The KarMMa study is a pivotal evaluation of ide-cel, a BCMA targeting CAR T-cell in relapsed/refractory multiple myeloma. Ide-cel is an autologous T-cell product which is transduced with a vector that incorporates an anti-BCMA targeting molecule. 4-1BB is a costimulatory molecule and CD3-zeta is a T-cell activator.
The eligibility in this study was very straightforward. Patients with three or more prior lines of therapy, having exposure to proteasome inhibitor, immunomodulator and also anti-CD38 antibody and refractory to the last cycle. Patients get leukapheresis, you collect the cells and produce CAR T-cells which takes around four to five weeks. In between patients can get bridging therapy if it’s in more aggressive disease. 88% in this study patients got bridging therapy. Prior to CAR infusion patients get lymphodepletion with fludarabine and Cytoxan. Then following CAR infusion a month later and beyond we measure the response.
128 patients have been treated on this study and the target dose ended up being 450 million cells. The primary endpoint was both PR and the secondary endpoint being a CR. An important point to keep in mind about this study is that the patients were very advanced disease, they were six years median from their diagnosis and they had received a median of six different chemotherapeutic options before they went on the study. 30-35% were high risk cytogentics, 39% had extramedullary disease, 84 were triple refractory, 94 were refractory to anti-CD38 antibodies, so a very advanced patient population.
In this patient population the overall response rate was 73% with a CR rate of 33%. If you look at the target dose the response rate was 82%, a CR of 39% and a median time to response of one month. So it’s very quick response. If you look at the depth of response, overall if you consider VGPR and better, 39% of patients got MRD negative status and at the target dose 48% of patients got MRD negativity. So really a very good response rate in these patients.
If you look at who gets this response it’s almost every subgroup we can look at get the same response, 70-75% response rate, whether high risk cytogenetics, extramedullary disease, triple refractory, penta-refractory, they all have very similar results. So the treatment works in almost all settings. The only place where there is a dose response is the dose of the CAR T-cells. So from 150 to 300 to 450 we see a clear dose increase so there is something to giving the target dose that is important.
The duration of response was around 10.7 months but if you look at the subgroups patients getting the 450 dose the DOR was 11.3 months and in patients getting CR it was 19 months. If you look at PFS the overall PFS was close to 9 months but in the subgroups at 450 it was 12 months and in patients getting CR the PFS was 20 months, quite interesting. However, patients who did not respond, their PFS was 1.8 months, telling us that these are a very advanced disease patient population. Overall survival in this study was 19.4 months, it’s still early and more patients are being followed.
Toxicity, considering CAR T-cells, was quite manageable. 84% of patients got CRS but only 4% of patients had a grade 3 or higher CRS. The CRS median time is one day, so it happens very quickly. The median time of duration of CRS is five days. Patients get treated with tocilizumab, 50% of patients got tocilizumab overall. Neurotoxicity is not very significant, 18% of patients get it, the majority of them are grade 1 and 2, only 3% at grade 3 neurotoxicity. They are treated either by tocilizumab or steroid. The toxicity to keep in mind is cytopenia – 90% of patients got grade 3 or greater neutropenia and it’s not because of the CAR as much as because of the lymphodepletion they get. That does put them to a risk of having infectious complications.
So, if I summarise this, ide-cel provides frequent, deep and durable responses. Toxicities are manageable and so it is a very attractive treatment in triple exposed patients with multiple myeloma.
The plan for the future as it becomes available in these patients with three and beyond cycles is that we need to use it and explore its use in the earlier setting. So in high risk patients that’s what we are doing right now. In high risk patients we can evaluate what they are. We have to combine it with some of the maintenance treatments. Right now CAR T-cells one infusion and nothing else, now we need to give maintenance so that the good response that we get can be sustained longer. Then various other combinations with the drug, multiple CAR T infusions etc. are all being explored in earlier stages of the disease and it will be very exciting. These results are across multiple other CAR studies so I think CAR T-cells have a great future in treating high risk myeloma and also advanced myeloma.
