Novel inhibitors of PI3K, Akt and mTOR have been developed recently, some of which have entered clinical trials. Although such compounds inhibit cell proliferation, their effects on cell survival, an important determinant of clinical response, are less distinct. Using a broad panel of myeloma cell lines and primary patient samples, we show that dual PI3K and mTOR inhibition can induce cell death. The effects are most marked in cells expressing the t(4;14) translocation, whereas t(11;14) cells are largely resistant. Using specific inhibitors of individual pathway components, we show that optimal induction of cell death requires inhibition of both PI3K and mTOR. This is due to a PI3K-independent component of mTOR activation downstream of the MAP kinase pathway. Novel mTOR kinase inhibitors, which block both TORC1 and TORC2 complexes thereby also reducing Akt activity, are less effective than dual PI3K/mTOR inhibitors because of feedback activation of PI3K signalling. Dual PI3K/mTOR inhibitors sensitise t(4;14) and t(14;16), but not t(11;14), expressing cells to the cytotoxic effects of dexamethasone. We have identified a robust cytogenetic biomarker for response to PI3K/mTOR inhibition--these results will inform the design and prioritisation of clinical studies with novel inhibitors in genetic subgroups of myeloma.