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First-line (1L) therapy for mantle cell lymphoma (MCL) continues to evolve rapidly, with several recent phase II and phase III trials consistently showing the activity of novel covalent Bruton's tyrosine kinase inhibitor (cBTKi) combinations. Historical treatment selection criteria such as patient age, fitness, and eligibility for autologous stem cell transplantation generally remain applicable for some, but not all, of these novel regimens. This potential for flexibility necessitates the consideration of additional factors during decision-making, such as MCL biology, patient risk tolerance, logistical and resource implications, and the impact on use of later-line options. This paper presents three illustrative patient cases to explore 1L therapy selection among these new and emerging cBTKi options. The realized and anticipated benefits, limitations, and challenges and persisting evidence gaps associated with these regimens are discussed.