CARTITUDE-4 is a phase III study comparing ciltacabtagene autoleucel, or cilta-cel, versus standard of care treatment in patients with lenalidomide-refractory multiple myeloma. This is the first phase III CAR T study to include patients after the first relapse.
The patients included are refractory to lenalidomide and having 1-3 prior lines of therapy. They are randomised in a 1:1 fashion to receive either CAR T-cell or standard of care. The standard of care are two highly effective standard of care regimens based on physicians choice – either DPd, that is daratumumab, pomalidomide and dexamethasone, or PVd, that is pomalidomide, bortezomib and dexamethasone. The primary endpoint is progression free survival and a number of secondary endpoints included overall response rate, complete response rate, MRI negativity rates, the cell-to-cell pharmacokinetics and quality of life data.
In the study design patients who were randomised to the cilta-cel arm underwent apheresis and one or more cycles of bridging therapy and lymphodepletion with fludarabine and cyclophosphamide for 3 days before receiving a cilta-cel infusion. In the bridging therapy, while they were waiting for cilta-cel, the patients received the same treatment, either PVd or DPd, based on physician’s choice. The time from randomisation to start of that PVd or DPd, either in the standard of care arm or bridging therapy, was similar.
The results showed that the the study met its primary endpoint and so significantly reduced the risk of disease progression or death versus standard of care. The hazard ratio was 0.26. The PFS benefit, the progression free survival benefit, was seen consistently in all subgroups including the key subgroups. For example, patients with high-risk disease, patients with soft tissue plasmacytomas, ISS stage 3 disease and triple class refractory disease. We also found that cilta-cel significantly improved the rates of response and depth of response versus standard of care. The overall response rate was 85% in the cilta-cel arm and was significantly higher compared to 67% in the standard of care arm.
The rates of complete response are better wtih 72% versus 22%. When looking at the MRD, the overall MRD negativity rates in patients in the cilta-cel arm, including all the intent to treat patients, were 61%, and that was significantly higher than 16% in the standard of care arm.
When you look at the patients who received cilta-cel as study treatment, which are 176 patients, the overall response rate was 99% and 86% achieved a complete response or better with 72% being MRI negative. The 12-month progression free survival rate from the time of apheresis was about 90%. So there is significant benefit, or very superior efficacy, of cilta-cel when compared to the standard of care which are highly effective standard of care regimens that are available.
What will be the clinical impact of these results?
Based on the impressive efficacy of the cilta-cel in patients with 1-3 prior lines of therapy, lenalidomide refractory, this could be a new standard of care for patients in that patient population. They are highly effective but, at the same time, they're very safe and the side effects are very manageable with appropriate supportive care, including the CAR T related adverse events. In fact, comparing to CARTITUDE-1, when patients were treated with three or more prior lines of therapy, we found lower incidence of CAR T specific adverse events, specifically cytokine release syndrome, ICANS, other neurotoxicities and cytopenia. The rates and severity were lower in this study compared to the CARTITUDE-1 population. So that suggests that cilta-cel in earlier lines is not only effective but also very well tolerated.
This is a very large study, one of the first randomised stage IIIs to include patients after first relapse. In this study we were able to show that using cilta-cel in early lines can be highly effective and can be managed with appropriate supportive care and can provide a significant benefit to our patients.