Ask an expert about Waldenström's macroglobulinemia 

Waldenström’s macroglobulinaemia (also known as lymphoplasmacytic lymphoma) is a rare form of bone marrow cancer, which is associated in most cases with the presence of an excessive amount of protein in the blood.

Waldenström’s macroglobulinaemia often develops over a long period of time and many people have no symptoms at all. This means that sometimes the condition is found by chance while having investigations for another condition or on a routine blood test.

Our expert is consultant haematologist Dr Shirley D’Sa who specialises in treating patients with Waldenström’s macroglobulinaemia and is on the advisory board for WMUK.

The conversation focussed on how the condition differs from other lymphomas, how it needs special consideration when being treated and how there have been rapid advances in the biology and treatment.

Live Blog Ask an expert about Waldenström's macroglobulinemia

Dr Shirley D’Sa answers your remaining questions...

Due to the high volume of questions received on the 14th January 2016 web chat, Dr D’Sa was not able to answer them all in the time available. She has now answered a selection of the outstanding questions which you will find below.

Although our web chats are usually designed to answer general questions, some of the questions here are quite specific and not necessarily applicable to your circumstances. We’d like to remind you of our web chat terms and conditions; please speak to your clinical team about have specific concerns you may have about your treatment.

Question from Lynda

I have just completed treatment for WM I have problems feeling cold all the time especially my feet. Is it the WM or the Bendamustine that is causing the problem?

Hi Lynda. Have you lost weight? This can sometime result in a feeling of cold due to loss of ‘insulation’. WM can cause problems with the circulation in the hands and feet- sometimes due to an association known as Raynaud’s syndrome (whether the extremities change colour in cooler weather) or a complication known as Cryoglobulinaemia. Such problems (if due to the WM) usually improve with treatment, as the WM is suppressed. On the other hand, such symptoms may simply be ‘one of those things’ and not specifically related. It is not likely to be caused by the Bendamustine in my view.

Question from Anne

Having had an excellent response to R-CVP 11 years ago IgM is now progressing. Would this still be preferred 2nd treatment?

Hello Anne, I am really pleased to hear that you have had such a decent response to R-CVP! Previously effective treatments can indeed be revisited and is not an unreasonable option but there may be more to gain from considering a ‘non-cross reactive’ option- in other words challenge the returning disease with different chemotherapy agents. Options include Bendamustine or Cladribine. If you’re fit enough to be considered for a stem cell transplant, this option may be worth considering after returning you to a remission, as this may help to prolong the second response. In general, when the disease comes back, it tends to be slightly less cooperative in response to chemotherapy, hence the need for a robust plan B!

Question from Audrey

I note you have mentioned stem cell transplant as treatment option in a few replies. Although not an issue at present, what age do you feel is cut off? I have been told it isn't an option. Except for the LPL, I am an otherwise healthy 57 years old.

Hi Audrey. In the UK, it is possible to carry out an autologous stem cell transplant (i.e. using yourself as your own donor) when a second remission (or beyond) has been achieved in WM- the transplanted is then funded on the NHS. In other words, the disease needs to be treated initially, then relapse and be treated again. As for age ‘cut-off’, this is not black and white- it depends more on biological fitness- you sound well within the realms of being eligible for a transplant. However, when fit patients approach their late 60s and 70 years of age, most doctors would feel nervous about proceeding to transplant, as it does require a robust enough constitution to be able to tolerate potential complications such as infections.

Question from Ron

Does a fast very good response indicate a longer remission? DRC did not work for me, but Benda R was rapid with no measurable paraprotein after two years.

Well, Ron - not necessarily. The speed of response does not always mean that there will be a good depth of response (clearance of disease) and vice versa. The need for speed is dictated by the patient’s symptoms - the more symptomatic the patient at the outset (fatigue, low blood counts, immunological complications) the more beneficial a quicker response. This is where agents like Bendamustine and Rituximab can help. Combinations like DRC frequently lead to a slow, but steady response. A recent analysis of the DRC regimen with a minimum of 7 years follow up showed that the progression-free survival was 3 years and the overall survival was 8 years. We do not yet have as mature data for Bendamustine.

