Baseline Monoclonal Protein Identifies Plasmacytic Differentiation and Shorter Progression‐Free Survival in Marginal Zone Lymphoma

Monoclonal protein is frequently tested in marginal zone lymphoma, but interpretation is often inconsistent in practice because prior studies used selective testing and rarely linked serologic findings to biology or post-treatment dynamics. We analyzed 235 adults with newly diagnosed MZL receiving first-line systemic therapy at a single center (2010-2025). All patients had baseline serum protein electrophoresis, immunofixation, and free light chain testing. Plasmacytic differentiation was reviewed by hematopathologists. M-protein response (IMWG criteria) was assessed in patients with post-treatment data. The primary endpoint was progression-free survival (PFS). Baseline M-protein was detected in 117 of 235 patients (49.8%), most commonly immunoglobulin M (IgM) (65.8%). M-protein positivity was associated with a higher frequency of plasmacytic differentiation (39.6% vs. 16.2%; adjusted OR 3.78). M-protein-positive patients had shorter PFS than M-protein-negative patients (median, 50.9 months vs. not reached; log-rank p = 0.044), and this association remained in multivariable analysis (hazard ratio [HR] 1.58). Overall survival (OS), progression of disease within 24 months (POD24), and histologic transformation did not differ significantly by M-protein status. Among 70 patients with evaluable post-treatment data, M-protein response of at least partial response (PR) was highly specific for clinical response and had a high positive predictive value, but response depth did not predict PFS. In uniformly tested MZL patients requiring systemic therapy, baseline M-protein identifies a subgroup enriched for plasmacytic differentiation and associated with shorter PFS. Post-treatment M-protein decline can support response confirmation when present, but it should not be used as a surrogate endpoint for durable disease control without prospective validation.