Post-doctoral Scholar University of Chicago, United States
Introduction: MS allows for sensitive detection of monoclonal protein in peripheral blood. Currently, MALDI-TOF MS is most frequently used due to the method’s high-throughput and cost-effectiveness. However, we hypothesized that for the identification of exceptional responders, more sensitive methods should be utilized. Samples that are negative by MALDI-TOF MS can also be tested by LC-MS, a method approximately 10 times more sensitive.
Methods: We pooled data from two prospective phase 2 studies in NDMM, wherein exploratory analyses included response evaluation with MS. Patients were treated either with carfilzomib, lenalidomide, and dexamethasone plus autologous stem cell transplant (KRd-ASCT, NCT01816971) or with daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd, NCT03500445). Samples for MS assessments were collected after 18 cycles and one year later in the KRd-ASCT, and after cycles 8, 12, and 24 in the Dara-KRd. MALDI-TOF MS evaluation was performed using the EXENT platform (The Binding Site, part of Thermo Fisher Scientific). Negative samples were reflexed for LC-MS testing. Bone marrow (BM) MRD by NGS (sensitivity threshold 10-6,clonoSEQ, Adaptive Biotechnologies) was performed at the same timepoints.
Results: A total of 74 patients with samples available for MS evaluation, out of 118 patients enrolled in both studies, were included in this analysis: 36 from the KRd-ASCT trial and 38 from the Dara-KRd. Median follow-up was 50.2 months (range: 7.1-128.9).
According to the standard IMWG criteria, best overall responses were sCR in 63 (85%) patients, CR in 3 (4%) patients and VGPR in 8 (11%) patients. EXENT(-) as a best response was reached in 45 patients (61%), all but one EXENT(-) patients were in sCR or CR. LC-MS(-) was achieved by 22 (30%) patients.
There were two PFS events in the LC-MS(-) group, one caused by death due to secondary malignancy; the only MM progression occurred more than 7 years after diagnosis in a patient with t(4:14). Hazard ratio for progression or death between LC-MS(-) and EXENT(+) patients equaled 0.12 (0.05-0.31, p=0.0007), between LC-MS(+)/EXENT(-) and EXENT(+) equaled 0.49 (0.21-1.15, p=0.12), and between LC-MS(-) and LC-MS(+)/EXENT(-) equaled 0.30 (0.07-1.19, p=0.12).
For the 44 patients who had BM MRD evaluable at the 10-6 threshold, the agreement between LC-MS and BM MRD was 68%. Among the discordant cases, the proportion of LC-MS(+)/BM MRD(-) patients was higher (25%). Notably, for the 32 LC-MS(-) OR 10-6 BM MRD(-) patients, the 5-year PFS rate was 96%. None of the 9 ‘double-negative’ patients have experienced disease progression.
Conclusions: In addition to the prognostic significance of MS(-) at any level, the depth of MS negativity is associated with longer PFS. LC-MS(-) and/or 10-6 MRD(-) patients experience long term disease control. The potential of LC-MS to enhance the prognostic potential of MRD at 10-6 for predicting longer disease control is currently under evaluation in a larger sample set.
