Could CAR-T Cure Myeloma? | 5-Year CARTITUDE-1 Results Explained | Sundar Jagannath, MBBS | EHA 2025

Hi, I'm Sundar Jagannath, Professor of Medicine at Icahn School of Medicine at Mount Sinai in New York. I am attending the IHA meeting 2025 in Milan and I had the opportunity to present one of the studies which was called Cartitude 1 Long-Term Results after a median follow-up of five years. Now, let us see what all these terminologies mean. Cartitude 1 was, as the number 1 says, was the first study for silted cell, CAR T cell clinical trial. So this was a phase 1b2 study. What it means is this CAR T cell therapy was given to patients who had already been exposed to the three major classes of drug, the PI or proteasome inhibitor, as you know, botazomib and carfilzomib or Velcade and Kyprolis, as you may know. So that is the PI. IMID is lanolidamide or pomalidomide or revlimid and pomelist. And thirdly, anti-CD38 monoclonal antibody, which is daratumumab or Darzalex, or you also have another monoclonal antibody, isotuximab. Patients who participated in the clinical trial, they were already exposed to all three classes of drugs and had received three or more prior lines of treatment and the cancer kept coming back. So when their cancer was still progressing on their last line of therapy, then they could participate in this clinical trial. Also patients who were double refractory when they are receiving a PI and an IMID and the cancer is progressing, they can also participate in this clinical trial. But generally, patients who participate in clinical trials are healthier. So these patients went through a pharesis to collect their lymphocytes from their blood. And after that, they received some chemotherapy if needed to keep the cancer in check because it took approximately two months to prepare those T cells and make them into CAR T cells. So these are T cells which have been programmed to attack the myeloma cells and the target was BCMA, which is expressed on the myeloma cells. So after that two months, once the CAR T cells were prepared and ready, the patient got lympho-depletion. So they got a little bit of cyclophosphamide and fludarabin over three days. And the purpose is that they don't reject the CAR T cells when they are given to them and that is why they get this is called lympho-depletion and immunosuppression. So they don't reject the CAR T cells. After that, they received CAR T cells. They got a fixed dose of CELTA cell, about 0.75 million CAR positive viable T cells were administered on day plus one. After that, the patients were followed closely for safety. They were followed for efficacy, which is the response and the duration of response. And finally, also for correlative studies, what else was happening that we could understand to make it better in the future. These results of CAR T1 have been previously reported and it was so positive that it resulted in approval by FDA, EMEA and Japanese authority. World over, CAR T cells were approved for patients who had relapsed and refractory myeloma and had been exposed to the three classes of drug and their cancer had still come back. That is a positive message. So the initial results were reported after 33 months of follow up, close to three years. And what was noted is the median progression free survival was 35 months and the median overall survival was not reached. These results were unprecedented. That's why all the world authorities immediately approved. Why do I say unprecedented? There was another study called locomotion in Europe and another study in the United States in which patients who met the eligibility criteria to go on the clinical trial, but they received only standard of care, not the CAR T cells to find out how they did. And what they noticed was their control of disease or progression free survival, which is control of disease, was accomplished only around four months, less than six months. And because the cancer came back at this stage and they had already been exposed to all three classes of drugs, even the life expectancy was limited to a year. And that is why to have median progression free survival that the cancer had not come back for beyond three years and the survival was not reached and the patients were all living well was unprecedented and the drug guard approved. So what am I doing here in this meeting? Okay, now I came here to present the five year long term follow up result. This is the first time ever people have presented long term follow up with a median follow up of five years in relapse refractory multiple myeloma clinical trial. Okay, so what did we find? We found that one third of the patients, there were 97 patients treated who got the Celtosal and that's it. It's one and done deal. They didn't get maintenance. They didn't get any subsequent therapy. In that one and done deal, we found that one third of the patients, the cancer never came back at five years and beyond. This was unprecedented. And