Cryo-EM structures of light chain fibrils from abdominal fat biopsies of multiple myeloma patients

Multiple myeloma (MM) is a hematological malignancy characterized by the abnormal proliferation of plasma cells in the bone marrow and is closely associated with systemic light chain amyloidosis (AL), a disease triggered by the amyloid aggregation of antibody light chain (LC). High-resolution structures of amyloid LC fibrils from MM patients remain largely unexplored. Here, we extracted LC amyloid fibrils directly from abdominal fat biopsies of two living MM patients. Using cryo-electron microscopy (cryo-EM), we further determined the structures of three distinct LC fibril morphologies, which differ significantly from previously reported fibril structures derived from AL amyloidosis patients. Structural comparisons and computational analyses suggested distinct LC fibrillation mechanisms in MM compared to AL amyloidosis, highlighting a potential role of elevated protein concentration in driving LC aggregation in MM. These findings provide essential molecular insights into LC fibril formation in MM and offer a structural foundation for biological diagnosis of living MM patients based on accessible abdominal fat biopsy samples.