A great deal of international collaboration and effort in recent years means that there are novel therapies becoming available for patients with Waldenstrom’s macroglobulinaemia (WM).

These therapies include agents which target chemical pathways within the lymphoplasmacytic (LPL) cells and also affect the way LPL cells collaborate with the environment in which they live (the bone marrow microenvironment). Others include ‘immunomodulatory’ drugs such as thalidomide.

Bortezomib (Velcade ®)

Bortezomib is a proteasome inhibitor and appears to kill lymphoplasmacytic (LPL) cells as well as hamper their support networks within the bone marrow. It has shown encouraging results in trials and appears to be especially effective at lowering a high level of IgM and may also be useful in dealing with high blood viscosity. It is given subcutaneously either twice a week for two weeks and then a week’s break; or weekly for four weeks followed by a week’s break. At present, bortezomib is not available in the NHS in England for patients with WM.

The main side effects of bortezomib are tingling, numbness or pain in the hands and feet, but this seems to be less of a problem now that it is given subcutaneously. It is important to highlight any symptoms of peripheral neuropathy that are present at the outset.

Ibrutinib (Imbruvica®)

Ibrutinib is an agent designed to specifically target and inhibit a signalling protein in cells called Bruton’s tyrosine kinase (BTK). Ibrutinib is a ‘first generation’ (original) BTK inhibitor. BTK is a key factor in B-cell survival. More than 90% of patients with WM have the MYD88 mutation, which is intimately connected to BTK. Ibrutinib plays a part in the deactivation of BTK in people with the MYD88 mutation.

Another mutation – C-X-C chemokine receptor type 4 (CXCR4) – has been identified as providing further insight into which patients are more likely to respond to ibrutinib. This genetic mutation plays a crucial role in modulating the biology of B-cell lymphoproliferative disorders.

Ibrutinib comes in the form of a 140mg tablet in Europe, usually taken three times a day, and also as a 420mg tablet taken once a day.

The Food and Drug Administration (FDA) in the United States granted ibrutinib ´Breakthrough Therapy Designation´ for use as a single agent in previously treated or resistant WM. It is also licensed in Europe by the European Medicines Agency.

In England and Wales, ibrutinib is currently available through the NHS via the Cancer Drugs Fund for adults who have received other treatment previously for WM. This funding arrangement will be reviewed by the National Institute for Health and Care Excellence (NICE) in 2020-2021. From September 2020, ibrutinib in combination with rituximab is available for through the NHS in Scotland for adults who have had at least one previous treatment.

Carfilzomib (Kyprolis®)

Carfilzomib is a ‘next-generation’ proteasome inhibitor related to bortezomib that is given intravenously. It has been analysed in conjunction with rituximab and dexamethasone in 31 patients with WM and shows a high response rate. It appears to be was well tolerated. Studies are ongoing in the US, and it is not yet possible to prescribe carfilzomib for WM outside of a clinical trial.

Ixazomib (Ninlaro®)

Ixazomib is an orally administered proteasome inhibitor which is being evaluated in WM in combination with dexamethasone and rituximab. It appears to be well tolerated. It is not yet possible to prescribe ixazomib for WM outside of a clinical trial.

Acalabrutinib (Calquence®)

This is second generation inhibitor of Bruton’s tyrosine kinase (BTK). It is not yet possible to prescribe acalabrutinib outside of a clinical trial.

Zanubrutinib (Brukinsa®)

Zanubrutinib is a potent and highly selective small molecule BTK inhibitor being developed for the treatment of a variety of lymphomas including WM. A trial comparing zanubrutinib and ibrutinib has completed and results are being analysed.


ONO/GS-4059 (tirabrutinib) is a highly potent and selective BTK inhibitor which is also being explored in clinical trials. Tirabrutinib forms a specific connection with a target in the BTK molecule and, like ibrutinib, irreversibly inhibits its activity.

Idelalisib (Zydelig®)

Idelalisib is another investigational drug in tablet form. However, a recent Phase II study evaluating the safety and efficacy of this drug in patients with WM was prematurely closed owing to the high incidence of liver damage.

Thalidomide (Thalomid ®) and lenalidomide (Revlimid ®)

Thalidomide and lenalidomide are two related drugs, known as immunomodulatory drugs. Both have been trialled in WM patients with limited success, due to problematic side effects (peripheral nerve damage in the case of thalidomide and marked anaemia in the case of lenalidomide). These difficulties, as well as the advent of other, newer, agents, have led to a cessation of trials of these agents at this time.

Pomalidomide (Imnovid ®)

Pomalidomide is a third-generation immunomodulatory drug. Pomalidomide can stop cancer cells from growing abnormally and may also stimulate the immune system to fight the cancer cells and possibly improve the effectiveness of the steroid dexamethasone and the monoclonal antibody rituximab to fight WM cells. This drug, which is taken in tablet form, has been used experimentally in a related condition called multiple myeloma. Research studies suggests that pomalidomide may help to reduce or prevent the growth of cancer cells. Clinical trials are underway which show promising results in WM without the kind of side effects noted with thalidomide and lenalidomide.

Checkpoint inhibitors nivolumab (Opdivo®) and pembrolizumab (Keytruda®)

Programmed cell death protein 1, also known as PD-1 and CD279, is a cell surface receptor that plays an important role in controlling the immune system. This protein is expressed on malignant B-cells in WM and signalling through PD-1 may promote WM cell growth and survival. By counteracting PD-1, nivolumab and pembrolizumab restore the body’s capacity to activate the anti-tumour response and fight cancer cells. A current clinical trial is looking at pembrolizumab in combination with rituximab.

Venetoclax (Venclexta®)

Venetoclax is a potent, highly selective small molecule that has been trialled in a variety of B cell lymphomas including a small number of patients with WM. It has shown decent response rates with an acceptable safety profile. It is not currently available for use for WM in the UK.

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