Liu, Yang

Abstract Background: Treatment of multiple myeloma (MM) commonly encompasses combination of drugs within the three drug classes including proteasome inhibitors (PIs), immunomodulators and (IMiDs), and monoclonal antibodies, both for newly diagnosed and relapsed disease. With increasing appreciation of disease heterogeneity based on underlying genetic abnormality, and demonstration of efficacy of venetoclax in patients with t(11;14) MM, the outcomes with commonly used MM regimens among the different cytogenetic subgroups are of great interest. Venetoclax, a BCL-2 inhibitor, is being studied in t(11;14) positive MM patients who have received at least two prior lines of treatment (NCT03539744; CANOVA). However, outcomes in previously treated t(11;14) MM patients using standard of care approaches in the real-world setting is limited. Patients and methods: This non-interventional, retrospective observational cohort study included patients with t(11;14) MM from the International Myeloma Working Group (IMWG) retrospective study of t(11;14) MM. From the overall cohort, patients with t(11;14) MM receiving pomalidomide + dexamethasone (PomDex) in ≥3 rd line were selected, similar to those being enrolled in the ongoing CANOVA trial. Patients were also required to have prior exposure to lenalidomide and a PI without a history of transplant within 16 weeks prior to PomDex initiation. Patients enrolled in a clinical trial were excluded. Overall best response, time to next therapy (TTNT) as a surrogate measure for progression-free survival (PFS) and overall survival (OS) were assessed after initiation of PomDex. All analyses were descriptive in nature and were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Results: Fifty-two patients who met the inclusion criteria were analyzed. Median age was 63 years, 60% were male. Patients had a median of 3 prior lines at start of PomDex, at a median of 4.3 years from diagnosis; 52% had a prior transplant. A PR or better was observed in 34% of patients with PomDex. The median TTNT for this cohort was 6.1 months and median OS was 19.2 months. Conclusion: This retrospective study of non-trial patients with t(11;14) MM provides a benchmark for newer therapies in this patient population for comparison with both venetoclax dexamethasone in the ongoing CANOVA study as well as combinations using the pomalidomide backbone. Disclosures Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Kumar: Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Gonzalez De La Calle: Celgene-BMS, Janssen, Amgen: Honoraria. Mangiacavalli: GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria. Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Esteves: AbbVie: Consultancy; BMS: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Delforge: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee: Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Adaptive: Consultancy; GSK: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Sanofi: Consultancy. Arriola: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Manthena: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services .

Abstract Abstract 2958 PURPOSE: Recent advances in understanding of the molecular alterations that occur at the genetic and epigenetic levels in Multiple Myeloma (MM) have led to major leaps in identifying molecular pathways that regulate progression and resistance to therapeutic agents. However, despite great scientific advances at the genomic level, studies to identify signaling pathways deregulated at the functional proteomic level in MM are limited. Using an antibody-based protein microarray technique, we identified Citron Rho Interacting Kinase (CRIK) as a protein that was highly expressed in primary multiple myeloma (MM) cells compared to normal plasma cell. We therefore sought to investigate the functional role of CRIK in MM cells. Methods: Primary CD138+ sorted MM cells were obtained from the bone marrow of patients after informed consent. We determined the protein expression level of 512 polypeptides in 12 samples of newly diagnosed patients with MM and 4 healthy control using high-throughput proteomic analysis with antibody-based protein microarray (Clontech, CA). MM.1S, OPM2, RPMI8226, and INA6 were used to perform functional validation. Protein expression has been studied by immunoblotting. Gene expression analysis has been assessed using the Affymetrix U133A platform and qPCR. Lentivirus was used to knockdown CRIK in MM cell lines (MM.1S, RPMI8226, OPM2, and INA6). DNA synthesis, cell survival, cell cycle profiling and apoptosis were assessed by BrdU, MTT, PI and Apo2.7 staining, and flow cytometry analysis, respectively. Results: We first showed that CRIK was overexpressed in 12 patients with MM compared to normal CD138+ cells obtained from healthy controls using high-throughput protein microarray. We further confirmed CRIK expression using immunohistochemistry in the same samples of MM patients. We next correlated CRIK gene expression level (CIT) with prognosis using previously published gene expression datasets and found that CRIK correlated with poor prognosis. Knockdown of CRIK in MM cell lines led to an anti-proliferative and pro-apoptotic effect in all MM cell lines tested. Indeed, CRIK-knockdown MM cells were characterized by a reduction of 60–80% in the proliferation rate, supported by reduction of DNA synthesis and G2/M phase cell cycle arrest. Moreover, induction of cytotoxicity of caspase-3, caspase-8, caspase-9, and parp cleavage was also demonstrated in CRIK knockdown cells compared to scramble probe transfected cells. We also showed that CRIK knockdown led to cytokinesis in MM cell lines, indicating a possible mechanism of inhibition of proliferation of these cells. Conclusion: In this study, we show that MM cells express a high level of a novel protein CRIK, and that inhibition of this protein leads to significant inhibition of proliferation and survival of MM cells. CRIK could be a critical therapeutic target in MM. Disclosures: Anderson: Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.