Quantitative MYD88 L265P and flow cytometry levels for outcome determination in IgM gammopathies: the SAL-TO study

Waldenström macroglobulinemia (WM) is a rare, indolent B-cell lymphoproliferative disorder, often preceded by a history of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (IgM-MGUS). In this retrospective, multicenter study, we collected real-life data from 577 patients with IgM gammopathy (221 symptomatic WM [sWM], 245 asymptomatic WM [aWM], 111 IgM-MGUS) from 22 Spanish centers with a validation cohort of 166 patients (73 sWM, 71 aWM, 22 IgM-MGUS) from the University Hospital of Torino, Italy. The median overall survival (OS) was 126.7 months for the Spanish cohort and 202.8 for the Torino cohort. A multivariate analysis identified age >65 years, male gender, diagnosis of sWM, and β-2-microglobulin >3 as significant predictors of a shorter OS. In addition, age >65 years, bone marrow (BM) biopsy infiltration, hemoglobin <11.5 g/dL, and platelets <100 000/μL were associated with a shorter time to first treatment (TTFT). Pooling data from both cohorts revealed that a baseline BM quantitative MYD88 L265P to wild-type MYD88 ratio of >0.162 (either by droplet digital polymerase chain reaction [PCR] or quantitative PCR), together with multiparameter flow cytometry (MFC) infiltration >4.39%, had a significant impact on OS and TTFT. The combination of MYD88 and MFC levels enabled stratification of patients into high-, intermediate-, and low-risk groups with patients with high-risk IgM gammopathy showing increased disease-related death in a competing risk analysis.