Introduction
Minimal residual disease (MRD) negativity is one of the most important measures of treatment success in multiple myeloma (MM) and is associated with improved progression-free and overall survival. Current MRD assessments are typically performed using bone marrow samples, which are invasive and difficult to repeat frequently.
Peripheral blood-based mass spectrometry (MS) offers a promising non-invasive method for monitoring M-protein over time. Two leading MS approaches are:
- EXENT: An intact immunoglobulin mass spectrometry assay that measures circulating M-protein and offers high throughput.
- EasyM: A personalized clonotypic peptide assay that sequences each patient’s unique M-protein and tracks disease using highly sensitive peptide-based monitoring.
Although both technologies are designed to monitor M-protein in blood, direct comparisons between EasyM and EXENT have been limited.
Study Summary
This retrospective analysis compared the performance of EasyM and EXENT in paired serum samples collected from patients enrolled in the Australasian Leukaemia and Lymphoma Group MM19 and MM21 clinical trials.
Eligible patients had measurable disease at baseline, defined as:
- M-protein ≥2 g/L by serum protein electrophoresis (SPEP), and/or
- Free light chain (FLC) ≥100 mg/L
The study included 53 patients and 215 paired serum samples collected longitudinally throughout treatment.
Patient isotypes included:
- IgG (n=42)
- IgA (n=6)
- Free light chain (FLC) (n=4)
- IgM (n=1)
Samples were evaluated at multiple treatment milestones including screening, pre- and post-autologous stem cell transplant (ASCT), during consolidation therapy, complete response (CR), and progressive disease (PD).
Key Findings
Strong agreement between EasyM and EXENT
- Across 171 quantifiable paired samples, EasyM and EXENT demonstrated a very strong correlation.
- Spearman correlation coefficient:
- ρ = 0.918
- p < 0.001
This indicates that both assays generally track M-protein levels similarly across a wide range of concentrations.
EasyM demonstrated superior analytical sensitivity
- Of 215 paired samples:
- 197 (91.6%) were concordant
- All discordant samples were EasyM-positive and EXENT-negative
- No samples were EXENT-positive and EasyM-negative
This suggests that whenever the assays disagreed, EasyM detected low levels of M-protein that were below the detection limit of EXENT.
Discordance increased with deeper responses
As patients achieved deeper responses to treatment, EasyM continued detecting M-protein more frequently than EXENT:
- Partial Response (PR):
- Discordance: 1.7% (1/58)
- Very Good Partial Response (VGPR):
- Discordance: 8.3% (4/48)
- Complete Response (CR):
- Discordance: 41.9% (13/31)
The difference between assays became most apparent in patients with very low levels of circulating M-protein.
Detection in complete response
Among patients classified as being in complete response (CR) by International Myeloma Working Group criteria:
- EasyM detected M-protein in 30 of 31 samples (96.8%)
- EXENT detected M-protein in 17 of 31 samples (54.8%)
These findings suggest that highly sensitive clonotypic mass spectrometry can detect very low levels of M-protein even after patients achieve a conventional complete response, highlighting its greater analytical sensitivity compared with intact immunoglobulin mass spectrometry.
EasyM detects M-protein at very low concentrations
- When EasyM concentrations were below 0.14 g/L, EXENT failed to detect M-protein in approximately half of samples.
- At concentrations ≥0.14 g/L, EXENT detection was nearly universal.
This indicates that EasyM maintains detection at very low M-protein concentrations where EXENT frequently becomes negative.
Rising EasyM levels may predict relapse earlier
Longitudinal patient analyses showed that increasing EasyM levels preceded clinical relapse in several patients, even when EXENT measurements remained stable or showed divergent trends.
This suggests EasyM may provide earlier warning of disease recurrence and could potentially support earlier clinical intervention.
Conclusions
This study demonstrates that EasyM and EXENT show strong overall correlation for monitoring M-protein in peripheral blood. However, EasyM consistently demonstrated greater analytical sensitivity, particularly in patients achieving deep responses.
These results support the growing role of blood-based mass spectrometry for non-invasive monitoring of M-protein in multiple myeloma. EasyM’s greater sensitivity suggests it may be better suited for detecting very low levels of disease, while EXENT provides a higher-throughput method.
Click to enlarge poster.
Authors
J. Zhao, T. Khong, Abir Khaled, Zac McDonald, Q. Lam, N. Jenkins, S. Mithraprabhu, N. Bingham, S. Lim, D. Wong, Liqiang Yang, and Andrew Spencer.
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