Blood-based MALDI-TOF mass spectrometry versus bone marrow MRD for monitoring multiple myeloma: CASSIOPEIA study results

Minimal residual disease (MRD) status is widely used to assess depth of response and predict outcome in multiple myeloma, but bone marrow MRD testing is invasive and subject to sampling variability. Blood-based mass spectrometry (MS), which measures patient-specific monoclonal immunoglobulins, offers a non-invasive approach to monitoring residual disease. Using the structured assessment schedule of the CASSIOPEIA trial, we compared serum MS with bone marrow MRD by next-generation flow cytometry (NGF) and next-generation sequencing (NGS). This retrospective post-hoc analysis included 237 patients from the CASSIOPET companion study with paired serum and bone marrow samples prospectively collected at predefined CASSIOPEIA time points from post-induction through maintenance. MRD results by MS, NGF, and NGS were evaluated for associations with progression-free survival, agreement between methods, longitudinal changes, and sustained MRD status according to International Myeloma Working Group criteria. At all time points, MRD negativity by any method was associated with longer progression-free survival, with comparable landmark prognostic performance across platforms. Agreement between serum MS and bone marrow MRD improved during maintenance, with high positive predictive value and high negative predictive value relative to a 10⁻⁵ marrow reference, but more limited rule-out performance against NGS at 10⁻⁶. Sustained MRD negativity over 1 and 2 years identified patients with favorable outcomes irrespective of method. These findings support a complementary, phase-adapted role for serum MS alongside bone marrow MRD testing, enabling frequent non-invasive monitoring during maintenance while preserving bone marrow assessment when maximum sensitivity is required. The Cassiopeia trial is registered at www.clinicaltrials.gov as NCT02541383.