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Lenalidomide + tafasitamab + rituximab + acalabrutinib is an investigational quadruplet regimen combining an immunomodulatory small molecule (lenalidomide), two anti‑CD B‑cell–depleting monoclonal antibodies (tafasitamab targeting CD19 and rituximab targeting CD20), and a highly selective covalent Bruton tyrosine kinase (BTK) inhibitor (acalabrutinib). It is being evaluated primarily as first‑line or early‑line therapy for high‑risk, newly diagnosed non‑germinal center diffuse large B‑cell lymphoma (non‑GCB DLBCL), including in the phase II Smart Stop trial where the quadruplet is used alone and with CHOP chemotherapy.[1][3][4][7][8] The regimen is designed to provide synergistic B‑cell cytotoxicity and immune activation through direct B‑cell receptor pathway inhibition, antibody‑dependent cellular cytotoxicity and phagocytosis, and lenalidomide‑mediated T‑cell and NK‑cell stimulation.
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