VIDEO: Positioning different targeted therapies for patients with multiple myeloma

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Think about picking one target over another. We have to think about the general principles, I would say would be efficacy, safety, convenience, and cost. I'll leave cost aside, I don't think there's a big difference and I'll leave convenience aside because, for the most part, these are subcutaneous products that are approved for targeting with bispecifics anyway. Teclistamab, elranatamab targeting BCMA and talquetamab targeting GPRC. The Sub-Q administration is quite convenient for all of them, so I think the main question is, is there a difference in efficacy and safety?

So when we look at efficacy, I would say generally we're looking at response rate of around 60 to 70% across the various drugs. I always caution from cross study comparisons because these were all single arm studies that led to accelerated approval, and so when you have single arm studies you really can't isolate out patient versus disease versus treatment, and that's what you need to randomize phase three. So until then we can only make some kind of broad strokes, and so I would say the response rates are probably 60 to 70%.

The progression through survivals range from one to one and a half years, and I think some of that difference may be, again, patient selection. Some of the newer antibodies have the benefit of knowing how to deal with infections and dose reductions and hold, something that the initial antibodies didn't have, right? Like, back when these studies started in I wanna say 2016, '17, we were very reluctant to hold a drug because these patients were heavily treated and were looking at hospice. So we didn't wanna hold the drug, and now that we know the responses are quite durable we can do that more, so that's why I would say efficacy I'm not sure there's a huge difference in terms of response in PFS.

One thing where I see a little bit of a difference is high risk disease, talquetamab's PFS in high risk and standard risk is nearly overlapping, which is unique, 'cause what we know about high risk myeloma is people respond but they don't tend to be as durable. And so often, even though high risk patients will have a response, their PFS is gonna be much shorter than the standard risk, and with talquetamab they're sitting on top of each other. Again, small single arm studies, but small numbers with high risk but looks very encouraging. So I would say that's unique, we're not seeing that same profile with BCMA. And then lastly is the side effect profile, and that's really what the targets really differ. I think with the BCMA bispecifics, very well tolerated but the main things are infections and including deaths.

And I really wanna spend a minute on deaths because what's the worst AE of all? It's death, right, and there's no coming back from death. And when we look at the BCMA bispecific studies, almost all of them have a non-zero rate of deaths not due to myeloma progression. And what that means is, of course, if you're treating with relapsed refractory myeloma, five lines of therapy, multi-drug refractory, unfortunately we will lose patients because they're heavily treated and they've had a incurable cancer for the most part at this stage. However, if myeloma is controlled and they're dying, that is a different safety signal that we need to pay attention to. And there's three examples of this in myeloma where Venetoclax, IMiDs plus checkpoint and melflufen all had encouraging response rate, all had encouraging PFS, but the overall survival was adversely affected by these products, and we have no approval for these agents.

So I just would caution people that we have BCMA bispecifics approved under accelerated strategy and we don't get have phase three studies, so we need to be really paying attention to those hypo gamma, giving the IVIG, preventing infections, PJP prophylaxis; those are modifiable but we need larger prospective data sets to confirm that we can reduce that.

With talquetamab or GPRC5D, we've not seen the same non progression deaths, in fact, very few deaths due to non-progression on talquetamab, maybe at most zero to two on the MonumenTAL-1 study. We're not seeing a market increase in infections so, for example, the rate of grade three infections is probably only 20% compared to 55% for the BCMA bispecific that has the most follow up, so much less infections but what you do see are kind of on target, off tumor side effects which include, I would say, oral, gastrointestinal, which is loss of taste, dry mouth, difficulty swallowing, weight loss. So that's kind of like that oral GI category. Next would be skin, so rashes or peeling of the hands and feet, and the third is the nails.

So I would say of these three the hardest to probably manage is the taste and weight loss, because you need to understand the mechanism, but... So what do I tell patients when I'm talking about these things? I said, "Well, first of all, the presence of these AEs actually correlates with the response." So that's unique in myeloma, we're having palmar-plantar peeling, having high grade rashes, having dysgeusia actually means there's a 20% higher likelihood of response in the first few months. Keep in mind though, that the response is already 70% so it's not like this is 100%, you can not have these AEs and still respond 'cause 70% of patients do respond, but having these AEs may actually mean that you're exquisitely sensitive to this treatment approach.

So good news is it can correlate with response, second good is the response are rapid, 70% response rate, median time to response is one month, median time to best response is three months. Why is that important? Because the third point is these AEs are dose related. So when I was doing the phase one study, the first few patients had none of these side effects. And in fact, when we graded them we said, "Oh, this isn't related, this isn't related," 'cause we'd already treated 40 patients who had none of these side effects. But it turned out when you get to these higher doses, that's when you start to see the side effect.

So when you put all of that together, if you have these AEs it probably means you're responding and it probably means that once you get your maximal response, you can back off on the dosing. And we showed that at ASH that when you decrease the dose intensity, either the dose or the schedule, you can decrease the onset of new side effects, all of those improve with the exception of weight loss, which may take longer to improve, but you don't compromise the efficacy. So that's really exciting because, again, if you die from a serious life-threatening infection there's no coming back. If you lose your taste and weight, your myeloma's responding, we can back off and you'll regain those things. So if that's why I think it's important that people know about these subtleties of the target differences.

And so lastly, I would say, when you put all that together, how do I pick between the two approaches? I would say if I have somebody with recurrent infections, COPD or a lung history, I might pick talquetamab because I'm worried about these patients getting respiratory infections. If, however, I have a very thin, cachectic patient who's already not very robust in terms of weight, I might pick the BCMA therapy. But eventually everybody gets everything, right, so until we are curing myeloma you get everything, it's just which do start with? And I use those kind of touchstones as an initial starting point.