Serum BCMA Is a Better Reflector of Tumor Volume Than IgM in the Induction Period of Waldenström Macroglobulinemia

Background: B-cell maturation antigen (BCMA) has recently been used as a therapeutic target for multiple myeloma. It increases with B cell maturation and is present in other B cell tumors, especially high in Waldenstrom macroglobulinemia (WM). Serum BCMA (sBCMA) has a shorter half-life of about 2 days compared to IgM of 5 days. However, in WM and IgM monoclonal gammopathies, the significance of sBCMA beyond IgM as a marker has not been explored.

Methods: This retrospective analysis included all patients with IgM monoclonal gammopathy between 2006 and 2024 at our hematology department of Kameda Medical Center. As a control, we have included randomly selected healthy people (n=50) and reactive gammaglobulinemia (T-cell lymphoma, autoimmune disorders, etc. n=27). sBCMA levels were measured using ELISA (R&D Systems). Tumor volume in bone marrow (BM) was calculated by multiplying the number of nucleated cells in BM aspiration by the CD20+ cell percentage in BM biopsy. The percentage of CD20+ cells in BM biopsies was calculated using QuPath.app (ver. 0.5.1). All data analyses were performed using R (ver. 4.1.1).

Results: In total, 73 patients with IgM monoclonal gammopathy were found in our electronic medical records (IgM-MGUS n=21, WM n=50, IgM-MM n=2). The median age of WM patients was 76 years (range 46–88), with male predominance (80%). Sixteen patients (32%) were initially treated with the bendamustine + rituximab regimen, and 15 (30%) received any type of Bruton’s tyrosine kinase inhibitor. Tumor volume in BM was calculated in 21 WM cases at diagnosis.

WM had the higher sBCMA levels of average 142 ng/mL [95%CI: 109–175] at diagnosis than healthy control of 42.1 [p<0.001]. The mean BCMA level of IgM-MGUS was 59.9 ng/mL [95%CI: 54.6–65.1].

At the diagnosis of WM, tumor volume in BM had good correlation with sBCMA level and log(sBCMA) [r=0.58 and 0.61, respectively] while IgM and log(circulating CD19+ in peripheral blood) did not have correlation [r=–0.1 and 0.2, respectively].

During the treatment courses of WM, the reduction of sBCMA and IgM was parallel at partial response (46.6% vs 42.4% of the initial serum levels) while sBCMA had a greater reduction than IgM at minor response (57.1% vs 67.3%, p=0.007), reflecting the shorter half-life of sBCMA. In very good partial response (n=6), IgM decrease was greater (9.5%) than the sBCMA decrease (31.7%), probably because of the baseline sBCMA level. Rituximab-related IgM flares were found in 9 patients with IgM levels increased to 132.6% of baseline, while sBCMA was decreased independently (81.0%) even in the middle of flare [p=0.01]. Furthermore, sBCMA levels were independent of plasma exchange (PE), while IgM levels were significantly disturbed, showing a steep decrease of IgM followed by a subsequent increase after PE.

Conclusion: This is the first study to demonstrate that sBCMA detect responses in WM earlier than IgM. Surprisingly, sBCMA levels were scarcely affected by PE and rituximab-related flares, probably reflecting the true tumor volume.