Abstract CT262: Durable responses following anti-TIGIT (BMS-986207) and anti-LAG3 (BMS-980616) in combination with pomalidomide in relapsed myeloma: MMRF MyCheckpoint trial

Background: T cell redirection with agents such as Chimeric Antigen Receptor T cells or bispecific T cell engagers is remarkably effective in relapsed multiple myeloma (MM), however, they are not curative. Translational studies suggest that T cell exhaustion, characterized by upregulation of immune checkpoints LAG-3 and TIGIT, is a potential resistance mechanism to T cell redirection. These findings support the hypothesis that checkpoint inhibition with anti-LAG-3 or anti-TIGIT mAbs may restore anti-myeloma T cell activity. There is an unmet need to assess the feasibility and safety of checkpoint blockade in this malignancy. Patients and Methods: MyCheckpoint (NCT04150965) is a phase 1/2 platform trial for relapsed MM patients who have received ≥3 lines of therapy, including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 mAb. Primary objectives were safety and tolerability of the investigational agents alone and in combination with pomalidomide (Pom) and dexamethasone (Dex) and overall response rates in each arm. In the phase 1 portion subjects were randomized to Arm B (anti-LAG-3) or Arm C (anti-TIGIT mAb). Subjects received one cycle (C1) of mAb therapy alone, with the addition of Pom and Dex starting with cycle 2 (C2) onward. Bone marrow aspirates and peripheral blood were obtained at screening, C2D1, C3D1, and end of study for correlative analysis. Results: Fourteen (14) eligible subjects were enrolled (seven subjects in Arm B dose level (DL) 1, one not evaluable; six subjects in Arm C DL1, and 1 subject Arm C DL2 not evaluable). The most common adverse events (AE) were anemia and dyspnea. Grade 3-4 AEs related to therapy in the anti-LAG-3 arm were dyspnea and neutropenia; those in anti-TIGIT arm were neutropenia, thrombocytopenia, and anemia. There was 1 death due to progression of disease unrelated to the study treatment. There was 1 death due to a serious adverse event of pneumonia (unrelated). There was one adverse event of special interest in Arm B DL1 (grade 1 AST elevation). No autoimmune AEs were reported. Best overall responses for Arm B DL1 were 1 very good partial response (VGPR), 1 partial response (PR), 4 stable disease (SD); for Arm C DL1, 1 VGPR, 2 PR, and 3 SD. Eight subjects withdrew from treatment for disease progression, 2 for AE, and 2 for patient decision. Two subjects continue in Arm C DL1 as of December 2022, 1 PR as of C16D1 and 1 VGPR (C23D1). Conclusion: Anti-LAG-3 and anti-TIGIT mAb alone and in combination with Pom are safe, feasible and clinically active in relapsed MM after Pom and anti-CD38 mAb. These data provide the first evidence of clinical activity of TIGIT and LAG-3 blockade in MM. Translational results utilizing serial analyses with mass cytometry suggest evidence of immune activation following combination therapy. Citation Format: Hearn J. Cho, Shambavi Richard, Alex Lesokhin, Noa Biran, Barry Paul, Ravi Vij, Matthew Pianko, Deon Doxie, Mercedes Martillo, Katie Wozniak, Kavita Dhodapkar, Madhav Dhodapkar. Durable responses following anti-TIGIT (BMS-986207) and anti-LAG3 (BMS-980616) in combination with pomalidomide in relapsed myeloma: MMRF MyCheckpoint trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT262.