IWWM-12: Latest updates and clinical developments in novel/emerging therapies

During the 12th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-12), the Lymphoma Hub was pleased to speak to Jorge Castillo, Dana-Farber Cancer Institute, Boston, US. We asked, What were the latest updates and clinical developments in novel/emerging therapies shared at IWWM-12?

In this interview, Jorge Castillo shares the advancements in targeted therapies and immunotherapies, including novel BTK inhibitors, BTK degraders, BCL-2 inhibitors, and novel therapeutic combinations. Castillo also discusses emerging research relating to antibody–drug conjugates, phospholipid–drug conjugates, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies, highlighting the potential for improved outcomes with fixed-duration therapies compared with continuous treatment, while reducing toxicity.

Key points

Targeted therapies

• Covalent BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, are well-established and effective treatments for Waldenstrom's macroglobulinemia (WM).
• Non-covalent BTK inhibitors, such as pirtobrutinib, show promising response rates of ~70% in patients progressing after covalent BTK inhibitors, with mild side effects such as rash and gastrointestinal issues, and reduced risks of bleeding and arrhythmias, compared with covalent BTK inhibitors.
• Novel drug classes include BTK degraders, which act to target and degrade the BTK protein rather than inhibiting it, with early data, for example for BGB-16673 and NX-5948, suggesting efficacy, even in patients previously treated with covalent and non-covalent BTK inhibitors.
• Novel BCL-2 inhibitors, such as sonrotoclax, have demonstrated early efficacy in venetoclax-resistant cells, indicating potential as an alternative therapeutic option.
• A novel method currently being explored in early-stage clinical trials involves combining BCL-2 inhibitors with BTK inhibitors, for example pirtobrutinib and venetoclax, offering potential for an all-oral, non-chemotherapy, fixed-duration treatment regimen.
• Clinical trials, such as the BRAWM (NCT04624906) trial, are investigating targeted agents combined with chemotherapy or rituximab-based regimens, and have shown promising depth of response.
• The goals of advancing targeted therapies and novel regimens are to limit treatment duration, improve accessibility, reduce treatment-related toxicities, and allow for future retreatment without resistance development.

Immunotherapies

• Antibody–drug conjugates and phospholipid–drug conjugates are being studied to deliver targeted therapy directly to malignant cells in WM, for example in the CloverWaM (NCT02952508) trial.
• Bispecific antibodies and CAR T-cell therapies are under investigation for WM, with early trial data showing promise.
• While there are no mature data for these immunotherapies specifically in WM, the latest data from ongoing trials are promising.

This educational resource was independently supported by BeiGene. All content was developed by SES in collaboration with an expert steering committee; funders are allowed no influence on the content of this resource.