Question from Martha

Does WM or chemotherapy cause carpal tunnel syndrome in WM patient?

Carpal tunnel syndrome is quite common, Martha, affecting approximately 3 to 6 per cent of adults in the general population. Although the cause is not usually determined, it can include trauma, repetitive manoeuvres, certain conditions like arthritis, and pregnancy. Symptoms are related to compression of the median nerve, which results in pain, numbness, and tingling. In severe cases, weakness of the hand/s can also occur. WM itself does not directly cause carpal tunnel syndrome, but in rare cases, may indirectly do so due to amyloid deposition. In this rare setting, there are typically other features indicative of amyloidosis, the deposition of an insoluble protein related to monoclonal light chains (the kappa or lambda of the M-protein). Chemo does not cause carpal tunnel syndrome, but some agents may cause a peripheral neuropathy that may result in similar symptoms. WM itself may also cause a peripheral neuropathy by other mechanisms. Again the symptoms can be similar to carpal tunnel syndrome but the two can usually be distinguished by a clinical examination and nerve conduction studies.

Question from Annette

Can hyperviscosity affect the heart, and if so should this be monitored on a regular basis?

Yes indeed, Annette- if the blood gets thickened up by proteins like IgM, there will reach a point if this has an impact on organs if the supply of oxygenated blood is slowed down. The effect on organs like the heart depends also on the wellbeing of the heart and its circulation. A person with a pristine blood supply to the heart (and other organs) will be able to tolerate a raised plasma viscosity much better than someone with narrowed arteries or high blood pressure. Akin to the flow of oil through a central heating system with furred up pipes as opposed to a brand new central heating system with clean pipes. The problem of hyperviscosity is more likely when the IgM is greater than 30 or 40 g/l and beyond. In this situation, it is a good idea to monitor the viscosity of blood and also look out for relevant symptoms.

Question from Ann

I am 67 and was diagnosed with WM in 2013 following another blood test for a 'painful thigh'. I had bone marrow tests followed by scans at The Royal Free. I see Dr Saad Rassam every 4 months for bloods and examination and at present everything is quite stable. Will I only have blood tests while on watch & wait?

Yes, that is correct, Ann. If you have a monoclonal protein to monitor, then this alongside the blood counts and general wellbeing of the patient can be the mainstay of monitoring the condition. The more invasive and detailed tests, like bone marrow and scans, only need to be repeated when treatment is being considered, to act as a clear baseline for future comparison.

Question from Martha

Should we go on maintenance stage of Rituximab every three months for two years after successful treatment with RDC x6 cycles?

Martha, there is currently insufficient evidence from trials to recommend maintenance Rituximab in WM. Whilst it would seem a sensible idea to continue to suppress the B cells and hence the disease to maintain a remission, there is a potential downside from using Rituximab, namely longer term immunosuppression and low antibody levels which can increase the risk of infections. Also, there is no evidence as yet for a ‘survival advantage’ from this approach. More studies are needed.

Question from Paul 

For patients with a very level of high bone marrow involvement, what are the implications for disease progression? Is there a relationship between the level of pre-chemotherapy bone marrow involvement and length of remission post-chemotherapy?

Hello Paul, I am not sure if you missed out the word ‘high’ or ‘low’! The effect of the level of bone marrow infiltration on disease progression and length of remission is not straightforward - other factors are likely to be relevant such as genetic features. This is the subject of on-going research and should shed more light on these important questions in the near future. Some patients can remain stable and well, even with a very high level of disease in the marrow, and with surprisingly good blood counts! It never ceases to amaze me how this can happen… As for the level of disease post-chemo, in general, the lower the better, but sometimes ‘modest’ responses can be enduring.

Question from Roger 

I was diagnosed with WM 18 months ago and finished chemotherapy 5 months ago. I am now getting frequent leg cramps at night. Is this likely to be due to WM or chemo, or some other cause?

Leg cramps are quite a frequently mentioned symptom in patients with WM, and are described at all stages of the illness. The triggers for cramp (which I take to mean painful muscle spasms usually in the calves) are varied and include mineral imbalances in the blood (such as low magnesium or calcium) which can be identified on a blood test and corrected with replacement. More often, cramp is unexplained by laboratory findings. They may be a ‘side effect’ of a neuropathy which may be due to the WM or some treatments. If severe and disturbing, then tonic water (some people add gin!) or quinine sulphate tablets may help.

