We demonstrate herein that MM cells post-translationally down-modulate the cell surface expression of the TRAIL receptor DR4 through ectodomain shedding by endogenous TACE, and that TACE inhibition is able to restore cell surface DR4 expression and the susceptibility of MM cells to TRAIL or an agonistic antibody against DR4. This evidence concerns the gene TNFSF10 and Miyoshi myopathy.