The proteasome inhibitor, bortezomib has dramatically changed the landscape of myeloma therapy. While bortezomib alone does not have significant activity, it has become clear that combinations of other drugs with bortezomib represent future directions for this agent. Our proposal seeks to further understand the molecular mechanisms at work when bortezomib is combined with another novel agent lonafarnib. Preliminary data suggest significant synergy when used together and a better understanding of the specific mechanisms at work will allow for improved trial design when this approach is tested in human, as well as helping to better understand the basic biology of multiple myeloma.