What should patients know about Bispecific antibody therapy and the risk for infection?

Well, I think that's an excellent question. What should patients know about bispecific antibodies and the risk of infection? So a bispecific antibody pulls together a tumor cell and an immune cell. And in the case of myeloma, the therapies that are being developed right now target B-cell maturation antigen. So that's on myeloma cells, but it's also on normal B cells that are making normal antibodies that you need to fight infection. So that's what happens is people are on bispecifics still have very low levels of normal antibodies. So you should be aware that that's a risk. Many people are offered intravenous gamma globulin as sort of a substitute, a fill in, if you will, of normal antibodies given monthly. But certainly there's some data out there that if you had, for example, a COVID infection and you're on treatment with, that really should take that quite seriously and seek out the appropriate treatment, whether it's the oral antiviral PAXLOVID or whether it's one of the antibody treatments. But there is a higher risk of infection and perhaps having a more serious infection.So that's a great question. So these bispecific antibodies, they target a receptor that's present on normal plasma cells and cancerous or malignant plasma cells.So that receptor is BCMA, and there are some other receptors as well. So BCMA, because it's present on normal plasma cells, and plasma cells are the cells that fight infection and they generate antibodies. These drugs, they're so effective at depleting normal plasma cells that there's a definitely an increased risk of infection. And this, you know, all of our drugs, one way or another, they deplete plasma cells.That's how, you know, myeloma treatment works, right? You kill those cancerous plasma cells. But Bispecific ability, particularly good at killing abnormal malignant plasma cells, as well as those normal plasma cells that that fight infection. So we definitely are seeing more infections than we otherwise see in in these patients. Now, a lot of these infections are, you know, viruses that, you know, upper respiratory infections, viruses that circulate in the community. But sometimes we see more rare forms of bacterial infections, fungal infections. There is a huge spectrum of infections that has been reported in in the clinical trials. So it's definitely something that we're all very concerned about, very vigilant about. And I think that appropriate antibiotic prophylaxis is something that we definitely should consider and that would include, you know, some an antiviral like acyclovir or valacyclovir that can decrease the likelihood of shingles that usually something people are on. But I think we also sort of need to be thinking outside the box, should we be covering for other more rare types of infections like there's like PJP pneumonia? Should should we also be giving like medications, like vaccine to try to prevent that? What about giving people IVIG? Right. Like bold antibodies from from donors that might have a role as well. So this is something that is an area of further investigation. And I think that as we use more and more by specifics and as we use these drugs earlier, we're going to learn more about the side effect profile and we're going to get better at managing it. But for today, it's very appropriate, very important to counsel our patients about these risks.

Should patients be up to date with their vaccines?

So I think that some protection is better than none. And we want to make sure that they're up to date on vaccines if it is at all possible. And it's probably better to start the vaccination before you start treatment. So that is something that we that holds true for, let's say, daratumumab, right? If you if you know somebody is about to start daratumumab next week or a few weeks later, you probably want to start the vaccine a little earlier before you put them on those treatment. But we often don't have that luxury, right? When people need treatment, they need to remain. You can delay it, but I would argue that you some protection is better than no protection. And generally speaking, if there's an important vaccine that they haven't gotten yet, and that includes COVID, that includes the flu vaccine leading to the the pneumonia vaccines, if they haven't gotten it yet, then you we probably should, even though we know that they're probably not going to mount the same response that they would have if they weren't on this treatment. 

What types of personal protection should individuals who are prescribed bispecific antibody therapy consider?

So we definitely have seen upper viral, upper respiratory infections in patients on bispecific therapies, and they had the potential to be more severe. Now, I think that everybody weighs the risks and benefits differently. So I have conversations with my patients. I do generally tell them that if they're going in, you know, crowded indoor areas, they probably ought to wear a high quality mask. And I would mean, you know, a good well-fitting N95 or a KN95. I you know, it's hard to know what the exact magnitude of protection that that's that's providing. But at least I believe that it is providing some protection and is I think it makes sense to do that for, you know, crowded indoor areas or flights, etc., especially if you are on bispecific therapies. I don't ask people to stop living their lives right. You know, people have been making these risk benefit decisions before COVID was a thing. There were other respiratory viruses. So everybody sort of views these risks and benefits differently. But I do think the use of masks, especially in high risk environments, makes sense for these people who are immunocompromised.

