Single-cell technologies in deciphering drug resistance of multiple myeloma: mechanistic insights and clinical translation prospects

The greatest hindrance to long-lasting remission in multiple myeloma (MM) is drug resistance and is modulated by the complex interaction of tumor-intrinsic plasticity and microenvironmental co-evolution. Multi-omics of single cells has transformed the exploration of this complexity, and has solved the dynamics of clonal architecture and ecosystem at an unprecedented resolution. The present review summarizes critical relapse-driver revealed by single cell technologies, including existing resistant subclones and non-genetic programs, as well as inflammatory stromal remodeling and immune exhaustion. We also discuss the problem of reproducibility crisis due to analytical heterogeneity critically, outlining computational best practices to distinguish robust biological signals to technical artifacts. Moreover, we comment on the translational imperative, emphasizing new target discovery, rational combination strategies and mechanism-based prognostic modeling. Ultimately, high-fidelity molecular profiling needs to be bridged with strict analytical principles to make precision oncology advance in MM.