IMW 2021 | The effects of Covid-19 on myeloma patients

I’m talking about new developments in COVID-19 disease and myeloma, monoclonal gammopathies. We are all aware that patients with monoclonal gammopathies, but more so, patients with full-blown myeloma, have an increased risk for infections, have an impaired immune system, which is mainly due to the immune-suppressive activity of the malignant clonal clones and may be even aggravated by therapy, by chemotherapy, and now more so by certain forms of immunotherapy.

So, this explains why, number one, myeloma patients have an increased risk for COVID infections. Secondly, they have an increased risk for more severe symptoms, and particularly for prolonged disease. And thirdly, they have an increased risk for mortality due to COVID. And when you analyze the data from different centers and countries, you find out that the mortality of hospitalized patients, patients hospitalized due to COVID, is around 35%. So, of course, we need to do our utmost to prevent the development of infections, and of course, all the clinical consequences.

Now we have, as you know, several vaccines. In the western countries, we have of course, RNA vaccines, but there are also DNA vaccines available, there are other vector vaccines available. And in other parts of the world, there are protein-based vaccines, or peptide-based vaccines available. And so, a whole range of vaccines, but the vaccines, which probably are used in the developed countries are those from Moderna, from BioNTech, from AstraZeneca, and from Janssen. But there are new providers coming like WHOOVAC, or Novavax, Inovio, and so on.

So, having said that, we know that vaccines are very active in myeloma, more active, but then for instance, influence of vaccines. But you have to vaccinate, with most vaccines, your patient at least twice. This is different for the Janssen vaccine, where you just need the one shot. But for AstraZeneca, Moderna and Pfizer, you need two shots.

The problem with this policy is that it works well for a significant proportion of our patients, and mainly in those patients with a very stable disease who are in remission. It works well in patients with MGUS. But the immune response is weakened already, weakened patients with smoldering myeloma, and maybe it’s really impaired in patients with multiple myeloma.

When we talk about immune response, we have to define what we are meaning. So, we are talking about humoral immune response, and that is usually measured by checking the IgG antibody levels against spike proteins, or IgM levels. But it’s probably more advanced to use what we say, neutralizing antibodies, because neutralizing antibody titers have been shown to correlate with protection in monkeys, in macaques. And there are some clinical data that neutralizing antibodies give you a clue about the protection of individual patients.

We should also consider that there is a cellular immune response. So, we should analyze this and explore this in greater detail. Cellular immune response seems to be very important, particularly for reinfections. And while we don’t measure in this point of time is the immune response in the mucosal tissue. So, the secretory IgA against COVID 19 trends is not measured at this point of time. So, of course, measuring antibody titers is something which is available, which can be seen widely used, but we need to consider that it has of course, certain limitations.

So, who is not responding, or who is likely not to show a very good response, antibody response, to COVID vaccines? These are first of all, very elderly patients, and that is not specific to myeloma. These are patients with uncontrolled disease. These are patients with more lines of therapy, with lines of therapy. And these may be patients who are on a longer standing therapy with anti-CD38 antibodies, or with bias against BCMA, or with a CAR T-cell therapy. So, many of those patients show no, or a very weak, immune response, humoral immune response, to spike proteins.

Now, what can we do if the patient does not respond accordingly? And here, we are not on very safe grounds, but of course one considers to use a third shot, or a second shot if you use Janssen, the Janssen, vaccine. And it should be probably, the heterologous vaccination. So, you shouldn’t use the same. Let’s put it other way. It’s probably more effective if you use another vaccine, than that which you have used for the person’s second dose, so we call it heterologous vaccination. This usually a booster to the immune system and we expect better antibody responses.

If this is not working, and if a patient does not yield any significant immune response, then the question is, what can we do? First of all, we have to rely on and what we call herd immunity. So, the more people being vaccinated, the better. We have to foresee that the patient is covered, or is treated in a setting which we call ring immunity, so that all his caregivers, or family members, contact people, are vaccinated. So, that’s important.

And of course, these patients are still required to stricter measures for protection; mask wearing, social distancing. And then you can watch how we do in patients. We have these deficient immune response to COVID, when they need high-dose therapy, or particularly when they have had the contact with a COVID-positive individual. And here, you can consider to use monoclonal antibodies. The monoclonal antibodies which have been shown to be effective, particularly in nursing homes, and so on. So, you can think about that, but we have to consider that this is not a group for those, for these indication at this point of time.

So, in the end, of course, we hope that many more people will be vaccinated, and that additional vaccinations in patients with myeloma result in higher or better immune response, and then that they are more or less protected. But we have to acknowledge that when you use intensive therapy, the antibody response wanes, once it’s after high-dose therapy, or after certain immunotherapies. So, that would need the re-evaluation of the immune status, after, or during, these procedures, in order to know whether the patient is protected.

There is one specific problem, which is still unresolved, because official centers, like the Center of Disease Control, or the FDA, do not recommend routine antibody testing in our patients. But when I ask them, what else do you recommend, you don’t get a good answer at this point of time. So, we have no other choice. And actually, two days ago, the FDA approved the third shot in patients with immunosuppressive states. And I think you shouldn’t, there’s no need to vaccinate again, a patient with a very good antibody response, even if he has myeloma, or she. But there is a great need to identify and to vaccinate those who have a sub-optimal immune response. And to follow the antibody titers during phases of active therapy, particularly active immunotherapies, and to intervene if the antibody titers go down again, and to use more precautions, and to inform the patient that they need to be more careful in this situation.

In the future, we’ll have more vaccines. We will have vaccines which can be administered via the nasal mucosa. These vaccines are supposed to produce or induce a local immune response, so a secretory IgA. We will have vaccines which target two different epitopes on the virus, for instance, the spike protein or the receptor-binding domain, some epitopes there. So, they will be more active in the future.

And of course, we have these virus variants, and now the variants, a particular concern is the Delta virus variant, which is highly transmissible. It is probably 100 times more transmissible than the original Wuhan strain. But still, our vaccines are able to cover and to limit the spread of the virus, but the activity of the titers, antibody titers, which are induced by these conventional vaccines is somewhat lower than against the original Wuhan, or other variants.

So still, this still, of course, highlights the difficult situation that we need to vaccinate as many people as possible, in order to restrict the time the virus has to mutate, and to develop even more transmissible, more infectious variants in the future.

So, hopefully, all your patients are vaccinated, and hopefully, most of them have a good antibody response, or will receive a good amount of antibody response after a third shot. With that, I would like to close. And thank you very much for listening to me so long. Thank you.