Screening for Systemic Light-Chain Amyloidosis in Patients Over 60 with λ Monoclonal Gammopathies

<b>Background/Objectives:</b> To reduce the early mortality of light-chain amyloidosis (AL), earlier diagnosis is needed. To pursue this goal, we conducted a multicenter study screening for AL λ-type (NCT04615572) in subjects > 60 years of age with λ smoldering myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS), a light-chain differential (dFLC, λ minus κ) > 23 mg/L, and no prior amyloid diagnosis. <b>Methods</b>: Variables included AL-related IGVL gene usage and clonal plasma cell cytogenetic abnormalities, such as t(11;14) or gain 1q, which are present in 75% of AL cases. Here, 9 out of 33 λ IGVL genes, accounting for 90% of AL λ cases, were considered to be AL-related. Bone marrow was obtained, plasma cell cytogenetics and next generation sequencing for IGVL genes were performed, and subjects with AL-related IGVL genes were screened for AL using tissue studies. <b>Results</b>: From 2021 to 2023, we enrolled 30 subjects (19 M/11 F) with a median age of 68.5 years old (IQR 64.3-73), 17 SMM and 13 MGUS, with a median of 6% marrow plasma cells (range, 3.5-40). Here, 11 SMM and 4 MGUS cases had t(11;14) or gain 1q; 10/17 SMM and 12/13 MGUS had AL-related genes, and AL was ultimately confirmed by tissue biopsy in 3 with SMM. SMM, AL-related IGVL genes, and t(11;14) or gain 1q were found in 6 SMM subjects, including the 3 with AL (3/6 vs. 0/16; <i>p</i> < 0.05, Fisher's exact, two-tailed). <b>Conclusions</b>: These results justify a larger study screening for AL in SMM to develop a likelihood algorithm for AL using dFLC, IGVL gene usage, and the presence of t(11;14) or gain 1q.