Multiple myeloma is an important hematopoietic cancer in humans and pet dogs. While clinical remission can be achieved using currently available antineoplastic agents, eventual drug resistant relapse is common. GS-9219, a novel double prodrug of the anti-proliferative nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine (PMEG), has been shown to have potent cytotoxic activity in vitro in human lymphoblasts and leukemia cell lines and in vivo in naturally occurring non-Hodgkin’s lymphoma in dogs (naive and refractory). We hypothesized that malignant plasma cells in multiple myeloma similarly would possess the intracellular enzymatic machinery necessary for the activation of GS-9219. To generate proof-of-concept, activity and safety data in multiple myeloma, a pilot study with GS-9219 monotherapy was initiated in pet dogs with naturally occurring chemotherapy-naive or refractory multiple myeloma. Three dogs with spontaneously occurring IgA myeloma (1 naive, 2 melphalan-refractory) have been treated with GS-9219 as a 30-minute intravenous infusion weekly for 2 weeks at 1 mg/kg, then every 3 weeks for another 3 treatments at 0.8 mg/kg (total of five GS-9219 doses). To date, major anti-tumor responses have been observed in all 3 multiple myeloma dogs treated with GS-9219. Two dogs are in complete remission as indicated by normalization of serum paraprotein and complete resolution of hypercalcemia, peripheral cytopenias and bone marrow plasmacytosis. The third currently has a strong partial response (normal marrow and >95% reduction in serum paraprotein). The only significant toxicity noted throughout the study was a single episode of transient neutropenia in one dog which resolved and, after a one week delay, treatment was continued without issue. Assessment of durability of response is currently ongoing, with all dogs remaining in remission to date; one dog has remained in complete remission for more than 5 months following completion of the treatment regimen. In conclusion, GS-9219 has significant anti-tumor activity in spontaneous melphalan-refractory or treatment-naive canine multiple myeloma.
Disclosure:Employment: D.B. Tumas, H. Reiser and G.H.I. Wolfgang are employees of Gilead Sciences, Inc. Consultancy: D.H. Thamm and D.M. Vail have served as paid consultants to Gilead Sciences, Inc. within the past two years. Ownership Interests:; D.B. Tumas, H. Reiser and G.H.I. Wolfgang are stockholders in Gilead Sciences, Inc. Research Funding: D.H. Thamm and D.M. Vail have received funding from Gilead Sciences, Inc. for the conduct of this research.