Abstract IA27: New insights into therapeutic targets in multiple myeloma.

Multiple myeloma (MM) is a remarkable example of rapid bench-to-bedside translation in new drug development. Our laboratory and animal studies have shown that the proteasome inhibitor bortezomib (V) and immunomodulatory drug (IMiD) lenalidomide (R) target MM cells, the tumor-host interaction, and the bone marrow (BM) microenvironment to overcome conventional drug resistance. We translated these studies to clinical trials as initial, consolidation, salvage and maintenance therapy, which have already extended MM patient survival two to three fold. Combinations of targeted therapies such as RV with dexamethasone (D) achieve unprecedented extent and universal responses, and the role of high dose therapy and stem cell transplantation is being re-evaluated in this context. Immune-based therapies under development include: elotuzumab (anti-CS1) and daratumumab (anti-CD38) MoAbs; MM cell-dendritic cell vaccines to treat minimal residual disease posttransplant or CD138, CS-1, and XBP-1 peptide vaccines to inhibit progression of smoldering to active MM; as well as TLR-9 agonists targeting plasmacytoid dendritic cells to abrogate their MM-promoting and augment their immunostimulatory activity. Next-generation targeted agents include: deubiquitinating enzyme (USP14/UCHL5) inhibitors to target protein degradation upstream of the proteasome and thereby overcome proteasome inhibitor resistance; chymotryptic (carfilzomib, opromazib, ixazomib) and more broad (marizomib) proteasome inhibitors; and next generation IMiD pomalidomide. Rationally-based combination therapies include proteasome inhibitors (carfilzomib, opromazib, ixazomib, marizomib) with IMiDs (lenalidomide and pomalidomide) to trigger dual intrinsic and extrinsic apoptotic signaling; MoAbs elotuzumab and daratumamab with IMiDs, which upregulate antibody dependent cellular cytotoxicity; proteasome inhibitors (carfilzomib, opromazib, ixazomib) with histone deacetylase (HDAC) inhibitors (vorinostat, panobinostat, and ACY1215) to block proteasomal and aggresomal degradation of protein, respectively. Novel targets include inhibitors of Btk, bromodomain 4, kinesin spindle protein, nuclear transport, and Akt. Finally, genomics has defined disease heterogeneity and novel targets (BRAF mutations); identified mechanisms of resistance (PSMB5 mutations conferring proteasome inhibitor resistance); and discovered novel treatment strategies. For example, we recently demonstrated that low expression of YAP1 in hematologic malignancies allows tumor cells to survive despite ongoing DNA damage; and conversely, that genetic knockdown of STK4 upregulates YAP1 and related P73 mediated apoptosis. These studies provide the framework for a synthetic lethal treatment paradigm using kinase inhibitor targeting STK4 to upregulate YAP1 and related apoptotic signaling in MM and other hematologic malignancies. Citation Format: Kenneth C. Anderson. New insights into therapeutic targets in multiple myeloma. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA27.