Waldenström macroglobulinemia (WM) is a rare blood cancer that usually progresses slowly. WM can be diagnosed by blood tests, bone marrow biopsy, and scans, and there are a range of treatment options available.

To learn more about WM, we spoke with Dr Shirley D’Sa. She is a Consultant Haematologist and Honorary Associate Professor at University College London Hospitals NHS Foundation Trust in London, UK. Furthermore, she is the author of the booklet “Fast Facts for Patients: Waldenström macroglobulinemia”, which is freely available online.

Note: The statements and opinions contained in the video and the podcast episode are solely those of the speaker.

Video Interview

Podcast Interview

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Transcript

What is Waldenström macroglobulinemia (WM)?

Waldenström macroglobulinemia, which is abbreviated WM, because it’s a very long pair of words, is a condition named after a Swedish physician called Waldenström. He described in 1944 thickening of the blood by a plasma protein. And that’s where the macroglobulinemia comes from. Globulin is a protein and macro is big. If we deconstruct that a little bit, what it is in real life, if you like, is the consequence of a buildup of lymphoma cells known as lymphoplasmacytic lymphoma. They tend to build up in the bone marrow for reasons that we do not understand. We do not know the trigger. They are part of the immune system and they are very well known for producing antibodies, so-called IgM antibodies. And that is their signature and that is often how the disease is diagnosed. So, basically Waldenström’s or WM is the presence of this lymphoma, called lymphoplasmacytic lymphoma, with the production of a monoclonal or paraprotein called IgM.

Can you tell us what causes WM?

There’s no clear answer to that question. In the vast majority of people, we have no idea what causes it. There are some familial clusters of Waldenström’s or diseases that are similar to Waldenström’s in family members. But this is not a strong association. There is no single gene inheritance pattern or anything like that. Clustering is something that’s being looked at by some researchers to look at the genetics. But as always, when you have clustering in families, the question is, is it due to the fact that families live in the same surroundings, or is it due to the fact that the families have a similar genetic background and makeup?

So, the main way I look at Waldenström’s is that it’s a disease of the immune system, and we must remember that our immune systems are busy working for us from the time we are born and throughout our lives. And so, when we encounter various stimuli, whether it’s an infection or some strange chemicals, and I have to say there are more and more of such chemicals in the world than ever before, through industrialization, etc., the immune system gets very busy in shielding us against things, in mounting a response, in sort of setting up a way of protecting us, and in the case of infections, finding a way to remember the infection that’s been before so that if we encounter it again, it can get ready and fight back, so-called memory. And that is what our immunity is.

Now, in conditions involving the cells inducing these immune reactions and antibodies, sometimes the control mechanisms don’t go quite right. And when you have an immune response instead of a very tiny battalion of cells being produced, which then retreat back to the bone marrow or the lymph nodes and stay quiet, they remain somewhat visible and give themselves away, usually through the production of a protein. And so there is this lingering of an immune population, and that, I believe, is what leads to Waldenström’s and similar conditions. Because what happens is this population of cells lingers around and then it may in fact be given a boost from time to time by some other stimulus. And eventually there is a gradual buildup of the population. So, that, I guess, is the way I look at it in a simple way.

The actual trigger we don’t know. It’s hard to tell that. But again, a lot of research is going into looking to what is the so-called cell of origin. Why does this happen? Who does it happen in? But for the most part, when you see a patient who’s developed it, we can think of no cause. We can identify no cause.

What are symptoms of WM?

I always say that Waldenström’s is a rather talented disease. And that is because it has a buildup of the lymphoma cells in the bone marrow and the lymph glands and maybe the spleen, which is a spongy organism, an organ in our abdomens, which is part of the immune system and helps filter out certain bacteria.

The buildup of cells in the bone marrow primarily tends to cause a gradual decline in normal cell production. And the bone marrow is responsible for producing red blood cells, white blood cells and platelets. And these cells function every day to help deliver oxygen, fight infections and clot the blood in case of breaching of the blood vessels, respectively. So, when these cells decline in numbers, they obviously don’t do the job that they are meant to do properly. And so one of the very common features of Waldenström’s is fatigue. Because when you become anemic, you are having less oxygen delivered to your tissues, especially when you exert yourself, and therefore there is more energy needed to do your normal tasks. And that is a very, very common feature of Waldenström’s. Fatigue is very complex of course, because we, many of us, feel fatigued anyway, even if we don’t have Waldenström’s, because life is busy and we are doing all kinds of things. So, it is very difficult to distinguish sometimes what is what, but we do try and correlate fatigue with laboratory parameters when someone is diagnosed with Waldenström’s.

The other main feature of Waldenström’s is the consequence of the protein that I mentioned. So, the IgM paraprotein is, what is it exactly? Well, it is an antibody, and antibodies are meant to fight infections. And so, you know, you might say, well, I’ve got more of these antibodies, isn’t that a good thing? Unfortunately, when copies of the same antibody are made in such a disease, they are not useful antibodies. They are sort of rather redundant. They’re being produced erroneously and the consequence of that is primarily twofold. One is that there’s less attention focused on normal antibodies, so the abnormal ones are produced at the expense of normal ones. People often have a deficit in their immune systems and may develop infections, because their bodies are producing too much of the abnormal protein.

