Exploratory Identification of Potential Serum Biomarkers Associated with Relapse in Multiple Myeloma

Background: Relapse remains a major clinical challenge in multiple myeloma (MM), highlighting the need to identify circulating proteins associated with relapse as candidates for disease monitoring and further biomarker development. Methods: An integrated proteomic and transcriptomic approach was used to identify candidate biomarkers associated with relapsed MM. Differentially abundant proteins were identified by LC-MS/MS profiling of paired serum samples collected at very good partial response (≥VGPR) and at relapsed/refractory MM (RRMM) diagnosis. A publicly available gene expression dataset (GSE47552) comparing malignant and normal plasma cells was analyzed to assess gene-protein concordance. Candidate biomarkers were subsequently evaluated by ELISA using paired serum samples from 40 patients collected at ≥VGPR and relapse. Associations with bone marrow plasma cell (BMPC) burden and CD30 expression by immunohistochemistry (IHC) were further explored. Results: LC-MS/MS profiling identified 938 proteins, including 84 increased and 39 decreased in RRMM compared with ≥VGPR. Based on predefined selection criteria, TNFRSF8 (CD30) and PTBP2 were prioritized as candidate biomarkers. Serum TNFRSF8 levels were significantly higher at relapse than at ≥VGPR (p < 0.001), whereas PTBP2 levels showed no significant change (p = 0.578). Serum TNFRSF8 levels were not associated with BMPC burden, and CD30 was absent on plasma cells by IHC, suggesting an increase independent of plasma cell expansion. Conclusions: This exploratory study identified serum TNFRSF8 as a candidate circulating biomarker associated with relapse in MM. Further mechanistic and clinical studies in larger, well-characterized prospective cohorts are warranted to clarify its biological basis and potential clinical relevance.