BCMA-directed CAR-T therapies have shown promising results in multiple myeloma (MM). However, patients continue to relapse. T cell exhaustion with increased TIGIT expression is a resistance mechanism which was confirmed in CAR-T cells from ARI0002h trial, an academic CAR-T developed in our institution. We aimed to analyze the impact of blocking TIGIT on the efficacy of ARI0002h. We used three different strategies to block TIGIT: Addition of an external blocking anti-TIGIT-antibody (Ab), Modify ARI0002h into a 4 generation CAR-T, named ARITIGIT, capable of secreting a soluble TIGIT-blocking scFv and TIGIT knock-out in ARI0002h using CRISPR/Cas9. Each strategy was evaluated and . Adding a TIGIT-blocking Ab to ARI0002h improved cytotoxicity, but failed to enhance mice survival. The new 4 generation CAR-T, ARITIGIT, was also unable to achieve better survival outcomes despite favoring the model by using a myeloma cell line with high expression of the TIGIT ligand PVR. Interestingly, when mice were challenged with a second infusion of tumor cells, mimicking a relapse model, a trend for improved survival with ARITIGIT was observed ( = 0.11). Finally, TIGIT-knock-out on ARI0002h (KO-ARI0002h) using CRISPR/Cas9 showed similar activity to ARI0002h. In an stress model, TIGIT KO-ARI0002h prolonged survival ( = 0.02). However, this improvement was not significant compared to ARI0002h ( = 0.07). This study failed to demonstrate a significant benefit of TIGIT-blockade on ARI0002h cells despite using three different approaches, suggesting that targeting a single immune checkpoint may be insufficient.