18th International Myeloma Workshop

Vaccinations in myeloma patients including for COVID-19

Prof Heinz Ludwig - Wilhelminen Cancer Research Institute, Vienna, Austria

One of the presentations I’m involved in is the presentation on the impact of COVID on patients with multiple myeloma. As you know, COVID is shown to be a successor of the SARS-CoV-1 virus which caused the SARS virus outbreaks in 2002 and 2004, mainly in China. Now we have this virus which threatens the entire population of our globe and, as you know, it is a coronavirus with a short, small genome that consists of about 30,000 nucleobases. It has these typical spikes which actually led to the name coronavirus. It enters the cells via a receptor called the ACE2 receptor and this is facilitated by activating a transmembrane serine protease which cuts one part of the receptor out and this enables the virus to enter the cell easily and to infect patients.

Now we know that patients with myeloma, or many of them, have an impaired immune system, mainly because of the disease itself and, in addition, because of specific therapies. So patients with myeloma have an increased risk for infection. Patients with myeloma have, of course, an increased risk for COVID infections and for a more severe course of the disease and actually, thirdly, for a higher mortality. The risk for mortality increases with age, with the number of prior therapies, is related to renal function, is associated with high-risk cytogenetics and is also associated with morbidity and with the number of morbidities. So that is now quite clear. So we have to do our utmost to protect our patients against COVID infections. Actually, the willingness of myeloma patients to comply with vaccination recommendations is very high. We did a survey in 335 patients and it clearly was much higher as compared to the general population, which is, in part, understandable.

So, which vaccines are available? Actually, as you know, in Europe and North America there are two types of vaccines presently approved for clinical use, these are the RNA-based vaccines and the vector-based vaccines. But in other parts of the globe there are other vaccines consisting of the whole virus, inactivated whole virus, or only of specific peptides from the virus or virus mimetics, as we call it, artificial virus. Now, these vaccines render in normal people an astonishing high response rate in terms of antibody production and cellular immunity but there is something which we need to keep in mind. There may be a discordance between the cellular and the humoral immune activity in a few individual healthy people. So some people may come up without an antibody production but show cellular immunity and vice versa.

In myeloma many patients respond well to the vaccines in terms of antibody production or even cellular immunity but this depends on their individual situation. If they have well controlled disease or if they are in a precursor status of myeloma like MGUS then they usually have a very good antibody response, close to normal. But in case they have ongoing disease, uncontrolled disease, in case they receive specific treatment, particularly treatment with antibodies against CD38, BCMA targeted treatment, CAR T-cells, then the response rate is low and those patients usually don’t respond well. So we end up with a proportion of patients which are poorly protected or not protected by their own immune system.

So what are the options for those patients? A few months ago a cocktail of monoclonal antibodies has been approved for use in patients with impaired immune systems or elderly patients who have come in contact with a COVID positive individual, so who are at high risk to acquire SARS-CoV-2 disease. When you use this monoclonal antibody cocktail, which is from Regeneron, you just administer 1,200mg subcutaneously and you can protect those patients or people from acquiring overt COVID disease. The difference between the treated and the placebo-treated patients is significant. So that is something which can be considered for patients with myeloma who either have come in contact with a positive person or who face aggressive therapy and will remain unprotected by their own immune system.

Otherwise, you can think about a third shot and you may have heard about the FDA decision that they recommend a third vaccine shot in patients with immune compromised immune systems. If you do that, if you have been vaccinated with an adenovirus vector vaccine first you should use then for the second or third shot an RNA vaccine, that gives you a better immune response. If you have been vaccinated with an RNA vaccine, for instance twice, it doesn’t help you a lot if you then select for heterologous vaccination using a vector-based vaccine. So there’s a difference between both vaccines.

What we should also mention is, of course, now we are no longer faced with the original Wuhan strain, there are now plenty of variants called alpha, beta, gamma, delta variants and the last one, which all of you certainly are aware of, is the delta variant. These variants differ in specific areas of the virus, particularly in the spike protein receptor binding domain. The mutations they acquire enable them to bind to the receptors, ACE receptors, with a higher lividity and they show a higher transmissibility but delta is also associated with a poorer protection by antibodies or the immune system induced by vaccines, slightly poorer, but they are still working well but not as well as against the original Wuhan strain. So that is something which we need to consider.

So a third shot, heterologous vaccination, can be considered and should be considered in those patients. In addition, although it’s not recommended by the Centre for Disease Control or by the FDA, in my opinion it’s important to assess the immune response in our patients because this helps us to manage them, to recommend further vaccination, to recommend to continue with social distancing, mask wearing and to recommend also ring vaccination, meaning that the contact persons the patient is close to in the family and so on need to be vaccinated as well. Of course it’s clear that the healthcare personnel who care for patients with multiple myeloma have to be vaccinated, have to prove that they have an active antibody response. When you ask if there are any clear criterion regarding which response protects patients against infection, this is still an open question. But in monkeys we have shown that neutralising antibodies at a specific threshold protects against infection and that is what gives us hope that the same principle applies to our patients and to ourselves, that higher antibody response, particularly in neutralising antibodies, and possibly cellular immune response is protective against the new variants, the delta variant, and particularly against acquiring symptomatic and particularly severe symptomatic COVID disease.

With that saying I would like to thank you for your attention, thank you very much, and close here.