The coexistence of the extranidal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) and multiple myeloma (MM) is an exceedingly rare situation. The rare situation precludes any evidence-based guidelines for MZL or MM.We presented a unique case of the coexistence of primary mediastinal MALT lymphoma and MM like polyneuropathy, organomegaly, endocrinopathy, M-protein, skin syndrome.The patient was first diagnosed with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin syndrome in the department of neurology, then MM in the department of hematology, and the mediastinal MALT simultaneously coexisting with MM was found by biopsy in the department of thoracic surgery. The patient received combination therapy with rituximab and bortezomib followed by lenalidomide maintenance. To understand MZL lymphoma with plasmacytic differentiation better, we analyzed cases of MZL lymphomas with plasma cell neoplasms. Most of these cases were MZL lymphomas with light chain-restricted plasmacytic differentiation. The lymphomas relapsed with plasma cell neoplasms or transformed into plasma cell neoplasms after anti-lymphoma therapy.The case demonstrated clinical complexity and the importance of the detailed assessment. The case and literature review demonstrated the value of detecting light chain-restricted plasmacytic differentiation for the treatment of MZL lymphoma with rituximab plus lenalidomide or bortezomib.Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.