A fundamental property of myeloma cells is the production and secretion of large amounts of antibodies. A substantial amount of this is incorrectly made and fails to be secreted. This buildup represents a significant stress; the cell must find ways to degrade these proteins to survive. The cell utilizes specific components of the ubiquitin system, which targets proteins for destruction, to degrade these proteins in a process known as endoplasmic reticulum-associated degradation (ERAD). If ERAD fails to compensate cell death occurs. Thus one way to selectively kill myeloma cells is to block ERAD. We have discovered a specific interaction between two crucial ERAD enzymes that is required for degrading proteins from the secretory pathway. Blocking this interaction using a specific peptide blocks ERAD. This blockade causes cellular stress and induces cell death selectively in a murine myeloma. We will expand our findings to a panel of human myelomas, develop ways to efficiently deliver the blocking peptide, determine if other ERAD proteins can be exploited to kill myeloma cells, study the structural relationship between the two interacting ERAD enzymes and most importantly, develop screens to identify compounds that block ERAD in myeloma as a step towards new therapeutics for treatment of this intractable malignancy.