What is IVIG or intravenous immune globulin? Intravenous immune globulin, IVIG, is a product made up of antibodies that can be given intravenously through a vein. Antibodies are proteins that your body makes to help you fight infections. Intravenous globulin is part of your blood's plasma. It has antibodies in it to fight germs or disease. When people donate blood, this part can be separated out. Then it can be given to you through a vein in your arm, or IV. IVIG is prepared from the plasma collected from a large number of individuals with a normal immune system, usually between 10,000 to 50,000. If you get IVIG, it can help strengthen your immune system so you can fight infections and stay healthy. Who can be an IVIG donor? Most people, healthy individuals, can be donors. Usually these donors are individuals who are paid to donate plasma and immune globulins from their blood. Because we need thousands of people donating, it is just the general population. There may be some exclusions around, like, prior medical conditions. One product can go to anybody. You don't need to be matched for IVIG. When is IVIG used? IVIG is used actually in multiple different conditions. It is used in primary immune deficiency syndromes, secondary immune deficiencies like multiple myeloma, autoimmune diseases, and sometimes even neurologic conditions like neuropathies. So there are many, many uses of IVIG, and the dosing schedule is a little different for each of them. One myeloma patient's doctor suggests using IVIG. Usually in myeloma, the main reason we usually suggest it is increased risk of sinopulmonary, I mean sinus and pulmonary infections, and a low IgG level, so immunoglobulin G in the blood if it is less than 400. And if they have recurrent infections, then that is a good indication for why to consider IVIG. How are levels of normal IgG antibodies determined? That's such an important question. So when we talk about immunoglobulin, we're talking about the normal immunoglobulin component. So if somebody has myeloma, part of it is myeloma immunoglobulin and part of it is the normal. So the way we calculate that is if you actually take the M-spike level and subtract the M-spike from the total IgG. This is only if a person is an IgG type myeloma. So if it's an IgA myeloma, this doesn't apply because the elevation would only be in the IgA protein from the myeloma and not the IgG. But if they are an IgG myeloma and their IgG, for instance, is 3000 and we are wondering at a normal low so that we can consider IVIG, we would have to subtract what the M-spike is. So the M-spike is 2.6. That is 2600. So 3000 minus 2600 would be 400. So they could meet the criteria for needing IVIG because their normal immunoglobulin G is less than 400. How does IVIG work? IVIG has multiple different methods in which it works. But one of the easiest ways to think about it is IVIG is proteins from other donors who have immunity to certain infections. So when we get the protein molecules from their plasma, we're basically getting their immunity with those proteins. These proteins are then able to go on to neutralize infections that are present in our bloodstream or otherwise. Other ways that IVIG also seems to work is maybe it has some anti-inflammatory properties affecting the complement system, T cells, cytokines and other things. But in myeloma, we are mainly using it for the neutralizing property to infections. How often will a myeloma patient need to get IVIG infusions? In general, for myeloma patients, we often do it every three to four weeks. And the dose is about 0.4 grams per kilo. And this dose is given IV once every four weeks. This is just a standardized, but there is a range in terms of how long the immune globulins last in different people. And so another way to do it is to look at the steady state levels of the immunoglobulin in the blood and see where they end up and decide the dosing intervals based on that. But in general, most doctors will just dose it every three to four weeks. How is IVIG administered? IVIG is usually, as the name suggests, it's intravenous immunoglobulin. So it is IV, but there are subcutaneous immunoglobulin and intramuscular preparations too. The subcutaneous can be easier to give and some patients take them at home as well. But in the myeloma setting, most patients end up getting IVIG and not the subcutaneous version. The subcutaneous I have seen more in people who have primary immune deficiencies or other reasons for it. So the idea of it may just be that it's harder to get those approvals for the subcutaneous and reimbursement maybe. It is a few hours. The infusion rate can vary for different patients and it's usually started very slow and then it's increased if a patient's tolerating it. And part of the reason is to prevent side effects such as infusion reactions, anaphylactic shock, or other side effects that can develop with faster infusion time. Are any pre-medications given before the IVIG infusion? Yes, some patients do need it. So a good way is to pre-medicate with Benadryl and Tylenol. And also it depends on the product. So if it's from a different company, then it may be different because sometimes it can be the solvent or some of the processing steps. They are not truly allergic to the proteins, but to something in the processing of it that they're allergic to and lead to these infusion reactions. So if you have a particular company or brand that works, it may be easier to just stick with that. Although I know that some hospitals or things we don't have the option of both choices, so you may have to switch. Also sometimes it could be a batch effect where a particular batch has certain proteins that lead to a reaction for patients. And as you get more, sometimes it could be over time people develop these reactions. What are some potential side effects of IVIG? So the most common one would be, I say, infusion reactions such as chills or fevers or shortness of breath or things that develop around the time of getting it or during the infusion. And that usually what is done is like you stop the treatment till the reaction gets over and then it could be possibly started