Monoclonal gammopathy defines distinct clinical subsets in chronic lymphocytic leukemia across therapeutic eras.

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 2075 patients with CLL (1999-2024), MG was detected in 18.47% cases, with immunoglobulin M (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 a younger age and a higher frequency of mutated immunoglobulin heavy-chain variable (IGHV). In contrast, IgM-MG was associated with unmutated IGHV, elevated lactate dehydrogenase and β2-microglobulin levels, higher frequencies of TP53 aberrations, and enrichment of MYD88, BIRC3, and 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, and overall survival. 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-International Prognostic Index (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 Bruton tyrosine kinase inhibitors in IgM-MG, immunofixation-based MG profiling may inform risk-adapted treatment strategies and personalized therapy selection.