From May 13–19, 2026, the 12th World Congress on Multiple Myeloma (COMy 2026) was held in Paris, France. As one of the most influential international meetings in the field of multiple myeloma and related plasma cell disorders, the congress brought together leading experts worldwide to discuss the latest advances in translational research, novel therapeutics, and patient care.During the meeting, Professor Steven P. Treon of the Dana-Farber Cancer Institute, Harvard Medical School, delivered a comprehensive overview of the remarkable progress achieved in Waldenström macroglobulinemia (WM) over the past decade and shared his perspective on the future direction of the field.
Genomic Discoveries Lay the Foundation for Precision Medicine in WM
The treatment landscape of Waldenström macroglobulinemia has undergone a dramatic transformation over the past decade, evolving from empiric chemoimmunotherapy to highly targeted therapeutic approaches. According to Professor Treon, this progress has been driven by a deeper understanding of the molecular biology underlying the disease.
The MYD88 L265P mutation, present in approximately 95%–97% of patients with WM, represents the central molecular driver of the disease. Through constitutive activation of the BTK signaling pathway and downstream NF-κB and ERK signaling, this mutation promotes tumor-cell survival and proliferation.
In addition, approximately 40% of patients harbor CXCR4 mutations, most commonly nonsense or truncating variants. Patients with CXCR4-mutated disease typically present with higher serum IgM levels, more pronounced hyperviscosity syndrome, slower responses to covalent BTK inhibitors, less profound remissions, and shorter progression-free survival.
Given these well-established genotype–phenotype associations, Professor Treon strongly advocated routine testing for both MYD88 and CXCR4 mutations before treatment initiation. Beyond their prognostic value, these biomarkers increasingly guide therapeutic decision-making and influence drug selection.
These genomic discoveries have transformed WM into one of the clearest examples of precision medicine in hematologic malignancies and have provided a strong biological foundation for the development of next-generation targeted therapies.
Optimizing Covalent BTK Inhibitor Selection: From ASPEN to Clinical Practice
Covalent BTK inhibitors have become the cornerstone of WM treatment, with agents such as ibrutinib, zanubrutinib, and acalabrutinib now widely available.
Professor Treon highlighted the pivotal ASPEN trial, the first phase III head-to-head comparison of zanubrutinib and ibrutinib in WM.
Although overall response rates were comparable between the two treatment arms, zanubrutinib demonstrated several clinically meaningful advantages.
Most notably, patients with MYD88 wild-type disease, who represent approximately 3%–5% of the WM population, appeared to derive greater benefit from zanubrutinib.
Safety outcomes also favored zanubrutinib, with significantly lower rates of atrial fibrillation and hypertension, although neutropenia occurred somewhat more frequently.
Importantly, among patients harboring CXCR4 mutations, zanubrutinib achieved deeper responses and longer progression-free survival.
Based on these findings, Professor Treon suggested that zanubrutinib should be strongly considered for patients with CXCR4-mutated disease and for those with MYD88 wild-type WM.
This recommendation reflects a broader principle of precision oncology: even within the same therapeutic class, treatment selection should be guided by the molecular characteristics of the individual patient.
Rethinking Frontline Therapy: Balancing BTK Inhibitors and Chemoimmunotherapy
The optimal frontline treatment strategy for newly diagnosed WM remains an area of active discussion.
Professor Treon reviewed data from both the Mayo Clinic and the European FILO cooperative group to compare BTK inhibitors with traditional chemoimmunotherapy regimens such as bendamustine plus rituximab (B-R).
In the short term, both approaches achieve high response rates and effective disease control in patients with MYD88-mutated disease.
However, long-term follow-up has revealed important limitations of chemoimmunotherapy.
Data from the FILO study demonstrated that approximately 50% of patients treated with B-R developed persistent cytopenias. Furthermore, treatment was associated with an increased risk of therapy-related myelodysplastic syndrome and acute myeloid leukemia.
Even more concerning, prior exposure to alkylating agents or nucleoside analogs was associated with a significantly higher frequency of TP53 mutations, which in turn correlated with inferior overall survival and disease-related mortality.
Based on these observations, Professor Treon argued that BTK inhibitors should generally be favored over chemoimmunotherapy as frontline treatment for most patients with WM.
Exceptions may include patients requiring rapid reduction of IgM levels because of severe hyperviscosity or selected cases where short-term cytoreductive therapy remains clinically necessary.
This perspective is increasingly influencing contemporary treatment algorithms and shifting the standard of care toward targeted therapy–based approaches.
Fixed-Duration Therapy: Opportunities and Challenges
Although BTK inhibitors provide durable disease control, their requirement for continuous administration creates challenges related to cost, adherence, and cumulative toxicity.
