Improving the Efficacy of Daratumumab in Multiple MyelomaAssessment of a New Therapeutic Combination and Characterization of Resistance Mechanisms

Résumé

Multiple myeloma (MM) is a hematological malignancy characterized by the clonal expansion of plasma cells in the bone marrow. The clinical symptoms of MM are known by CRAB acronym which stands for: hypercalcemia, renal insufficiency, anemia and lytic bone disease. MM is one of the neoplasms that has experienced the highest progress in the last two decades. Importantly, the improvement of myeloma treatment with the introduction of new therapeutic strategies, including immunotherapy, has resulted in better responses leading to longer survival, and even enabling a large proportion of patients to achieve negative measurable residual disease. In the context of immunotherapy, the anti-CD38 mAb daratumumab has reported remarkable results in myeloma patients. However, despite the well established clinical efficacy of this mAb, there is substantial heterogeneity in quality and duration of response among patients and, what is more, eventually almost all patients become refractory to daratumumab due to resistance mechanisms. The data collected in this dissertation support the effect of tinostamustine in improving the efficacy of daratumumab, partly due to the enhanced expression of CD38 as well as MICA and MICB, two ligands for NK cell activating receptors. Indeed, these results suggest that tinostamustine could be an appropriate candidate to improve the anti-myeloma efficacy of anti-CD38 mAbs, such as daratumumab, in the clinic. Furthermore, through the characterization of a cellular model of acquired resistance to daratumumab, our work provides an overview of potential molecules that could be involved in the mechanism of resistance to this mAb. Specifically, functional studies point to the implication of Clusterin overexpression in resistance to daratumumab-mediated CDC. We hope that these results may contribute in the future to improve the outcome of MM patients treated with daratumumab.