Exploiting Protein Translation Dependence in Multiple Myeloma with Omacetaxine-Based Therapy

Abstract

Purpose: The prognosis of patients with multiple myeloma (MM) who are resistant to proteasome inhibitors, immunomodulatory drugs (IMiDs), and daratumumab is extremely poor. Even B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cell therapies provide only a temporary benefit before patients succumb to their disease. In this report, we interrogate the unique sensitivity of MM cells to the alternative strategy of blocking protein translation with omacetaxine. Experimental Design: We determined protein translation levels (n = 17) and sensitivity to omacetaxine (n = 51) of primary MM patient samples. Synergy was evaluated between omacetaxine and IMiDs in vitro, ex vivo, and in vivo. Underlying mechanism was investigated via proteomic analysis. Results: Almost universally, primary patient MM cells exhibit >2.5-fold increased rates of protein translation compared to normal marrow cells. Ex vivo treatment with omacetaxine resulted in >50% reduction in viable MM cells. In this cohort, high levels of translation serve as a biomarker for patient MM cell sensitivity to omacetaxine. Unexpectedly, omacetaxine demonstrated synergy with IMiDs in MM cell lines in vitro. In addition, in an IMiD-resistant relapsed patient sample, omacetaxine/IMiD combination treatment re-sensitized the MM cells to the IMiD. Proteomic analysis found that the omacetaxine/IMiD combination treatment produced a double-hit on the IRF4/c-MYC pathway, which is critical to MM survival. Conclusion: Overall, protein translation inhibitors represent a potential new drug class for myeloma treatment and provide a rationale for conducting clinical trials with omacetaxine alone and in combination with IMiDs for patients with relapsed/refractory MM.