As a result, fixed-duration treatment strategies have emerged as a major area of investigation.
Professor Treon provided a balanced assessment of the progress made thus far.
An early attempt combining ibrutinib and venetoclax was terminated prematurely because of increased rates of atrial fibrillation and less favorable progression-free survival than anticipated.
Nevertheless, several ongoing studies—informally referred to as the “Zebra” trials—are exploring fixed-duration approaches incorporating BTK inhibitors and chemoimmunotherapy.
In Canada, the Zebra study evaluating acalabrutinib plus B-R has reported rare but encouraging cases of minimal residual disease (MRD) negativity.
Similarly, a Chinese study investigating zanubrutinib plus B-R has demonstrated exceptionally high MRD-negative rates at the 10^-4 threshold.
In the United States, another trial is evaluating zanubrutinib combined with only four cycles of B-R in an effort to define the shortest effective treatment duration.
Professor Treon noted that if fixed-duration strategies ultimately prove successful, they could fundamentally alter the treatment paradigm by allowing patients to achieve durable remissions without lifelong therapy.
However, longer follow-up is still required before definitive conclusions can be drawn.
Overcoming BTK Inhibitor Resistance: The Emergence of Degraders and Non-Covalent Inhibitors
As BTK inhibitors become more widely used, acquired resistance is emerging as an increasingly important clinical challenge.
Professor Treon highlighted two particularly promising therapeutic approaches for patients who develop resistance to covalent BTK inhibitors.
The first is the development of non-covalent BTK inhibitors, exemplified by pirtobrutinib.
Among patients previously treated with covalent BTK inhibitors, pirtobrutinib has achieved overall response rates approaching 80%. However, activity appears more limited in MYD88 wild-type disease.
The second—and potentially more transformative—strategy involves BTK degraders based on PROTAC technology.
Agents such as NX-2127 and BGB-16673 bind alternative sites on the BTK protein and promote ubiquitination and proteasomal degradation, thereby overcoming multiple resistance mechanisms, including the well-characterized C481S mutation.
Preclinical and early clinical data have demonstrated impressive antitumor activity with these compounds.
Even more exciting is the development of a first-in-class dual HCK/BTK degrader (DFCI-00206) by Professor Treon’s group. By simultaneously targeting BTK and its upstream activator hematopoietic cell kinase (HCK), this molecule has shown broad activity against multiple resistance-associated mutations in preclinical studies and is currently advancing toward clinical development.
These next-generation degraders may ultimately provide highly effective second- and third-line treatment options for patients with BTK inhibitor–resistant disease.
Immunotherapy and Cellular Therapy: Looking Beyond Targeted Inhibition
For patients with TP53-mutated disease or those who have exhausted multiple lines of therapy, novel immunotherapeutic approaches may offer new opportunities.
Professor Treon reviewed several emerging strategies.
Among antibody-drug conjugates, loncastuximab tesirine, which targets CD19, has demonstrated deep responses—including complete and very good partial responses—in patients with TP53-mutated WM.
Its efficacy may stem from its DNA cross-linking mechanism, which induces irreparable damage in tumor cells lacking functional TP53-mediated repair pathways.
Several bispecific antibodies are also entering clinical evaluation, including agents targeting:
- CD20 × CD3
- CD19 × CD3
- BCMA × CD3
Professor Treon emphasized that WM clones encompass multiple stages of B-cell and plasma-cell differentiation. Consequently, dual targeting of antigens expressed at different developmental stages—such as CD20 and BCMA—may provide broader and more effective disease coverage.
CAR-T cell therapy represents another promising frontier.
A unique challenge in WM is the need to eradicate malignant cells spanning multiple stages of maturation. Accordingly, the development of multi-target CAR-T constructs is already underway.
Although cellular immunotherapy remains at an early stage in WM, the depth of response observed in heavily pretreated patients suggests that these approaches may eventually enable a transition from long-term disease control toward genuine clinical cure.
Conclusion
Professor Steven P. Treon’s presentation vividly illustrated the remarkable evolution of Waldenström macroglobulinemia from a rare disease with limited treatment options to one of the most compelling success stories in precision oncology.
The field now stands at the intersection of genomics, targeted therapy, protein degradation technology, and advanced immunotherapy.
Looking ahead, Professor Treon emphasized that the goal of WM management should extend beyond symptom control and survival prolongation. Through genomics-guided treatment sequencing, earlier incorporation of next-generation degraders, and strategic deployment of cellular immunotherapies, the field is moving toward a future in which more patients can achieve durable, treatment-free remissions.
What once seemed unattainable—the possibility of clinical cure in Waldenström macroglobulinemia—may increasingly become a realistic objective in the decade ahead.
