Background: Emerging clinical data demonstrate that adoptive cellular therapy has potential to be practice-changing in the management of relapsed/refractory multiple myeloma (MM). NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR capable of recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A2. In prior studies, encouraging clinical activity has been observed with GSK3377794 treatment in patients with synovial sarcoma, melanoma, myxoid/round cell liposarcoma, and in MM patients receiving GSK3377794 after autologous stem cell transplant (ASCT). NY-ESO-1 and LAGE-1a are immunogenic cancer/testis antigens frequently overexpressed in MM and are linked to poor clinical outcome. While a number of phase 1 and 2 trials are evaluating GSK3377794 in solid tumors, this abstract presents a trial in progress aiming to evaluate safety and efficacy of GSK3377794 alone or in combination with the anti-PD1 inhibitor, pembrolizumab, in patients with MM. PD-1 expression on CD8 T cells has been observed in MM patients previously treated with GSK3377794 and can limit adaptive immune response. This has also been described as a mechanism of resistance and relapse in CD19 CAR T-cell trials (Fraietta et al, Nat Med 2018). Thus, we hypothesize that combining GSK3377794 and pembrolizumab may result in a synergistic antitumor effect. Study design and methods: This is an open-label, pilot study (NCT03168438) of GSK3377794 in patients who are HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive and have NY-ESO-1/LAGE-1a positive relapsed/refractory MM. Twenty patients who have received at least three prior therapies containing at least one of the following drug classes as separate or combined lines of therapy (including ASCT): an immunomodulatory imide, proteasome inhibitor, alkylator, CD38 monoclonal antibody, and glucocorticoid, will be assigned to one of two arms: GSK3377794 alone as a single infusion (Arm 1, n=10) or GSK3377794 as a single infusion in combination with pembrolizumab 200 mg IV every 3 weeks (Arm 2, n=10). Enrollment of Arm 1 will be completed before enrolling subjects to Arm 2. Administration of pembrolizumab will start from Week 3 (or Week 6 if toxicities preclude Week 3 treatment). Patients will undergo leukapheresis to obtain cells for the manufacture of autologous NY-ESO-1-specific T cells. Each patient will then undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by GSK3377794 infusion of 1−8x109 transduced T cells. Primary and secondary objectives are to assess safety and tolerability, and antitumor activity, respectively, of GSK3377794 treatment (with and without pembrolizumab). Patients will be monitored for adverse events and combination-related treatment-limiting toxicities; efficacy will be assessed using International Myeloma Working Group Response Criteria (Rajkumar et al, Blood 2011). In Arm 2, enrollment will be temporarily paused for a 3-week safety review period after the first 3 patients have received their first dose of pembrolizumab. Efficacy, safety, and biomarker assessments will be conducted at each visit. Patients will complete the treatment phase upon progression of disease or 108 weeks after GSK3377794 infusion. After completion of the treatment phase, patients will transfer to the long-term follow-up study (NCT03391778) to continue safety and survival monitoring for up to 15 years. As of January 27, 2019, 50 patients have undergone screening for HLA status and NY-ESO-1/LAGE-1a antigen expression. Among 50 patients screened for HLA, 25 (50%) tested positive for HLA-A*02:01, 05, and/or 06. Of these patients, bone marrow samples from 12/21 (57%) tested positive for NY-ESO-1, LAGE-1a, or both, illustrating high expression of this antigen in MM. To date, 3 patients have been treated with GSK3377794, demonstrating feasibility of identifying and treating HLA/antigen-positive patients with relapsed/refractory MM. Further work is underway towards introducing flexibility in screening procedures in order to permit wider screening of patients and to minimize time between screening and leukapheresis and for cell manufacturing, which will enhance patient eligibility. Acknowledgment: Medical writing support by O Conn PhD of Fishawack Indicia Ltd, funded by GSK. This study (NCT03168438) is funded by GSK. Disclosures Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Kaufman:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AbbVie: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; TG Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Blouch:GSK: Employment, Equity Ownership. Pandit:GSK: Employment, Equity Ownership. Butler:GSK: Employment, Equity Ownership. Jain:GSK: Employment. Wu:GSK: Employment, Equity Ownership. DeYoung:GSK: Employment, Equity Ownership. Hasan:GSK: Employment, Equity Ownership; Atara Biotherapeutics: Patents & Royalties; Merck: Equity Ownership.