Dr Chari on the Risks and Benefits Associated With Earlier CAR T Use in R/R Multiple Myeloma

Ajai Chari, MD, director, Multiple Myeloma Program, professor, clinical medicine, University of California, San Francisco (UCSF), UCSF Helen Diller Family Comprehensive Cancer Center, discusses the potential role for CAR T-cell therapies in the early-relapsed setting for patients with multiple myeloma, highlighting how the risk of developing neurologic toxicities or secondary malignancies may factor into the decision-making process.

Updated data from the phase 3 CARTITUDE-4 (NCT04181827) and KarMMa-3 (NCT03651128) trials have shown clear benefit with ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), respectively, in patients with relapsed/refractory multiple myeloma, Chari begins. Although these data suggest that CAR T-cell therapy may confer clinical benefit in the early relapsed setting, the optimal line and time point during which to utilize these agents is less clear, he says.

Cilta-cel is FDA approved for adult patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an IMiD, and who are refractory to lenalidomide (Revlimid). The regimen is particularly effective for patients considered functionally high risk—such as those who have relapsed within 18 months post-transplant—making its use a clear choice in these cases, Chari states. For standard-risk patients who haven't experienced early relapse, the decision becomes more nuanced, as alternative regimens could also be viable options, he notes.

Prior to the FDA approval of cilta-cel, the FDA's Oncology Drug Advisory Committee (ODAC) voted in favor of cilta-cel in the treatment of patients with early relapsed/refractory myeloma on March 15, 2024. This decision came following a discussion of key data from CARTITUDE-4, Chari continues. Although most clinicians are familiar with the risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), safety concerns have shifted, he says. Data from the phase 1/2 CARTITUDE-1 trial (NCT03548207) highlighted potential neurologic toxicities, parkinsonism, and secondary malignancies associated with cilta-cel, which were reported at rates as high as 10%. However, these adverse effects appeared less common in CARTITUDE-4 and were more manageable in treated patients, Chari notes. Moreover, it was noted in the ODAC meeting that patients who progressed prior to lymphodepletion in CARTITUDE-4 exhibited higher rates of CRS and ICANS, both in all grades and high grades, along with slightly elevated neurologic toxicity rates. The presence of a patient with Parkinsonism raised concerns but was not unexpected, Chari emphasizes.

The ODAC also voted in favor of the risk-benefit profile of ide-cel for patients with relapsed/refractory multiple myeloma, reinforcing the potential for CAR T-cell therapies in earlier treatment lines. Ultimately, the risks associated with secondary malignancies and neurotoxicity will play a significant role in decision-making, especially for patients who do not present as high-risk candidates for aggressive therapies, Chari concludes.