Soluble BCMA As a Surrogate Biomarker for Tumor Burden in Multiple Myeloma: Correlations with Various Biomarkers and Treatment Responses

Background: B-cell maturation antigen (BCMA) is a transmembrane receptor on plasma cells (PC) and is cleaved from the cell surface and released into the circulation as soluble BCMA (sBCMA). sBCMA is a potential non-invasive biomarker for monitoring multiple myeloma (MM). This study investigated the relationship between sBCMA levels and parameters representing tumor burden at diagnosis and during treatment in multiple myeloma.

Methods: Longitudinal serum samples were collected from 203 MM patients at Kameda Medical Center (2014-2023) and stored at -40°C. sBCMA levels were measured using an enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN). The relationship between sBCMA levels and tumor burden was assessed using bone marrow (BM) smear and analysis of CD138 whole slide imaging using QuPath(version 0.5.1; University of Edinburgh, Edinburgh, Scotland), multicolor flow cytometry (MFC), and imaging techniques, including total diffusion volume (tDV) from whole-body diffusion-weighted MRI and metabolic tumor volume (MTV) using PET/CT. The relationship between various IMWG response criteria and sBCMA levels was also examined.

Results: The median sBCMA level of MM at diagnosis was significantly elevated at 281.6 ng/mL compared to 41 ng/mL in healthy controls (P <0.001). Involved immunoglobulin showed a strong correlation with sBCMA levels (in IgG myeloma patients, R=0.511; in IgA myeloma patients, R=0.605; both p<0.05), but the involved FLC levels (R=0.466, p<0.05) had a weaker correlation. sBCMA levels showed a significant positive correlation with BM plasma cell (BMPC) levels determined with MFC, bone marrow smear, and percentage of CD138+ cells stained (Pearson's R = 0.516, 0.489, and 0.56, respectively. all P <0.001). A relatively strong correlation was also found between circulating tumor cells and sBCMA levels (R=0.526, p<0.001). Next, we examined sBCMA levels and ISS, R-ISS and R2-ISS stages. sBCMA levels progressively increased with stage 1, 2 and 3 in both ISS and R-ISS, with median values of 185.7 ng/mL, 257. 3 ng/mL and 835.0 ng/mL for ISS; 151.4 ng/mL,312.4 ng/mL and 765.3 ng/mL for R-ISS. For R2-ISS, it was 148.1 ng/mL, 257.3 ng/mL, 379.3 ng/mL and 1022.8 ng/mL for R2-ISS stages 1, 2, 3, 4.In the different IMWG response criteria, there was a clear trend showing decreasing sBCMA levels with better response categories. The median sBCMA levels were 94.55 ng/mL in partial response (PR), 46.10 ng/mL in very good partial response (VGPR), 37.92 ng/mL in complete response (CR), 35.70 ng/mL in stringent complete response (sCR), and 172.1 ng/mL in progressive disease (PD), with significant differences noted (P <0.05) except between CR and sCR. The relationship between amount of measurable residual disease using with MFC and sBCMA values was studied. The median sBCMA levels were 378.7 ng/mL for BMPC above 10%, 163.2 ng/mL for BMPC between 1% and 10%, 92.55 ng/mL for BMPC between 0.1% and 1%, 38.20 ng/mL for BMPC between 0.01% and 0.1%, 39.05 ng/mL for BMPC between 0.001% and 0.01%, and 39.05 ng/mL for BMPC below 0.0001%. The differences in sBCMA values were significant (P <0.001, P=0.054, P=0.01, P=0.64, P=0.98, respectively) when comparing BMPC greater than 0.01% to lower proportions, though it was challenging to stratify tumor burden when BMPC was less than 0.01%.

The correlations of tDV and MTV with sBCMA levels were weak (R = 0.305 and R = 0.174, respectively) suggesting that other factors may be involved as measured by advanced imaging techniques. We also examined the association between FISH abnormalities with sBCMA. sBCMA levels were significantly higher with 1q gain and 1q amplification, with median sBCMA levels of 255.2 ng/mL without 1q, and 659.4 ng/mL with 1q gain, and 787.4 ng/mL with 1q amplification (p=0.007 and p=0.009, respectively). No significant differences were found in other FISH abnormalities.

Conclusion: We demonstrated that sBCMA is a surrogate biomarker that reflects the total tumour burden in MM. The significant correlations observed between sBCMA levels and BMPC and various response support the potential utility of sBCMA in monitoring disease status and treatment response. However, the weak correlations with imaging parameters suggest that sBCMA may primarily reflect bone marrow tumour burden rather than overall disease burden. Further research is needed to validate these findings and to explore the role of sBCMA in the context of BCMA-targeted therapies.