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.