The preclinical discovery and clinical development of ciltacabtagene autoleucel (Cilta-cel) for the treatment of multiple myeloma

ABSTRACT

Introduction

Despite remarkable therapeutic advances over the last two decades, which have resulted in dramatic improvements in patient survival, multiple myeloma (MM) is still considered an incurable disease. Therefore, there is a high need for new treatment strategies. Genetically engineered/redirected chimeric antigen receptor (CAR) T cells may represent the most compelling modality of immunotherapy for cancer treatment in general, and MM in particular. Indeed, unprecedented response rates have led to the recent approvals of the first two BCMA-targeted CAR T cell products idecabtagene-vicleucel (‘Ide-cel’) and ciltacabtagene-autoleucel (‘Cilta-Cel’) for the treatment of heavily pretreated MM patients. In addition, both are emerging as a new standard-of-care also in earlier lines of therapy.

Areas covered

This article briefly reviews the history of the preclinical development of CAR T cells, with a particular focus on Cilta-cel. Moreover, it summarizes the newest clinical data on Cilta-cel and discusses strategies to further improve its activity and reduce its toxicity.

Expert opinion

Modern next-generation immunotherapy is continuously transforming the MM treatment landscape. Despite several caveats of CAR T cell therapy, including its toxicity, costs, and limited access, prolonged disease-free survival and potential cure of MM are finally within reach.

KEYWORDS:

• Multiple myeloma (MM)
• second-generation CAR T cells
• B cell maturation antigen (BCMA)
• cytokine release syndrome (CRS)
• immune effector cell-associated neurotoxicity syndrome (ICANS)

Article highlights

• Based on the pivotal CARTITUDE1 trial ciltacabtagene autoleucel (‘Cilta-cel’) is the second BCMA targeted CAR T cell product that has been approved for the treatment of RRMM patients after ≥4 (FDA) and ≥3 (EMA) prior lines of therapy, respectively, including an IMiD, a PI, and a CD38 mAb.

• The unique biepitopic ectodomain of Cilta-cel is intended to boost avidity against human BCMA, to enhance antiMM activity, and to lower immunogenicity.

• Real-world data of the LocoMMotion and MAMMOTH studies as well as of the Flatiron Health MM registry strongly support efficacy data of Cilta-cel obtained in the CARTITUDE1 trial.

• Impressive results of the first phase 3 CAR T cell trial in MM, the CARTITUDE4 trial implies that Cilta-cel becomes a new standard of care for patients with lenalidomide-refractory MM at first relapse. The approval of Cilta-cel in this setting is expected in 2024.

• Caveats of CAR T cell therapy include its toxicity, costs, and limited access (particularly for groups that are socioeconomically, racially/ethnically and geographically marginalized), as well as a potential selection bias based on the utilization of modified intention to treat (mITT) populations, and unknown prolonged disease-free survival data.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.