Mor Zada, Anna Kurilovich, Noam Shapira, Shuang-Yin Wang, Reut Sharet-Eshed, Shlomit Kfir-Erenfeld, Miriam Schlossberg, Elina Zorde, Nathalie Asherie, Chamutal Gur, Paulina Chalan, Rotem Shalita, Maya Ben Yehuda, Pascale Zwicky, Michelle von Locquenghien, Florian Ingelfinger, Kfir Mazuz, Eyal David, Anna Gurevich-Shapiro, Natan Melamed, Iuliana Vaxman, Irit Avivi, Assaf Weiner, Polina Stepensky, Yael Cohen, Ido Amit
Multiple myeloma (MM) is a plasma-cell malignancy with extensive genomic and transcriptional heterogeneity, limiting disease classification and precision therapy. Here we generated a clinically annotated, population-scale, single-cell atlas of MM from 341 individuals spanning the disease and treatment continuum. We identified five recurrent malignant transcriptional archetypes and an orthogonal proliferative program associated with genomic features, therapeutic resistance and clinical outcomes. Validation in the independent CoMMpass cohort demonstrated robustness, prognostic relevance and portability across platforms. We developed a single-cell, target-discovery pipeline prioritizing malignant enrichment, cell-type specificity and tissue restriction, identifying FCRL2 as a plasma-restricted or B cell-lineage-restricted surface target expressed by malignant plasma cells. FCRL2-targeted chimeric antigen receptor T cells demonstrated antigen-specific activity in vitro and survival benefit in vivo. Together, these data provide a clinically actionable blueprint for patient stratification and precision target nomination in plasma-cell malignancies.