Question from Liz 

Is there any data to suggest that watch and wait is now an outdated approach, and early intervention may be a better option?

Hi Liz, at present there is no evidence that treatment with any of the currently available treatments of asymptomatic or smouldering WM is beneficial. In the future, it would be useful to undertake a study of one of the novel, oral therapies such as BTK inhibitors in the setting of smouldering WM, especially if there are features that may predict for earlier progression. At present the focus is on establishing the role of these agents in the treatment of symptomatic WM.

Question from Jean

I was diagnosed with WM in 2006 and have had several treatments of varying success. It has now been discovered that I have WM cells in the tissues of my lung sacks. This was thought to be the reason for the constant formation of pleura fluid in the lungs which had to be punctured regularly. After 3 months of a 6-month cure with Bendamustine, the production of pleura fluid slowed down, but my thrombocytes became drastically low (11). I have now stopped the Bendamustine treatment and the thrombocytes are back to normal but the pleura fluid is increasing once more. I would be interested to know how you would treat this condition.

This is an unusual complication of WM - a build-up of pleural fluid may result from compression of lymph vessels or invasion of the thorax by lymphoma tissue. An examination of the fluid to look at the colour (?blood stained), for WM cells and rule out infection, and the amount of protein in the fluid can help. Sometimes, the exact mechanism for the fluid accumulation is not clear, but the usual approach is to treat active disease with chemotherapy to reduce this underlying tendency. If the build-up of pleural fluid does not reduce even after effective treatment of the WM, then consideration may need to be given to so-called talc pleurodesis, in which a substance designed to irritate the pleura (lung sack) is injected by a thoracotomy resulting in a glue-like effect, to prevent re-accumulation of the fluid. Such a procedure needs a short general anaesthetic.

Question from Kevin

I was diagnosed with WM in October after presenting with anaemia. I am on the second cycle of six receiving RCD. I suffer incredibly from nausea and for cycle 3 I dare say my anti-nausea meds will change again. In your experience what provides the best defence and what self-help measures are there to help? Recognising of course that everyone with WM seems to be different!

Sorry to hear about your difficulties with nausea, Kevin. The approach is to try varying combinations of anti-emetics which each act in different ways - trial and error is the only way, since people are different. A couple of suggestions: cyclophosphamide can be given intravenously on day 1 instead of orally over 5 days - this can sometimes help. There is an anti-sickness drug called Aprepitant that can help to improve intractable sickness. It may be worth discussing these options with your team.

Question from Hans

I was on R-CD for four months and in-between had to have Plasmapharisis twice, three sessions each time. I am now on my final month of Bortezomib (Velcade) with on the 11th day Rituximab and using Dexamethase which started off at 8mg x5 per week and has now been dropped to 2 mg x3 per week. They did say that I might have a chance at stem cell therapy, but my bone marrow is still at 46% so they are waiting to see if it drops more. I am being treated in the I.P.O Lisbon, Portugal and was wondering if this would be the same chemo programme that you would use? I was diagnosed last June and went into chemo straight away, after having two plasma and two blood transfusions.

Dear Hans, R-CD and VRD are both effective regimens to treat WM, but the disease takes time to respond, so patience needs to be exercised in waiting for a response. As long as the disease is showing evidence of a response (improvement in Hb, lowering of paraprotein, even if gradual), then the aim should be to achieve maximal response and then the possibility of a stem cell transplant may be considered.

In the UK, we have no funding on the National Health Service for this in ‘first response’, but if this is available in Portugal, then it is worth considering, at a point when the disease has been sufficiently reduced (in our centre we aim for a bone marrow level of 10-15% before harvesting).

