Chemo-RaST with bortezomib inhibits multiple myeloma relapse

<b>Rationale:</b> Multiple myeloma (MM) is a hematological malignancy with a high relapse rate that ultimately leads to patient mortality. Current therapies often fail to achieve sustained remission due to adaptation of clonally heterogeneous tumor populations. We hypothesized that Chemo-RaST, a therapeutic strategy combining bortezomib with ⁸⁹Zr-daratumumab-mediated radionuclide dynamic therapy (RaST), would synergize photophysical generation of cytotoxic reactive oxygen species (ROS) with mitochondrial ROS induction to block clonal adaptation and prevent MM relapse. <b>Methods:</b> We evaluated chemo-RaST in MM.1S-luc subcutaneous and disseminated MM mouse models. RaST consisted of zirconium-89 (⁸⁹Zr)-labeled daratumumab to target MM cells and continuously activate orthogonally delivered titanium dioxide-transferrin-titanocene (TiO₂-Tf-TC) nanoparticles for sustained cytotoxic ROS production. Bortezomib, a proteasome inhibitor, was administered in parallel to amplify mitochondrial ROS. Therapeutic efficacy was evaluated using bioluminescence imaging (BLI), positron emission tomography (PET), and histopathology. <b>Results:</b> <i>In vitro</i>, RaST reduced MM.1S-luc cell viability to 48.4 ± 2.0% versus untreated controls (98.7 ± 1.5%), TiO₂-Tf-TC nanoparticles alone (96.6 ± 0.8%), or ⁸⁹Zr-daratumumab alone (91.3 ± 3.4%). <i>In vivo</i>, RaST suppressed tumor progression, but relapse occurred. In contrast, chemo-RaST achieved complete tumor regression in 60% of disseminated MM models and significantly extended progression-free survival. Histopathology confirmed elimination of CD138-positive MM cells and restoration of normal hematopoiesis in Chemo-RaST cohorts. <b>Conclusions:</b> Tracer doses of long-lived ⁸⁹Zr for sustained photosensitizer activation, combined with subtherapeutic bortezomib, represent a clinically translatable strategy to limit off-target toxicity, prevent relapse, and overcome therapy resistance in multiple myeloma.