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Objective: Response to treatment in multiple myeloma (MM) is routinely measured by serum and urine M-protein and free light chain (FLC), as described by the International Myeloma Working Group (IMWG) consensus statement. A non-negligible subgroup of patients however present without measurable biomarkers, others become oligo or non-secretory during recurrent relapses. The aim of our research was to evaluate soluble B-cell maturation antigen (sBCMA) as a monitoring marker measured concurrent with the standard monitoring in MM patients at diagnosis, at relapse and during follow up, in order to establish its potential usefulness in oligo and non-secretory disease. Method: sBCMA levels were measured in 149 patients treated for plasma cell dyscrasia (3 monoclonal gammopathy of unknown significance, 5 smoldering myeloma, 7 plasmacytoma, 8 AL amyloidosis and 126 MM) and 16 control subjects using a commercial ELISA kit. In 43 newly diagnosed patients sBCMA levels were measured at multiple timepoints during treatment, and compared to conventional IMWG response and progression free survival (PFS). Results: sBCMA levels among control subjects were significantly lower than among newly diagnosed or relapsed MM patients [20.8 (14.7–38.7) ng/mL vs. 676 (89.5–1,650) and 264 (20.7–1,603) ng/mL, respectively]. Significant correlations were found between sBCMA and the degree of bone marrow plasma cell infiltration. Out of the 37 newly diagnosed patients who have reached partial response or better per IMWG criteria, 33 (89%) have had at least a 50% drop in sBCMA level by therapy week 4. Cohorts made similarly to IMWG response criteria—achieving a 50% or 90% drop in sBCMA levels compared to level at diagnosis—had statistically significant differences in PFS. Conclusion: Our results confirmed that sBCMA levels are prognostic at important decision points in myeloma, and the percentage of BCMA change is predictive for PFS. This highlights the great potential use of sBCMA in oligo- and non-secretory myeloma.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed and refractory multiple myeloma (MM), with BCMA-directed products demonstrating unprecedented response rates in heavily pretreated patients. Despite these advances, variabilities in response durability, treatment-related toxicities, and the emergence of resistance underscore the need for strategies that extend beyond CAR construct design alone. Accumulating evidence has indicated that the therapeutic outcomes of this approach are determined by a complex interplay between tumor burden, antigen dynamics, CAR T-cell functional fitness, and host immune context at the time of infusion. Effector-to-target balance and antigen load, in particular, have emerged as modifiable biological determinants of efficacy and safety, with pre-infusion disease control and response to bridging therapy exerting a profound influence on post-infusion CAR T-cell expansion, persistence, and clinical outcomes. Soluble BCMA (sBCMA) has also gained increasing attention as a practical biomarker that integrates tumor burden and antigen dynamics to facilitate the biologically informed optimization of treatment timing and patient selection. In addition to tumor- and antigen-related factors, the intrinsic properties of CAR T-cell products—including the spatial organization and clustering of CAR molecules on the T-cell surface—represent an additional layer of biological determinants that correlate with treatment responses. The quantitative functional assessment of CAR T-cell products may complement conventional clinical and tumor-based biomarkers and improve the prediction of therapeutic potency prior to infusion. This review summarizes recent advances in CAR T-cell therapy for treating MM, focusing on key mechanisms of resistance, the optimization of pre-infusion disease control, the integration of biological markers into clinical decision-making, and emerging combinations and sequential strategies. We also propose a design-oriented and patient-centered framework that integrates CAR engineering with disease biology and host immune factors to enhance the consistency, durability, and safety of CAR T-cell therapy. Such biologically guided optimization strategies will likely prove critical for fully realizing the transformative potential of CAR T-cell therapy across the evolving treatment continuum of MM.

Background: B-cell maturation antigen (BCMA) directed therapies have transformed the treatment landscape for relapsed or refractory multiple myeloma (RRMM). Soluble BCMA (sBCMA), a circulating product of the membrane-bound BCMA shedding, has emerged as a potential biomarker reflecting tumor burden and disease biology. This systematic review and meta-analysis aimed to evaluate the prognostic value of baseline circulating sBCMA in patients with multiple myeloma receiving BCMA-directed therapies, with progression-free survival (PFS) as the primary endpoint. Methods: A systematic literature search of PubMed/MEDLINE, Embase, Scopus, and Web of Science databases was conducted in accordance with PRISMA guidelines. Studies enrolling patients with multiple myeloma treated with BCMA-directed therapies and reporting baseline circulating sBCMA measured in serum or plasma in relation to survival outcomes were included. Hazard ratios (HRs) for PFS and overall survival (OS) were pooled using random-effects models. Risk of bias was assessed using the QUIPS tool. Results: Four independent RRMM cohorts fulfilled the eligibility criteria and were included in the quantitative PFS meta-analysis. Elevated baseline circulating sBCMA was significantly associated with inferior PFS (pooled HR = 2.64, p < 0.05), with a consistent adverse prognostic direction across all studies. Moderate to substantial heterogeneity was observed (I2 = 63.2%), potentially reflecting differences in BCMA-directed therapy modalities across cohorts and methodological variability, including study-specific sBCMA cut-off definitions, assay procedures and sampling timepoints. Exploratory subgroup analysis suggested that the prognostic impact of baseline sBCMA on PFS may differ according to BCMA-directed therapy class. Overall risk of bias was judged as low to moderate. Conclusions: Elevated baseline circulating sBCMA is associated with inferior progression-free survival in patients with multiple myeloma treated with BCMA-directed therapies. These findings support the prognostic relevance of sBCMA as a risk stratification marker, although harmonization of assays and cut-offs and prospective validation are required before clinical implementation.

