What is Waldenström's (Waldenström's macroglobulinemia)?

From the Guidelines

Waldenstrom's macroglobulinemia should be treated with bendamustine-rituximab as primary therapy for bulky disease, profound hematologic compromise, or constitutional symptoms attributable to WM, as recommended by the Mayo Clinic Cancer Center Myeloma, Amyloidosis and Dysproteinemia and Lymphoma Disease-Oriented Groups 1.

Treatment Overview

Waldenstrom's macroglobulinemia (WM) is a rare type of slow-growing blood cancer that begins in white blood cells called B lymphocytes. It's characterized by an overproduction of a protein called immunoglobulin M (IgM), which causes the blood to become thick, leading to various symptoms.

Key Considerations

• Treatment is typically initiated when patients become symptomatic.
• Other effective options include rituximab-based combinations such as rituximab-cyclophosphamide-dexamethasone (RCD) 1.
• For patients with hyperviscosity syndrome, plasmapheresis may be urgently needed to reduce IgM levels, as it can remove 80% of the IgM protein and is effective in relieving the related signs and symptoms of hyperviscosity 1.
• The choice of appropriate therapy should take into account the candidacy of a patient for high-dose chemotherapy because prolonged use of both alkylating agents and nucleoside analogs can deplete hematopoietic stem cells 1.

Monitoring and Follow-up

• Treatment response is monitored through IgM levels, with complete remission being rare but long-term disease control being achievable.
• The disease course is typically indolent with a median survival of 5-11 years, though outcomes vary based on factors like age, hemoglobin levels, and genetic mutations.
• Regular monitoring is essential even during remission periods to detect early signs of disease progression.

Additional Recommendations

• Cyclophosphamide-based therapy such as R-CHOP or DRC could be an appropriate choice if control is needed, as cyclophosphamide can be used in patients who are transplantation candidates because it is not toxic to stem cells 1.
• Early reports for the combination of bortezomib, dexamethasone, and rituximab are encouraging and may represent an ideal choice for patients with hyperviscosity in whom rapid reduction of the paraprotein is needed 1.

From the Research

Definition and Diagnosis of Waldenström's Macroglobulinemia

• Waldenström's macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein 2, 3.
• Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity 2, 3.
• The presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis 2, 3.
• The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS patients 2, 3.

Treatment Options for Waldenström's Macroglobulinemia

• Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop 2, 3.
• Rituximab-monotherapy is inferior to combination regimens 2, 3.
• Recommended first-line therapy can be chemoimmunotherapy or a covalent Bruton tyrosine kinase inhibitor 2.
• The preferred Mayo Clinic induction is either rituximab and bendamustine or zanubrutinib 2.
• Alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenström's macroglobulinemia 4.
• Ibrutinib plus rituximab has shown sustained efficacy in Waldenström's macroglobulinemia, with a significant improvement in progression-free survival and response rate compared to placebo plus rituximab 5.

Relapsed or Refractory Waldenström's Macroglobulinemia

• Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, pirtobrutinib, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM 2, 3.
• Reuse of a previous regimen or another primary therapy regimen are acceptable options for previously treated patients with Waldenström's macroglobulinemia who had an initial durable response 4.
• Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging options for the treatment of Waldenström's macroglobulinemia 4.