The following is a personal view - if you are medically fit enough for an autologous stem cell transplant and have an IPSSWM score (prognostic score) that is intermediate or high, you may well benefit from a stem cell transplant, which in our experience can help to deepen the response and produce a prolonged remission (in the region of 7-10 years on average). The downside to a stem cell transplant is the risk from the procedure which involves high dose chemotherapy and places you at risk of severe infections for 10-12 days, as well as inducing significant temporary inflammation and malfunction (mucositis) of the gut. This is why it is important to be fit enough. Without a transplant, your remission would be estimated to be 5-7 years.

Question from Philippa

When on watch and wait, what are the symptoms we need to watch out for that indicate that WM might be causing irreversible damage?

Any symptoms that are persistent and progressive need to be taken seriously. This might include fatigue, weight loss, peripheral neuropathy, sweats and recurrent infections. The rate of change in the symptoms is also important. Most changes are reversible once treatment is instituted.

Question from Guest

I'm in the watch and wait stage, my Hgb is at 10 and slight lymph node enlargement, but no other difficult symptoms. Are there foods, herbs or vitamins that would help?

There is no evidence that supplements over and above the nutrients contained in a good and varied diet provide additional benefit. If there are any identified deficiencies, such as Vitamin B12 or Vitamin D, then these should be replaced in appropriate doses. Your anaemia is most likely due to the presence of the lymphoma cells in the bone marrow.

Question from Joseph

I am due to start treatment using Ibrutinib / Imbruvica later this month in Bordeaux, France. I have been treated using Rituximab / Fludarabine / Cyclophosphamide for many years. Do you already have positive feedback using this drug at UCLH and what are the side-effects please?

Bonjour, Joseph. Both Ibrutinib and another BTK inhibitor, ACP-196 are most definitely showing promising results in WM patients. Our experience is very limited with Ibrutinib, as the drug is not available for routine prescribing in the UK. This class of drug is undoubtedly of significance in diseases such as WM; we look forward to the setting up of future trials to help to establish their place in the treatment armamentarium of WM.

Question from Dick

I have had WM since 2008 and had chemo in 2013. Since then I have been in remission. I seem to feel the cold more and need the heating higher than my wife. Is this a usual side effect of WM?

Many patients have mentioned this ‘thermostat’ problem, Dick. The cause of this is not clear; it is difficult to specifically attribute it to the disease or treatment. One way of thinking about these symptoms is that the body’s physiology seems somehow altered by having WM and this alteration seems to persist even after successful treatment. I wish I knew why!

Question from Sandra

I have been on watch and wait since being diagnosed with lymphoplasmacytic lymphoma in 2010. My paraprotein level has fluctuated but remained reasonably stable. Since a recent bout of a flu type illness my CRP and ESR levels have remained at 40 and 80 respectively. I have been given a course of antibiotics, but still have tiredness, sore throat and my temperature raises by a degree most days. My consultant has mentioned doing a CT scan or an immunoglobulin infusion. Even though my paraprotein level is stable, could this be a sign that the lymphoma is progressing?

As long as your disease parameters (such as the paraprotein) are stable, the persistent elevation of your ESR and CRP are not likely to herald progression of the disease. Low grade persistence of symptoms of infection seems very common in the winter months, and I do not think this is restricted to WM patients. Some viruses can be very virulent and take a long time to be eradicated. It is likely that people with WM, even after treatment, have a reduced ability to mount a robust response to such pathogens, so some degree of infection or the immune response to the infection persists sometimes for weeks. Your consultant’s plan of a CT scan to seek out a focus of infection (lungs or sinuses), and the possibility of an immunoglobulin infusion (if your own antibody production is low) sound good if the situation persists to the detriment of your well-being.

Question from Audrey

I was diagnosed in Sept 2014 with ppl IgA. Information has been very difficult to source. I was stage 4 B. I have had treatment w with CRP. I’ve had lots of problems with Rituximab, but fairly good response. My current paraprotein levels are 9. They were 31 at diagnosis. Is the outlook similar to Waldenstroms without the viscosity issues, etc?

Hi Audrey, while the vast majority of patients with the lymphoma known as lymphoplasmacytic lymphoma (LPL) produce an IgM paraprotein, and hence earn the diagnosis known as Waldenströms macroglobulinaemia, a small number either produce no protein (non-secretory) or an alternative protein such as IgG or IgA and we refer to them as LPL.

