In summary, this study showed that CD38‐EVs, targeting myeloma cells and reducing the uptake by non‐tumour cells and tissues, along with CD38‐EVs‐DoxMNs, offer a non‐invasive, site‐specific and effective treatment for plasmacytoma with favourable safety and histocompatibility compared to intravenously delivered CD38‐EVs‐Dox. This evidence concerns the gene CD38 and plasmacytoma.