Longitudinal profiling of tumor and immune compartments uncovers patterns of dysregulation and associations with response in multiple myeloma

Abstract

Abstract Multiple myeloma (MM) is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment. To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T cell memory after autologous stem cell transplant, while naïve B cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48, p = 2.3e-4). At disease progression, MM cells upregulated cancer-testis antigens and immune effector genes, with concurrent B cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune-tumor interactions, identifying naïve B cell reconstitution as a biomarker of durable response, and cancer-testis antigens as potential targets for high-risk disease at progression.

Affiliated Institutions

• Fred Hutch Cancer Center US
• Translational Genomics Research Institute US
• Beth Israel Deaconess Medical Center US
• Emory University US
• Dana-Farber Cancer Institute US
• Georgia Institute of Technology US
• Piedmont Cancer Institute US
• Icahn School of Medicine at Mount Sinai US
• Washington University in St. Louis US
• Mayo Clinic in Arizona US
• Multiple Myeloma Research Foundation US
• Winship Cancer Institute
• University of Colorado Anschutz Medical Campus US

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