Why are myeloma patients prone to infection?

Why are myeloma patients prone to infections?

So myeloma is a disorder that inherently affects a group of B cells called plasma cells that are responsible for the manufacture of antibodies. And these are the protein bullets that get developed as we grow from infancy all the way through adulthood and help us fight infections. And we know that there is, in many patients at the time of diagnosis, impairment of this system; they may not be making normal levels of antibodies and the system may be overwhelmed by the production of these abnormal antibodies.

So that's one factor at the very beginning. And we know from some epidemiological studies that at diagnosis before any treatment, people with myeloma are about seven times more likely to have bacterial infections and about 11 times more likely to have viral infections. So really a pretty striking risk. But then on top of that, we put some of our therapies that make this worse.

And so those include things like steroids, which lower the production of normal antibodies, and certainly some of the more, if you will, targeted therapies that we have now, like anti-CD38 antibodies, and anti-BCMA drugs tend to reduce not just myeloma cells, but also normal cells that are making antibodies. And there was, again, very interesting data presented at this meeting this morning by Dr. Van de Donk talking about how anti-CD38 therapy seems to be lowering the healthy myeloma cells even more because they have a higher concentration of CD38 on the surface, that means they're more affected by those drugs.

There are many reasons why patients with multiple myeloma are at risk for infections. Multiple myeloma is a cancer of the immune system. And when multiple myeloma cells expand, they prevent other normal immune system cells from functioning. So the immune system is suppressed due to the disease. The way it's suppressed is that antibodies, which are proteins that help our bodies fight infection, are not made at normal quantities and in as diverse a repertoire to fight an array of infections. 

Furthermore, the therapies that we use to treat multiple myeloma are designed to target plasma cells. They do mostly good for us because they target myeloma cells, but also they have off-target effects on the similar normal plasma cells. So therapy itself also promotes increased risk of infectious disease. And then sometimes there are other effects that therapy has on different cells in the immune system, neutrophils, macrophages, that further impair our ability to fight infection.

Do some anti-myeloma therapies damage the immune system more than others? It's definitely the case that there are more therapies that are damaging to the immune system than other therapies. We learn the most about this actually from recent studies of the effect of anti-myeloma therapies on COVID vaccination response. Therapies that target the B-cell maturation antigen, which include both of the FDA-approved CAR-T products, ABECMA and CARVYKTI, belantamab mafodotin, and then teclistamab, which is a bispecific antibody that will likely be FDA approved by the end of the year. Those therapies have been shown to most significantly reduce the antibody response to vaccination and stand to reason put us at particularly high risk of infection.

Anti-CD38 monoclonal antibodies also have been shown to impair response to vaccination and have been shown in trials to correlate with increased risk of infection, although translation to increased risk of infection is relatively modest for those drugs. Autologous stem cell transplant, which works to deplete the immune system for a period of at least 3 to 4 weeks in terms of the myeloid lineage, and then longer for the plasma cells, has further effects that suppress the immune system and put us at risk for infection.

What are the most common types of infections?

We've known for a long time that one of the big ones is pneumococcal pneumonia, which is a pretty common infection. It's been around for centuries. This is not a new one. And in particular, that is an infection, to guard against it, you need to have some antibodies around. And that is one infection in particular that we've known, again, regardless of treatment, that people with myeloma are more likely to get. 

We are seeing that, for example, myeloma patients might have lower responses to vaccines. So we've seen some data a few years ago that what we would call a double dose flu vaccine would be helpful because myeloma patients look like they're more likely to have influenza. Now, I think we all know that the mask-wearing that we've had with COVID has actually changed this quite a bit, that we haven't seen as much of viral issues in influenza, for example. 

Certainly, COVID is a big concern that we believe that myeloma patients, unfortunately, have been more susceptible to COVID. Some of that depends on what patients are receiving for treatment in terms of that susceptibility. But, you know, we really think that it's very important for people to be vaccinated with- certainly with COVID for all four recommended doses at this point, as well as other vaccines such as pneumococcal that I mentioned, and certainly still influenza.

So the most common infections that are seen in patients with multiple myeloma are respiratory viral infections, which are the most common infections that people without multiple myeloma will get. The disease itself, because of the suppression of the antibody-producing cells in the immune system, does increase the relative risk of those infections. In this day and age, the most common infection just about everybody is getting is COVID. And that's true for patients with multiple myeloma. Fortunately, the outcomes of patients with multiple myeloma who have COVID are getting better, primarily due to high rates of vaccination uptake and improved ability to treat COVID. The next most common types of infections are sinopulmonary infections, so pneumonia, bacterial sinus infection, things of that nature. And then beyond that, really, the list gets pretty long and the individual infections get pretty uncommon. But respiratory viruses, bacterial, sinopulmonary infections are the most common.