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

TL;DR

This paper explores how selinexor can be used before CAR-T therapy in multiple myeloma to improve treatment outcomes by enhancing immune responses and tumor control.

Contribution

The paper introduces selinexor as a promising bridging therapy to optimize CAR-T outcomes in relapsed/refractory multiple myeloma.

Findings

Selinexor enhances CD8+ T-lymphocyte and NK cell activation and re-polarizes macrophages.

Selinexor increases CD8 and granzyme B expression in T-cells from patient bone marrow samples.

Selinexor may improve CAR-T outcomes when used as bridging therapy without compromising results.

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.

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