Experts Review Considerations in Cilta-Cel Versus Ide-Cel, Bispecific Antibodies for Relapsed or Refractory MM

In a review article, experts from the Cleveland Clinic, the Fred Hutchinson Cancer Center, and the Mayo Clinic have examined recent clinical trial data to clarify the role of ciltacabtagene autoleucel (cilta-cel) in the management of relapsed or refractory multiple myeloma (MM). Their article was published in Cancer Management and Research.

“Overall, cilta-cel has demonstrated remarkable activity in both early and later lines of therapy for RRMM [relapsed or refractory MM]. Notably, it is a maintenance-free treatment option, which is important for patients’ quality of life, who often need to receive continuous therapy without breaks until progression,” wrote first author Utkarsh Goel, MD, and colleagues.

Cilta-cel, an autologous second-generation chimeric antigen receptor (CAR) T-cell therapy, was originally only approved by the FDA for MM treatment after 4 prior lines of therapy. Following its success in the phase 3 CARTITUDE-4 trial, it was approved in April 2024 for use after only 1 or 2 lines of therapy.

The authors reviewed the previous clinical trials that investigated cilta-cel for heavily pretreated MM—the LEGEND-2, CARTITUDE-1, and CARTIFAN-1 trials, along with the ongoing multi-cohort CARTITUDE-2 trial, which also explores use in newly diagnosed disease. The success of the CARTITUDE-4 trial has spurred research into use of cilta-cel for earlier lines of therapy, with the upcoming CARTITUDE-5 and CARTITUDE-6 trials to be focused on newly diagnosed MM, and the CAR-PRISM study, on high-risk smoldering MM.

The authors also surveyed these trials’ data for prevalence of adverse events associated with cilta-cel. These include cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), neurotoxicity-linked movement and cognitive disorders, hematologic toxicities, and second primary malignancy.

Regarding use of cilta-cel or idecabtagene vicleucel (ide-cel) for relapsed or refractory MM, the 2 FDA-approved CAR T-cell therapies for this disease, the authors recommend they be considered for all patients with at least 4 prior lines of therapy. However, because of toxicities, such as those measured by the authors in the cilta-cel trials, CAR T-cell therapy should only be used in earlier lines of treatment if patients have a high-risk disease phenotype.

When a choice between CAR T-cell therapy and a bispecific antibody—another treatment approved by the FDA for patients with relapsed or refractory MM—is being made, the authors advise attempting CAR T-cell therapy first. They acknowledge, however, that CAR T-cell therapy is a more time-consuming and clinically taxing approach and is not as widely or quickly available as bispecific antibodies.

The authors then made specific comparisons of cilta-cel with ide-cel and bispecific antibodies as treatments for relapsed or refractory MM. Real-world and trial data show cilta-cel is more effective than ide-cel, but cilta-cel carries greater toxicity concerns than either ide-cel or bispecific antibodies, such as in the incidence of CRS and ICANS.

“Most importantly, cilta-cel has been linked with unique non-ICANS delayed MNTs [movement and neurocognitive treatment-emergent adverse events] such as nerve palsies, Guillain–Barré syndrome, and parkinsonism,” wrote Dr. Goel and colleagues.

Moreover, despite greater overall effectiveness, in some subpopulations with high-risk disease, cilta-cel has diminished effectiveness. Certain noteworthy clinical trial findings, such as those from the phase 1b/2 RedirecTT-1 study, also suggest that a bispecific antibody management approach might be more effective in these patients, such as those with extramedullary disease.

“Given these impressive outcomes, bispecific combination may become the preferred regimen in heavily pretreated patients with extramedullary disease soon, even among those who qualify for standard-of-care or experimental CAR T-cell therapies,” elaborated Dr. Goel and colleagues.

The authors point out the difficultly of determining the role of these treatments relative to one another in relapsed or refractory MM management, given the need for more clinical research. Head-to-head randomized trials to compare these approaches are lacking, and it is difficult to draw reliable conclusions from cross-trial comparisons. Moreover, other CAR T-cell therapies under development, such as anitocabtagene autoleucel or arlocabtagene autoleucel, may offer efficacy comparable to that of cilta-cel with less toxicity.

“Optimal sequencing of these agents remains unclear, and treatment selection is mostly influenced by patient parameters, disease characteristics, patient and physician preference, and logistics,” explained Dr. Goel and colleagues.

Reference

Goel U, Zanwar S, Cowan AJ, Banerjee R, Khouri J, Dima D. Ciltacabtagene autoleucel for the treatment of relapsed/refractory multiple myeloma: efficacy, safety, and place in therapy. Cancer Manag Res. 2025;17:357-372. doi:10.2147/CMAR.S510408