IMS 2026 | APRIL depletion and loss of durable antibody-mediated immunity in multiple myeloma

So this is a very recent study that we concluded in the lab. And the main results really essentially show that patients with multiple myeloma and also myeloma precursor conditions progressively lose a lot of the immunity that they have acquired throughout their lives. And so we think we may have understood why. And to give context to those results, I think it’s important to really start by emphasizing that although multiple myeloma is a cancer of the bone marrow, with symptoms mostly localized to the bones themselves or to the kidneys, one of the main dangers for patients are still infections. We know that infections are responsible for about a third of deaths within three months of diagnosis. So obviously, a big importance to studying this phenomenon and understanding why the immune system of patients with multiple myeloma does not respond as well to encounter pathogens as the immune system of healthy individuals do. So in order to try to answer this question, what we did is that we followed a little over 700 patients between 2020 and 2022, which were the years during which the first rollouts of vaccination against COVID-19 were taking place. And we thought that it would be a great way to, in a very standardized way, probe the immune system of patients at different stages of progression to the disease and then with patients with overt symptomatic myeloma to see how patients at each stage are actually able to respond to the vaccine and build, in consequence, very long-lasting and effective immunity. And what we found is that although myeloma patients are initially able to build titer levels, which are the ones that we expect to see in healthy individuals, they seem to not be able to maintain them on the short term. And we see that those titers actually dwindle just four months after getting vaccinated, which is a very short time frame. And it’s obviously pretty concerning because it means that the vaccines are not as effective in patients with myeloma, but also with the asymptomatic precursor conditions. So our next step was then to investigate whether this phenomenon was specific to the COVID-19 vaccine or whether it was a symptom of a larger, more widespread issue. So, we then looked at the titer levels for measles, mumps, and rubella because most individuals get vaccinated against MMR early in their childhood. And we thought that if indeed we had some symptoms of a wide immune dysregulation, then we should see that while healthy individuals are able to retain good levels of titers against MMR decades after vaccination, it should maybe not be the case in patients with myeloma. And it is unfortunately exactly what we saw. We saw that the titers against all three pathogens were very low or even absent in patients with multiple myeloma. And just to be clear, it doesn’t mean that the vaccines did not initially do their jobs and did not protect these patients for decades. It just suggested that there was something linked to the growth of the tumor that was causing all titers to become very low or absent. And so the next logical step was then to try to understand what was the underlying cause to those defects. So we analyzed for months several molecules, several proteins that we thought could be related to this phenomenon. And we found that there is a specific protein, which is called APRIL, and which was found to decrease in levels as the tumor progressed. And what was very interesting about APRIL is that it is a protein which is known to be essential for the survival of the cells that actually produce the antibodies. So we then conducted an experiment to try to see whether there was a direct relationship between APRIL levels and the loss of immunity that we observed. And we did find a lot of evidence showing that tumor cells seem to be consuming the available APRIL proteins, leaving none or very little for the normal antibody-producing cells, which eventually become functionally impaired or die. And so with them is lost all the immunity that they carried, maybe two months, for example. So these are the main results of this study. There’s a lot of implications to those results. The main one, maybe the obvious one, is that we uncovered a specific protein and pathway that can then be leveraged to develop therapies to maybe cure myeloma, hopefully, but maybe in the shorter term to help patients to actually be able to respond to vaccination well and maybe mitigate those immune dysfunction issues that we observed. A big implication is one on the public health front because we know that about 5% of adults over 50 carry a myeloma precursor condition, but these are asymptomatic conditions. So many of them are undiagnosed and unaware of the consequences associated with these conditions. During this study, we found, we show that one of those consequences is the inability to respond well to vaccines. So these results are maybe pushing us to advocate for a different vaccination strategy for patients with myeloma precursor conditions, as well as maybe increased frequency of testing, of screening for the populations that are at risk of getting these precursor conditions. And I think that a last important implication is the one on current therapies on cancer vaccines, which are becoming important contenders as therapies for many different cancers. But in myeloma, we show that patients are not able to respond well, as well to vaccines as maybe patients suffering from other cancers. So this is maybe pushing us to rethink the way that cancer vaccines can actually be used to treat myeloma. I think our clinical implications would definitely involve a more frequent monitoring of those antibody titers because, again, most of the symptoms associated with myeloma can be pretty dire, but infections are also a major risk. And I think it would be important for physicians to be conscious of those immune dysregulation and maybe per patient basis know who will be able to actually build immunity and who has serious immune dysregulation, not allowing them to respond appropriately to vaccination, but also to the encounter of pathogens in the daily lives of the patients. And then, of course, clinical implications on what therapies may work on some patients and what patients may be eligible for.

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