Focusing on Selinexor for Holding and Bridging Prior to CAR-T in Relapsed/Refractory Multiple Myeloma

Abstract

Background: The remarkable efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy (CAR-T) has had a significant impact on treatment strategies for relapsed/refractory multiple myeloma (RRMM). However, response durability remains a concern, necessitating the optimization of CAR-T procedures. Therapies preceding CAR-T therapy are crucial for disease control and preserving T-cell fitness. Methods: This review summarizes the evidence supporting the potential of selinexor-based regimens as holding or bridging therapy with preclinical research, demonstrating selinexor's ability to foster an anti-inflammatory tumor microenvironment. Results: Selinexor enhances CD8+ T-lymphocyte and NK cell activation, re-polarizes macrophages, and inhibits immunosuppressive cells. Bone marrow samples from patients in clinical studies show that selinexor increases CD8 and granzyme B expression in T-cells. Selinexor also disrupts NK cell inhibition, enhances anti-tumor activity, and reduces pro-inflammatory cytokines. Selinexor may upregulate BCMA expression and increase myeloma cell immunogenicity. Real-world data suggests selinexor as bridging therapy does not compromise CAR-T outcomes and may even improve them. Conclusions: Overall, the evidence indicates selinexor's potential to optimize CAR-T outcomes, warranting further investigation as a holding or bridging therapy for CAR-T.

Keywords: BCMA; CAR-T; T-cell exhaustion; bridging; selinexor.

Figure 1

Overview of selinexor-mediated immunomodulation. Selinexor-mediated inhibition of XPO1 activity is associated with increased antibody-directed cytotoxicity of NK cells against cancer target cells and associated with increased CD8 and granzyme B expression of CD3+ T-cells without induction of immune checkpoints. XPO1 inhibition can reduce proinflammatory cytokine signaling (often through the NF-κB pathway), lower MDSC immunosuppressive activity by transforming MDSCs into neutrophil-like cells, and polarize macrophages towards M1 and away from a tumor-promoting M2 state. In addition to inducing cell cycle arrest and apoptosis of cancer cells, selinexor is also associated with enhanced immunogenicity of surviving myeloma cells. Created with Biorender.com.