# Soluble B-Cell Maturation Antigen as a Prognostic Marker for Progression-Free Survival in Multiple Myeloma Treated with BCMA-Directed Therapies: A Systematic Review and Meta-Analysis

## TL;DR

Higher levels of a blood marker called soluble BCMA predict worse outcomes in multiple myeloma patients treated with BCMA-targeting therapies.

## Contribution

This study is the first to systematically show that baseline soluble BCMA levels are a consistent predictor of treatment response in BCMA-directed therapy for multiple myeloma.

## Key findings

- Elevated baseline soluble BCMA is significantly linked to shorter progression-free survival in multiple myeloma patients.
- The association is consistent across multiple independent patient groups, despite some variability in study methods.
- The study suggests soluble BCMA could be used for risk stratification in future clinical trials.

## Abstract

New treatments that target a protein called B-cell maturation antigen have greatly improved outcomes for patients with multiple myeloma, but treatment responses vary widely. Simple blood tests that could help predict treatment outcomes are still lacking. Soluble B-cell maturation antigen is a blood marker that can be measured before treatment begins and has been proposed to be associated with disease activity. In this study, we reviewed and combined available clinical evidence to evaluate whether baseline levels of this marker are linked to treatment outcomes in patients receiving B-cell maturation antigen-directed therapies. Across several independent patient groups, higher baseline levels were consistently associated with shorter periods of disease control. These results suggest that this blood marker may help identify patients at higher risk of early disease progression and could support improved risk stratification in future clinical trials and treatment planning.

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.