Monoclonal gammopathy defines distinct clinical subsets in Chronic Lymphocytic Leukemia across therapeutic eras Open Access

• We leveraged a largest known retrospective cohort of 2075 CLL patients (1999-2024).

• We discovered that the presence of an IgM-MG identifies a clinically and genetically distinct subgroup of CLL patients

Monoclonal gammopathy (MG) in chronic lymphocytic leukemia (CLL) portends heterogeneous outcomes, yet its molecular drivers and therapeutic implications remain undefined. In this retrospective analysis of 2,075 CLL patients (1999-2024), MG was detected in 18.47% cases, with IgM (8.18%), IgG (8.09%), light-chain (1.14%) and IgA (1.06%) subtypes demonstrating divergent clinicogenomic profiles. Patients with IgA-MG were older at diagnosis, whereas those with IgG-MG had younger age and a higher frequency of mutated IGHV. In contrast, IgM-MG was associated with unmutated IGHV, elevated LDH and β2-microglobulin, and higher frequencies of TP53 aberrations and enrichment of MYD88, BIRC3, DDX3X mutations. IgG-MG was associated with shorter time to first treatment (TTFT) only, whereas IgM-MG correlated with significantly inferior TTFT, progression-free survival (PFS), and overall survival (OS). Subgroup analyses revealed that the adverse prognostic impact of MG was pronounced in IGHV-mutated CLL but attenuated in unmutated cases. Prognostic discrimination by the CLL-IPI remained robust regardless of MG status. Notably, patients with IgM-MG did not experience significant survival benefit from targeted therapy compared with conventional regimens. These findings demonstrate that MG subtypes, particularly IgM-MG, define biologically and clinically distinct subsets of CLL. Given the limited efficacy of BTK inhibitors in IgM-MG, immunofixation-based MG profiling may inform risk-adapted treatment strategies and personalized therapy selection.