We evaluated the ability of 2 human mAbsdirected against TRAILR1 (HGS-ETR1)and TRAILR2 (HGS-ETR2) to kill humanmyeloma cells. HGS-ETR1 and HGS-ETR2mAbs killed 15 and 9 human myeloma celllines (HMCLs; n22), respectively. IL-6,the major survival and growth factor forthese HMCLs, did not prevent their kill-ing. Killing induced by either HGS-ETR1or HGS-ETR2 was correlated with thecleavage of Mcl-1L, a major molecule formyeloma survival. Mcl-1L cleavage andanti-TRAILR HMCL killing were depen-dent on caspase activation. Kinetic stud-ies showed that Mcl-1L cleavage oc-curred very early (less than 1 hour) andbecame drastic once caspase 3 was acti-vated. Our data showed that both theextrinsic (caspase 8, Bid) and the intrin-sic (caspase 9) pathways are activated byanti–TRAIL mAb. Finally, we showed thatthe HGS-ETR1 and, to a lesser extent, theHGS-ETR2 mAbs were able to induce thekilling of primary myeloma cells. Of note,HGS-ETR1 mAb was able to induce thedeath of medullary and extramedullarymyeloma cells collected from patients atrelapse. Taken together, our data clearlyencourage clinical trials of anti–TRAILR1mAb in multiple myeloma, especially forpatients whose disease is in relapse, atthe time of drug resistance.