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Publications

Journal Article Ahead of print

PubMed: 42897348 DOI: 10.1038/s41591-026-04692-0

Molecular predictors of minimal residual disease in newly diagnosed multiple myeloma treated with quadruplet therapy.

Nat Med

Authors: Florence Magrangeas, Mia Cherkaoui, Victor Bessonneau-Gaborit, Jennifer Derrien, Céline Chevalier, Catherine Guérin-Charbonnel, Benjamin Diamond, Mehmet Kemal Samur, Cyrille Hulin, Denis Caillot, Lionel Karlin, Bertrand Arnulf, Ola Landgren, Nikhil C Munshi, Hervé Avet-Loiseau, Ludovic Martinet, Jill Corre, Aurore Perrot, Philippe Moreau, Cyrille Touzeau, Stéphane Minvielle, Eric Letouzé

Affiliations

  • Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France.
  • Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France.
  • Institut de Cancérologie de l'Ouest, Nantes, France.
  • Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
  • Department of Data Science, Dana Farber Cancer Institute, Boston, MA, USA.
  • Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Service d'Hématologie, Hôpital Haut Lévêque, Centre Hospitalier Universitaire de Bordeaux, Pessac, France.
  • Service d'Hématologie, Centre Hospitalier Universitaire de Dijon, Dijon, France.
  • Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d'Hematologie, Pierre-Benite, Université Claude Bernard Lyon 1, Lyon, France.
  • Immuno-hématologie, Hôpital Saint Louis, APHP, Université Paris Cité, Paris, France.
  • Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • VA Boston Healthcare System, Boston, MA, USA.
  • Cancer Research Center of Toulouse, INSERM, CNRS, Université Toulouse III-Paul Sabatier, Toulouse, France.
  • Institut Universitaire du Cancer, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
  • Université de Toulouse, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Service d'Hématologie, Toulouse, France.
  • Service d'Hématologie, Centre Hospitalier Universitaire de Nantes, Nantes, France.
  • Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France.
  • Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France.
  • Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France.
  • Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France.

Abstract

Quadruplet therapy, combining anti-CD38 antibodies, immunomodulatory drugs, proteasome inhibitors and dexamethasone, is now the standard induction treatment for newly diagnosed multiple myeloma (NDMM). However, treatment response is heterogeneous and molecular predictors are needed to guide early therapeutic decisions. We performed integrated genomic, transcriptomic and epigenomic profiling of 423 tumor samples from patients with NDMM from the MIDAS cohort to characterize molecular heterogeneity and its association with measurable residual disease (MRD) after quadruplet induction with isatuximab, carfilzomib, lenalidomide and dexamethasone (Isa-KRd). Postinduction MRD-negativity rates varied significantly across gene expression subtypes, with HP1/HP3 and MS groups showing superior responses compared to the MF and CD2 subtypes. B cell differentiation was associated with MRD positivity, while proliferation and MYC programs were associated with MRD negativity. These MRD-associated transcriptomic features were independently validated in the CASSIOPEIA cohort. Whole-genome sequencing revealed both known (APOBEC mutagenesis, chromothripsis) and new genomic instability phenotypes validated in the MMRF cohort. New driver alterations were identified with independent validation across three external cohorts with multiple myeloma (MMRF, MANHATTAN and CASSIOPEIA; 1,451 cases). Genomic instability features and driver genes such as CCND1 and MYC correlated with differential MRD outcomes. DNA methylation profiling identified nine MRD-linked subgroups distinguished by the extent of hypomethylation in quiescent chromatin and cis/trans signatures of driver translocations. A multimodal random forest model integrating genomic, transcriptomic and epigenomic features predicted MRD status after induction, with an area under the curve of 0.77, outperforming clinical and genomic models, while providing comparable discrimination and improved calibration relative to the transcriptomic and epigenomic models. These findings define a multiomic classification of NDMM linked to Isa-KRd response. ClinicalTrials.gov identifier: NCT04934475 .

MeSH

Genes, Epigenomics, Molecular Biology, Dexamethasone, Multiple Myeloma, Neoplasm, Residual, Therapeutics