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.
Yan et al. (Wed,) studied this question.
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