GS-9219 - A Novel Prodrug of the Acyclic Nucleotide PMEG Has Antitumor Activity Against Naive and Melphalan-Refractory Spontaneous Myeloma in Pet Dogs.

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.