Cancer Therapy: Preclinical Reovirus as a Viable Therapeutic Option for the Treatment of Multiple Myeloma

Purpose: Despite the recent advances made in the treatment of multiple myeloma, the disease still remains incurable. The oncolytic potential of reovirus has previously been shown and is currently in phase III clinical trials for solid tumors. We tested the hypothesis that reovirus can successfully target human multiple myeloma in vitro, ex vivo, and in vivowithout affecting human hematopoietic stem cell (HHSC) repopulation/differentiation in a murine model that partially recapitulates human multiple myeloma. Experimental Design:Humanmyeloma cell lines and ex vivo tumor specimens were exposed to reovirus and oncolysis andmechanisms of cell deathwere assessed. RPMI 8226GFPþ cells were injected intravenously to non-obese diabetic/severe combined immune deficient (NOD/SCID)mice and treated with live reovirus (LV) or dead virus (DV). Multiple myeloma disease progression was evaluated via whole-body fluorescence and bone marrow infiltration. HHSCs exposed to LV/DV were injected to NOD/SCID mice and repopulation/differentiation was monitored. Results: A total of six of seven myeloma cell lines and five of seven patient tumor specimens exposed to reovirus showed significant in vitro sensitivity. Tumor response ofmultiplemyeloma by LV, but not DV, was confirmed by comparison of total tumor weights (P 1⁄4 0.05), and bone marrow infiltration (1/6, LV; 5/6, DV).Mice injectedwith LVorDV-exposedHHSCsmaintained in vivo re-population/lineage differentiation showing a lack of viral effect on the stem cell compartment. Reovirus oncolysis was mediated primarily by activation of the apoptotic pathways. Conclusions: The unique ability of reovirus to selectively kill multiple myeloma while sparing HHSCs places it as a promising systemic multiple myeloma therapeutic for clinical testing. Clin Cancer Res; 1–11. 2012 AACR.