The Emerging Role of Bruton's Tyrosine Kinase Inhibitors in Multiple Myeloma

Abstract

Multiple myeloma (MM) remains an essentially incurable plasma cell malignancy despite major advances with proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and autologous transplantation. Bruton’s tyrosine kinase (BTK), a non-receptor kinase central to B-cell receptor signaling, is selectively overexpressed in myeloma stem-like cells and drives both tumor-intrinsic survival pathways and BTK-dependent osteoclast genesis in the bone marrow niche. Ibrutinib, the first covalent BTK inhibitor evaluated in relapsed/refractory MM, showed modest single-agent activity but meaningful responses in combination regimens, though acquired C481S-mediated resistance limited its development. Newer covalent agents improved selectivity without escaping this resistance mechanism, while the non-covalent inhibitor pirtobrutinib and BTK-degrading PROTACs offer mutation-independent strategies. We argue that biomarker selected, combination based, and next generation BTK targeted approaches deserve renewed and focused clinical investigation in multiple myeloma.