Lynelle Oygenblik

Background: Waldenström macroglobulinemia (WM) is a rare B-cell lymphoma, characterized by the excessive production of IgM. It affects approximately 3 out of every 1,000,000 individuals, with only about 10% of people who have WM being under the age of 50^1,2. Currently, there is no universal consensus or standardized guidelines for the treatment of WM. While treatments like Rituximab and Ibrutinib have been effective, the existing options remain suboptimal in preventing relapse and intolerance, as well as, most importantly, minimizing their impact on patients quality of life³.

Methods: This review was conducted by utilizing PubMed and Google Scholar for key phrases and words such as “Rituximab WM,” “BTK inhibitors WM,” “QoL WM,” “WM Treatment,” and “cell engineering B cell lymphoma.” Relevant studies were selected based on motivation behind the conduction of study in addition to recency.

Results: Various approaches to WM care have been identified in the literature, differing based on whether treatment is centered around disease state, age, or pre-existing conditions. However, current treatment options each come with significant limitations. Rituximab, the primary treatment for the past two decades that targets CD20 on malignant B cells, has been associated with a high incidence of “R-induced IgM flare.” Additionally, intolerance reactions, relapses, and resistance cases have been widely reported.^4,5 Bruton-tyrosine kinase (BTK) inhibitors, such as Ibrutinib, often lead to worsening neuropathy, muscle aches, and fatigue.⁶ Proteasome inhibitors like Bortezomib frequently cause peripheral polyneuropathy, with approximately 30% of patients opting to discontinue the medication due to its severity.⁷ Newer medications, including Sovlepinib and Ixazomib, were developed to minimize side effects within their respective drug classes—SYK inhibitors (downstream to BTK) and proteasome inhibitors.^8,9 However, these treatments are still in the early stages of clinical trials for WM and are not yet available. Given that over 90% of WM patients have an MYD88 mutation and approximately 30% carry a mutation in CXCR4—mutations that are rare or absent in other B-cell malignancies—targeting these genetic markers may offer promising avenues for future therapeutics.¹⁰ One potential strategy could involve the development of targeted adenoviral vectors.¹¹

Conclusions: When determining a treatment plan, physicians must carefully weigh treatment choice and side effects alongside factors such as the patient’s age, WM genomic profile, and existing comorbidities. Current clinical trials show potential for the improvement of pre-existing WM treatment options, but targeting the MYD88 or CXCR4 gene may be a future approach. Overall, further WM treatment research is needed.

Works cited:

1. Gertz, M. A. (2023). Waldenström macroglobulinemia: 2023 update on diagnosis, risk stratification, and management. American Journal of Hematology.
2. International Waldenstrom’s Macroglobulinemia Foundation. (2023). Young Patients with Waldenstrom’s Macroglobulinemia Fact Sheet.
3. Boutilier, A. J., Huang, L., & Elsawa, S. F. (2022). Waldenström macroglobulinemia: Mechanisms of disease progression and current therapies. International Journal of Molecular Sciences, 23(19), 11145. https://doi.org/10.3390/ijms231911145
4. Zhou, X., Hu, W., & Qin, X. (2008). The role of complement in the mechanism of action of rituximab for B-cell lymphoma: Implications for therapy. The Oncologist, 13(9), 954–966. https://doi.org/10.1634/theoncologist.2008-0089
5. Treon, S. P. (2015). How I treat Waldenström macroglobulinemia. Blood, 126(6), 721–732. https://doi.org/10.1182/blood-2015-01-553974
6. Alu, A., Lei, H., Han, X., Wei, Y., & Wei, X. (2022). BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies. Journal of Hematology & Oncology, 15(138). https://doi.org/10.1186/s13045-022-01334-9
7. Kersten, M. J., & Amaador, K. (2022). Combining Ixazomib with subcutaneous rituximab and dexamethasone in relapsed or refractory Waldenström’s macroglobulinemia: Final analysis of the phase I/II HOVON124/ECWM-R2 study. Journal of Clinical Oncology, 40(1), 40–51. https://doi.org/10.1200/jco.21.00105
8. Song, Y., & Cao, J. (2024). Phase I study of the SYK inhibitor sovleplenib in relapsed or refractory mature B-cell tumors. Haematologica. https://doi.org/10.3324/haematol.2022.282401
9. Tedeschi, A., & Tam, C. S. (2024). Health-related quality of life in patients with Waldenström macroglobulinemia: Results from the aspen trial. Future Oncology, 20(25), 1789–1798. https://doi.org/10.1080/14796694.2024.2355079
10. Thapa, S. B., Kaldas, D., Laborde, J., Modukuri, S., Ionescu, F., Blue, B., Chavez, J. C., Alsina, M., Bello, C. M., Pinilla-Ibarz, J., Shain, K. H., Baz, R. C., & Grajales-Cruz, A. (2024). Clinical characteristics and outcomes of patients with MYD88 positive Waldenström macroglobulinemia: A single center retrospective analysis. Blood, 144(Supplement 1), 3021.https://doi.org/10.1182/blood-2024-208701
11. Rice-Boucher, P. J., & Mendonça, S. A. (2023). Adenoviral vectors infect B lymphocytes in vivo. Molecular Therapy, 31(9), 2600–2611. https://doi.org/10.1016/j.ymthe.2023.07.004