What is Immunoparesis? Why does it occur? How is it managed?

What is immunoparesis?

Immunoparesis is something that happens in patients and can even start in MGUS already where we see that if a patient, for example, has an IgG myeloma or MGUS when the other immunoglobulins are reduced, we know that the plasma cells in the bone marrow take up some space. But there seem to be even other effects of the myeloma or the MGUS cells on the rest of the bone marrow. And we see that the healthy plasma cells that are supposed to produce this other IgA, IgM, whatever is the healthy part, that they are reduced in their function. So if, for example, an IgG patient has a reduced IgA or IgM, that we call immunoparesis. The same as for an IgA patient who has reduced IgG or IgM. And same for IgM.

Why does immunoparesis occur?

Immuno is the immune system and paresis means weak. So the immune system is weak. So first, let's talk about why it happens. A couple of reasons. I think the biggest reason why immunoparesis can happen is that, you know, normally we have all sorts of functional plasma cells. Plasma cells are immune cells that make antibodies. Antibodies help protect us against infections. They mount our response to vaccines. Sometimes the antibodies also can omit autoimmune disorders; they're not always good, but typically they are helpful. In multiple myeloma, if so much of the nutrition in the bone marrow is going to work for dysfunctional or cancerous plasma cells, the normal plasma cells don't have enough nutrients to actually produce, but they are trying to produce. And so you might end up with low levels of functional antibodies. For most patients with myeloma, that antibody, the M spike, the M protein, the abnormal protein that we see in the SPEP, that is an antibody. But it's not actually binding to anything. It's not doing them any good. It's not actually helping protect them in any way or form. If anything, the sheer number of resources going towards those myeloma cells is preventing the normal immune cells from functioning. So some patients can have an immunoparesis diagnosis. And that can either be, as I alluded to, a blood finding just with the immunoglobulin G being low, or it can be that some patients are diagnosed in the setting of having frequent infections. Many, many years ago, actually, that was considered a myeloma defining event, just to have many infections. That is no longer considered to be myeloma defining by itself because many patients can have frequent infections for other reasons. But some people can have a diagnosis. Many of our treatments cause immunoparesis. So, you know, the nice thing about myeloma therapy is that for most patients diagnosed today, at least, the induction therapy is chemotherapy free. We're not giving true classical chemotherapy for the first 4 to 6 months of therapy. So those patients are not losing their hair. We're not trying to slam the bone marrow and kill everything that moves because we're using precision targeted therapies that only attack plasma cells. Unfortunately, again, as I alluded to, plasma cells can be both good and bad. The bad plasma cells are the cancer; I want them out. That's the myeloma. The good plasma cells that are making good antibodies to help fight infections and so forth are also getting knocked out by bortezomib, lenalidomide, Velcade, Revlimid, so forth. But daratumumab (Darzalex) can do it too. And so many patients become hypogammaglobulinemic. That's the other word for this. Or develop immunoparesis following therapy. CAR-T is another good example where CAR-T therapy very potently knocks out cells as well. Those patients may be at risk of infection.

How is immunoparesis managed?

What do I do about it in that case? Those are the patients where I may recommend, for example, more antimicrobials or more anti-infection medications. In some settings, if someone's having infections or their status post or they've gotten CAR-T, we actually may recommend giving them antibody transfusions. So antibodies from other patients in the area to help fight whatever is circulating. The medical word for that is IVIG (intravenous immunoglobulin), but it’s controversial. We actually are still figuring out how best to manage this because there are some risks with doing all these interventions. And some patients— I have plenty of patients who have immunoparesis or hypogammaglobulinemia in terms of blood work, but no infection whatsoever. So it's not that simple. And I think we're still trying to figure out how best to tailor our level of support for immunoparesis to what the patient actually has.