The other consequence is that this antibody can seek out targets within the body, which is actually part of the person, but it thinks of it as foreign and begins to attack it. So-called autoimmune activity is a big problem in Waldenström’s for many patients. Typical targets include sometimes the blood cells, to be honest, so the red cells can be targeted. You can get an autoimmune hemolytic anemia where red cells are broken down. Platelets can be targeted, and that is resulting in low platelets through an immune mechanism. Nerve cells can be targeted, causing nerve damage and so-called neuropathy. And that can lead to a variety of symptoms such as tingling and numbness and weakness and poor balance. And there are other features of paraprotein that can be problematic, such as they form little collections if the temperature is cooler in a condition known as cryoglobulinemia.

So, there is a range of antibody-mediated symptoms in Waldenström’s and for the most part, these symptoms build up quite gradually. They may creep up on a patient without them realizing. And so people may feel a sense of chronic ill health without knowing what it is. Or there may come a point where a tipping point is reached and people then resent their physicians. And sometimes piecing it together can be difficult because it’s a rare disease, and not all physicians immediately think this must be Waldenström’s. They will go through a diagnostic process and, you know, so it can produce a variable range of symptoms. And that’s what makes it sometimes tricky to deconstruct and understand. But the important thing is for someone to listen to symptoms from the patient and go through in a rather systematic way in the presence of, say, anemia and paraprotein, so that we can make sense of what is affecting the patient.

With a range of different symptoms, how is WM diagnosed?

Owing to the fact that Waldenström’s is primarily a bone marrow disorder, once we have clues of its presence through the blood tests, so, finding the paraprotein level, the IgM exceed a higher level, we do need to look then at the bone marrow, because this is where the action is taking place. The cells are building up in the bone marrow and that therefore requires a bone marrow biopsy. And this is taken from the back of the pelvis under local anesthetic, using a needle. In fact, two needles are used in sequence after anesthetic is placed into the soft tissues. One needle is used to remove liquid bone marrow, which is smeared onto a slide. This is then examined under the microscope after some stains. The result can be available even the same day, to be honest. Some of the liquid marrow is typically sent for something called flow cytometry, which is when special antibodies are applied to the cells, to try and identify them in more detail. And this can give rise to the sort of characteristic signature of Waldenström’s, using these markers.

Furthermore, liquid marrow can be sent for genetic analysis to look at the molecular signature of Waldenström’s. And in more than 90% of patients, there is a mutation of a gene called MYD88. And this is not entirely exclusive to Waldenström’s. Waldenström’s is a disease in which it is most prevalent as a proportion of patients. And this mutation happened, this gene is, what it does by becoming mutated is to give the Waldenström’s cells a survival advantage, and that’s what makes them grow and develop and accumulate. So those sort of markers are also looked for in a bone marrow.

But, in my opinion, actually a very important part of the bone marrow is the biopsy, and that is a small core of bone taken with the second needle. The core of bone looks a bit like the lead of a pencil, but not as long, I assure you. It’s usually about a centimeter long. This takes a bit longer to analyze, because the bone needs to be taken away, it needs to be decalcified, if you like: dissolved, using chemicals. That takes five or seven days, after which the sample can be sliced in the laboratory and then analyzed using again special stains. What this tells us is, it gives us more of a picture of the bone marrow, because the sample is bigger than the liquid. And you can see an architectural view of that section, to see how much are these sort of lymphoid cells? How many are plasma cells? Because, as I mentioned earlier, Waldenström’s is a lymphoplasmacytic lymphoma, there’s a mixture of these cells. It also gives us a percentage as, you know, as opposed to the normal cells. And that is very helpful as a baseline as well as to confirm the diagnosis.

So, that is, I guess, fundamentally making the diagnosis. But in order to understand the extent of the disease, it’s also important, especially before treatment, to do a CT scan of the body, which is a whole-body, a cross-sectional scan, which is based on X-rays. And this tells us to what extent, if at all, lymph nodes and the spleen is involved. This is important to know before treatment, because in the future one can then compare the results of the treatment by repeating the scan. So, that is really the way diagnosis is made. Of course, I’m now assuming that blood tests have already been taken. A full blood count, which gives you the hemoglobin, white count etc., is a very routine test done by many doctors, as are kidney tests and liver tests. Measuring the protein, the paraprotein, is not something done routinely. It has to specifically be done using something called protein electrophoresis. And furthermore, measuring the paraprotein level is also a specialist test. So, that wouldn’t be done by family doctors typically. It would be done in the hospital setting.

It’s a question of putting together the story and trying to move towards a diagnosis, if it’s suspected, and getting all these tests done. Once the diagnosis is made, then a few additional tests are done to try and identify what’s called prognostic factors, things that might predict the way the disease might behave going forwards. But that doesn’t really tell us how to treat patients. Primarily, we treat patients based on their symptoms, and we obviously follow guidelines too, which are based on evidence, as far as possible, as to how best to treat patients taking account of existing and newer therapies.

What kind of treatment is currently being offered to help patients with WM?

