In Vivo Anti-Tumor Efficacy of Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®) in Multiple Myeloma (2008)

Abstract Multiple myeloma (MM) is a bone marrow-based malignancy characterized by expansion of plasma cells that produce monoclonal immunoglobulin. Although many new options are available to treat MM, patients develop resistance to these agents. Thus, new therapeutic options are necessary for patients. Vincristine has been used to treat MM but its neurotoxic side effects and low level of anti-MM activity have limited its clinical use. Pharmacokinetic studies on a different formulation of this vinca alkaloid, vincristine sulfate liposomes injection (VSLI, Marqibo®), have shown that the altered distribution and elimination phases with this drug may lead to increased exposure within the tumor versus traditional vincristine. Thus, this new agent offers the potential to both reduce the neurotoxicity and increase the anti-MM effects compared to standard vincristine. In the present study, we evaluated the anti-MM effects of Marqibo and vincristine using two severe combined immunodeficiency (SCID) murine models of human MM. These models were developed from intramuscular (i.m.) implantation of bone marrow biopsies from a MM patient before (LAGκ-1A) and following (LAGκ-1B) the development of both melphalan and bortezomib resistance clinically and have been successfully passaged. One week following implantation i.m., mice were treated with Marqibo, vincristine or vehicle alone. Marqibo was administered intravenously (i.v.) once weekly for three weeks at 0.5, 1, and 2.5 mg/kg and vincristine was given three times per week (M, W, F) i.v. at 0.3 mg/kg. Mice were bled in order to obtain sera to measure human immunoglobulin (Ig) G levels and tumor volume measured weekly. hIgG levels were measured by ELISA and tumor volume using standard calipers. Treatment of LAGk-1A–bearing mice with Marqibo at 0.5, 1 and 2.5 mg/kg inhibited paraprotein secretion as determined by hIgG levels (P = 0.0001; P = 0.0002; P = 0.0055, respectively) compared to mice receiving vehicle. A reduction in tumor volume, compared to control mice, was also observed in mice treated with Marqibo at the specified doses (P = 0.0001; P = 0.0001; P = 0.0001, respectively) and also when compared to vincristine (P = 0.0006; P = 0.0003; P = 0.0001, respectively). In fact, mice treated with vincristine showed no reduction in tumor volume compared to vehicle alone-treated mice. Marqibo at 0.5 mg/kg contained almost half the quantity of free vincristine compared to vincristine administered at 0.3 mg/kg, yet a significant inhibition of both human paraprotein secretion and reduction of tumor volume was observed in LAGκ-1A-bearing mice treated with this dose of Marqibo. The vincristine dose was administered three times more often than Marqibo, contained almost 100% more free vincristine compared to Marqibo at 0.5 mg/kg and most importantly was less effective. Mice bearing a slower growing MM tumor, LAGκ-1B, have recently begun treatment using the same doses and schedules as the LAGκ-1A study. This study is currently ongoing but preliminary data show inhibition of tumor volume growth and inhibition of IgG levels using Marqibo at 0.5, 1 and 2.5 mg/kg (hIgG; P = 0.011, P = 0.0045 and P = 0.0060, respectively). The results of this study show that Marqibo, a novel liposomal formulation of vincristine, produces anti-MM effects in this SCID-hu model of human MM whereas vincristine showed no anti-MM tumor volume growth activity. Further studies are currently being conducted to explore the optimal schedule and effects of this new agent in combination with other active MM agents. These studies should provide the rationale for further clinical development of Marqibo for the treatment of MM patients.