EHA 2025 | Evidence supporting the use of cilta-cel in earlier lines of therapy for RRMM

Great question. So most recently at ASCO of this June, we saw the updated five-year follow-up analysis from the CARTITUDE-1 trial, which was the initial trial leading to the approval of cilta-cel in heavily pretreated multiple myeloma patients who had received four or more prior lines of therapy. So long-term follow-up of the CARTITUDE-1 trial showed that one-third of patients remained treatment and progression-free for the last five years after cilta-cel infusion without any maintenance or subsequent therapy following the infusion, which in my opinion is pretty impressive. So cilta-cel therapy has now moved into the earlier lines of therapy based on the randomized phase three CARTITUDE-4 trial, which basically compared cilta-cel versus standard of care regimens in patients with one to three prior lines of therapy, basically in patients that had received one to three prior lines of therapy. So cilta-cel was associated with a significantly higher overall response rate and progression-free survival. In addition, CARTITUDE-4 reported a dramatic improvement in quality of life of these patients, which is pretty important. Cilta-cel also showed improved progression-free and overall survival compared to standard of care regimens across multiple subgroups in the CARTITUDE-4 trial, including patients with high-risk cytogenetics, extramedullary disease, and those treated in the second line setting or beyond. So as of April of 2024, cilta-cel is now approved after one prior line of therapy, including a proteasome inhibitor and lenalidomide refractory. So I would say overall, the most compelling argument for earlier line cilta-cel use is its remarkable efficacy. However, there are several reasons to basically advise caution with early cilta-cel use. So as we know, CAR T-cell therapies can be associated with serious risks, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and delayed neurotoxicity, which includes cranial nerve palsies and Parkinsonism, as well as high-grade infections, which actually represent the most common cause of non-relapse mortality after CAR T-cell therapy. Other toxicities with cilta-cel, which are less common, are, I mean, for example, a recently characterized syndrome of immune effector cell-associated enterocolitis that presents as delayed onset diarrhea with negative infectious workup. And most recently, the risk of second primary malignancies, such as T-cell lymphomas following cilta-cel in multiple myeloma has also gained increasing attention. I personally believe that the potential benefits of earlier CAR T-cell therapy use are undeniable because CAR-T offers deep and durable responses. Although, of course, careful consideration of toxicity, cost, and accessibility is important, the robust evidence basically strongly supports integrating CAR T-cell therapy into earlier lines of myeloma therapy. Of course, the risks and benefits of cilta-cel should be carefully weighted when considering its early use, taking of course into account individual patient’s clinical profile. Some factors such as frailty, aggressive disease kinetics, lack of a dedicated caregiver or geographical limitations may preclude some patients from receiving cilta-cel.

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