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Finding highly active treatment for patients with relapsed/refractory multiple myeloma is an unmet clinical need. The immune-based treatment approaches in this population of patients have shown notable anti-myeloma activity, with deeper and durable responses; however, they are not curative due to development of resistance, which is cell intrinsic as well as environment dependent and T-cell dependent. Our group has a long-term expertise in studying drug resistance in myeloma and in recent years have established multiple in vitro and in vivo models to elucidate various mechanisms of drug resistance in myeloma. Our data show that resistance is multifactorial and myeloma cells show very high plasticity in terms of treatment adaptation. Moreover, we have established genome-wide CRISPR-Cas9 based screens in our lab to elucidate specific vulnerabilities of drug resistant myeloma in vitro.
We believe that using CRISPR-Cas9 genome-wide screening in vivo in two independent mouse models that differ in the functionality of their immune system; we can elucidate the myeloma-intrinsic genetic factors that contribute to myeloma immune evasion. This study therefore aims to elucidate and further validate such genetic contributors and molecular mechanisms in mouse myeloma model, with a potential of a direct translation and validation of the findings in myeloma patients