Multiple myeloma (MM) holds a unique position amongst haematological malignancies owing to the presence of accessible biomarkers of disease, namely clonal intact immunoglobulin and/or clonotypic kappa or lambda light chains in the serum. Quantitation of these biomarkers enables both disease monitoring and response attribution. However, with increasingly efficacious therapeutics deeper levels of response, not able to be defined by conventional serum biomarker quantitation, namely measurable residual disease (MRD) positivity or negativity, with the latter being a powerful indicator of extended disease-free survival, are being used. Both next generation sequencing (NGS) and multi-parameter flow cytometry (next generation flow - NGF) evaluation of bone marrow aspirates are utilised for MRD determination. The pitfalls of both approaches include the invasive nature of the test, high dependence on sample quality and the inability to overcome the spatial heterogeneity of MM within the intramedullary compartment. In this context, a range of highly sensitive blood-based mass spectrometric approaches have been evaluated with varying costs, complexity and sensitivity, and have clearly demonstrated a high level of utility that will hopefully obviate the need for bone marrow biopsies in the determination of MM disease response within the coming decade.