There are no treatments that can cure WM, although in most cases the disease is indolent (slow growing) and can be effectively managed with appropriate therapies.

Overview of Treatments

There are many different treatment options available for WM patients, and they are increasing as researchers discover more about the biology and genetics of the disease.

Treatment may consist of just one drug (single-agent therapy), or two or more drugs (combination therapy).  Most studies seem to indicate that combination therapies are more effective, resulting in better and/or longer-lasting responses.

Treatment can usually be administered in an outpatient setting or at home.  It may be oral, by intramuscular or subcutaneous injection, or by intravenous therapy.  Some treatments require that certain medications be taken the day before or the day of treatment in order to minimize associated side effects.

Treatment cycles may take several weeks to months, depending on the course of therapy chosen. It is not unusual to have a round of therapy and then wait a week or a month before another round of treatment, although some of the newer oral therapies require daily dosing instead. Hematologist-oncologists follow established protocols for treatment but may make adjustments depending on side effects or response to therapy.

Most of the treatments in use today were originally approved for the related cancers of follicular lymphoma, chronic lymphocytic leukemia, and multiple myeloma.  Once additional Phase 1 and Phase 2 clinical trials established that these treatments had both an acceptable safety profile and were effective for WM patients as well, they were prescribed for “off label” use in WM.

The standard first-line treatment protocol (i.e., the typical first treatment for a WM patient) in Canada, across all provinces, is currently Bendamustine plus Rituximab.  But all WMers are unique and different.  Your oncologist may recommend other approaches, based on your individual symptoms and circumstances.  Below, we provide:

  • an overview of the breadth of treatments available today for WM,
  • a few words about the class of drugs known as BTK inhibitors, and their status in Canada, and
  • a pointer to information about CAR-T therapies.

More information can be obtained by visiting the various subsections in Education on our website.

Treatment options for Waldenstrom’s macroglobulinemia may include the following:

  • OBSERVATION (Watch and Wait)
    If IgM proteins are found in your blood, but you don’t have any signs or symptoms, you may choose to wait before beginning treatment. Your doctor may recommend blood tests every few months to monitor your condition. You may go years without needing further treatment. This is called Watch and Wait.

  • SUPPORTIVE THERAPY
    Such as transfusions or growth factors to boost red blood cells, white blood cells, and platelets.  A typical example is supplying immunoglobulins (IG) to boost the immune system; this can be done either in a hospital setting intravenously (IVIG), or self-injected subcutaneously (SubQ IG or SQIG).

  • PLASMA EXCHANGE
    If you experience signs and symptoms related to having too many IgM proteins in your blood, your doctor may recommend plasma exchange (plasmapheresis) to remove the proteins and replace them with healthy blood plasma.

  • CHEMOTHERAPY
    is a drug treatment that kills quickly growing cells, such as the abnormal blood cells produced by Waldenstrom’s macroglobulinemia.

    Chemotherapy may be used alone or combined with other drug treatments as an initial treatment for people who experience signs and symptoms of Waldenstrom’s macroglobulinemia. High-dose chemotherapy may also be used to suppress your bone marrow production in preparation for a bone marrow transplant. Chemotherapy usually includes alkylating agents such as chlorambucil, cyclophosphamide, and bendamustine or with nucleoside analogs such as fludarabine and cladribine.

  • TARGETED THERAPY
    Targeted therapy drugs kill cancer cells by focusing on the specific abnormalities present in the cancer cells that allow them to survive.  For WM, typical targeted therapy drugs include BTK inhibitors and everolimus, which target B-cell signalling pathways.  Targeted therapy drugs may be used alone or combined with other medications, such as chemotherapy or biological therapy.  Whether alone or in combination, they can be used as an initial treatment for Waldenstrom’s macroglobulinemia, or in cases where the cancer returns despite treatment.

  • BIOLOGICAL THERAPY
    Biological therapy drugs use your immune system to kill cancer cells. Biological therapy drugs can be used alone or in combination with other medications as an initial treatment or as a treatment for recurrent Waldenstrom’s macroglobulinemia.  The most common biological therapy drugs are monoclonal antibodies such as rituximab and ofatumumab.

