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B-cell malignancies comprise a biologically diverse group of neoplasms, with only rare reports describing the co-occurrence of two distinct lymphoid entities. While concurrent presentation of mature B-cell neoplasms has been documented, the simultaneous occurrence of B-cell acute lymphoblastic leukemia (B-ALL) and plasma cell neoplasm (PCN) has previously been reported rarely. Such cases may provide insight into the clonal architecture and evolutionary pathways underlying lymphoid malignancies.

We report a 76-year-old man presenting with cytopenias and leukocytosis, in whom initial bone marrow evaluation and immunophenotyping established a diagnosis of B-ALL with a pre-B phenotype. At the time of diagnosis, flow cytometry also identified a distinct population of aberrant plasma cells, raising the possibility of a concurrent plasma cell neoplasm. Follow-up bone marrow analysis confirmed the coexistence of two immunophenotypically and morphologically distinct malignant populations: immature lymphoblasts consistent with B-ALL and clonal plasma cells. Initial ALL-directed therapy induced remission of both components. However, subsequent disease evolution demonstrated a clear phenotypic shift, with relapse characterized by expansion of a plasmablastic/plasma cell population consistent with PCN, while the B-ALL component remained undetectable by minimal residual disease assessment. Treatment was therefore redirected toward a myeloma-based regimen, which was limited by toxicity and failed to achieve disease control. Genomic analysis supported the presence of two clonally related but distinct malignancies.

These findings support a model of early clonal divergence from a common progenitor rather than independent malignancies or linear differentiation. This case highlights the complexity of clonal evolution in B-cell malignancies and underscores the importance of integrated genomic and immunophenotypic analysis in understanding disease biology.