How I treat plasma cell leukemia

ABSTRACT: Plasma cell leukemia (PCL) represents an exceptionally aggressive plasma cell malignancy defined by ≥5% circulating plasma cells in the peripheral blood of patients otherwise meeting the diagnostic criteria for multiple myeloma (MM), per the International Myeloma Working Group consensus. This ultrahigh-risk disease exhibits distinctive clinical features including frequent extramedullary involvement, severe cytopenias, hypercalcemia, renal insufficiency, and/or significantly elevated β2-microglobulin and lactate dehydrogenase levels. The molecular landscape includes high-risk cytogenetic abnormalities and mutations that promote accelerated proliferation, apoptotic resistance, immune evasion, and bone marrow microenvironmental independence through dysregulated adhesion molecule and chemokine receptor expression. Although autologous stem cell transplantation, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies improved historical outcomes, the therapeutic paradigm continues to evolve. Novel therapeutic approaches including B-cell maturation antigen-directed therapies (bispecific antibodies and chimeric antigen receptor T-cell therapy), G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted therapy, and B-cell lymphoma 2 (BCL-2) inhibition demonstrate promise in treating both primary and secondary PCL. Despite these advances, PCL remains inadequately studied, with treatment approaches predominantly extrapolated from MM trials in which patients with PCL have largely been excluded. This review synthesizes current evidence and presents illustrative clinical cases demonstrating practical treatment approaches, while highlighting critical knowledge gaps requiring dedicated prospective clinical trials to meaningfully improve outcomes in this challenging disease entity.