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Ed Forum 2016


A diagnosis of WM can be a daunting experience, especially when trying to fully understand new medical terminology and acronyms.  Below is a guide to some commonly asked questions about WM and how best to manage your disease, organized into five key categories.


Should I get the shingles vaccine?
No. The shingles vaccine is a live virus vaccine, and people with WM should not receive live virus vaccines. If you are a WM patient on certain treatment regimens (fludarabine, bendamustine, bortezomib), have undergone stem cell transplantation, or have had shingles previously, you should ask your doctor to consider a prophylactic anti-viral oral medication such as acyclovir to help prevent shingles.

Should I get a flu shot? What about the nasal mist vaccination?
You should get a flu shot. The shot is a killed virus vaccine and is therefore safe to use. The nasal mist vaccination called FluMist is a live virus vaccine and is not recommended for people with WM.

Should I get the pneumonia vaccine?
Yes. In the U.S., The Centers for Disease Control recommends that all adults over the age of 65 receive the pneumococcal polysaccharide vaccine (PPSV) and that adults younger than 65 receive it if they have a condition that lowers the body’s resistance to infection. Lymphoma is listed as one of these conditions. Re-vaccination is recommended five years after the first dose for individuals under the age of 64 who are at high risk for fatal pneumococcal infection or rapid antibody loss.

What should I do to protect my immune system?
Wash your hands frequently and avoid touching your hands to your face, especially during cold and flu season. Keep up to date on your flu and pneumonia vaccinations. Eat a healthy, well-balanced diet and get the proper amount of sleep. Avoid close contact with people who are exhibiting obvious symptoms of colds, flu, or other diseases. Be sure to wash raw fruits and vegetables before eating and make sure that meat is cooked to the proper temperature. These are all common sense things that everyone should do, no matter their state of health.

Will I still be able to travel?
You should still be able to travel, but possibly with some limitations or additional precautions. Enclosed places like airplanes, crowded airports, and public transportation are sources of infection, especially during cold and flu season. If your disease is progressing to a point where you require treatment or if you are currently in treatment that can adversely affect your immune system, you should ask your hematologist-oncologist if any travel restrictions are necessary. You should also consult your physician if you are planning to travel to unusual or exotic destinations where specific disease alerts might be in effect or where additional vaccinations are required. You should keep up-to-date on your recommended vaccinations and exercise common sense by washing your hands frequently and watching your diet in areas that are prone to food- and water-borne diseases.

How often should I see my hematologist-oncologist?
This depends greatly on your disease status or whether you are receiving treatment. If you have smoldering WM and are stable, you may not need to see your hematologist-oncologist more than once or twice a year. If you are newly diagnosed or have progressing disease, your hematologist-oncologist will want to follow you at more frequent intervals, perhaps once every 2-3 months. If you are currently being treated, your hematologist-oncologist may choose to monitor you even more frequently (possibly weekly) during this period because some treatments can cause side effects, which need to be recognized early and managed appropriately.

Should I get a second opinion? If so when?
It is not unusual for newly diagnosed patients or patients needing treatment to get a second opinion from a recognized WM expert, or at least from a hematologist-oncologist who is familiar with the treatment of WM. WM is a rare disease and as a result, many local hematologist-oncologists have had little experience dealing with WM patients over the course of their careers.

How do I find a good doctor for a second opinion?
Generally speaking, large medical universities/teaching hospitals see more WM patients and have staff physicians more experienced with WM. The IWMF website maintains a list of experts.


Who was Waldenström? What does “macroglobulinemia” mean?
Dr. Jan Waldenström (1906-1996) was a Swedish physician who in 1944 first described two patients with symptoms of what is now known as Waldenström’s macroglobulinemia. “Macroglobulinemia” is a compound word – “macro” meaning large. and “globulinemia” meaning protein in the blood. In the case of WM, the large protein in the blood is IgM, produced by the cancer cells.