  • BONE MARROW TRANSPLANT
    In certain highly selected situations, a bone marrow transplant, also known as a stem cell transplant, may be used to treat Waldenstrom’s macroglobulinemia. There are two types of bone marrow transplants. Autologous, where the patient’s own stem cells are removed before receiving high-dose chemotherapy or radiation treatment. (Some times the stem cells are treated before removal). After these treatments are done, the cleaned stems cells are given back to the patient. The second is the Allogeneic or Donor bone marrow transplant, where stem cells are removed from another person, called a donor. Most times, the donor must have the same or similar genetic makeup as the patient, so that he or she is a “match” to the recipient. During this procedure, a lighter dose of chemotherapy is used to wipe out your diseased bone marrow. Healthy donor blood stem cells are infused into your body where they can rebuild healthy bone marrow.

  • CLINICAL TRIALS
    Clinical trials give you a chance to try the latest in Waldenstrom’s macroglobulinemia treatment. Participation in a clinical trial can actually be the best or even the only option available – and should be seriously considered by the patient.  See one of the Common Canadian Questions for more information on clinical trials.

  • CORTICOSTEROIDS
    Including prednisone and dexamethasone

  • IMMUNOMODULATORY DRUGS
    Including thalidomide and lenalidomide.

  • PROTEASOME INHIBITORS
    Such as bortezomib and carfilzomib

A few words about BTK Inhibitors

BTK inhibitors are daily oral drugs that target the Bruton’s tyrosine kinase (BTK) pathway in B-cell growth and development.

With the exception of Bendamustine + Rituximab (BR), no other drug therapy routinely gives such long remissions.  BTK inhibitors are typically less toxic than BR, and the newer-generation of BTK inhibitors improve on the older ones, although they have not been studied as long.  However, BTK inhibitors are “forever drugs”, in that one takes them until there is disease progression or drug toxicity.  And with that comes a much, much higher cost, whether to the medical system or to the patient.

In the Canadian context, the following BTK inhibitors are visible:

  • Imbruvica (ibrutinib) by Janssen.  This was the first BTK inhibitor, and the first drug specifically designated for the treatment of WM, approved by the US FDA in 2015.  It has since been approved by Health Canada for the treatment of WM.
  • Brukinsa (zanubrutinib) by Beigene.  This was approved in May 2021 by Health Canada for the treatment of WM.
  • Calquence (acalabrutinib) by Astra Zeneca.  This has been approved by Health Canada for CLL but is also in a WM clinical trial across Canada.  See our coverage of the BRAWM trial.
  • Pirtobrutinib (formerly Loxo-305) by Loxo Oncology.  This drug is in clinical trials in the US.  It is in a new class of BTK inhibitors known as “non-covalent” BTK inhibitors.  Importantly, it has shown that it can be effective even after patients have relapsed on Ibrutinib.  These trials are open to suitable Canadian WM patients.  However, costs for Canadians to participate in US clinical trials vary widely, by site.  For more information on participating in a US trial, as a Canadian, contact us.  Also, see one member’s experience in such a trial.
  • Nemtabrutinib (formerly ARQ 531 and MK-1026) by Merck.  This drug is in clinical trials in the US and in Canada (see our coverage).  It is another member of the class of non-covalent BTK inhibitors.

The status of funding for BTK inhibitors by the provinces is mixed — at this point (mid-2023), some do and some do not.  Provinces do have the option of granting patients Compassionate Access to these drugs under specific conditions.  See more discussion of paying for BTK inhibitors in our list of Common Canadian Questions.  The cost of the treatment should never be a barrier if it is the best option for you.

CAR-T Therapies

One of the more exciting developments is CAR T-cell therapy, which is being used, successfully, on WM patients in clinical trials and is considered to be potentially curative.  There are, however, very few of those clinical trials in Canada.

CAR-T therapy involves taking a patient’s T cells, performing genetic engineering on them.  That engineering gives the T cells new receptors, which allows those T cells to target a specific molecule typically present on the surface of a specific type of cancer cell.  The new receptors are called chimeric antigen receptors (CARs) and thus (since we are dealing with T-cells), we have CAR-T therapy.  Scientists harvest T cells from people, genetically alter them, multiply them, then infuse the resulting collection of CAR T cells into patients to attack their tumors.

As noted above, the use of CAR-T therapy for WM is still at the clinical trial stage, and rare.  The Princess Margaret Hospital in Toronto has developed an 8-part video course for patients thinking about CAR-T therapy.  If you are contemplating CAR-T, or it has been mentioned to you by your medical team, this set of videos may be of value.

Also, see our post at CAR T-cell Progress in Canada for more information and links about CAR-T therapies.

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