Advances in multiple myeloma blood-based monitoring and its clinical applications.

Multiple myeloma (MM) is currently still considered incurable. The recent introduction of novel therapeutic options has significantly improved patient outcomes, with more patients achieving positive responses. While this is positive, these deep remissions pose a challenge in disease monitoring and early detection of relapse, causing uncertainty of disease status among patients and healthcare providers. Current blood-based M-protein diagnostics are not sensitive enough to detect minimal residual disease (MRD) and the gold standard method for MRD-evaluation relies on invasive bone marrow biopsies. Several blood-based methods are currently being investigated as potential minimally invasive alternatives. Of these, mass spectrometry-based methods targeting clonotypic peptides (MS-MRD) offers up to 1,000 times higher sensitivity than traditional electrophoresis and immuno-based techniques for M-protein quantification in blood. In addition, methods initially developed for detecting clonal plasma cells in bone marrow are now being explored in peripheral blood, where circulating myeloma cells and cell-free DNA provide independent prognostic value. Next to its value as biomarker of disease activity, the unique M-protein can also play a direct role in causing tissue damage through a variety of different mechanisms. Currently, no diagnostic tests are available that assess M-proteins pathogenicity. Mass spectrometry-based techniques are suited to characterize the structural properties, stability, and post-translational modifications of M-proteins. This may improve our understanding regarding the pathogenic potential of M-proteins and pave the way for novel diagnostics and early identification of those patients who are at risk. This review highlights the emerging landscape of blood-based diagnostics in MM and their potential for clinically relevant applications.