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Clonotypic B cells have been proposed as a potential disease reservoir in multiple myeloma and light-chain amyloidosis, but Gonzalez and colleagues demonstrate that they do not necessarily share the malignant potential of disease clones. Their study shows that the key genetic hallmarks of disease are largely restricted to the plasma-cell compartment and raises caution that assays detecting minimal residual disease may yield false-positive results by detecting rare clonotypic B cells. See related article by Gonzalez et al., p. XX .