back again at a much slower rate. Other things to do is hydrate really well before or give some high pre-hydration before getting it. Another common side effect is headaches. So some people tend to have headaches the day after or two days after. Again, that's something that would just be managed with Tylenol or things and see if that could be resolved. The next kind of side effect when I talk about anaphylactic shocks, that is when the whole body kind of shuts down because of such a bad immune reaction to it. That is extremely, extremely rare with IVIG. So I don't think that's something we routinely see, but mostly the first doses should be given in a medical center so that if any reaction happens, somebody is there to take care of it. Other side effects are renal failure can develop, hemolytic anemia, so where the red cells break up because of these other proteins that could be antibodies to the red cells. Other things is because IVIG comes with fluid and also sodium content. Some patients do not tolerate the volume if they have some heart failure or other symptoms like that. And then the last thing I'd say is thromboembolic events, like there's increased risk of clots post IVIG, and that's a warning many of them give. So another way to prevent it is to stay active and not be prolonged immobilization periods post IVIG and also keep your IVIG infusions, hydrate well before it. And if you need to slow the infusion time so that the body is able to adjust to it better. Would taking aspirin help manage the risk of developing blood clots? I don't think there is data for specifically just IVIG, but I know that most of our myeloma patients are on aspirin, especially when they are on imids like Revlimid or pomalidomide. So they are on blood thinners if it's a combination based on their risk of clotting. So I think that if they're already on something like that, the risk probably is lower, but I'm not aware of study looking at that. Can IVIG be given on the same day as other myeloma treatments? You can very much get it on the same day, other than if you have like significant heart failure issues or things and you're already getting an IV drug like suppose carfilzomab or things. I would say that it might be too much volume on the same day and also just the time. But if you're open to staying that long and you're tolerating both well, then I think it could save a visit for most patients and do it all on the same day would be fine. Which myeloma therapies are most likely to potentially cause a need for IVIG? Some of these immune therapies like daratumumab, because it is so effective in targeting CD38 protein on the plasma cells, it does drop the production of these proteins which are made by plasma cells. So one of the ways which Darzalex increases risk for infection is through the reduction in immunoglobulin G levels. And so IVIG could help if the levels are below 400, but they don't drop for everybody below 400. So I wouldn't do IVIG for everybody on Darzalex, but only if their IgG levels are below 400 and they've been having frequent infections. Because as I mentioned, there are side effects with IVIG too and it requires you coming in every month for a few hours. So teclistumab is another drug where it looks like there is a signal with like, you know, in CAR T cell the same thing, they're all BCMA targeting drugs. So when targeting BCMA seems to drop IgG levels as well quite a bit. And so patients post CAR T cell, post teclistumab, these drugs are probably going to need IVIG as well to prevent infection. Another way to do it is because sinopulmonary infections are more in the winter where, you know, the flu season and all of that. Sometimes it can be that IVIG is just given around the winter time and stopped during the summer. When is IVIG treatment stopped or is it ongoing? Technically, we should stop. When you're giving IVIG, the levels will go up because the IVIG increases the IgG levels in the blood if you test it. So it will look like it's higher. So periodically what you can do is pause on the IVIG and see what the IgG levels are doing. If they're staying above 400 now, then maybe you don't need the IVIG anymore. Does IVIG treatment interfere with vaccinations? So IVIG because it is proteins from other donors and it can neutralize immune responses. It is theoretically possible that the immune response to a vaccine could be dimmed by the IVIG. However, this has not been shown or suggested with like the COVID vaccine. With the COVID vaccine, it's OK to give both at the same time if necessary. With the live vaccines, I think this is more of an issue like the vaccines like polio or measles, which are live attenuated vaccines. So I would say that for the most part, it would be if it's convenient to do it on different days, then that's probably better. But if you have to do it on the same day, I don't think it's that big an issue. Does IVIG have COVID antibodies in its formulation? Can it provide protection against COVID? So IVIG in the beginning when the COVID pandemic hit, since IVIG is basically a pooled proteins from donors, it's what the immunity in the herd immunity of the population around. So at that time, nobody had immunity to COVID. So doing IVIG didn't mean that you would have antibodies to fight COVID. Now, as people have gotten vaccines and been exposed to COVID, I think that it's possible that IVIG may have some protection over time to COVID. Other things to think about is like with IVIG is just general from healthy donors. There's something called hyperimmune globulin, which is very similar to IVIG, except it is usually to treat a particular or directed against a particular infection. So hyperimmune globulin against COVID would be taking donors who recently had COVID and taking proteins from their blood and pooling them together and giving this. And this would be hyperimmune globulin to COVID or other similar infections like that. The other thing would be convalescent plasma. So that's like fresh frozen plasma. So this is not the protein part, but the plasma from a donor who just had COVID. And that can be also given to get some of the antibodies which are in the plasma.