Minimal residual disease measurement in blood by mass spectrometry identifies long-term responders in multiple myeloma. Open Access

• Achieving LC-MS negativity is associated with excellent prognosis in patients with newly diagnosed multiple myeloma

• EXENT (MALDI-TOF) mass spectrometry complements bone marrow MRD for better prognostication in MRD-negative patients

Modern multiple myeloma treatment enables deep and sustained responses, necessitating assessment of minimal residual disease (MRD) in the bone marrow to refine response categorization. Recently, mass spectrometry (MS) - based methods have emerged as highly sensitive tools for measuring MRD in peripheral blood. However, the role specific MS techniques play in response categorization has yet to be established. We pooled data from 97 patients treated in three prospective phase 2 trials evaluating carfilzomib-based triplets and quadruplets, with or without autologous stem cell transplantation. MRD was assessed in bone marrow using next-generation sequencing (NGS) and in peripheral blood with two MS methods: MALDI-TOF (EXENT) and the more sensitive liquid chromatography-MS (LC-MS). EXENT negativity was associated with superior progression-free survival (PFS) and overall survival (OS). LC-MS-negativity identified patients with long-term responses. EXENT complemented NGS MRD, with double-negative patients experiencing longer PFS than those negative in only one modality. Patients negative by both LC-MS and NGS MRD at 10^-6 had a 5-year PFS rate of 89%. These findings support incorporating MS into MRD response assessment and in prognostic algorithms in myeloma. In addition, our results indicate that LC-MS can provide valuable endpoint in future studies aiming for functional cure.