Advances in minimal residual disease monitoring in multiple myeloma

Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells and the excretion of a monoclonal immunoglobulin (M-protein), or fragments thereof. This biomarker plays a key role in the diagnosis and monitoring of MM. Although there is currently no cure for MM, novel treatment modalities such as bispecific antibodies and CAR T-cell therapies have led to substantial improvement in survival. With the introduction of several classes of effective drugs, an increasing percentage of patients achieve a complete response. This poses new challenges to traditional electrophoretic and immunochemical M-protein diagnostics because these methods lack sensitivity to monitor minimal residual disease (MRD). In 2016, the International Myeloma Working Group (IMWG) expanded their disease response criteria with bone marrow-based MRD assessment using flow cytometry or next-generation sequencing in combination with imaging-based disease monitoring of extramedullary disease. MRD status is an important independent prognostic marker and its potential as a surrogate endpoint for progression-free survival is currently being studied. In addition, numerous clinical trials are investigating the added clinical value of MRD-guided therapy decisions in individual patients. Because of these novel clinical applications, repeated MRD evaluation is becoming common practice in clinical trials as well as in the management of patients outside clinical trials. In response to this, novel mass spectrometric methods that have been developed for blood-based MRD monitoring represent attractive minimally invasive alternatives to bone marrow-based MRD evaluation. This paves the way for dynamic MRD monitoring to allow the detection of early disease relapse, which may prove to be a crucial factor in facilitating future clinical implementation of MRD-guided therapy. This review provides an overview of state-of-the-art of MRD monitoring, describes new developments and applications of blood-based MRD monitoring, and suggests future directions for its successful integration into the clinical management of MM patients.