Remarkably, CAR T-cell therapy has become a widely adopted treatment for various hematological cancers, such as acute and chronic leukemia, lymphoma, and multiple myeloma. Despite early concerns about its effectiveness and safety, CAR T-cell therapy has established itself as one of the most promising and powerful treatment options. 

Anti-BCMA CAR T-cell therapy, CARVYKTI (ciltacabtagene autoleucel) was first approved by the US Food and Drug Administration (FDA) in February 2022, for treating adults with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The approval is based on data from the pivotal CARTITUDE-1 study. Recently in April 2024, Johnson & Johnson received another US FDA approval of CARVYKTI for the treatment of adult patients with RRMM who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide. FDA approval is based on positive results from the Phase III CARTITUDE-4 study, which demonstrated that the earlier use of CARVYKTI reduced the risk of disease progression or death by 59% compared to standard therapies—pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd)—in adults with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy.

CARTITUDE-2 (NCT04133636) is a Phase II, multicohort study evaluating CARVYKTI (cilta-cel) across various clinical settings. Cohort D is evaluating cilta-cel ± lenalidomide maintenance in patients with newly diagnosed multiple myeloma (NDMM) who achieved less than complete response.

In the CARTITUDE-2 cohort D, Cilta-cell demonstrated deep responses, with 94.1% of patients achieving an overall response rate (ORR) and 88.2% attaining a stringent complete response (sCR). Among minimal residual disease (MRD) evaluable patients, the MRD negativity rate was 80%. The study reported high progression-free survival (PFS) and overall survival (OS) rates, with an 18-month duration of response (DOR) rate of 93.3%, and 18-month PFS and OS rates of 93.8% each. 

Safety findings aligned with the known profile of Cilta-cell, showing that 52.9% of patients experienced serious treatment-emergent adverse events (TEAEs), 29.4% developed infections, and 41% had prolonged cytopenias. No death due to TEAEs  at the time of data cutoff. No cases of movement and neurocognitive treatment-emergent (MNT) AEs/parkinsonism were observed.

KOL insights

“The CARTITUDE-2 study's findings on ciltacabtagene autoleucel ± lenalidomide maintenance are indeed compelling for patients with NDMM showing suboptimal response to frontline ASCT. Achieving MRD negativity could significantly improve outcomes.”– MD, United States.

Conclusion 

In the setting of NDMM, achieving a complete response (CR) post-autologous stem cell transplantation (ASCT) is a critical goal, as it is often associated with better long-term outcomes. However, not all patients reach this milestone, which necessitates additional therapeutic strategies. In patients with NDMM who did not achieve CR after frontline ASCT, treatment with a single infusion of CARVYKTI, with or without subsequent lenalidomide maintenance therapy, has shown promising results. 

In the realm of multiple myeloma treatment, sustained remission is a key indicator of therapy success, as it implies prolonged disease control and potential survival benefits. The durability of these responses is particularly noteworthy. Cohort D had robust CAR-T expansion, but numerically shorter persistence compared to patients with lenalidomide-refractory multiple myeloma and one to three prior Line of therapies (CARTITUDE-4) and heavily pretreated patients (CARTITUDE-1). The deep responses observed suggest that cilta-cel can induce a significant reduction in disease burden, even in patients who have residual disease post-ASCT.