In this study, we found that one of the mechanisms through which c-Myc inhibition reduced cell survival of both MM and PEL cell lines was the interruption of the cross-talk that c-Myc establishes with the IRE1α/XBP1 axis, which was accompanied by the upregulation of CHOP, the downregulation of RAD51 and BRCA1 and the increase of DNA damage. This evidence concerns the gene XBP1 and primary effusion lymphoma.