Chromosome 1q Gain Defines a Plasma Cell-Dominant Adverse-Risk Subtype in AL Amyloidosis With Inferior Long-Term Survival.

Abstract

The prognostic relevance of multiple myeloma (MM)-defined high-risk (HR) cytogenetic abnormalities in AL amyloidosis is incompletely defined. We retrospectively evaluated 517 newly diagnosed AL amyloidosis patients seen at Mayo Clinic between 2012 and 2021 who had baseline plasma cell FISH. HR cytogenetics were defined as t(4;14), t(14;16), t(14;20), del(17p), or 1q gain/amplification (+1q). HR abnormalities were identified in 151 patients (29%); +1q accounted for most HR cases (122/151, 81%). Compared with standard-risk (SR), patients harboring +1q demonstrated a greater clonal disease burden, including higher dFLC and bone marrow plasma cells, greater intact immunoglobulin secretion, higher plasma cell proliferative index, and enrichment for modified SLiM-CRAB features. Hematologic and organ response patterns of +1q patients were generally comparable to SR patients, whereas non-1q HR patients had a higher proportion of early hematologic responses. Patients harboring +1q demonstrated significantly inferior overall survival (OS) compared with both non-1q HR patients and SR patients (median OS 57 months vs. not reached vs. 120 months, p = 0.02). In multivariable piecewise Cox analysis, the adverse prognostic impact of +1q was most evident beyond 24 months from diagnosis (HR 2.89, 95% CI 1.64-5.09, p < 0.001), whereas non-1q HR lesions were not independently prognostic. These findings suggest that +1q identifies a biologically distinct AL amyloidosis subset characterized by plasma cell-dominant features and inferior long-term disease control. In contrast, other MM-defined HR cytogenetic abnormalities appear to have limited prognostic relevance in AL amyloidosis.