What should individuals know about eating out at a restaurant?

t's a very obviously a very controversial topic. And I think that, you know, everybody weighs these these risks differently. I've had these conversations with my patients. I was like, you know, even before COVID, like, you know, you would catch other respiratory infections when you would go to restaurants. And now while you can catch them and you can also catch COVID, but it's part of living a normal life, right? And I think that different people weigh those risks differently. And I also think that you can't think of a one size fits all approach for patients with myeloma, depending on where you're at in your treatment journey. The risk of COVID and the risk of immunosuppression and might be very different, right? but some discretion is probably a good thing. I probably would like them to avoid very crowded indoor public areas, especially if that counts are low when their on bispecifics

What testing is used to monitor a patient's increased risk for infection?

really what you look at is many of the people on bispecific treatments have very undetectable antibody levels. And so I think if it's certainly if a person knows that they have that situation, that would be a person that would be recommended for that intravenous gamma globulin, probably also prophylactic antibiotic sometimes are used. So, for example, a drug like sulfamethoxazole/Trimethoprim, like Bactrim, is sometimes given for prophylaxis or Levaquin something like that. I think you should be vaccinated for sure. Again, you may not have antibodies that we can detect, but vaccines are probably very useful. So again, if you're on a bispecific, I would make sure your vaccines are up to date So Bispecific are very, very effective against the myeloma cells, but because of this, they also wipe out the normal plasma cells which are responsible with the production of of antibodies. So patients get to a state of what we call hypogammaglobulinemia In theory, it means that their antibody levels are really very, very low. And this can certainly cause a vulnerability towards infections. And one way to overcome this is a treatment with I.V. Gamma globulins called IVIG, administered once a month. The’re usually intravenously, though there is now even a subcu formulations becoming available. And so this certainly can help with infections. Also where there is antiviral prophylaxis, that is giving be pjp prophylaxis. And all these these measures can certainly be be helpful. And of course if there is any sign of infection, it's wise to seek medical attention as soon as possible, knowing that the immune system is compromised. So a rapid intervention with antibiotics can be of of great importance.

Is treatment stopped if an individual develops an infection?

So the way we manage infections, usually we we a put the treatment on hold while the patient has an active infection. We treat the infection and usually we try and resume the treatment if it's possible to way apply measures like if preventive measures. And that's a good thing to do. What does the clinical trial data Tell us about infection rate. So bispecific antibody therapies are this new class of immune therapy that we have approved for patients with relapsed refractory myeloma. So this is approved for patients who've got four or more lines of therapy and we have currently an FDA approved product called teclistamab that is approved for patients with relapsed refractory myeloma. So the risk of infection, but BCMA targeting bispecific antibody has been observed across various phase one two studies and also from Real-World Data Set, and it's approaching in the 70 to 80% range and about 50% of these infections are what we call severe infection of grade three and higher infection. In addition, we also find that somewhere between 8% of patients had a grade five, meaning that infection leading to a death, which is very concerning for our patients, and it's at least in our in our dataset, we've we've noted that he patients who had an infection passed to be were mostly in remission and deep remissions where by there they had a mildly negative, complete response in the bone marrow. So this is obviously very concerning to us. So we as a myeloma community are working on optimizing infection monitoring and prophylactic strategies that can minimize the risk of infection and hopefully in the next 1 to 2 months, we will have, you know, publications coming out. We already had seen a publication from the European Myeloma Network, which kind of outlines the infection, preventative strategies that we could employ for patients who are getting bispecific as well as CAR-T therapy. And there are several ongoing studies that we've seen at the ASCO 2023 meeting investigating alternative treatment schedules whereby instead of going weekly, some of these agents are going to go to every two weekly, specifically teclistamab and we also have ongoing clinical trials that will investigate a fixed duration of teclistamab