moreover, 12 of those patients were followed by us at Monsignor. We methodically followed those patients doing bone marrow for MRD every year, blood tests and a PET CT every year for five years and beyond. What did we see in our 12 patients who are part of these, you know, one third of patients or 32 patients who were in remission five years and beyond? These 12 patients were in complete remission, MRD negative in the bone marrow and PET CT negative. That means they had no trace of cancer in the body every year for five years and beyond. And that is the definition of cure in myeloma. So we are establishing a definition for cure in myeloma in an incurable disease. That itself is a major breakthrough. And the fact, you know, we were striving hard, but Balagi was doing total therapy in newly diagnosed myeloma patient to cure myeloma. He always was interested in curing myeloma, but it was a newly diagnosed myeloma patient. Nobody have ever dared to show they cured relapsed refractory myeloma patient who were ready for hospice and being cured. And here we took patients who were potentially for hospice and took them to a cure. And that is why it is getting all the attention. And it even came in New York Times. So what do I wanted to say is that we are moving the needle from an incurable disease in multiple myeloma to a potentially curable disease. Now how do we accomplish that? What did we learn from this study? There were some correlative studies we did. So it showed us when there are a lot of T cells in circulation compared to white blood or neutrophils, those patients had good T cells for cardiac manufacturing. And those are the patients who did very well long term. So having good immune cells or T cells in the body at the time of collection is important. The next thing we noted is the drug product when we are giving the CAR T cells, having a lot of CAR positive naive T cells, which could be programmed to kill the cancer effectively, having a lot of CAR positive naive T cells is also good. So the product should also be good. And finally, when we actually gave the CAR T cells to the patient, you got to remember these are living cells. They multiply in the patient's body according to the amount of cancer cell in order to wipe out all the cancer in their body. And we noted that in those patients where the CAR T cells multiplied robustly so that the T cells were more compared to the tumor cells, what we call as effector to target ratio. So having a lot of CAR T cells, CAR positive T cells expanding in the patient's body after administering those are the patients where the cancer disappeared completely and it never came back. So this is an important finding. What does that mean? That means a potentially curative treatment option should not be kept at the end stage of life of a myeloma patient. It should be moved earlier in the treatment paradigm, which was done. So patients who had failed only one to three lines of therapy and were lenolomide refractory, there was another study done called CAR T4. So either they got the CAR T cells or on the other arm, they got the standard of care that they had, erythema, pomalidomide, dexamethasone, continuously until progression of disease or well-cared pomalidomide and dexamethasone until continuously until progression of disease. What did we find? That patients who get CAR T cells in the one to three lines in the earlier lines of the treatment, the cancer disappeared in most of the patient and not only cancer disappeared in 80% of the patient, the cancer disappeared completely. They were in CR, MRD negative in the bone marrow. That means not even a trace of cancer cell in the bone marrow and PET CT was negative. And at the end of one year, we found 50% still had absolutely no trace of cancer. What about the standard of care with the daratumumab, pomalidomide, dexamethasone, which they are still getting? Only 10% had persistent disappearance of cancer at that time. So it was like day and night giving CAR T cell earlier, the cancer is able to disappear. And what is the outcome when we look at how long the cancer stays away, the progression free survival as we call it, was consistently much superior in patients who received CAR T cell as opposed to standard of care. But what was my first statement? If we move the CAR T cell from the end stage, later stage versus an earlier stage, does it make a difference? So we looked at the same time point, 30 to 34 months, when we did CAR T cell in CAR T1, there were only about 50% of the patients or 45% of the patients where the disease was still in remission at 30 months. Whereas when we did it earlier in CAR T cell 4, we found that almost 70% of the patients, the cancer stayed away. So giving the CAR T cell earlier means the patient get a better outcome. So this also needs longer follow up to see at the end of five years of follow up whether more patients have been cured. But this is the excitement in this EHA 2025 in Milan. Thank you.