Bispecific Antibodies and Precision Medicine Insights on Myeloma Prognosis | Ola Landgren, MD | EHA 2024

Hi, I'm Ola Langerun. I'm a professor of medicine and I'm the chief of the Myeloma Division at the University of Miami. I'm here in Madrid at the IHA 2024 meeting. I just was part of a morning discussion at one of the symposia focusing on the new bispecific one-on-one coronal active on the synoptic myeloma. I had the great pleasure of talking about how they can be used in the clinic, sequencing, what to think about to avoid different types of side effects, and also patterns of biomarkers. I had the great pleasure of going over data with the Clistamab, Talcretamab, and Elvanatamab. And I went over some analysis of these drugs can be given to patients who have extra medullary disease, patients who have a lot of disease in their bodies, patients that were older or younger, and also patients who were frail or not frail. And what all the data show consistently is that the efficacy of these drugs is very, very high, translating into great response rates, typically over 60%, very high rates of MRD negativity, and also long progression for a survivor. I also try to dig a little bit deeper into where the field is going in terms of sequencing of the drugs. So a lot of doctors and patients are asking, which of the drugs do you have to give first? Do you give the cortisone first? Should you give the bispecifics first? Which of the bispecifics should you give first? Or does it not really matter? And what I showed from studies that have been published and presented was that there is very good response in patients receiving a BCMA targeted bispecific, even if they previously received a CAR T cell or even an antibody drug, for the same target BCMA. And also I showed the other way around, patients who had been on the bispecific antibodies, if they went on and got CAR T cells, that also there is efficacy that's very strong in those patients. It should be emphasized that there is probably more information that we really need to generate on the details. For example, if a patient were to get a CAR T cell and unfortunately didn't really work as well as it would do for the majority of patients, to go straight to a bispecific for the same target may not really work as well. However, if a patient got the CAR T cell therapy and it worked really well for many years, which it seems to do for the majority of patients, if there eventually would be a reoccurrence of the disease, going back to a bispecific even with the same target seems to work in many patients. You could of course go to other bispecifics with other targets because now we have multiple targets. You could also go to other combinations of drugs and then you could go back to the bispecifics. So the message was really that there is efficacy. You start with A and go to B or you start on B and you go to A. There are more details that we need to figure out. Lastly, talking of details, I also shed light on some of the data presented at ASCO 2024 in Chicago, which just happened a week ago. I had two studies that I highlighted. One was on something called soluble BCMA. BCMA, a long time ago, was a biomarker. It was not a target for drugs. It was a biomarker you could measure in the blood and you still can do that. It is actually something that is released by the myeloma cells. And for ASCO, I showed data from one of those presentations where they had measured BCMA in relation to how much disease a patient had. And they had showed in the ASCO presentation that patients with less disease are lower levels and patients with more disease are higher levels. I also showed that if they were very high stage or high phosphoryl numbers, you could see the same pathway. So now if you stratify the response to a bispecific antibody that goes after BCMA in a patient where the concentrations of the soluble BCMA is very high in the blood, there is less good of a response compared to a patient who has lower levels. Probably this indicates that the drug gets trapped by the circulating BCMA instead of going to the disease cells that have BCMA. So clinically, probably we need to think about maybe we need to debug, give some other therapy first, and then go to the bispecifics in those extreme cases with very high amounts of BCMA. That could be one thing. It's not final, but that's what the data suggests. And I also think that it tells us that if you can bring down the disease, maybe you could even have lower dosing, maybe lower milligrams, could have less frequent doses instead of doing once a week. You could do every other week or once a month with a bispecific once the concentrations are lower and there's less disease in the patients. Lastly, I showed the biomarkers how patients that get the bispecifics, they can unfortunately in the resistance pattern develop mutations. And I showed that the mutations are not the same in every patient and the mutations can correspond with what's called epitopes. So even if the patient has a mutation in BCMA in a particular epitope in BCMA, that means that if a drug goes after that particular epitope, that drug may not work. But another drug that's also BCMA-trovita drug that goes for another epitope, that drug could still work. So again, the devil see the details. There are mutations that are more unique. And I think the field needs to further characterize patterns of these mutations when the resistance happens, so we can better make decisions and do precision medicine. That's the future for my alarm.