Waldenström Macroglobulinemia is a rare, indolent B-cell lymphoproliferative disorder classified by the WHO as a lymphoplasmacytic lymphoma that secretes monoclonal immunoglobulin M (IgM). It accounts for approximately 2% of all non-Hodgkin lymphomas and is characterized by bone marrow infiltration with lymphoplasmacytic cells and the presence of monoclonal IgM in the serum. 

EHA 2025 brought various abstracts, among which BeiGene gained attention with its data of BGB-16673 for the treatment of Waldenström Macroglobulinemia. The Phase I/II CaDAnCe-101 study is evaluating the therapy for B-cell malignancies. As of December 17, 2024, 30 patients with Waldenström macroglobulinemia were treated (100 mg: 10; 200 mg: 11; 350 mg: 9). Median age was 72.5 years, and patients had a median of 3 prior therapies, including covalent BTK inhibitors (100%), BCL2 inhibitors (23.3%), and noncovalent BTK inhibitors (13.3%). BTK and TP53 mutations were found in 37.9% and 51.7% of patients, respectively. Median follow-up was 8.1 months.

Treatment-emergent adverse events occurred in 96.7% (Grade ≥3 in 56.7%; serious in 30%). Most common were neutropenia (43.3%), diarrhea (30.0%), bruising (26.7%), anemia (23.3%), fever (20.0%), and thrombocytopenia (20.0%). One patient discontinued due to anemia, and one died from septic shock during progression.

Among 29 response-evaluable patients, overall response rate was 89.7%, major response rate was 75.9%, and very good partial response rate was 31.0%. Median time to response was 0.95 months; to major response, 1.9 months. Responses were seen at the lowest dose (100mg, 10/10), in patients previously treated with a cBTKi (26/29 [89.7%]) and an ncBTKi (4/4 [100%]), and in patients who discontinued prior BTK inhibitor due to PD (21/23 [91.3%]). Responses were independent of mutations in BTK (with, 11/11; without, 14/17), MYD88 (with, 23/25; without, 2/3), CXCR4 (with, 14/14; without, 11/14), and TP53 (with, 15/15; without, 10/13). Median progression-free survival was not reached.

KOL insights

“Many patients with WM will benefit from BTK inhibitor therapy. The fast, deep, and durable responses attained with these agents should be balanced against their unique side effect profile and the indefinite duration of therapy. BTK inhibitor therapy can be optimized by selecting patients who are more likely to benefit and by managing adverse effects.” – Expert Opinion

Conclusion

Bruton Tyrosine Kinase (BTK) inhibitors are highly effective against Waldenström macroglobulinemia. In 2015, IMBRUVICA (Ibrutinib) and in 2021 BRUKINSA (zanubrutinib) were approved by the US Food and Drug Administration (FDA) as a BTK inhibitor, for patients with Waldenström Macroglobulinemia. 

Despite the availability of several safe and effective treatments for Waldenström macroglobulinemia, significant unmet needs remain. These include a low rate of complete responses, reduced effectiveness of BTK inhibitors in patients with nonsense CXCR4 mutations, and the need for continuous treatment with currently FDA-approved therapies. Given their low toxicity, strong anti-lymphoma activity in Waldenström macroglobulinemia, and convenient oral dosing, BTK inhibitors are well-suited for use in effective, chemotherapy-free combination regimens designed to safely enhance the depth and duration of response.

BGB-16673 has shown the potential to overcome all known BTK resistance mutations seen with both covalent and non-covalent BTK inhibitors. As resistance remains a challenge, new approaches to target BTK and the B-cell receptor pathway are needed. Unlike traditional inhibitors that block BTK activity, BTK degraders eliminate the BTK protein itself. Several of these degraders, including BGB-16673, Bexobrutideg (NX-5948), are currently being evaluated in clinical trials.