For many, many years there has been a range of chemotherapy drugs in the traditional sense. Treatments that are designed to attack the DNA or the genetic material of these cells. These treatments which include drugs like cyclophosphamide, chlorambucil, bendamustine, they’ve been around for variable periods of time, but actually quite a long time overall. They’ve been very well tried and tested. There are some other agents that were used more in the past, such as fludarabine, which are not ineffective, but have been or are less used because of their toxic effects. This traditional group of treatments are very effective in Waldenström’s, and they are still in use. The use varies from country to country depending on what is available. And they are typically used in conjunction with antibodies that target B cells, and the one that’s most commonly used is called rituximab. And that targets something on the protein, on the surface of the cell called CD20, so they are called anti-CD20 antibodies.

And in current times, chemotherapy, a chemotherapy agent in conjunction with rituximab forms the backbone of therapy for many patients’ frontline when they’re first diagnosed and need treatment. And such treatments are usually given for a fixed period of time, spanning 4 to 6 months, in which the treatments are given probably in monthly intervals or every three weeks or so. You can read more about these individual components in the booklet, because there’s quite a lot to take in. The other groups of therapies are what are called biological agents. Again, there’s an increasing range of these kind of treatments, and they are extremely clever treatments, because they’ve been developed on the back of biological discoveries about how cells actually function.

One example of this is something called a proteasome inhibitor, which is, an example, bortezomib. This is something that is not a chemotherapy drug, but is used and very effective. What it does is, it sort of stops the cells from using their systems of garbage disposal, and by blocking that, the cells simply cease to function after a while. Such treatment is also given in conjunction with rituximab, sometimes even with chemotherapy agents as well. So, when you combine drugs together, they work in their own way, but in conjunction with each other. And then you can get a net benefit. Then there’s a newer group of drugs called the BTK inhibitors, so-called as it stands for Bruton’s tyrosine kinase inhibitor. And these drugs are based on the fact that all cells, and immune cells particularly, you know, this is a very important factor for immune cells, communicate with the outside of their environment, using what are called signaling molecules.

If you think about a cell, it’s like a sort of a ball and within it is a smaller ball. And in the smaller ball, the nucleus, that’s the genetic material, that’s the brain of the cell that tells the cell what to do. If you think about the cells, the immune cells, as members of an army, they don’t act alone. They have to communicate with what’s going on around them. They get signals about intruders. They need to know who’s the good guy, who’s the bad guy. So, the only way they can do that is by communicating from the nucleus to the surface of the cell through these signaling pathways. And in diseases like Waldenström’s, some of these signaling pathways are excessively expressed, which leads in the first place to the cell being slightly out of control of its normal processes of controlling growth. By targeting some of these proteins, and BTK is one of them, we can try and switch off that advantage and beat the disease.

And really speaking, this is a huge step forward. It’s very different to chemotherapy, because the mechanism of action is different. It’s given in a different way: It is taken by tablet or capsule on a daily basis, on a continuous basis, as long as it’s effective. So examples of this include ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib. And now again, as these kind of treatments evolve, and the sort of newer versions of them, if you like, are tweaked to try and improve on them and improve on them, to make them less toxic, to overcome some of the resistance that can develop. And where we are with them is that they are proven to be very effective in this disease and many other lymphomas. But we’re still working on how best to use them, when to use them, whether we combine them with other treatments.

Are there any clinical trials about WM, and what do they involve?

There are many trials ongoing in Waldenström’s, which is fantastic, given the rarity of the disease. And as time goes on, we’ll have a better idea of how these drugs are best used, how to limit some of the side effects that we see coming through, and how to perhaps use them in a way that’s not continuous forever, but used perhaps for a limited period of time.

And that really brings me on clinical trials. They are very important in making advances in therapeutics, because what they do is build onto previously gathered experience and then develop that further. Many centers do run clinical trials. They’re not available in all hospitals, more so in a disease which is rare like Waldenström’s, because you do need a number of patients within the center to make the trials justifiable for that center. So, if trials are not being run in your hospital, you can ask your doctor about a center that’s nearby that perhaps has trials, because it may be that that is something very much worth your while in participating in, because you may benefit from a new therapy, it may give you different options. And at the end of the day, what would happen is you get information about the trial, what it involves. You get written information in great detail. You’d be able to assess that. The doctors would explain to you pros and cons of being inside the trial, and you would make the decision yourself, with their help, so that you can then decide whether this is something that would work for you.

Trials are really, really important, trials that are running at the moment. A number of them are actually on; again, this varies from country to country. And there is a list of trials on various websites, including clinicaltrials.gov that is a slightly technical site, but if you were to look on them and want further information, then you should seek that from patient advocacy organizations or indeed your doctor. Because they can sort of translate some of the jargon and help you understand where are the trials available, whether you might be eligible, etc. So, I would suggest that that is what you do, because if I mentioned one or two trials now, then before long, the interview will be out of date. But I assure you that there are a number of ongoing trials of new therapies. It’s a very positive situation now in the development of WM treatments. And I advise you to and encourage you to get involved, ask questions and gain some knowledge about the disease so that you are empowered to live with it well.

Many thanks for your time and for the interview.