Multiple myeloma (MM) can co-occur with B-cell non-Hodgkin lymphoma (NHL). However, the simultaneous presence of both malignancies without prior chemotherapy is rare, lacks evidence-based guidelines, and is scarcely reported in medical literature.

To report a case of untreated B-cell NHL subsequently diagnosed with MM.

A 68-year-old woman with a cardiac left bundle branch block was diagnosed with indolent B-cell NHL based on peripheral blood (PB). Despite an IgG M-component of 500 mg/dL, her bone marrow biopsy was normal. She was under a “watch and wait” follow-up for 10 years until she developed severe anemia, fatigue, fever, weight loss, lack of appetite, sweating, hand arthritis, and bone pain. At this point, she exhibited lambda IgG monoclonal gammopathy of 3 g M-component and was MYD88 wild type. She did not present with lymphadenopathy, splenomegaly, abnormal calcium levels, renal dysfunction, or irregularities on positron emission tomography. PB flow cytometry revealed 58.3% B mature lymphocytes with the abnormal phenotype CD5-/CD23- and lambda light chain. BM analysis indicated simultaneous B-cell lymphoma and IgG MM, with 60% plasma cell infiltration and both monoclonal cell phenotypes present during disease progression. Additionally, a FISH panel for lymphomas was negative, but a pathogenic deletion (p.Leu188Trpfs*59) was identified in the TP53 gene with a 5% variant allele frequency. The patient was treated with a combination of rituximab, bendamustine, bortezomib, and dexamethasone, resulting in symptom and laboratory abnormality improvements.

Sequential changes in flow cytometry and BM biopsy indicated different stages of disease development. The pathological mechanism involved likely leads to lymphoma cell differentiation into plasma cells, resulting in plasmacytoma in a therapeutic-free environment. The identified TP53 variant typically confers a poor prognosis in hematological neoplasms. However, no molecular evidence suggests that MM developed from NHL cells, implying that the two tumors could have occurred independently. The treatment regimen considered the patient's age and comorbidities to address both malignant phenotypes due to the lack of standard guidelines.

This case highlights the complexity of hematological malignancy pathophysiology. Managing concomitant B-cell NHL and MM poses significant diagnostic and therapeutic challenges. Our report adds valuable clinical, pathophysiological, and molecular insights into this rare occurrence of sequential malignancies.