An Update on the Use of Bispecific Antibodies in Myeloma | Mohamad Mohty, MD | IMS 2024

I'm Mohammed Mouti from the Sorbonne University and Saint-Odoine Hospital in Paris in France. And we are here in this beautiful city of Rio de Janeiro at the 20th annual Congress of the International Maloma Society. And it has been a fantastic meeting with a lot of new data, bringing a lot of hope to all patients and families struggling with multiple maloma. I can spend hours actually speaking about all the novel, exciting things that were presented, but I would rather focus on something I had the privilege to moderate and discuss in an earlier session about the use of bispecific antibodies. As you probably know, these bispecific antibodies represent a breakthrough in terms of immunotherapy of multiple maloma. The mechanism of action is quite fascinating because this is like a sort of an immune therapy in vivo. On one hand, the antibody will link to a tumor antigen. This is what is expressed on the malignant plasma cell. This is a target. But on the other hand, the antibody will link into CD3, which is actually the marker of the lymphocyte. And these are the soldiers of the immune system. And by linking into the CD3 to the lymphocyte, it brings the soldier in close contact with the malignant plasma cell. And obviously this contact, this is what we call the immunological synapse, will lead to the creation of a sort of a cytotoxic activity, a cytotoxic reaction. And at the end of the day, the lymphocyte will end up killing the plasma cell. And this is exactly how it works in multiple maloma. And today we're very fortunate that there are several bispecific antibodies which are approved or under development, several targets. For instance, we have BCMA, the B-cell maturation antigen, and two bispecifics are approved, the teclistomab, rhenetomab. Another two are under development, but rather very advanced development, limvosetalomab and ABBV383, something like this. We have also talcetomab, which targets GPRC5D. And last but not least, we have, for instance, sevostomab targeting FCRH5. And it's very important to have different targets because obviously at some point if you would like to eliminate, radically kill the maloma cell, you would rather have different port of entries to attack the maloma cell. And this is why having these different options is crucial because then we are able to sequence but even also in clinical trials they are being combined and this is even more powerful. Obviously the efficacy is there, including in patients with very advanced disease, heavily pre-treated, almost like in palliative care. So really incredible hope for these patients. Obviously there's no free lunch. There are side effects. The side effects are about the so-called CRS, cytokine release syndrome, usually very mild, not a big matter of concern because the physician know how to use it and they usually use up a sort of a step-up dosing. So you just go mild dose and you increase the dose and then you increase it and then with this the patient will not encounter this sort of cytokine storm. So it's sort of an inflammatory phenomenon. But the other phenomenon is the risk of infectious complications. And why is this? Because you know the immune system is crucial to defend our body against the bugs, especially the viruses, the bacteria, the fungus. So by using, mobilizing all the lymphocytes to fight against the tumor cells, actually you're exhausting these lymphocytes, these T cells. And obviously they will become a little bit more lazy when it comes to fighting against the viruses, against the microorganism in general. And this is why the rate of infectious complications was relatively high in the registration trial. But now it is very good news to know that these infections have significantly decreased and they are less severe. And why? Because we know how to use them. We know how to do prophylaxis prevention. And most importantly, we supplement the patient. We do give immunoglobulins. And immunoglobulins, these are antibodies that allow the body to fight against the bacteria, the viruses, and other nasty microorganisms, I would say. Of course, you need to give it on a regular basis in general every month, every few weeks. But this is crucial and it is allowing to decrease the rate of infections. So you can see the future looks really bright. The by-specific antibodies being used as single agents are highly effective. The next step is about combinations, of course. And my feeling is that the combinations are going to be even more effective. We'll have to figure out the security, the safety profile, but this is work in progress. And last but not least, the next step is going to be, okay, if the by-specific are extremely effective in late stage of the disease, why don't I bring them earlier into the course of the disease? And this would be probably a huge step forward. And at the end of the day, it's about extending the survival of the patient. And in my opinion, it's about living long and well. And I think we are already going in the right direction.