Can patients respond to a second line BCMA treatment?

A very relevant question in science and very important to the patient is if one patient has received a given agent targeting BCMA. After relapse, unfortunately, can this patient receive another agent, different agent, targeting BCMA? And the short answer is yes. Obviously, we don't have yet controlled prospective trials looking carefully into this sequence. But I think we have sufficient data from different studies showing, for instance, that patients who have received antibody drug conjugate or bispecific antibodies, they can still respond to CAR T cells. And we have the same story the other way around. If you have received CAR T cells and if unfortunately the disease is progressing again, then you can give these bispecific antibodies or antibody drug conjugate. So in summary, I would say it's rather a good news that a same target, as long as it is still present, can be targeted by different agents. The big question is what would be the optimal sequence and hopefully the future trials would allow us to answer this question, whether we should use ABC or BAC or CAB or CBA? And I think the answer is yes. Probably the group that's out there in the biggest numbers have received BALANTIMAB. So BALANTIMAB was available starting a couple of years ago. Commercially, your viewers will know it was recently pulled from the market because of not meeting a progression-free survival endpoint, although still did very well. But patients who've had BALANTIMAB before, there's been mixed reporting about whether that has influenced their responses later on to other types of CAR T, for example, CAR T or bispecifics. I think we still don't know for sure whether there's an absolute time period that if you've had a drug antibody conjugate like BALANTIMAB that you shouldn't then go ahead and get a bispecific or you shouldn't get a CAR T. On personal experience, we have certainly done that and found, I think, mixed things, that sometimes a person who has had a CAR T transplant who then gets a bispecific doesn't respond at all, but we've also seen the exact opposite, that a person who had a CAR T transplant didn't respond, does beautifully with a bispecific. So I think it's still a lot that we don't understand about, certainly about sequencing. And the other big issue out there is when people fail T-cell directing therapy, why do they fail it? And there's theories. One theory in CAR T, at least, is that the CAR T cells, because they have been altered, don't survive, that they are recognized in some capacity by the immune system as being foreign or different, so they are not allowed to continue to grow. And certainly in some studies, you can show that T-cell persistence, CAR T cell persistence is a very important entity. So that's one issue. One of the others that comes up is, are those T-cells not very functional? And let's talk about exhausted T-cells. And there have been some studies looking at that perhaps the T-cells just aren't as fit or maybe not as, like, younger T-cells that just haven't been exposed to lots and lots of drugs. There has been some interest in whether the myeloma cells lose the target of interest. So in other words, they lose B-cell maturation antigen, the most common one that's targeted. There's a few case reports of that happening, but that is probably not the dominant mechanism. A very interesting study that was presented at ASH was looking at people failing BALANTIMAB, and this was a study run by the company. And what they were expecting to see was the amount of soluble BCMA, that's what BCMA, the protein on the cells, that gets cut off. They assumed that they would see this big increase in the level as people stopped responding to BALANTIMAB, and they actually really didn't see that, which was sort of different than they thought. And so I think that just tells you that this is a complex issue that we still need to have some understanding about.