What is WM?
Waldenström’s macroglobulinemia (WM) is a lymphoma, or cancer of the immune system. It occurs in a type of white blood cell called a B-lymphocyte or B-cell, which normally matures into a plasma cell whose job is to manufacture immunoglobulins (antibodies) to help the body fight infection. In WM, there is a malignant change to the B-cell in the late stages of maturing, and it continues to proliferate into a clone of identical cells, primarily in the bone marrow but also in the lymph nodes and other tissues and organs. These clonal cells over-produce a specific immunoglobulin called monoclonal IgM. Under the microscope, WM cells have characteristics of both B-lymphocytes and plasma cells, and for that reason it is classified as type of non-Hodgkin’s lymphoma called lymphoplasmacytic lymphoma (LPL).

What’s the difference between WM and LPL (lymphoplasmacytic lymphoma)?  Are they the same disease?
Sometimes WM and LPL (lymphoplasmacytic lymphoma) are used interchangeably although WM is really a subtype of LPL. However, it comprises about 95% of all LPL.  The cancer cells of LPL have the appearance of both B-lymphocytes and plasma cells, hence the term lymphoplasmacytic.  LPL cells can secrete IgM, IgA, or IgG, but if they secrete IgM then the disease should be called WM.

What is IgM and how does it relate to WM?
IgM is an immunoglobulin, also called an antibody. When you are exposed to something that can cause an infection, one of the things that your body does to fight it is to make antibodies specifically against that disease-causing agent. These antibodies are made by immune system cells called B-lymphocytes (or B-cells) and plasma cells. The antibodies are classified into several types, one of which is IgM. In WM some of the B-cells, instead of automatically dying when they are no longer needed, keep proliferating and keep making IgM of one kind. Basically, those B-cells and the IgM antibody they produce are out of control in WM.

My doctor said WM was a rare disease. How rare is it?
In 2016, the American Cancer Society estimated that there were approximately 1,685,000 cancer cases diagnosed in the US (excluding basal cell and squamous cell skin cancers, which are not reported in its registry). Of these, approximately 1,500-1,700 were WM. This means that roughly one-tenth of 1% of all new cancers were WM.

My doctor says WM is an orphan disease. What does that mean?
An orphan disease is any disease that affects only a small percentage of the population. Typically such a disease does not command much in the way of attention or research dollars because there are few financial incentives for pharmaceutical companies to seek a cure.

What causes WM? Is there an environmental cause?
The specific cause(s) of WM are unknown. The known risk factors are IgM MGUS (monoclonal gammopathy of undetermined significance), male sex, Caucasian race, and increasing age. Other suggested risk factors include a familial history of WM or other B-cell disorders, chronic infectious diseases such as hepatitis or AIDS, and exposure to certain solvents, dyes, and pesticides.

Is there a cure for WM?
No, although quality of life and disease-specific survival for WM patients are continuing to improve because of better treatments.

Is there a familial predisposition to WM? Do I have to worry about my kids getting it?
There is a familial predisposition to WM, with most studies suggesting that approximately 20-25% of patients have a history of the disease or related B-cell disorders in their families. At this time, there is no test that will predict which, if any, family members of a WM patient will ultimately develop WM, although those with IgM MGUS (monoclonal gammopathy of undetermined significance) are at greater risk. We recommend that you don’t worry excessively about your children as WM is primarily a disease of older people and treatments are improving for it.

Does diet have an effect on the course of WM?
There is no specific type of diet or supplement which will have a direct effect on WM. You should follow recommended guidelines for a healthy diet. Some supplements may be helpful and supportive (for instance during treatment), but dietary supplements should be taken only after consulting with your hematologist-oncologist.

How long can I expect to live after being diagnosed with WM?
No one can predict this. A significant percentage of patients may remain on watch and wait (asymptomatic and smoldering WM) for years before requiring treatment. You may see survival numbers of 5-7 years on the Internet, but this is no longer true. Newer and less toxic treatments such as Rituxan are prolonging life expectancy for many WM patients.

