One of the major reasons for the fact multiple myeloma (MM) remains an incurable disease is the ability of myeloma cells to survive during initial treatment with chemotherapeutic drugs. Our previous studies have demonstrated that bone marrow stroma (BMS) where MM cells reside plays an important role in survival of MM cells. We have identified that Notch-1 could mediate this survival. We will test whether the targeting Notch pathway with a new class of compounds γ-secretase inhibitors will disrupt BMS-mediated protection of MM cells and restore their responsiveness to the commonly used chemotherapeutics. This may dramatically enhance the effect of chemotherapy.