Point-Counterpoint
Chimeric Antigen Receptor T-cell Therapy for First Relapse in Multiple Myeloma: A Promising Strategy

Chimeric antigen receptor T-cell (CAR-T) therapy has heralded a transformative era in the treatment of multiple myeloma (MM) following the first relapse. In the context of triple-class-exposed MM, CAR-T cells targeted against B-cell maturation antigen (BCMA) have yielded response rates and outcomes that surpass the capabilities of existing therapeutic options (Table).^1,2  Extended follow-up data from the CARTITUDE-1 and LEGEND-2 studies have reinforced this significant stride forward, emphasizing the profound and enduring responses that can be achieved in a majority of heavily treated patients with MM using a “one-and-done” CAR-T approach.^3,4  Given these results, there is an urgent need to explore the potential of CAR-T therapy in earlier lines of treatment.

In a pivotal development, results from two randomized trials published in 2023 illuminated the advantages of CAR-T therapy over the standard of care (SOC) in the early lines of MM treatment.^5,6  The CARTITUDE-4 trial compared ciltacabtagene autoleucel (cilta-cel) with the SOC in patients with lenalidomide-refractory MM who had received one to three prior lines of therapy.⁵  Concurrently, the KarMMa-3 trial evaluated idecabtagene vicleucel (ide-cel) against the SOC in patients with two to four prior therapies.⁶  Both trials not only affirmed the safety of a single CAR-T infusion but also underscored its remarkable therapeutic potential by demonstrating a favorable risk–benefit profile when compared with that for the SOC. The standout finding was from the CARTITUDE-4 trial, shedding light on the advantages of CAR-T therapy even for patients experiencing their initial relapse. Patients in early stages of relapse appeared to derive more pronounced benefits than their counterparts in later stages of relapse, with these advantages expected to be further accentuated with extended follow-up. It is noteworthy that, in the U.S., the majority of patients facing their first relapse have lenalidomide-refractory disease, historically enduring poor outcomes with a median progression-free survival (PFS) of less than 1 year.^7,8  Notwithstanding the FDA’s approval of various regimens in this therapeutic realm, the unprecedented efficacy of CAR-T therapy in this patient subgroup renders it an appealing therapeutic option. This approach also allows for a “treatment-free” interval — a rare benefit for patients with MM.

Moreover, administration of CAR-T therapy has been associated with a decreased incidence of CAR-T-specific adverse events in patients with a lower disease burden.⁵  These patients exhibit heightened disease sensitivity, reducing the necessity for bridging and alleviating concerns about the time-consuming manufacturing process for CAR-T cells. Embracing this approach will position patients with MM (including those with lenalidomide-refractory MM) to reap more substantial benefits from CAR-T therapy than have been achieved in later lines of therapy, when treatment attrition rates tend to be higher.

In conclusion, the remarkable efficacy of CAR-T therapy when compared with that of currently available treatments, particularly in the case of lenalidomide-refractory MM, underscores the importance of its early integration at the first relapse stage. This approach not only enhances patient outcomes but also diminishes the likelihood of patient attrition during transitions between treatments. The early adoption of CAR-T therapy represents a promising strategy in the evolving treatment landscape for MM. Ongoing and forthcoming trials are actively investigating the role of CAR-T therapy in the frontline setting for MM — an acknowledgment of its transformative potential. As such, CAR-T therapy is poised to become a pivotal tool in our ongoing pursuit of a potential “cure” for MM.