What is BTK? What is its significance in WM?
BTK stands for Bruton’s tyrosine kinase. It is an important enzyme in the development and activation of B-cells. When B-cells are exposed to antigens, they are activated through cell pathways that include BTK. If BTK is over-expressed, as it is in WM, it increases the proliferation of WM cells and promotes their survival. BTK is the target of a new oral drug called ibrutinib (trade name Imbruvica), which is being used as treatment for WM. On January 29, 2015, Imbruvica was specifically approved for the treatment of WM by the US Food and Drug Administration, the first drug to achieve this approval. It has since been approved by the European Medicines Agency for use in the European Union and by Health Canada. New BTK inhibitors, including BGB-3111 and ACP-196 (acalabrutinib) are in development to improve effectiveness and reduce side effects.

What is MYD88 and what is the MYD88 mutation I’ve heard about in WM patients?
MYD88 is a protein coded by a gene called myeloid differentiation primary response 88. When B-cells are exposed to antigens, MYD88 initiates several downstream cell pathways that result in the expression of factors critical to the development and activation of B-cells, one of which is BTK. A single specific mutation in the MYD88 gene is designated MYD88 L265P, and this mutation was discovered to have a wider prevalence in WM (approximately 90% of patients) than in most other kinds of blood cancers.

What is the significance of the MYD88 L265P mutation in WM?
Its significance is still not completely understood. Although it is prevalent in WM (approximately 90% of patients), at this point we do not believe it causes the disease. However, it does appear to play an important role in the proliferation and survival of WM cells by leading to over-expression of proteins such as BTK that are involved in B-cell development and activation. Because of its prevalence in WM, its presence or absence may become useful as part of the diagnostic workup of patients with suspected WM or related diseases.

Are there other gene mutations important in WM?
Researchers are looking at several other gene mutations found in significant percentages of WM patients. Such work is still very preliminary, but several mutations in the gene CXCR4 are found in approximately 30% of WM patients, where they appear to be an adverse factor in the prognosis of WM and may lead to the proliferation of WM cells in tissues outside the bone marrow. The IWMF is currently sponsoring research to study CXCR4 mutations and develop treatments to target them.

If I have WM, do I have a greater risk for other cancers?
Several studies have suggested an increased risk for certain cancers, including prostate, breast, skin, other blood cancers, lung, and thyroid. Some of these, particularly other blood cancers, may be related to certain therapies for WM, including alkylating agents and nucleoside analogs. WM patients should remain vigilant about routine screening for other types of cancer.


What kind of skin problems are related to WM?
Skin problems are relatively rare with WM. Sometimes, the WM cells can infiltrate the skin, or the IgM secreted by WM cells can deposit in the skin. Symptoms can include skin thickening, nodules, or rashes. If you have these symptoms, you should see a dermatologist to rule out other causes for skin problems. Occasionally, people with WM may have thrombocytopenia (low platelets) or their high IgM may cause bleeding problems in the skin, leading to bruising, purpura (small red or purple areas), or petechiae (tiny spots).

What is the cause of night sweats in WM?
Drenching night sweating is one of the B-cell symptoms associated with lymphoma. We do not have a definitive answer as to the cause, but one possible mechanism is that the progression of lymphoma and the body’s way of fighting infection have some things in common—both may lead to the mobilization of immune cells and associated proteins called cytokines, and their activities may account for fever, muscle aches, and night sweats.

How can WM affect my eyes?
WM can affect the eyes in several ways. The IWMF quarterly newsletter, the Torch, has published an excellent article on this subject, called “Waldenström and the Eye,” written by Dr. Maureen Hanley, a doctor of optometry.

What is peripheral neuropathy? What does it feel like?
Peripheral neuropathy (PN) is a dysfunction of those nerves that extend from the spinal cord out to the peripheral portions of the body. It is estimated that approximately 20-30% of WM patients have PN. PN occurs not just from the disease itself but can be a consequence of certain treatments for it, and diabetes and other disorders can also cause it. The symptoms of PN are often related to sensation, including tingling or prickling, numbness, cold, tightness, burning, shooting or stabbing pains, and sensitivity to contact. These symptoms usually begin in both feet and can eventually extend upward so that both hands are affected. PN can also affect the motor nerves, resulting in weakness, difficulty in rising from a sitting position, and decreased grip strength. PN of the involuntary (autonomic) nerves may result in lightheadedness upon standing, dry eyes and mouth, early satiety (sensation of fullness after eating), constipation or diarrhea, difficulty voiding, lack of sweating, and erectile dysfunction.


