FDA Approves Cilta-Cel for Relapsed/Refractory Myeloma After 1 Therapy

Ciltacabtagene autoleucel is now indicated in those who have received at least 1 prior line of treatment, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.

The FDA has approved ciltacabtagene autoleucel (cilta-cel; Carvykti) for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of treatment, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.

The approval is based on findings from the phase 3 CARTITUDE-4 trial (NCT04181827), which showed that that cilta-cel reduced the risk of disease progression or death by 59% vs pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or daratumumab (Darzalex), pomalidomide and dexamethasone (DPd) in adults with relapsed and lenalidomide-refractory multiple myeloma who received 1 to 3 prior lines of therapy.¹

This cilta-cel indication marks the first and only BCMA-targeted therapy that is indicated for the treatment of patients with multiple myeloma in the first relapse setting at the earliest.

"Carvykti demonstrated remarkable efficacy as a personalized, one-time infusion in the earlier treatment of relapsed/refractory multiple myeloma as shown through the CARTITUDE-4 study results," Binod Dhakal, MD, associate professor, Medical College of Wisconsin, Division of Hematology and Oncology, said in a news release. "With this approval, I'm excited for patients who may have the opportunity for a treatment-free period for their multiple myeloma as early as first relapse, with the hope of eliminating the burden of having to be on continuous treatment while living with this challenging disease."

In March 2014, the FDA’s Oncologic Drugs Advisory Committee voted 11 to 0 that the benefits of cilta-cel outweigh its risks for the treatment of adult patients with relapsed/refractory multiple myeloma in this setting.³

The vote followed a discussion of results from the phase 3 CARTITUDE-4 trial. In the study, 419 patients were randomized to receive either cilta-cel (n = 208) or standard care therapy (n = 211). In the standard-of-care (SOC) arm, 183 patients received DPd, and 28 received PVd. In the cilta-cel arm, 176 patients received study treatment vs 208 in the SOC arm.

Additional data showed that the median OS was not estimable (NE; 95% CI, NE-NE) for cilta-cel vs NE (95% CI, 33.97-NE) for the standard arm (HR, 0.57; 95% CI, 0.40-0.83). Two-year OS rates were 79% and 66%, respectively.

Furthermore, the overall response rate was 84.6% for patients in the cilta-cel arm vs 67.3% in the SOC arm (risk ratio, 2.2; 95% CI, 1.5-3.1; P <.001; OR, 3.0; 95% CI, 1.8-5.0). Complete responses or better was observed in 73.1% of patients in the cilta-cel arm vs 21.8% in the SOC arm (risk ratio, 2.9; 95% CI, 2.3-3.7; P <.001; OR,10.3; 95% CI, 6.5-16.4).

An ongoing response at 12 months was estimated to occur in 84.7% of patients in the cilta-cel arm vs 63.0% in the SOC arm.

In 60.6% of patients in the cilta-cel arm, minimal residual disease (MRD) negativity was observed vs 15.6% in the SOC arm (risk ratio, 2.2; 95% CI, 1.8-2.6; P <.001; odds ratio, 8.7; 95% CI, 5.4-13.9). Additionally, MRD negativity for patients with evaluable samples was observed in 87.5% vs 32.7%, respectively.

Cilta-cel's indication includes a boxed warning for cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, Parkinsonism and Guillain-Barre syndrome and their associated complications, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged and recurrent cytopenias and secondary malignancies including myelodysplastic syndrome, acute myeloid leukemia and T-cell malignancies.

Additional warnings include increased early mortality, hypogammaglobulinemia, infections, hypersensitivity reactions and effects on ability to drive and use machines.

On CARTITUDE-4, grade 3/4 adverse effects (AEs) were reported in 96.6% of patients on cilta-cel vs 94.2% on SOC. Serious AEs occurred in 44.2% vs 38.9%, respectively, and secondary primary cancers occurred in 4.3% of patients on cilta-cel arm vs 6.7% on SOC.

Grade 3/4 infections occurred in 26.9% vs 24.5% of patients in each arm, respectively. Thirty-nine patients died in the cilta-cel group vs 46 in the SOC group. Causes of death included disease progressions (n = 14 vs 30) and AEs from treatment (n = 10 vs 5). Fifteen deaths in the cilta-cel group and 11 in the SOC group occurred from AEs that were unrelated to treatment.

Cytokine release syndrome occurred in 76.1% of patients who received cilta-cel. The median time to onset was 8 days, and the median duration was 3 days.

References

1. CARVYKTI® is the First and Only BCMA-Targeted Treatment Approved by the U.S. FDA for Patients with Relapsed or Refractory Multiple Myeloma Who Have Received at Least One Prior Line of Therapy
2. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Eng J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379
3. March 15, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/watch?v=VSjdGeeXb40