ABSTRACT Minimal residual disease (MRD) has emerged as a central biomarker in hematologic malignancies, enabling highly sensitive detection of tumor persistence beyond conventional morphologic assessment and serving as an increasingly important surrogate endpoint in clinical trials. Despite these advances, MRD remains predominantly conceptualized as a quantitative variable reflecting residual tumor burden below assay detection thresholds. While this paradigm has enabled standardization of response criteria and cross‐trial comparisons, it does not fully explain key clinical observations, including heterogeneous outcomes among MRD‐positive patients, durable remissions despite detectable disease, and discordance between molecular and imaging‐based assessments. Here, we propose a conceptual framework in which MRD is redefined as a biologically determined trait—a functional phenotype of persistence—rather than a purely quantitative state. We review the mechanisms that shape this phenotype, including therapy‐driven clonal selection, epigenetic and transcriptional plasticity, metabolic adaptation, immune evasion, and microenvironmental niche protection. These processes collectively define the functional fitness of residual tumor cells and their capacity to survive therapeutic pressure, remain dormant, and ultimately drive relapse. This framework provides a mechanistic explanation for clinically observed phenomena—including molecular–imaging discordance and variable relapse kinetics—arguing that these are not merely technical artifacts but reflect distinct, partially independent biological dimensions of residual disease. We further outline a multidimensional model of MRD integrating molecular, spatial, immune, metabolic, and functional dimensions. Operationally, we define MRD as a biological trait across five interacting axes: (i) clonal fitness, (ii) phenotypic plasticity, (iii) metabolic adaptability, (iv) immune evasion, and (v) microenvironmental dependence. Conceptualizing MRD as a dynamic biological trait offers a more comprehensive and testable model of disease persistence and supports the development of mechanism‐based MRD‐directed therapeutic strategies in hematologic malignancies.
Caserta et al. (Sun,) studied this question.