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Genomic and immune determinants of resistance to daratumumab-based therapy in relapsed refractory multiple myeloma.
Ziccheddu, Bachisio; Giannotta, Claudia; D'Agostino, Mattia; Bertuglia, Giuseppe; Saraci, Elona; Oliva, Stefania; Genuardi, Elisa; Papadimitriou, Marios; Diamond, Benjamin; Corradini, Paolo; Coffey, David; Landgren, Ola; Bolli, Niccolò; Bruno, Benedetto; Boccadoro, Mario; Massaia, Massimo; Maura, Francesco; Larocca, Alessandra.
Afiliación
  • Ziccheddu B; Myeloma Division, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
  • Giannotta C; Laboratory of Blood Tumor Immunology, Molecular Biotechnology Center "Guido Tarone", Department of Molecular Biotechnology and Health Sciences, Università di Torino, Torino, Italy.
  • D'Agostino M; Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
  • Bertuglia G; Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
  • Saraci E; Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
  • Oliva S; Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
  • Genuardi E; Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
  • Papadimitriou M; Myeloma Division, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
  • Diamond B; Myeloma Division, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
  • Corradini P; Division of Hematology and Bone Marrow Transplant, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • Coffey D; Myeloma Division, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
  • Landgren O; Myeloma Division, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
  • Bolli N; Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Bruno B; Department of Oncology and Onco-Hematology, University of Milan, Milan, Italy.
  • Boccadoro M; Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
  • Massaia M; European Myeloma Network, (EMN), Torino, Italy.
  • Maura F; Laboratory of Blood Tumor Immunology, Molecular Biotechnology Center "Guido Tarone", Department of Molecular Biotechnology and Health Sciences, Università di Torino, Torino, Italy.
  • Larocca A; SC Ematologia, AO S. Croce e Carle, Cuneo, Italy.
Blood Cancer J ; 14(1): 117, 2024 Jul 19.
Article en En | MEDLINE | ID: mdl-39030183
ABSTRACT
Targeted immunotherapy combinations, including the anti-CD38 monoclonal antibody (MoAb) daratumumab, have shown promising results in patients with relapsed/refractory multiple myeloma (RRMM), leading to a considerable increase in progression-free survival. However, a large fraction of patients inevitably relapse. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676). We conducted an integrated analysis using whole-genome sequencing (WGS) and flow cytometry in patients with RRMM. WGS before and after treatment pinpointed genomic drivers associated with early progression, including RPL5 loss, APOBEC mutagenesis, and gain of function structural variants involving MYC and chromothripsis. Flow cytometry on 202 blood samples, collected every 3 months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38-positive NK cells, persistence of T-cell exhaustion, and reduced depletion of regulatory T cells over time. These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns. Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd in patients with RRMM.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Resistencia a Antineoplásicos / Anticuerpos Monoclonales / Mieloma Múltiple Límite: Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Blood Cancer J Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Resistencia a Antineoplásicos / Anticuerpos Monoclonales / Mieloma Múltiple Límite: Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Blood Cancer J Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos