Front Immunol. 2026 ;17
1934257
Maria Eugenia Alvaro,
Enrica Antonia Martino,
Santino Caserta,
Antonella Bruzzese,
Nicola Amodio,
Eugenio Lucia,
Virginia Olivito,
Caterina Labanca,
Francesco Mendicino,
Fortunato Morabito,
Ernesto Vigna,
Massimo Gentile.
The therapeutic landscape of multiple myeloma (MM) has undergone a profound transformation, with highly effective combination regimens and immune-based therapies enabling unprecedented rates of deep and durable responses. As a result, conventional baseline risk stratification alone is increasingly insufficient to explain the heterogeneity of clinical outcomes or to guide treatment throughout the disease course. This evolving paradigm has shifted attention toward dynamic, response-adapted disease monitoring centered on measurable residual disease (MRD) and the biological interaction between residual tumor cells and the host immune system. Bone marrow-based next-generation flow cytometry and next-generation sequencing currently represent the most extensively validated approaches for MRD assessment, while functional imaging, mass spectrometry, circulating tumor DNA, and other minimally invasive technologies are expanding the ability to monitor spatially heterogeneous disease and longitudinal clonal evolution. Although sustained MRD negativity has emerged as one of the most powerful prognostic biomarkers in MM, its clinical significance is influenced by multiple factors, including timing of assessment, sensitivity, durability of response, baseline disease biology, imaging findings, and the quality of immune reconstitution. Increasing evidence indicates that relapse following MRD negativity reflects not only residual tumor burden below the limits of detection but also a dynamic biological process driven by clonal evolution, microenvironmental protection, immune escape, and therapeutic selection pressure. Immune profiling provides complementary information by characterizing immune competence, including T-cell and natural killer-cell function, immune reconstitution after therapy, regulatory and myeloid immunosuppressive networks, and the immune fitness required for effective T-cell redirection and the capacity to sustain effective antitumor immune surveillance. Integrating longitudinal MRD kinetics with immune biomarkers has the potential to improve risk discrimination, identify biologically discordant disease states, and support rational strategies for treatment intensification, de-escalation, or discontinuation within prospective clinical trials. In the era of anti-CD38 antibodies, CAR T-cell therapy, bispecific antibodies, and emerging multi-antigen immunotherapies, disease monitoring is evolving beyond the assessment of tumor burden alone. Future of MM management will likely rely on multidimensional monitoring frameworks that integrate MRD, immune competence, spatial disease assessment, circulating biomarkers, and computational risk modeling to enable truly personalized, biology-driven patient care.
Keywords: CAR T cells; bispecific antibodies; dynamic risk assessment; immune profiling; immune reconstitution; liquid biopsy; measurable residual disease; minimal residual disease