Background: Immune checkpoint blockade (ICB) improves overall survival and provides long-term disease control in 35-40% of pts with MM. However, more than a third of pts experience no clinical benefit (de novo resistance) and many progress even after achieving an initial response (acquired resistance). Our group has demonstrated that increased activation of phosphatidylinositol 3-kinase (PI3K) pathway, most commonly through loss of the tumor suppressor gene PTEN, plays a critical role in resistance to ICB. PTEN loss occurs in up to 30% of MM pts and correlates with decreased T cell infiltration and inferior outcomes to ICB. In preclinical models, we showed that loss of PTEN inhibits T cell mediated tumor killing and decreases T cell trafficking into tumors, and that selective inhibition of the PI3Kβ-subunit with GSK2636771 was superior to pan-PI3K inhibitors and significantly increased the activity of ICB, and the number of infiltrating CD4+ and CD8+ T cells. We therefore hypothesized that PI3Kβi will reverse resistance to ICB in MM with PTEN-loss. To test this hypothesis, we are conducting a Phase I/II study of the PI3Kβ inhibitor GSK2636771 in combination with P in pts with PD-1 refractory MM and PTEN loss. Methods: The primary objective of the Phase I portion is to determine the safety and Maximum-Tolerated Dose (MTD) and/or the Recommended Phase II Dose (RP2D) of GSK2636771 in combination with P in pts with PD-1 refractory disease and PTEN loss. Pts will be treated with P given at 200 mg IV q 3-wk cycle. GSK2636771 will be given orally starting at a dose level of 300 mg PO qd for 21 days and escalated to a maximum dose of 400 mg PO qd using a “3+3” design. The Phase II portion will enroll a total of 35 pts at the MTD/RP2D. Continuous monitoring for both toxicity and futility will be assessed. The primary objective of the Phase II portion is to determine the safety, tolerability, and efficacy of the combination as defined by Objective Response Rate (ORR) by RECIST 1.1 in MM with PTEN loss. Secondary Objectives include the PKs of GSK2636771 and correlation with ORR and pharmacodynamic effects in tumor tissue as measured by pathway inhibition and T cell trafficking into tumors. Clinical trial information: NCT03131908