Since human MM remains incurable, novel biologically based therapies are urgently needed. Monoclonal antibodies (mAbs) and mAb-based reagents have achieved impressive clinical benefit, i.e. humanized anti-CD20 mAb rituximab, both alone and in combination with chemotherapy. We previously showed that the majority of MM cells express CD40 and defined the biological sequelae of CD40 activation in MM. This project would continue to investigate the therapeutic impact of several humanized anti-CD40 mAbs on MM and delineate molecular and cellular mechanisms underlying these processes. We will further provide preclinical evaluation of novel combination therapy using humanized anti-CD40 mAbs and immunomodulatory drug ImiD3 by defining the role of apoptotic/anti-apoptotic proteins and individual effector cell populations in ADCC and CDC. Thse studies will provide the preclinical rationale for novel therapies targeting CD40, alone or with ImiD3, to improve patient outcome in MM.