Combinations Of Belantamab Mafodotin With Lenalidomide, Pomalidomide, Bortezomib And/Or Dexamethasone Synergize In Vitro And Potentiate In Vivo Anti-Tumor Activity In Multiple Myeloma

Multiple myeloma (MM) is a hematological malignancy that affects plasma cells and leads to devastating clinical features. Typically, front-line and relapsed/refractory multiple myeloma (RRMM) treatments comprise standard of care (SOC) combinations that include proteasome inhibitors (e.g., bortezomib), immunostimulatory drugs (e.g., lenalidomide or pomalidomide) and/or a steroid (e.g., dexamethasone). While these therapies have significantly improved patient outcomes, the disease remains incurable and novel targeted therapies are urgently needed. Belantamab mafodotin is as a promising candidate for the treatment of multiple myeloma, achieving a 60% overall response rate in a phase 1 clinical trial. Belantamab mafodotin targets the B-cell maturation antigen (BCMA) protein, highly expressed in multiple myeloma and other B cell malignancies. Belantamab mafodotin is an immuno-conjugate that consists of a humanized afucosylated anti-BCMA monoclonal antibody conjugated to the microtubule inhibitor monomethyl auristatin-F (MMAF) that enables anti-tumor activity by: 1) direct cell kill, 2) antibody-dependent cellular cytotoxicity or cellular phagocytosis, and 3) immunogenic cell death. To determine potential combinatorial activity, we conducted in vitro and in vivo studies of belantamab mafodotin in double and/or triple combinations with MM SOC agents (bortezomib, dexamethasone, lenalidomide or pomalidomide) in two multiple myeloma models: OPM-2 and MOLP-8. In vitro, belantamab mafodotin as single agent demonstrated direct cell kill activity in OPM-2 and MOLP-8 cells, after 72 hours of exposure. Treatment of OPM-2 cells with bortezomib, dexamethasone, lenalidomide or pomalidomide also led to direct cell kill. However, direct cell kill of MOLP-8 cells was only observed with bortezomib treatment. Combining belantamab mafodotin with each SOC agent led to synergistic activity in both cell lines. In vivo, belantamab mafodotin significantly induced tumor growth inhibition and provided survival advantage when administered as monotherapy to immune-compromised mice bearing OPM-2 and MOLP-8 xenografts. Combinations with lenalidomide, pomalidomide, or bortezomib enhanced this anti-tumor activity and provided additional survival benefit compared to each single agent. The observed synergy in cell cultures and in vivo xenograft models provided preclinical evidence for combining belantamab mafodotin with IMiDs or bortezomib in MM. Selected combinations are currently under clinical evaluation in RRMM in the DREAMM-6 trial. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed. Drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT® Technology licensed from BioWa. Citation Format: Rocio Montes De Oca, Ira Gupta, Chris Shelton. Combinations of belantamab mafodotin with lenalidomide, pomalidomide, bortezomib and/or dexamethasone synergize in vitro and potentiate in vivo anti-tumor activity in multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6711.