The MRZ reaction (MRZR) comprises the three antibody indices (AIs) against measles, rubella, and varicella zoster virus, reflecting an intrathecal polyspecific B cell response highly specific for multiple sclerosis (MS). Thus, MRZR can be used to confirm a diagnosis of primary progressive MS (PPMS) but its pathophysiological and wider clinical relevance is unclear. This study aimed to investigate whether PPMS patients with a positive MRZR (MRZR+) differ from those with a negative MRZR (MRZR-) according to cerebrospinal fluid (CSF) biomarkers of B cell activity, neuroaxonal damage or glial activity, and clinical features. (1) Methods: In a multicenter PPMS cohort (n = 81) with known MRZR status, we measured B cell-activating factor (BAFF), chemokine CXC ligand 13 (CXCL-13), soluble B cell maturation antigen (sBCMA), soluble transmembrane activator and CAML interactor (sTACI), and chitinase-3-like protein 1 (CHI3L1) in the CSF with enzyme-linked immunosorbent assays (ELISAs). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were detected in serum and CSF using single molecule array (SIMOA) technology. (2) Results: MRZR+ patients (45.7% of all PPMS patients) revealed higher levels of NfL in CSF compared to MRZR- patients (54.3%). There were positive correlations between each of sBCMA, sTACI, and intrathecal immunoglobin G (IgG) synthesis. Additionally, NfL concentrations in serum positively correlated with those in CSF and those of GFAP in serum. However, MRZR+ and MRZR- patients did not differ concerning clinical features (e.g., age, disease duration, Expanded Disability Status Scale (EDSS) at diagnosis and follow-up); CSF routine parameters; CSF concentrations of BAFF, CXCL-13, sBCMA, sTACI, CHI3L1, and GFAP; or serum concentrations of GFAP and NfL. (3) Conclusions: In PPMS patients, MRZR positivity might indicate a more pronounced axonal damage. Higher levels of the soluble B cell receptors BCMA and transmembrane activator and CAML interactor (TACI) in CSF are associated with a stronger intrathecal IgG synthesis in PPMS.

This study aimed to investigate whether soluble B-cell maturation antigen (sBCMA) levels could be predictive biomarker for short-term and long-term therapeutic efficacy and survival outcomes following anti-BCMA CAR-T cell therapy in relapsed/refractory multiple myeloma (R/R MM). We enrolled 29 R/R MM patients who received anti-BCMA CAR-T cell therapy. In short-term observation, proportion of MM cells, expression of B-cell maturation antigen (BCMA) and sBCMA in bone marrow (BM) were evaluated, along with adverse events, correlation between sBCMA levels and short-term efficacy or survival outcomes were evaluated. In long-term observation, expressions of sBCMA were observed up to 24 months after therapy or until disease progression again in patients who achieved an objective response (ORR). Progression-free survival (PFS), overall survival (OS), correlation between sBCMA levels, and long-term outcomes were analyzed. In short-term observation, high expressions of sBCMA in BM were associated with poor efficacy of CAR-T cell therapy, while the proportion of MM cells in BM and BCMA expression in MM cells were not associated with poor efficacy of therapy. After 2 months of infusion, sBCMA levels decreased significantly, especially in patients who obtained ORR. In long-term follow-up, for patients who achieved ORR, the sBCMA levels significantly increased again when their disease progressed once more. Notably, R/R MM patients with extramedullary disease (EMD) demonstrated a higher likelihood of disease progression again. In patients achieved ORR, peaks of CAR-T cells correlated with proportion of MM cells, not with BCMA and sBCMA expression. Additionally, sBCMA levels were independent of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) severity. We suggest that sBCMA levels in BM might serve as a predictive biomarker for anti-BCMA CAR-T cell therapy efficacy prior to treatment and for disease progression during long-term monitoring. The trail register name is China Clinical Trial Register. URL are https://www.chictr.org.cn/bin/project/edit?pid=28999 and https://www.chictr.org.cn/bin/project/edit?pid=53962. Registration numbers are ChiCTR1800017051 and ChiCTR2000033925. Graphical Abstract