This is a reflection of exactly where along the course of B cell development the malignant process has arisen. There comes a time in the life of many B cells that they further evolve (‘differentiate’) into plasma cells- those are the ones actually responsible for producing the paraprotein. The malignant event in LPL occurs at some point during this process. Once these transitioning cells begin to produce their immunoglobulin, it starts with the IgM ‘isotype’; at some point, the cells may encounter an antigen and then so-called ‘isotype switching’ occurs and the cell produces IgG or IgA instead. If the malignant process happens before isotype switching the protein is IgM, if it happens after, then it will be IgG or IgA. And that’s the end of the science lesson! To get back to your question, for purposes of diagnosis, prognosis and treatment, there is no evidence for any difference. The treatment approach is the same and the outlook is regarded as the same. There is less likelihood of hyperviscosity problems though, as you mentioned.

Question from Helen

Dear Dr D'Sa, I am almost 4 years post treatment B and R and my remission continues to hold. No tumour marker measurable I wonder if patients have/can been deemed as “cured"?

Hello Helen, I am pleased to hear that you have un-measurable disease! Prediction of how long this may last is impossible. In general, a low level of disease bodes well, but on the other hand, many patients achieve less than a complete response, but their partial response can last a very long time. Such are the vagaries of diseases such as WM. In a disease which is indolent (slow growing), it is very difficult to eradicate every last cell from the body with currently available chemo agents, which tend to depend of cell division to undermine the cells’ lifespan. As the cell divides, the chemo drug interferes with the cell cycle by a particular mechanism (different drugs have different mechanisms, hence the combinations that are used). Cells that divide slowly are less susceptible to this onslaught compared to those that divide rapidly (which is why aggressive lymphomas are regarded as potentially curable). Indolent lymphomas are certainly knocked back- sometime for many years, but they tend to regroup eventually. This is why the introduction of novel agents that act completely differently such as Ibrutinib, ACP-196, Idelalisib and Venetoclax to mention a few are hugely important as they target diseases like WM from a different angle. So whilst I cannot give you the reply you would like to hear, I can at least say that plans are afoot to move closer to this objective.

Question from Donald

Can low paraprotein levels measured by a blood test mask a high level of Paraprotein in the bone marrow? Why do we need bone marrow aspirate tests?

Well, Donald, each person’s WM has its own paraprotein ‘identity’ (perhaps we should coin a new phrase ‘parapersona’) - in some cases the protein level is very low, and in others very high and others somewhere in between. This is a reflection of the biology of the disease in that individual. For the most part, the level of protein reflects the burden of lymphoma in the marrow, but some patients have a low protein but a lot of marrow disease. The other thing to bear in mind is that the lymphoma: lymphoplasmacytic lymphoma is just that- a mixture of lymphocytes and plasma cells. It is the plasma cells that produce the protein and the balance of these two populations varies from person to person. So there is no getting away from the fact that the marrow is where the action is and it is important to look at the marrow itself at important junctures such as diagnosis, before and after treatment.

Question from Paul

I wanted to ask about the link between WM and low immunity. I have WM. This winter I seem to have been unwell since October – and on-going. Throughout late October/early November I had a bad cough and cold, severe congestion and unable to sleep through coughing. I had a minor op on Nov 24th under GA, and by 29th I had started developing a serious herpetic infection on my lips and face. I was treated with Acyclovir. This lasted until at least mid-December, and now for the last 3 weeks I have had yet another cold/chest infection with herpetic lip infection, also treated with penicillin and acyclovir. Is this a usual pattern of infection? Could you speculate as to why my immunity seems to be so low this year – all bloods seem normal? Is there any recommended approach for boosting immunity? Is there anything my GP should know?

