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ASH 2022 | Developments in the use of bispecific antibodies in myeloma and challenges in this space

Mohamad Mohty, MD, PhD, Saint-Antoine Hospital, Paris, France, shares some insights into the use of bispecific antibodies (BsAbs) for treating multiple myeloma (MM). All currently tested BsAbs, such as teclistamab, elranatamab, and alnuctamab, are highly effective at treating very advanced patients with relapsed/refractory (R/R) disease. Moreover, Prof. Mohty explains that BsAbs are being developed against various targets – including BCMA, GPRC5D and FcRH5 – with studies indicating that these novel BsAbs induce high response rates even in patients that have already received T-cell directed therapy. However, Prof. Mohty acknowledges that there are limitations associated with the use of these agents, such as T-cell exhaustion and increased rates of opportunistic infections, and highlights that further research is needed to overcome these challenges. This interview took place at the 64th ASH Annual Meeting and Exposition congress in New Orleans, LA.

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Transcript (edited for clarity)

I think this ASH 2022 in New Orleans is another great ASH, great here for multiple myeloma. To make a long story short, the keyword, and the only keyword, is about the bispecific antibodies. And it is quite amazing to see the speed of development, but also the increasing evidence about the efficacy of these novel agents, which are really a breakthrough, in my opinion, in the immune therapy of multiple myeloma...

I think this ASH 2022 in New Orleans is another great ASH, great here for multiple myeloma. To make a long story short, the keyword, and the only keyword, is about the bispecific antibodies. And it is quite amazing to see the speed of development, but also the increasing evidence about the efficacy of these novel agents, which are really a breakthrough, in my opinion, in the immune therapy of multiple myeloma.

It can take me hours to go through all the presentations and posters that tackled the use of bispecific antibodies in multiple myeloma. However, I would say the take-home message is that all of the currently tested bispecific antibodies, including the approved one teclistamab of course, but elranatamab, the alnuctamab, and many other ones, the Regeneron one, the AbbVie one, et cetera, are highly effective in the relapsed/refractory setting in very advanced patients.

The other piece of information we have is about the efficacy of these bispecific antibodies, including in patients, for instance, who have already received CAR T-cells and relapsed after CAR T-cells.

And another important piece of information is about the development of bispecific antibodies against different targets. So, for instance, we have a big bunch of drugs against BCMA, the B-cell maturation antigen. But now we have quite amazing results against two other targets, namely GPRC5D and FcRH5. And this is about cevostamab but also talquetamab.

And interestingly, simultaneously to the presentation of the results of talquetamab today by Dr Ajai Chari, we have the publication in the New England Journal of Medicine about the activity of this agent, which is giving a very high rate of response rate. But what is really striking in the study is the level of response in those patients who have already received T-cell directed therapy. So this is absolutely great news.

However, we need to be aware of some, I would say, issues, problems and questions we need to solve. This is about T-cell exhaustion. So for the time being, there is no consensus on how to overcome this problem. One pathway which is being explored with cevostamab, for instance, is about the fixed-duration treatment. Which is very attractive and would probably maybe allow to diminish or to decrease this story of T-cell exhaustion. There are other venues to explore, like maybe having a treatment-free interval and so on. And why is this important? Because this is likely contributing to the higher risk of opportunistic infections in these patients. And this is something we need to be aware of. Because on one hand you have the efficacy and this is great, but on the other hand you need to manipulate these agents to use them cautiously. And this is about a learning curve, in my opinion, but also this is about developing some recommendations and guidelines on how to prevent, how to do the right prophylaxis, and how to identify, how to monitor these patients, and how to identify quickly the emergence of these side effects.

Last but not least, what we have seen here are also new data about the combinations of these agents with other monoclonal antibodies, but also bringing them into the frontline setting. And this is about the IFM trial, for instance, in the elderly population exploring daratumumab and teclistamab in the first-line setting, while trying to maybe avoid the side effects of dexamethasone.

But, to be be fair, I mentioned the bispecific against BCMA, against GPRC5D, FcRH5, but we have also bispecific against CD38. So this is a little bit tricky, because obviously patients are receiving anti-CD38 monoclonal antibodies. And one may wonder whether with bispecific antibodies directed against CD38, you may be able to overcome the resistance to anti-CD38.

So overall, I think this story of bispecific antibodies in multiple myeloma is really fascinating. And actually they do represent now, I think, a true pillar of the new regimens that are going to be investigated in the field of multiple myeloma, not only in advanced stages, but also in early stages.

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