, Pamplona, Spain
Cordón L:
Hospital Universitario La Fe, Valencia, Spain
Vidriales MB:
Hospital Universitario de Salamanca, Salamanca, Spain
Flores-Montero J:
Cancer research center-University of Salamanca, Salamanca, Spain
Gutierrez N:
Hospital Universitario de Salamanca. Centro de Investigación del Cáncer
Calasanz MJ:
University of Navarra, PAMPLONA, Spain
Martin Ramos ML:
Hospital 12 de Octubre, Madrid, Spain
Lara-Astiaso D:
Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain
Vilas-Zornoza A:
Centro de Investigacion Medica Aplicada, Pamplona, Spain
Alignani D:
Centro de Investigacion Medica Alplicada. Universidad de Navarra., Pamplona, Spain
Rodriguez I:
Division of Hematological Oncology, Center for Applied Medical Research CIMA, University of Navarra
Sarvide S:
Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain, pamplona, Spain
Alameda D:
Clinica Universidad de Navarra, Pamplona, Spain
Garcés JJG:
Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), Pamplona, Spain
Rodríguez S:
University of Navarra, PAMPLONA, Spain
Fresquet VJ:
CIMA, Pamplona, Spain
Celay J:
University of Navarra, PAMPLONA, Spain
Garcia-Sanz R:
University Hospital of Salamanca, Salamanca, Spain
Martinez-Lopez J:
Hospital Universitario 12 de Octubre. Instituto de Investigacion 12 de Octubre. Univ Complutense, Madrid, Spain
Oriol A:
ICO - Hosp Germans Trias i Pujol, Badalona, Spain
Rios R:
Hospital Universitario Virgen de las Nieves, Granada, Spain
Martín Sánchez J:
Hospital Universitario Virgen del Rocío, Sevilla, Spain
Martinez R:
Hospital Clínico San Carlos, Madrid, Spain
Sarra J:
ICO-Hospital Duran i Reynals, L'Hospitalet del Llobregat, Spain
Hernandez MT:
Hospital Universitario de Canarias, La Laguna. Tenerife, Spain
:
Hospital Universitario Dr. Peset, Valencia, Spain
Krsnik I:
Hospital Universitario Puerta de Hierro, Madrid, Spain
Moraleda JM:
Hospital Universitario Virgen de la Arrixaca. University of Murcia, El Palmar. Murcia, Spain
Palomera L:
Hospital Clínico Universitario "Lozano Blesa" IIS Aragon, Zaragoza, Spain
Bargay J:
hospital Son LLatzer, Palma Mallorca, Spain
Martinez-Climent JA:
Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Orfao A:
University of Salamanca, Salamanca, Spain
Rosiñol L:
Hospital Clínic, Institut d'investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
Mateos MV:
University Hospital of Salamanca/IBSAL/Cancer Research Center, Salamanca, Spain
Lahuerta JJ:
Insituto de Investigación.Hospital Universitario 12 de Octubre, Madrid, Spain
Bladé J:
Hospital Clínic i Provincial, Institut de Investicacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
San Miguel J:
Universidad de Navarra, Pamplona, Spain
Paiva B:
Clinica Universidad de Navarra, Pamplona, Spain
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