What is a bone marrow biopsy? What should I expect?
A bone marrow biopsy is performed to look for abnormalities in the bone marrow, which is the spongy tissue inside the larger bones where blood cells are produced. This procedure can be performed in a physician’s office or in a monitored setting (such as a hospital) under local anesthetic or light sedation. The specimen is usually obtained from the posterior iliac crest (back of the hip bone) by using a large-bore needle. Both a liquid bone marrow sample and a solid bone sample may be taken. A pathologist examines the bone marrow cells under a microscope and may also perform additional testing with special stains of the cells to identify the presence of an abnormality. There may be some discomfort or a feeling of pressure if a local anesthetic is given. The biopsy site may be bruised and sore for a few days following the procedure.

How often do I need to have a bone marrow biopsy?
Every WM patient should have received at least one because it is necessary to establish the diagnosis of WM. Frequent bone marrow biopsies are not usually recommended for disease monitoring because this is a costly and invasive technique. However, there may be situations where additional biopsies are warranted, such as during the course of a clinical trial, to help determine if a patient needs treatment, or to decide how a patient's bone marrow is responding to therapy.

Which measurement is more reliable/valuable – IgM or SV (serum viscosity)?
In general, the IgM measurement is more reliable and is one of the more important parameters used in determining a WM patient’s disease status, although it is not the only one. Some WM patients never develop high serum viscosity but have other symptoms associated with their disease (anemia, peripheral neuropathy, etc.). However, the SV measurement can be important for those patients who tend toward high IgM levels and need to monitor their serum viscosity as one way to help determine if they need treatment.

Are IgG and IgA levels an important measurement to follow too?
WM patients tend to have low levels of both these immunoglobulins for reasons that are unknown. If a patient has recurrent infections (sinus infections or bronchitis, for example), then low IgG and IgA levels may be responsible, and possible treatment could include IVIG (intravenous IgG) infusions. If a WM patient is not experiencing recurrent infections, this measurement is probably less important.

What are the key numbers in my blood testing?
Generally speaking, the most important blood tests to monitor are IgM (either total IgM or monoclonal IgM), hemoglobin/hematocrit, and platelets. Patients with special issues, for instance WM-related kidney disease, amyloidosis, cryoglobulinemia or enlarged lymph nodes may need to monitor their disease progression with additional tests. More about these special conditions can be found here.


Why am I on watch and wait and not being treated?
At this time, treating asymptomatic WM does not save lives, increase the quality of life, cure the disease, or change the long-term outlook. Patients without significant symptoms affecting quality of life receive no benefit from early treatment and therefore should not be treated. The IWMF is supporting research to explore what factors trigger IgM MGUS and asymptomatic WM to become full-blown WM. One important goal of this research is to identify those asymptomatic patients who are most likely to progress and might benefit from early, relatively non-toxic treatment to prevent further development of the disease.

When should I get treatment?
Patients should be treated when they become symptomatic. To some extent, the decision to begin treatment is dependent on a particular patient’s tolerance of symptoms and how they are affecting quality of life. The IgM level in and of itself is not an indication for treatment. Click here for more information about specific indications for treatment.

What treatments are approved for WM?
There is only one FDA-approved treatment for WM in the US, and that is Imbruvica (ibrutinib). US FDA approval typically requires Phase III trials with large numbers of participants, and such trials are very infrequent for a rare disease like WM, although approval was expedited in the case of Imbruvica. Most treatments are based upon results achieved for similar diseases such as follicular lymphoma, chronic lymphocytic leukemia, and multiple myeloma. Smaller Phase I and Phase II studies are done with WM patients to establish safe and effective dosing regimens. There are a number of treatment options available for WM patients, and many of these can be accessed here. Several major cancer centers have developed guidelines for WM treatment that are available here. Novel therapies are continually being discovered and tested in clinical trials. For an updated list of trials, go to www.clinicaltrials.gov.

