A case of incidental detection of Waldenstrom macroglobulinemia following multi-cancer early detection testing

Multi-cancer early detection (MCED) tests, which utilize cell-free DNA methylation patterns, such as the Galleri test, have emerged as novel tools for identifying cancer signals before symptoms develop. While not diagnostic, they can prompt targeted investigations and earlier detection. We present a case in which an MCED result suggestive of hematologic origin led to further evaluation and diagnosis.

A 77-year-old man with no significant medical history underwent the Galleri MCED test, which detected a "cancer signal" with methylation profiling suggestive of lymphoid or plasma cell lineage. He was otherwise well apart from chronic hoarseness. Computed tomography showed mildly enlarged right level 4 lymph nodes (11 mm) and borderline mediastinal and supraclavicular lymphadenopathy.

Laboratory work-up revealed mild normocytic anemia (hemoglobin 12.2 g/dL), elevated total protein (9.1 g/dL), elevated IgM (3,707 mg/dL), low IgA (61 mg/dL), and elevated serum viscosity (2.98). Serum protein electrophoresis with immunofixation revealed a large immunoglobulin M kappa monoclonal protein (2.7 g/dL). Kappa free light chains measured 84.3 mg/L (ratio of 8.18). A bone marrow biopsy revealed low-grade B-cell non-Hodgkin lymphoma with plasmacytic differentiation, partially CD5-positive, and involving 20–30% of the cellularity. Cytogenetic analysis showed 45, XY,-6, add(15)(q14)[3]/46, XY[17]; next-generation sequencing identified an MYD88 mutation; amyloid staining was negative, confirming a diagnosis of Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma. As he had asymptomatic, medium-risk disease and did not meet treatment criteria, watchful waiting with three-month monitoring was recommended.

This case illustrates how liquid biopsy and non-invasive diagnostics can detect malignancies prior to symptom onset. Combined with imaging and laboratory data, MCED testing enabled the diagnosis of asymptomatic Waldenström macroglobulinemia and supported a surveillance-based management plan. It also highlights ethical considerations, including managing incidental findings and balancing early detection with risks of overdiagnosis. MCED testing integrates genomic medicine and biomarker discovery into oncology, enabling earlier, targeted evaluations aligned with precision oncology principles. Nevertheless, the overall risk–benefit of early detection must be reassessed continually as diagnostic technologies become more sensitive and sophisticated, always prioritizing the best interests of our patients.