Abstract In systemic light-chain (AL) amyloidosis monoclonal immunoglobulin light-chain proteins from clonal plasma cells cause fatal multiorgan disease. Patient age is a critical factor; among those diagnosed with heart involvement, older age independently predicts for earlier death. Among those who have excellent hematologic responses to initial therapy, patients older than 60 at diagnosis have a median survival of 8 years because of the burden of organ damage while those younger than 60 have 80% survival at 8 years. Patients older than 60 are often too sick at diagnosis to undergo intensive therapy such as autologous stem cell transplant. Diagnosing AL before significant and symptomatic organ dysfunction occurs is an urgent unmet need, especially in individuals older than 60. This can be accomplished by screening patients with smoldering multiple myeloma (SMM) or monoclonal gammopathy of unknown significance (MGUS), many of whom progress annually to AL with organ damage because of delays in diagnosis. Every AL patient has an Ig variable region light-chain gene (IGVL) that encodes the pathologic light-chain protein and can be identified by RT-PCR. The proposed mulitcenter study tests the hypothesis that screening for the λ IGVL germline gene can diagnose AL and the risk of AL in asymptomatic SMM or λ MGUS patients before symptomatic organ damage occurs. Eighty percent of AL cases are due to λ light chains. Nine of the 33 λ IGVL germline genes on chr 22q11.2 cause 90% of the cases of AL λ-type. In the single-center pilot study (NCT02741999), 70% of the λ SMM and λ MGUS patients screened had AL-related λ IGVL genes identified and 10% had undiagnosed AL. In the proposed multicenter study we seek to expand to 6 centers and to develop a CLIA-validated next- generation sequencing test for λ IGVL gene identification by screening the clonal marrow plasma cells of 50 λ SMM or λ MGUS patients. This project will shift the paradigm for λ SMM and λ MGUS patients from watchful waiting for AL and organ damage to screening for early identification of AL and risk of AL, and will save lives by enabling earlier diagnosis before organ damage occurs and by permitting older patients to receive more intensive therapy.