Measurable Residual Disease in Multiple Myeloma

Multiple myeloma remains largely incurable despite therapeutic advancements with proteasome inhibitors, immunomodulatory drugs, monoclonal and bispecific antibodies, autologous stem cell transplantation, and chimeric antigen receptor T cells. Because most patients now achieve a complete response, traditional monitoring metrics—including monoclonal protein, serum free light chains, and bone marrow plasma cell counts—can no longer distinguish varying depths of response, leading measurable residual disease (MRD) to 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, an outcome that predicts progression-free and overall survival independently of cytogenetic risk and disease stage, and which the US Food and Drug Administration has accepted as an early endpoint for accelerated approval.

Three primary technologies are currently used to assess MRD. Next-generation flow cytometry is standardized via the EuroFlow two-tube, eight-color protocol, delivering same-day results across all patients without requiring a baseline sample. Next-generation sequencing of clonal immunoglobulin gene rearrangements offers higher sensitivity, can be performed on stored specimens, and tracks clonal evolution as well as emergent resistance mutations. In peripheral blood, mass spectrometry detects patient-specific clonotypic immunoglobulin with higher sensitivity than standard electrophoretic methods, facilitating frequent, minimally invasive assessment that complements rather than replaces bone marrow testing. Given the uneven disease distribution across marrow, extramedullary sites, and peripheral blood, evidence suggests that pairing marrow- and blood-based modalities may identify residual disease most accurately; however, this combined strategy lacks prospective validation and should currently be utilized within clinical trials.