Gain or Amplification of 1q21 in Systemic Light Chain Amyloidosis Is Associated with Advanced Mayo Stage, Plasma Cell Disease and Worse Overall Survival

Systemic light chain amyloidosis is an acquired protein misfolding disease characterized by extracellular deposition of misfolded amyloidogenic immunoglobulin light chain fibrils secreted most often from clonal plasma cells in the bone marrow. Interphase fluorescence in situ Hybridization (iFISH) is an essential method to characterize disease biology and to define the treatment approach in multiple myeloma. In this retrospective study we included 169 patients with AL amyloidosis who presented between 2015-2024 and analyzed the role of iFISH aberrations on clinical characteristics and outcome. The most commonly detected aberrations were t(11;14) in 56.2%, deletion 13q14 in 33%, +1q21 in 21%, hyperdiploidy in 20.3% and deletion 16q23 in 16.4%. Significant elevations in dFLC levels were observed in patients with +1q21 (median 406 vs. 208 mg/l, p = 0.02), deletion 16q23 (median 476 vs. 203, p = 0.005), with a trend noted in t(11;14) (median 272 vs. 140 mg/l, p = 0.055). Only +1q21 was significantly associated with increased levels of biomarkers for cardiac damage including NTproBNP (median 8845 vs. 3482 pg/ml, p = 0.002) and hsTnT (median 104 vs. 52 ng/l, p = 0.001). This resulted in an increased proportion of patients with Mayo stage IIIb (53% vs. 26%, p = 0.02). Patients positive for +1q21 also had more advanced plasma cell disease (p = 0.001). In the overall population, +1q21 showed worse overall survival after a median follow-up time of 38 months (p = 0.006). In light of current induction regimens with bortezomib and daratumumab, our study is the first that identifies +1q21 as the main chromosomal aberration that predicts poor survival.

Michel:Bayer: Consultancy; Alnylam: Consultancy; AstraZeneca: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy. Rassaf:Mycor GmbH: Other: co-founder of mycor GmbH. Reinhardt:CDL Therapeutics GmbH: Current equity holder in private company; Gilead: Research Funding; Merck: Consultancy, Honoraria; Vertex: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Carpinteiro:Alexion: Consultancy; Alnylam: Consultancy.