Multiple myeloma (MM) is the second most common hematological malignancy in the United States, and remains an incurable disease since nearly all MM patients will eventually relapse and develop resistance to currently available drugs. Sphingolipid metabolism is being increasingly recognized as a key pathway in tumor biology. In particular, sphingosine kinases (SK1 and SK2) provide a potential site for manipulation of the ceramide/ sphingosine 1-phosphate (S1P) rheostat that regulates the balance between tumor cell proliferation and apoptosis, as well as tumor sensitivity to drugs and radiation. We have recently demonstrated that SK2 is overexpressed in MM and that inhibition of SK2 in MM cell lines by ABC294640 down-regulates c-Myc expression and promotes apoptosis in MM cells. Importantly, ABC294640 also effectively inhibits tumor growth in vivo in myeloma xenograft models. ABC29460 has recently completed phase I testing in patients with advanced solid tumors, and we hypothesize that this drug will be useful for the treatment of MM patients. In this phase 2 SBIR project, we will conduct the following Specific Aims: 1: Perform a phase Ib clinical trial to determine the safety, pharmacokinetics and pharmacodynamics of ABC294640 when combined with dexamethasone in relapsed/refractory MM patients. We will perform a phase 1b trial with up to 18 patients to determine the safety, maximal tolerated dose (MTD), pharmacokinetics and pharmacodynamics of ABC294640 combined with dexamethasone in relapsed and/or refractory MM patients who have previously been treated with both a proteasome inhibitor and an immunomodulatory agent; and 2: Perform a phase II clinical trial to determine the preliminary efficacy of ABC294640 combined with dexamethasone in relapsed/refractory MM patients. Once the MTD has been established, up to 36 additional patients with refractory/relapsed MM will be enrolled at the MTD to confirm safety and to investigate preliminary efficacy in this population. We expect that this clinical trial will have important implications in the treatment of MM. We believe that the proposed studies constitute a focused approach for developing a novel treatment for patients with MM, a disease with a high unmet clinical need. If positive, these data will provide justification for a larger, multi- center phase III study.