What are the treatment options for Waldenström's Macroglobulinemia (WM)?

From the Guidelines

The most effective treatment option for Waldenström's Macroglobulinemia (WM) is a combination of rituximab with either bendamustine or a proteasome inhibitor like bortezomib, with the DRC regimen (dexamethasone-rituximab-cyclophosphamide) being a safe and active treatment choice for first-line treatment of WM 1.

Treatment Options

The treatment of WM typically begins with a watch-and-wait approach for asymptomatic patients, initiating therapy only when symptoms develop.

• First-line treatment usually involves a combination of rituximab (anti-CD20 monoclonal antibody) with either bendamustine or a proteasome inhibitor like bortezomib.
• The standard rituximab-bendamustine regimen consists of rituximab 375 mg/m² on day 1 and bendamustine 90 mg/m² on days 1-2 of a 28-day cycle for 4-6 cycles.
• For patients with specific genetic mutations like MYD88 L265P, Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib (420 mg daily), zanubrutinib (160 mg twice daily), or acalabrutinib (100 mg twice daily) are highly effective options 1.

Special Considerations

• Plasmapheresis may be necessary for hyperviscosity syndrome, removing excess IgM proteins from the blood.
• Treatment decisions should be individualized based on the patient's age, comorbidities, symptoms, and genetic profile, with the goal of controlling symptoms and preventing complications rather than achieving complete remission, as WM remains incurable but often manageable as a chronic disease for many years.
• The DRC regimen is an active and safe treatment choice for first-line treatment of WM with a manageable toxicity, and it can be considered in frail patients requiring combination therapy 1.

Recent Guidelines

• The eighth international workshop on Waldenström's macroglobulinemia recommends the use of plasmapheresis for patients with symptomatic hyperviscosity, and the use of rituximab in combination with other agents such as bendamustine or bortezomib for first-line treatment of WM 1.
• The guidelines also recommend the use of ibrutinib as a single agent or in combination for symptomatic WM patients who are not candidates for chemoimmunotherapy 1.

From the FDA Drug Label

The safety and efficacy of IMBRUVICA in patients with WM were demonstrated in two single-arm trials and one randomized, controlled trial. Study 1118 (NCT01614821), an open-label, multi-center, single-arm trial was conducted in 63 previously treated patients with WM IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed prior rituximab-containing therapy and received single-agent IMBRUVICA. The INNOVATE study, a randomized, double-blind, placebo-controlled, phase 3 study of IMBRUVICA or placebo in combination with rituximab (NCT02165397), was conducted in treatment naïve or previously treated patients with WM

The treatment options for Waldenström's Macroglobulinemia (WM) include:

• Ibrutinib (IMBRUVICA) as a single agent
• Ibrutinib (IMBRUVICA) in combination with rituximab 2 2

From the Research

Treatment Options for Waldenström's Macroglobulinemia (WM)

The treatment options for WM include:

• Alkylating agents, nucleoside analogues, monoclonal antibodies, and proteasome inhibitors as single therapeutic agents or as combination therapies 3
• Chemoimmunotherapy or a covalent Bruton tyrosine kinase inhibitor as recommended first-line therapy 4, 5
• Rituximab and bendamustine (without rituximab maintenance) or zanubrutinib as preferred Mayo Clinic induction 4, 5
• Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, bendamustine, and venetoclax as active agents in relapsed WM 4, 6, 5
• Ibrutinib as a suitable treatment option for both treatment-naïve and relapsing WM patients 7
• Bendamustine-containing therapy, which has been shown to produce durable responses in previously treated WM, both as monotherapy and with CD20-directed monoclonal antibodies 6

Factors Influencing Treatment Selection

The selection of treatment for WM is influenced by factors such as:

• Age, albumin, hemoglobin level, platelet count, β2 microglobulin, Lactate dehydrogenase (LDH), and monoclonal IgM concentrations, which are predictive of outcomes 4, 5
• The presence of the L265P mutation in MYD88, which is detectable in more than 90% of patients and is found in most IgM MGUS patients 4, 5
• The reduction of therapy toxicity, which is an important part of treatment selection given WM's natural history 4, 5