Cilta-cel for relapsed/refractory MM: updated results from the CARTITUDE-1 and CARTITUDE-2 trials

Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen-directed autologous chimeric antigen receptor T-cell therapy currently under investigation for patients with relapsed/refractory multiple myeloma (RRMM). The phase Ib/II CARTITUDE-1 trial (NCT03548207) was designed to assess the safety and efficacy of cilta-cel for patients with heavily pre-treated RRMM, and the use of cilta-cel in earlier lines of treatment is being evaluated in the CARTITUDE-2 trial (NCT04133636) of lenalidomide-refractory patients with MM who have received 1–3 prior lines of therapy.

One-year follow-up data from the CARTITUDE-1 trial has previously been reported on the Multiple Myeloma Hub and recently published in Lancet.¹ The overall response rate for cilta-cel for patients with RRMM who had received ≥3 prior therapies was 97%, with a stringent complete response rate of 67%, and 12-month progression-free survival and overall survival rates of 77% and 89%, respectively.

The extended 18-month results from CARTITUDE-1 and initial results from CARTITUDE-2 were reported by Saad Usmani^2,3 and Mounzer Agha⁴, respectively, during the 2021 ASCO Annual Meeting and the European Hematology Association (EHA)2021 Virtual Congress. Here we summarize their findings.

CARTITUDE-1 updates^2,3

The CARTITUDE-1 trial design, previously described on the Multiple Myeloma Hub, is summarized in Figure 1.

Figure 1. Trial design*

CAR, chimeric antigen receptor; cilta-cel, ciltacabtagene autoleucel; Cy, cyclophosphamide; Flu, fludarabine; PD, pharmacodynamics; PK, pharmacokinetics; PRO, patient-reported outcome.
*Data from Usmani, et al^2,3.

Efficacy

Efficacy outcomes after a median follow-up of 18 months (range, 1.5–30.5 months) are summarized in Table 1.

• Responses deepened after the extended follow-up, with an increase in the stringent complete response rate from 67.0% at 12 months to 80.4% at 18 months.
• Response rates were comparable across different subgroups, including number of prior therapy lines, refractoriness, extramedullary plasmacytomas, and cytogenetic risk.
• Almost all evaluable patients were minimal residual disease negative at 10⁻⁵ (91.8%).
• For all patients, 18-month progression-free survival and overall survival rates were 66.0% and 80.9%, respectively.

Table 1. Efficacy outcomes*

Safety

No new safety signals were observed with the extended follow-up. Although 94.8% of patients had cytokine release syndrome (CRS), 94.6% of these events were Grade 1 or 2, and resolved within 14 days of onset in 98.9% of patients.

There was no new incidence of neurotoxicity, and no additional movement and neurocognitive treatment-emergent adverse events (TEAEs) were identified. The five patients (5%) with movement and neurocognitive TEAEs had ≥2 of the following risk factors:

• high tumor burden;
• Grade ≥2 CRS;
• immune-effector cell-associated neurotoxicity syndrome (ICANS); and
• high chimeric antigen receptor T cell expansion and persistence.

Patient management strategies have now been successfully implemented in new and ongoing CARTITUDE trials of cilta-cel to prevent or mitigate these TEAEs, including:

• enhanced bridging therapy to reduce tumor burden;
• early and aggressive treatment of CRS and ICANS; and
• handwriting assessments and extended monitoring.

Cilta-cel in earlier lines of therapy: initial results of CARTITUDE-2⁴

Further clinical investigations of cilta-cel include its evaluation for the treatment of lenalidomide-refractory patients with MM after 1–3 prior lines of therapy in the phase II CARTITUDE-2 study. A detailed overview of the trial design and initial results were provided by Mounzer Agha during his interview with the Multiple Myeloma Hub, which can be viewed below. 

Concerning neurotoxicity, 15% of patients (n = 3) had ICANS, all were either Grade 1 or 2 and resolved upon treatment with steroids. One patient (5%) exhibited Grade 2 isolated facial paralysis, was treated with dexamethasone, and recovered after 51 days. With the implementation of patient management strategies, no patients experienced movement or neurocognitive TEAEs seen in the CARTITUDE-1 trial.

Conclusion

Extended follow-up data from the phase Ib/II CARTITUDE-1 study has shown that cilta-cel has durable efficacy and a manageable safety profile for heavily pre-treated patients with MM. For earlier lines of treatment, initial data from the phase II CARTITUDE-2 trial indicates that cilta-cel promotes early and deep responses, with an overall response rate of 95% and complete response or better in 75% of patients. Toxicity was considered manageable, and with the implementation of patient management strategies there was no incidence of movement or neurocognitive TEAEs in this preliminary analysis.

The phase III CARTITUDE-4 (NCT04181827) trial is now underway to compare the performance of cilta-cel with either daratumumab + pomalidomide + dexamethasone or pomalidomide + bortezomib + dexamethasone for patients with 1–3 prior lines of therapy.