What is plasmapheresis? What should I do before, during, and after plasmapheresis?
During plasmapheresis (PP) whole blood is removed from the body, it goes into a centrifuge where various components are separated, the desired component is removed, and then everything else is returned to the body. In the case of PP for WM, the plasma (which contains the IgM) is discarded and the remaining blood returned to the patient. The removed plasma must be replaced, typically with albumin or fresh frozen plasma, in order to maintain the proper blood volume. Improvement of symptoms is usually rapid. PP does not reduce the tumor cell burden; therefore, the WM cells continue to make IgM.  PP is usually used to reduce IgM prior to therapy, with the expectation that therapy will reduce the tumor burden, making PP no longer necessary. Some patients can be treated with PP on a long-term basis if they cannot tolerate therapy. The process itself is about 1½-2 hours long, so patients should use the bathroom just prior to the procedure. If a patient’s veins are large enough, a needle is inserted in each arm, one to draw the blood out and the other to return the remaining blood; otherwise, a special catheter is inserted. Catheter insertion is an outpatient procedure performed under local anesthetic or light sedation. Patients should eat and drink prior to the procedure and should wear short-sleeved shirts and loose-fitting clothes. The procedure can cause lightheadedness due to a temporary drop in blood pressure, and blood pressure will be monitored closely during the procedure. The anti-coagulant used during the process can cause low calcium levels in the blood, and tingling of the lips may be an early sign that calcium levels are dropping. Patients should be alert to these or any other unusual symptoms during the PP process and communicate them to the PP technician. It is advisable to have someone drive the patient home following PP.

What is Rituxan? What’s involved in treatment with Rituxan?
Rituxan is a monoclonal antibody, part human and part mouse, which stimulates the body’s immune system to fight disease. Specifically, it is targeted against a protein called CD20 that is found on the surface of almost all B-cells. The advantage of Rituxan and other monoclonal antibody therapies is that they are not toxic to other cells in the body, unlike traditional chemotherapy. The standard dose of Rituxan is calculated by a formula based on weight and height, and the drug is infused intravenously. Rituxan is typically given as one infusion per week for 4-8 weeks, although other dosing protocols have been used. It can be used as a single agent or in combination with other treatments. Most of the side effects of Rituxan occur during the first infusion, with subsequent infusions causing fewer problems. These side effects can include fever, chills, dizziness, flushing, shortness of breath, headache, and itching. If you are experiencing any of these side effects or notice any other unusual symptoms, it is important to notify your infusion nurse so that these side effects can be managed. Depending on your body’s reaction to the infusion, it usually takes 2-4 hours to administer Rituxan, and pre-medications such as Tylenol and Benadryl are given to reduce the side effects of these reactions.

I’ve heard that Rituxan can cause IgM flare.  What is that?
Rituxan treatment can cause a temporary increase in IgM known as IgM flare. This has been reported in 40-50% of patients using Rituxan alone and can induce symptomatic hyperviscosity in some patients. Flare may last up to four months. There is no way to predict which patients will have an IgM flare with Rituxan treatment, although those with an already high IgM level before treatment are more at risk from it. If a patient with high IgM elects to undergo Rituxan-based therapy, plasmapheresis to reduce IgM before treatment is a good way to minimize flare. If Rituxan is being used in combination therapy, waiting until the second or third round of therapy to administer Rituxan may be another way to reduce the risk of flare. Patients with high IgM at the start of therapy should have their IgM monitored frequently during treatment.

What can I expect from treatment for WM?
There is currently no treatment that cures WM. The goal of treatment is to reduce or relieve the severity of the symptoms you had when you began treatment, to improve your quality of life, and to maintain that state for an extended period of time. While you are undergoing treatment and for a while afterward, you may experience temporary symptoms related to treatment side effects. Some of these may occur during an infusion and may be alleviated by certain pre-medications. Others may remain throughout the course of the therapy and for a short while afterward. These include fatigue, nausea, hair loss, weight loss, low blood counts, and fever, to name a few. Treatment side effects vary according to the specific type of treatment, and you should consult your physician to determine exactly what to expect.

