Tumor relapse in scar tissue is uncommon in cancer patients. Likewise, extramedullary plasmacytoma (EMP) relapse in scar tissue in the setting of multiple myeloma (MM) has been rarely reported. We report a series of 3 patients whose disease progressed as EMP at the site of a wound from previous invasive procedures. All 3 patients were treated for the relapsed disease with different treatment modalities, but failed to respond adequately and died several months after relapse. At original MM diagnosis, all had advanced-stage disease. They were treated with novel agents with or without autologous hematopoietic stem cell transplantation and achieved either a complete or very good partial response. We suggest that these treatments, which have become the standard of care in MM, may permit a predominance of myeloma subclones which are independent of the bone marrow microenvironment. These myeloma subclones then gain a survival advantage in the active scar-tissue niche, allowing for their uncontrolled proliferation. This case series might represent an underreported phenomenon and therefore may indicate an emerging and difficult-to-treat disease in the era of targeted therapies in MM. Physicians treating MM should be aware of this phenomenon, especially when referring their patients for invasive procedures.