Phase 2 mosunetuzumab CD20×CD3 bispecific antibody + pirtobrutinib noncovalent BTK inhibitor in R/R WM.

University of Utah’s MPOWER is a Phase 2, open-label study testing safety/tolerability and early activity of mosunetuzumab plus pirtobrutinib for relapsed/refractory Waldenström macroglobulinemia after prior covalent BTK inhibitor therapy. Mosunetuzumab (Roche/Genentech) is a CD20×CD3 T‑cell–engaging bispecific monoclonal antibody designed to redirect T cells to kill CD20-positive malignant B cells. Pirtobrutinib (Lilly) is a highly selective, reversible (noncovalent) Bruton tyrosine kinase (BTK) inhibitor intended to retain activity even when resistance emerges on covalent BTK inhibitors. Two dosing strategies differ by when subcutaneous mosunetuzumab begins (cycle 2 vs cycle 3), with response-adapted continuation (pirtobrutinib-only after complete response vs continuing both drugs for lesser responses). Clinically, this targets a common real-world problem—patients whose WM progresses on covalent BTK inhibitors—where current care often becomes sequential therapy with rituximab-based chemoimmunotherapy, proteasome inhibitor–based regimens, venetoclax off-label in some settings, or clinical trials; this study explores whether adding an “off-the-shelf” T‑cell engager can deepen responses beyond BTK inhibition alone.