NRF1 is an essential gene in cancer cell lines and silencing results in decreased proliferation of myeloma cells. The NRF1 promoter had constitutive chromatin accessibility in all the tested MM cells. An enhancer element ∼170 kb downstream of the NRF1 promoter was looped such that it contacted the promoter. This region was accessible in their ATAC-seq analysis in myeloma samples. Targeting the expression of this enhancer RNA (eNRF1) resulted in decreased expression of NRF1 and diminished cell growth. Importantly, targeting eNRF1 was also effective in other tumor cell lines that expressed NRF1 but not in lines where this enhancer was not active. Targeting NRF1 resulted in decreased protein ubiquitination and sensitized MM cells to bortezomib.