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 IgM monoclonal gammopathy of undetermined significance (IgM-MGUS). In this retrospective multicentric study, we collected real-life data from 577 IgM gammopathy patients (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 University Hospital of Torino, Italy. Median overall survival (OS) was 126.7 months for the Spanish cohort and 202.8 for the Torino cohort. Multivariate analysis identified significant age > 65 years, male gender, diagnosis of sWM and beta-2-microglobulin >3 as significant predictors for shorter OS. Additionally, age > 65 years, bone marrow (BM) biopsy infiltration, haemoglobin <11.5 g/dL and platelets <100.000/mmc were associated with shorter time to first treatment (TTFT). Pooling data from both cohorts revealed that baseline BM quantitative MYD88 L265P/MYD88 WT ratio > 0.162 (either by ddPCR 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 allowed to stratify patients into high-, intermediate-, and low-risk groups, with high-risk IgM gammopathy patients showing increased disease-related death in competing risk analysis.