Abstract
PURPOSE: Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies. EXPERIMENTAL DESIGN: A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1. RESULTS: There were no dose-limiting toxicities, patients reached the 3 × 10(10) TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months. CONCLUSIONS: Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers.