Dimethylaminoparthenolide (DMAPT) in Multiple Myeloma

Abstract

Background: The nuclear factor kappa B (NFkB) signaling pathway is constitutively activated and central to the pathogenesis of multiple myeloma (MM). We previously published the antitumor activity of the NFkB inhibitor parthenolide in MM. Dimethylaminoparthenolide (DMAPT) is a water-soluble analog of parthenolide. The improved bioavailability of DMAPT makes its appealing for clinical development.Objectives: To validate the effects of DMAPT both in vitro and in vivo MM models and to develop a rational strategy for a combination of DMAPT with other anti-MM agents.Methods: The in vitro cytotoxicity of DMAPT was tested in human MM cell lines and primary samples both alone and in combination with bortezomib and lenalidomide. The in vivo activity of DMAPT was tested in a model of NOD/Scid mice intravenously transplanted with GFP-tagged NCI-H929 MM cells.Results: Based on MTT assays on MM cell lines and primary MM cells, the IC50 for proliferation inhibition of DMAPT was similar to that of parthenolide (1–3 μM). When used in combination with bortezomib, we observed synergy (combinatorial index < 1.0) at higher doses of DMPT and bortezomib (DMAPT 2.5–5 μM and bortezomib 5–12.5 nM), while an antagonistic effect was observed at lower doses. Similarly, when combined with lenalidomide, synergy was observed at DMAPT doses 1.6–6.4 μM and lenalidomide doses 0.5–2 μM, while an antagonistic effect was observed at lower doses.The in vivo cytotoxicity of DMAPT was explored in a model of NOD/Scid mice intravenously transplanted with GFP-tagged NCI-H929 cells. At 3 weeks post-transplantation, all animals had measurable serum human kappa light chain levels, as measured by ELISA assays. Animals were randomized to receive either 50 mg/kg/day DMAPT (n=12), 100 mg/kg/day DMAPT (n=12) or vehicle (n=10) via oral gavage for a duration of 6 weeks or until criteria for euthanasia were met. Weight loss of over 15% and hind leg paralysis were criteria for euthanasia. Toxicities in both treatment groups were minimal. Weight loss correlated with serum human kappa light chain levels and, hence, represented disease progression. At the end of treatment, there were 2 animals alive in the control group, while 5 were alive in each of the treated groups. Using Kaplan-Meier curves and log-rank analysis, the mean overall survival (OS) was 56.3 days in the control cohort versus 61.0 days and 62.4 days in groups treated with 50 and 100 mg/kg/day DMAPT, respectively. There was no statistically significant difference in the mean OS of mice treated with the two doses of DMAPT (p=0.07).Prior to treatment initiation, the serum levels of human kappa light chains were similar in all groups (ANOVA test, p= 0.38). At 2 weeks and 4 weeks post treatment (Week 5 and week 7, respectively; See table), the levels of human kappa light chains were significantly lower in the DMAPT treated groups (ANOVA test p = 0.017 and 0.0061, respectively).Week 3Week 5Week 7Control10.46 ± 5.79531.31 ± 2386272.1 ± 3211DMAPT 50 mg/kg/day6.94 ± 4.48264.03 ± 1982928.8 ± 2131DMAPT 100 mg/kg/day7.99 ± 7.21334.15 ± 1983374.9 ± 1835ANOVA (P value)0.380.0170.0061Conclusions: DMAPT demonstrated excellent efficacy in preclinical models of MM and supports a rationale for its clinical development in MM patients with relapsed MM either alone or in combination with bortezomib or lenalidomide.