Multiple Myeloma Measurable Residual Disease: Spotting Three Different Detection Methods

Multiple myeloma (MM) is the second most common hematologic malignancy. It is still largely incurable, but treatment has changed greatly with proteasome inhibitors, immunomodulatory drugs, monoclonal and bispecific antibodies, autologous stem cell transplantation and chimeric antigen receptor T cells. Most patients now achieve a complete response. As a result, conventional criteria, based on monoclonal protein, serum free light chains and bone marrow plasma cell counts, can no longer distinguish different depths of response. Measurable residual disease (MRD) has therefore become the reference endpoint. The International Myeloma Working Group defines MRD negativity as the absence of clonal plasma cells among at least 100,000 bone marrow cells. MRD negativity predicts progression-free and overall survival, independently of cytogenetic risk and disease stage. The US Food and Drug Administration has also accepted it as an early endpoint for accelerated approval. This review examines the three main technologies now used to assess MRD in MM. Next-generation flow cytometry is standardized through the EuroFlow two-tube, eight-color protocol. It gives same-day results and can be applied to all patients without a baseline sample. Next-generation sequencing of clonal immunoglobulin gene rearrangements is more sensitive and can be used on stored samples. It can also follow clonal evolution and the appearance of resistance mutations. Mass spectrometry is performed on peripheral blood. It detects the patient-specific clonotypic immunoglobulin with much higher sensitivity than electrophoretic methods and allows frequent, minimally invasive monitoring. For now, however, it complements marrow-based testing and does not replace it. For each method, we discuss analytical principles, sensitivity, standardization, pre-analytical requirements, clinical validation and limitations, and we briefly consider the growing contribution of artificial intelligence. The review also covers the role of cytogenetics and fluorescence in situ hybridization in baseline risk assessment. Finally, we discuss the limits of MRD testing in a disease that is often unevenly distributed between marrow, extramedullary sites and peripheral blood. Current evidence suggests that combining marrow-based and blood-based assays may identify residual disease most accurately. This combined approach has not yet been validated prospectively, and for now it should be used within clinical trials.