New Advances in Waldenström Macroglobulinemia

Waldenström Macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by the malignant accumulation of IgM-producing lymphoplasmacytic cells in the bone marrow and other organs.1 Recurrent somatic mutations in MYD88 and CXCR4 are observed in approximately 90% and 40% of patients with cancer, respectively, and give the malignant cells a survival advantage through apoptosis escape mechanisms.2,3

The genomic profile impacts the clinical presentation of patients with WM. For example, patients with CXCR4-mutated disease typically present with high serum IgM levels, symptomatic hyperviscosity, and acquired von Willebrand disease.4 In contrast, patients with MYD88 wild-type disease have a higher risk of an aggressive transformation and experience inferior survival outcomes.5

One-third of patients are diagnosed with WM in an asymptomatic phase, also known as smoldering or inactive WM. These patients have an overall survival similar to age-, sex-, and race-matched individuals of the general population.6 The asymptomatic WM risk scoring system uses the percentage of bone marrow involvement, serum IgM, albumin, and beta-2-microglobulin levels to identify patients at high, intermediate, and low risk of needing therapy.7 As WM is currently incurable using standard therapies, and the available therapies can induce adverse effects, therapy should be reserved for patients with symptomatic WM whose activities of daily living are impacted by the disease.8
Approximately 80% of patients with asymptomatic WM will require therapy within 10 years of diagnosis.7 Criteria for treating WM include symptomatic anemia; constitutional symptoms such as fevers, drenching night sweats, or unintentional weight loss; symptomatic hyperviscosity; progressive neuropathy; and symptomatic lymphadenopathy or organomegaly. Other rare indications to treat include symptomatic cryoglobulinemia, cold agglutinin syndrome, systemic light chain amyloidosis, and the rare Bing-Neel syndrome, in which WM cells invade the central nervous system.

Several treatment options exist for patients with symptomatic WM, but no large, randomized studies have compared the commonly used regimens. Therefore, treatment selection is highly personalized and should consider the patient’s clinical presentation, comorbidities, concurrent medications, genomic profile, treatment objective, and personal preferences.9 The modified staging system for WM is an externally validated multi-institutional prognostic model to estimate the survival of patients with active, symptomatic WM and uses age, serum beta-2-microglobulin, lactate dehydrogenase, and albumin to classify patients into low-, low-intermediate, intermediate, and high-risk disease.10
Rituximab (Rituxan)-containing regimens, also known as chemoimmunotherapy, are commonly used with a long track record and evidence of durable responses.11-15

Beyond deep and durable responses, advantages of chemoimmunotherapy include a fixed duration, potentially allowing patients to be off therapy for years. However, chemoimmunotherapy can induce cytopenias, a higher risk of infections, and the development of myeloid neoplasms.

Over the past decade, Bruton tyrosine kinase (BTK) inhibitors have become a standard treatment option. Ibrutinib was highly effective in WM and induced deep and durable responses.16,17 The combination of ibrutinib (Imbruvica) and rituximab induced deeper and more durable responses than rituximab plus placebo in the phase 3 INNOVATE study (NCT02165397).18 Zanubrutinib was as effective as ibrutinib but was associated with lower rates of diarrhea, rash, and atrial fibrillation in the phase 3 ASPEN study (NCT03053440).19

These findings supported the FDA approval of ibrutinib in 2015, ibrutinib and rituximab in 2018, and zanubrutinib in 2021 for the treatment of patients with WM. The advantages of BTK inhibitors include the ease of oral administration and the absence of risk of myeloid neoplasms. On the other hand, BTK inhibitors are associated with unique adverse events, such as an increased risk of bleeding, hypertension, and arrhythmia. The duration of therapy is indefinite and should continue until disease progression or unacceptable toxicity.

Beyond chemoimmunotherapy and BTK inhibitors, BCL2 antagonists such as venetoclax and noncovalent BTK inhibitors such as pirtobrutinib are safe and effective options.20,21 The National Comprehensive Cancer Network guidelines endorse both agents to treat patients with WM with previously treated disease. Tumor lysis monitoring is essential when ramping up the dose of venetoclax (Figure 1).

Clinical trial participation is essential to develop safer and more effective agents to treat WM. Any patient with WM should consider clinical trial participation at any stage of the disease.

In the frontline setting, a series of randomized European trials are comparing chemoimmunotherapy regimens, such as cyclophosphamide, dexamethasone, and rituximab vs ibrutinib plus rituximab in the phase 2/3 RAINBOW trial (NCT04061512) or vs venetoclax plus rituximab in the phase 2 VIWA-1 study (NCT05099471). Single-arm studies are evaluating BTK inhibitors in combination to provide fixed-duration therapy, including acalabrutinib (Calquence), bendamustine (Bendeka), and rituximab in the phase 2 BRAWM trial (NCT04624906); zanubrutinib (Brukinsa), bendamustine, and rituximab in the phase 2 ZEBRA trial (NCT06561347); and zanubrutinib and sonrotoclax in another phase 2 trial (NCT05952037).

In the relapsed setting, the phase 2 CLOVER-WaM study (NCT02952508) evaluating the radioconjugate iopofosine I-131 has completed accrual of patients, and results are expected soon. A number of other agents are under active clinical development and assessment in trials, including the following: pirtobrutinib plus venetoclax in a phase 2 study (NCT05734495), the second-generation BCL2 inhibitor sonrotoclax as monotherapy and in combination with zanubrutinib in a phase 2 study (NCT05952037), and the BTK degrader BGB-16673 in a phase 1/2 study (NCT05006716). Others include NX-5498 in a phase 1a/1b trial (NCT05131022), NX-2127 in another phase 1a/1b trial (NCT04830137), the anti-CD19 antibody-drug conjugate loncastuximab tesirine in a phase 2 study (NCT05190705), and the anti-CD20 bispecific antibody epcoritamab (Epkinly) in another phase 2 trial (NCT06510491). Additionally, chimeric antigen receptor T-cell therapy will soon enter clinical trials for patients with WM.

Clinical trials for special WM populations include a phase 2 study (NCT05065554) evaluating the combination of acalabrutinib and rituximab for patients with IgM monoclonal gammopathy of undetermined significance or WM with predominantly demyelinating neuropathy. Given WM’s rarity, clinical trials are essential to advance the field, and multi-institutional collaboration is crucial.

In Europe, the European Consortium for Waldenström’s Macroglobulinemia (ECWM), under the direction of Christian Buske, MD, was formed to improve the understanding of the biology of WM and develop therapies to enable patients with WM to live a life without compromise, with the final goal of achieving a cure. Dana-Farber Cancer Institute, in Boston, Massachusetts, under the direction of Jorge Castillo, MD, and in partnership with the International Waldenström’s Macroglobulinemia Foundation, created a US-based think tank to advance clinical research in WM, known as the WM-NET.

The WM-NET comprises more than 20 academic institutions in the US and will help design and support scientifically driven multi-institutional clinical trials in the US (Figure 2).

Other projects include the development of an academic prospective database aimed at answering questions that are unlikely to be answered by clinical trials and establishing a biorepository for blood and marrow samples from clinical trial participants to enhance WM-specific research efforts further (Figure 2). A cross talk between the ECWM and the WM-NET is being planned.

References

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