Are there any foods that are beneficial or harmful to eat while on the various therapies?
You should try to eat a healthy, well balanced diet rich in whole grains, fruits, and vegetables and minimize your intake of fatty foods, sweets, and red meat. This applies to patients at any stage of their disease, whether undergoing treatment or not. Avoid hot or spicy foods if you have mouth sores, dry mouth, or gastrointestinal problems while on treatment. Patients with neutropenia (greatly decreased neutrophils, a type of white blood cell) should avoid raw fruits, raw vegetables, and raw seafood during the period of low blood counts. Studies have suggested that grapefruit, green tea, and fish oil may interfere with the effectiveness of certain treatments or may increase treatment side effects. Always ask your physician if there are any particular foods you should avoid while on treatment and advise him or her of any dietary supplements you are taking.

How can I treat my peripheral neuropathy? Will it improve with treatment?
First, the cause of your peripheral neuropathy (PN) must be determined. If WM is the cause, treating the disease may cause some improvement, although unfortunately it is very difficult to restore nerve function once it has been damaged. The goal of most treatments is to try to keep the neuropathy stable and prevent it from becoming worse. Rituxan may have some effectiveness, but better data is needed to confirm this; plasmapheresis may also be helpful. There are topical or oral agents that reduce symptoms, but they do not completely alleviate the discomfort – the goal is to reduce it to a manageable level. Chemotherapy-induced neuropathy can be treated by reducing or discontinuing treatment or by using topical or oral agents to reduce symptoms. For more information on WM and peripheral neuropathy, please read Dr. Todd Levine's article, "Waldenstrom's and Peripheral Neuropathy," in the April 2010 edition of The Torch.

Are there any treatments that target the MYD88 mutation in WM patients?
There are no treatments that target the MYD88 L265P mutation. However, there are drugs that target some of the downstream proteins in the MYD88 pathway. Ibrutinib (trade name Imbruvica) is an oral therapy developed to inhibit Bruton’s tyrosine kinase (BTK). Other BTK inhibitors are also in development, as are drugs that inhibit IRAK-1 and IRAK-4, which are additional proteins in the downstream pathway of MYD88.

Are there any alternative medicine treatments for WM?
No. Certain complementary therapies, such as yoga, tai chi, acupuncture, massage, etc., can improve your emotional well-being and quality of life as a cancer patient, but they should not be substituted for conventional treatments. If you are considering dietary supplements, you should consult your physician first. You can read more about complementary and alternative medicine here.

How do I learn about the availability of drug trials?
You can search for clinical trials by disease or by disease and geographic region on the National Institutes of Health website at www.clinicaltrials.gov. You should also consult with your hematologist-oncologist about the local availability of clinical trials.

If I am a relatively young patient, should I consider a stem cell transplant early in my disease or wait until later?
An autologous stem cell transplant (one that uses your own stem cells) is one possible option for younger patients. Autologous transplantation has become a much safer option now than in the past and is achieving good responses. It appears that patients have a better chance at improved survival and quality of life if they don’t wait until they have been heavily treated before transplant. Current thinking is that younger patients may want to consider transplant after one or two treatment regimens. Patients may also consider collecting or “banking” stem cells for a future autologous transplant, as stem cells can safely be stored for 20 years or more. It is possible that the continued development of newer and less toxic drug therapies may make the use of autologous stem cell transplant a somewhat less-considered treatment option for young patients in the future.As a general rule, allogeneic transplant (one that uses stem cells from a donor) is not recommended for WM patients unless they have aggressive disease that is not responding to treatment.

What if my treatment doesn't work?
Some treatments work faster than others, so you should allow adequate time for your treatment to work. Just because you don’t see immediate results doesn’t mean you have treatment failure. Since WM is usually slow-growing, it is frequently not necessary to achieve immediate results in order to save life. Treatment options are increasing all the time, and if your treatment has truly failed, you and your physician should be able to determine an alternate course of therapy, perhaps with the advice of a WM expert. The IWMF website maintains a list of experts.

I am considering treatment with ibrutinib (trade name Imbruvica). What can I expect?
The IWMF quarterly newsletter, the Torch, has published an excellent article on the most common questions that WM patients ask about ibrutinib, called “Ibrutinib in WM,” written by Dr. Jeffrey Matous of the Colorado Blood Cancer Institute.

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