Integrative single-cell analysis reveals malignant archetypes and proliferative hierarchies in multiple myeloma [Part 4 of 4: Illumina NovaSeq X; MARS_v2]

Multiple myeloma (MM) is a plasma cell malignancy characterized by substantial genomic and biological heterogeneity, limiting disease classification and development of more targeted therapies. Here, we present a population-level single-cell atlas of MM and detailed clinical annotations from 342 patients representing MM disease and treatment continuum. Our analysis identifies five distinct malignant transcriptional archetypes (MM1–MM5), and a proliferative module variably expressed across archetypes. This proliferation signature emerges as a context-dependent program with independent prognostic value across archetypes. Combined archetype classification with proliferation scoring defines therapeutic resistance, genomic instability, and clinical outcomes. External validation using the CoMMpass cohort confirms the biological robustness and prognostic relevance of this stratification across platforms. Leveraging the resolution of our single-cell atlas, we applied a computational pipeline for therapeutic target discovery based on malignancy, cell-type specificity and tissue restriction. This approach highlights FCRL2 as a promising MM-specific therapeutic target, with selective expression in malignant plasma and B cells at both transcriptomic and protein levels. This integrative analysis provides a clinically actionable blueprint for patient-specific stratification and precision medicine in plasma cell malignancies.