IMS 2025 | IVIG prophylaxis should be given for patients with myeloma on bispecifics, regardless of IgG levels

This is a paper that I published earlier this year, Dr Noopur Raje from MGH, was a senior author on it. It’s one of my proudest papers this year where we really took a stand, the principal stand, and rolled with it. And our principal stand is that Ig replacement therapy, so IV Ig or sub-Q Ig, if available, should be given routinely followed by bispecific antibodies regardless of IgG levels. To put this in context, IgG replacement has had a long history in myeloma, right? There was a time most patients with myeloma, particularly receiving CAR-T and bispecific often developed hypogammaglobulinemia, which is where their antibody levels fall because normal plasma cells are also being depleted by the therapies. There was a time many years ago where actually hypogammaglobulinemia and immunoparesis was actually myeloma defining actually, where if you saw that the myeloma cells were preventing the body from making normal antibodies and people were getting infections, that was called myeloma, just as an example. So it’s always been very closely intertwined, hypogammaglobulinemia and myeloma. Many studies have looked at whether IgG replacement with intravenous immunoglobulin, IVIG, or subcutaneous immunoglobulin, sub-QIG improves outcomes. As early as 1950, there was a study of intramuscular immunoglobulin, seeing if it worked, et cetera. Long-construed myeloma, most trials have been negative. Most countries, IVIG is very expensive. And so the consensus has generally been not to give IVIG routinely to patients with myeloma unless they’re having frequent infections. Bispecific antibody recipients are at uniquely high risk of infections, particularly BCMA-targeted bispecific antibody recipients. So, you know, teclistamab, elranatamab, linvoseltamab, etc. But all bispecifics have this issue because the moment you start knocking at normal plasma cells, you’re starting to have people at risk of infections. And unlike with CAR-T, with the bispecific, you’re giving treatment again and again and again. You’re depleting all their plasma cells. And actually, really a nice analysis from the Memorial Sloan Kettering Group showed that pound for pound, the risk of infections is actually higher with bispecifics than with CAR-T therapy. Most of us assume that bispecifics are safer than CAR-T, and in many ways they are. But when it comes to infections, bispecifics are far riskier than CAR-T therapy or than anything else in a myeloma arsenal. How do we fix it? Most guidelines, including IMWG guidelines published two years ago, say that, well, when the IgG level falls below 400 grams per deciliter or four grams per liter, for the unit conversion, when it falls below that threshold, to start IVIG supplementation at that point in time. In our paper, we make a very principled stand that we should not wait for then. Three factors that we think about here. One, again, I understand the history of IVIG and myeloma is long sorted goes back well before I was born, but bispecifics are different. The risk of infections is very, very high, and honestly, infections are the highest cause of non-relapse mortality with bispecific antibodies in multiple myeloma, so it is a very big deal. That’s issue number one. Issue number two, you know, IVIG is pretty safe. If IVIG was a very risky, you know, lots of side effects for it, I would say or maybe the benefit-risk ratio needs to be calibrated here. But I think here, IVIG is very well tolerated for our patients. They’re coming in anyways every one to two weeks for treatment. Once a month, IVIG is very easy to do. Subcutaneous immunoglobulin is actually even easier to do. And point three, the biggest part of our argument is that, again, papers often talk about waiting for the IgG level to fall below a given threshold to start IVIG. Then that’s not scientifically based on anything. 400 in real life, the risk of infections is a binary risk. 400 is kind of an arbitrary number. More importantly, for patients with IgG paraproteins, which is probably about a third to a half of patients with relapsed myeloma, for those patients, they actually, you know, the IgG level may be falsely normal. They may still have a normal IgG level for months after bispecific antibody initiation but be at a profound risk of infection. And at the end of the day, it’s actually simpler to say, look, don’t wait for the level, because if you have to wait for a level, how often do you check for the level? You know, how do you correct for the IgG paraprotein, et cetera? So many issues with it. Instead of preemptively waiting for IgG level and then starting IVIG, just starting it during cycle one makes a far simpler approach. And again, because the IgG level can be faulty elevated, because the patient’s at risk of infections very rapidly, primary prophylaxis is the way to go. One critique that we’ve gotten that will be published shortly is that, you know, the question is, well, if you give everybody IVIG from the very beginning of the bispecific antibody therapy, some of them may not be eligible for vaccines. We typically recommend not giving vaccines to someone who is active on IVIG therapy. I think both are important. And I do recommend to my patients that consider vaccinations against things like COVID and influenza, et cetera. But especially for bispecific antibody recipients, their immunoparesis, their hypogammaglobulinemia is so profound that honestly, every study that’s looked at this show the vaccines don’t really work for them. IVIG often contains donor antibodies against things that are circulating in the ecosystem, including influenza, COVID, et cetera. So I would say in terms of preventing infections, IVIG probably is the way to go. And the last thing I’ll say about this is that, at this meeting, well, two things. One, Dr Meera Mohan presented data showing that even after stopping a bispecific antibody, you still need to continue IVIG for months afterwards because the risk of infections persist, kind of supports the point that we’re making. And two, Dr Marc Raab presented data from the Majestic 5 study looking at TEC-DARA-VR, TEC-DARA-R, different combinations of teclistimab, a BCMA bispecific, in frontline induction for transplant eligible patients. I won’t talk about the efficacy beyond a sentence. Basically, it worked amazing. 100% of patients achieved MRD negativity, 100% response rate. In the future, maybe those patients won’t even need transplant. We’ll see. We don’t know that yet. But what I think was also interesting is many of us are nervous about bispecific antibodies in the frontline setting, again, because of this infection risk. In that study, almost everybody got IVIG, and there honestly were not that many high-grade infections at all compared to what we’ve seen before. So it’s a good example here that in the same way that with high-dose melphalan, it would be absurd to give someone high-dose melphalan and not give them appropriate nausea prophylaxis to prevent nausea from chemotherapy, I would say that in the future it will be seemingly absurd to give someone a bispecific antibody and not give them IVG prophylaxis as an important tool of supportive care.

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