Table 4:
Risk and benefit considerations in ciltacabtagene autoleucel’s approval:
| Decision Factor | Evidence and Uncertainties | Conclusions and Reasons |
|---|---|---|
| Analysis of Condition | Multiple myeloma (MM) is the second most common hematologic malignancy and accounts for 1.8% of all cancers and 17% of all hematologic malignancies. Therapy for patients with relapsed or refractory myeloma has improved considerably over the past three years with approval of multiple new therapies with improvement in response rate and progression free survival. However, relapsed, and refractory myeloma remains incurable, with a 5-year survival rate of 52%. |
Relapsed or refractory multiple myeloma is a serious and life-threatening condition with need for effective and safe salvage therapies. |
| Unmet Medical Need | Patients with relapsed or refractory myeloma have unmet medical need. | Patient with relapsed or refractory myeloma have unmet medical need. |
| Clinical Benefit | In this single-arm multicenter study for patients with relapsed and refractory myeloma, lymphodepleting chemotherapy followed by ciltacabtagene autoleucel administered at dose range of 0.5 to 1.0 x 106 CAR+ T cells per kg body weight produced: Stringent CR rate of 78.4% (95% CI:68.8%,86.1%) according to IMWG 2016 criteria. ORR for the efficacy evaluable population, by independent review committee (IRC) assessment, of 97.9% (95% CI: 92.7%, 99.7%) with median duration of response of 21.8 months (95% CI:21.8, NE). |
Based on the ORR, CR rate and DOR, ciltacabtagene autoleucel at the recommended dose range has clinically meaningful benefit in relapsed and refractory myeloma who have received a proteasome inhibitor, an IMiD agent, and an anti-CD38 antibody therapy. |
| Risk | Major AEs associated with ciltacabtagene autoleucel were cytokine release syndrome, neurologic toxicities, prolonged cytopenias; with some cases requiring stem cell rescue , infectious complications, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), and hypogammaglobulinemia. | Available evidence indicates that the risk of ciltacabtagene autoleucel while substantial, does not outweigh the benefit to adult patients with relapsed and refractory myeloma. |
| Risk Management | The most substantial risks of ciltacabtagene autoleucel are CRS, neurologic toxicity (NT; includes ICANS, parkinsonism, GBS, peripheral neuropathy, cranial nerve palsy), HLH/MAS, prolonged and recurrent cytopenias, infections and persistent hypogammaglobulinemia. CRS and NT were mitigated in the trial by careful site selection and training of investigators. There are theoretical risks of secondary malignancy with this genetically modified immunotherapy based on the potential for replication competent lentivirus due to the risk of insertional mutagenesis. |
The risks associated with ciltacabtagene autoleucel warrant boxed warnings - a REMS particularly for CRS,NT HLH/MAS and prolonged cytopenia requiring stem cell rescue therapy, and a long term follow up study for risk assessment of subsequent malignancy attributable to insertional mutagenesis. |
Data from Source: BLA clinical review memorandum 125746/05