First of all, there is much more to immunity than we can pick up using our rather crude blood tests. The consequence of infections results from two things: how vulnerable is the host (low or normal immunity) and how powerful are the bugs (how virulent or nasty). In the winter, viruses tend to have the upper hand - conditions are in their favour- cold and damp conditions which allows bugs to go forth and multiply easily. As they spread through the population they get cleverer and adapt. This can result in anyone getting a nasty infection which they cannot shake off. If you additionally have impaired immunity due to the WM itself (reduced production of normal antibodies is a frequent finding) or its treatment (chemo and Rituximab can impair immunity for many months), and you encounter a vicious bug, you could be in for trouble. This may come in the form of a vigorous infection which knocks you for six, may cause an acute illness that needs admission to hospital or a lower grade, grumbly affair which simmers away in the background and can last for weeks. Most of the culprits are viruses but sometime bacteria can intervene and make things worse. Remember antibiotics don’t work against viruses. There are few antiviral drugs such as Aciclovir (which acts against the Herpes virus group including Herpes simplex -‘cold sores’, and Varicella zoster- chicken pox and shingles). If recurrent infections necessitating repeated antibiotics do occur, and your antibody levels are low, then it is worth considering immunoglobulin replacement (regular infusions of antibodies)- these can now be given by weekly self-injection under the skin as well as intravenously on a monthly basis.

Question from Will

Given the appearance over recent years of BTK inhibitors such as Ibrutinib and others as highly effective treatments for Waldenströms, how long might it be before these become available as a primary treatment course, rather than only for relapsed patients? I'm 40 years old and was diagnosed 6 years ago and underwent a course of FC-R chemotherapy. I started to relapse early in 2015, and have been on the ACP-196 trial for 6 months, and that's going very well.

Will, this is a very pertinent question for us all. New drug development is a complex process, starting with taking the theory to the bench (in the laboratory) and then from bench to bedside. Add to this are the convoluted regulatory processes to get these drugs then approval by the FDA and EMA (the European equivalent). This is followed by healthcare systems weighing up how to pay for these expensive drugs, by making an effort to judge cost-effectiveness (versus all those other drugs out there that are being developed for other diseases).

It is a frustrating process all round, but it is also important to ensure that new drugs are put through their paces and develop a track record in the clinical setting. It is only with use over time, through clinical trials that clinicians become aware of how drugs actually behave in patients, who responds, who doesn’t (despite identical lab data), who tolerates the drug and who doesn’t, and why this is….and how best to combine these agents with other existing drugs to optimise the outcome.

There have been patients receiving BTK inhibitors as primary treatment in trials; the next step is stage II trials, in which these agents are combined with other drugs first line. Such trials are in the pipeline, I am pleased to say. I am afraid it is really difficult to put an accurate timescale on this issue though, Will.

Question from Lesley

My mother had the condition which she knew as 'Waldenström's lymphoma', I don't think it caused her any distress, she was monitored regularly. My question is, is it hereditary?

First-degree relatives of LPL/WM patients have an increased risk (1.5 to 2 times more than normal) of several lymphoma and related disorders. This is a modest increase in the risk of getting what is a rare disease, so no recommendations are made to screen relatives for WM. There is also a familial tendency to some other immune-related conditions, implying that there may be a shared susceptibility to LPL/WM and other lymphoma-like disorders. Future work is needed to uncover the underlying mechanisms of the observed associations- the relative contribution of the shared environmental factors or shared genetic susceptibility.

Question from Jean

My husband was diagnosed three years ago. His mother died from WM two years previous to his diagnosis. Unfortunately he suffered symptoms straight away (hence the diagnosis) and complications (primarily osteomalacia which caused his bone marrow to seep into his bones) meant that he's already had his first round of chemo (RC-P) and been graded stage IV B. Is it vital that irutinib is available as a treatment to WM's and does it work for all cases given that there are so few every year?

Jean, there are many very effective therapies already available for WM- success does not only hinge on drugs like Ibrutinib. Most people respond very well to chemo such as RC-P and so should he. Once a maximal response is achieved, treatment will be suspended and then he should be monitored. I would not worry about the stage IV side of things. Virtually ALL patients with WM have bone marrow involvement at diagnosis- it is a bone marrow-based disease, so in fact we don’t really use the stage I to IV method in WM. It sounds like he has some thinning of the bones as well- osteoporosis? This should be managed in its own right. It could be a consequence of the WM, and may be made worse by the use of steroids (which are an important part of the treatment), so a bone density scan and appropriate treatment (bisphosphonates) may be advisable if not underway already. I wish him well.

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