Disease Course and Risk Model Validation of Asymptomatic Waldenström Macroglobulinemia Patients - a Single Center Experience
Authors: Akhlaghi Theresia , Fernandez-Rengifo Jose , Mejia Saldarriaga Mateo , Rutherford Sarah C. , Rosenbaum Cara , Monge Jorge , Martin Peter , Allan John N. , Furman Richard R. , Niesvizky Ruben , Bustoros Mark 
Published: December 2024

Introduction
Waldenström Macroglobulinemia (WM) is a low-grade lymphoma characterized by clonal proliferation of lymphoplasmacytic cells in the bone marrow and immunoglobulin M (IgM) monoclonal protein in the serum. Asymptomatic (Smoldering) Waldenström Macroglobulinemia (AWM) is an asymptomatic precursor stage to WM, which includes patients with varying risks of progression. In 2019, Bustoros et al. characterized the disease course of AWM based on the largest cohort of AWM patients to date, and developed a progression-risk calculator based on continuous measures of bone marrow infiltration, serum IgM, beta-2-microglobulin (B2M), and albumin levels (AWM model), which was made widely available as a web page application. In this study, we aim to provide a single-center experience of the disease course of AWM, and to validate the AWM model in a demographically diverse patient population in a large metropolitan city.
Methods
We included AWM patients presenting to Weill Cornell Medical Center between 1998 and 2021, with follow-up until July 2024. Date of diagnosis and progression, and baseline laboratory and pathology data were manually reviewed. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons between groups. The primary endpoint of the study was progression to symptomatic WM that required treatment. Symptomatic WM was defined according to the criteria for treatment initiation by consensus panel recommendations from the Second International Workshop on Waldenstrom Macroglobulinemia. Patients who had not progressed by the end of study or were lost to follow-up were censored at the date of the last visit. A Cox proportional hazard model was used to estimate risk factors for progression with hazard ratios (HR) and 95% confidence intervals (CI).
Results
A total of 79 patients with AWM were identified with a median follow-up time of 7.3 years (95% CI: 5.7-10). The median age at diagnosis was 67 years, median serum IgM level was 1,550 mg/dL (IQR: 813-2,345), bone marrow infiltration was 20% (IQR: 8-45), albumin 4.15 g/dL (IQR: 3.9-4.5), and B2M was 2.4 mg/L (IQR: 1.9-3.1). The overall median TTP was 6 years (95% CI: 4-7.5).
In a univariate analysis, we found that bone marrow infiltration, serum IgM, albumin, and B2M levels were associated with progression to overt WM. In a multivariate analysis, only bone marrow infiltration was an independent risk factor for progression. Applying the AWM model to our cohort successfully separated the patients into 3 distinct risk groups (high, intermediate, and low including 11, 19, and 42 patients, respectively) according to the risk score assigned to each patient. Patients in the high-risk group had a significantly shorter median TTP compared to the intermediate-, and low-risk groups (1.2 vs 3.8 vs 11.5 years respectively, log-rank p &lt;0.0001). The C-index for the model in our cohort was 0.74, indicating high accuracy in predicting the progression risk.
Conclusion
We studied and analyzed a diverse cohort of AWM patients at a large academic center in a metropolitan city, and found that these patients have significantly different risks of progression to active WM, warranting different management and follow-up recommendations. Moreover, we validated the AWM model in this real-world cohort and found that it accurately identifies high vs low-risk AWM patients and predicts their risk of progression to symptomatic WM, warranting its use in the clinical management of asymptomatic WM.