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Simple Summary: Whilst multiple myeloma (MM) remains incurable, two clinical priorities are to prolong remission and reduce complications, of which fragility fractures are a major source of morbidity. To this end, there is the need to develop biomarkers that can accurately track tumour burden and bone loss to guide treatment decisions. Here, we conducted a pilot feasibility study exploring the value of novel serum bone turnover and plasma cell burden markers and Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) when added to standard clinical assessment in patients with MM, monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM). We show serum DKK1 and BCMA as possible correlates of tumour burden, and that serum sclerostin may correlate with bone mineral density. Furthermore, we validate DW-MRI in longitudinal assessment of tumour volume. Our study highlights emerging serum and radiological biomarkers for assessment of tumour burden and bone loss, which require further study in larger cohorts to validate these findings and understand their clinical utility. Novel biomarkers for tumour burden and bone disease are required to guide clinical management of plasma cell dyscrasias. Recently, bone turnover markers (BTMs) and Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) have been explored, although their role in the prospective assessment of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) is unclear. Here, we conducted a pilot observational cohort feasibility study combining serum BTMs and DW-MRI in addition to standard clinical assessment. Fifty-five patients were recruited (14 MGUS, 15 smouldering MM, 14 new MM and 12 relapsed MM) and had DW-MRI and serum biomarkers (P1NP, CTX-1, ALP, DKK1, sclerostin, RANKL:OPG and BCMA) measured at baseline and 6-month follow-up. Serum sclerostin positively correlated with bone mineral density (r = 0.40−0.54). At baseline, serum BCMA correlated with serum paraprotein (r = 0.42) and serum DKK1 correlated with serum free light chains (r = 0.67); the longitudinal change in both biomarkers differed between International Myeloma Working Group (IMWG)-defined responders and non-responders. Myeloma Response Assessment and Diagnosis System (MY-RADS) scoring of serial DW-MRI correlated with conventional IMWG response criteria for measuring longitudinal changes in tumour burden. Overall, our pilot study suggests candidate radiological and serum biomarkers of tumour burden and bone loss in MM/MGUS, which warrant further exploration in larger cohorts to validate the findings and to better understand their clinical utility. [ABSTRACT FROM AUTHOR]