Multiple Myeloma and the Bone Marrow Niche

Abstract

e4 fusion of bendamustine with vorinostat that aims to increase the efficacy of the alkylator through the HDACi-mediated chromatin relaxation to make DNA more accessible to the damaging effect of bendamustine. It induced a high rate of response in Vk*MYC MM that was sustained for more than three months in mice receiving only two doses, one week apart. The IAP antagonist LCL161 results in rapid degradation of cIAP1/2 with stabilization of NIK and constitutive activation of NFkB. In vivo this results in activation of the innate immune system, with a cytokine release syndrome the dose limiting toxicity. In Vk*MYC mice with MM LCL161 results in a phagocytic-cell dependent, NK and T-cell independent anti-tumor response that is augmented with the addition of cyclophosphamide. Inhibition of coinhibitory receptors CTLA4, PD1 or PDL1 was ineffective, however activation of the costimulatory receptor CD137 with agonist antibody resulted in NK and CD8 T-cell dependent anti-tumor responses. These preclinical studies suggest that the Vk*MYC model can be successfully used to rationally develop novel targeted and immunotherapies for the treatment of MM.