P-165: Advanced circulating tumor DNA (ctDNA)Profiling: Enhancing Non-Invasive Detection and Characterization of Measurable Residual Disease (MRD) in Multiple Myeloma (MM)

Introduction: MRD assessment in bone marrow (BM-MRD) is a crucial prognostic indicator in MM. Despite MRD testing is well-established in MM clinical trials, it is not yet common in routine practice. Implementing less invasive methods to monitor MRD in peripheral blood (PB) could enhance its adoption in standard clinical settings.

Methods: This study involved 243 patients undergoing monitoring during MRD assessment in PETHEMA/GEM clinical trials, with BM-MRD processed using next-generation flow (NGF) cytometry. PB-MRD was analyzed in 83 of these patients using ctDNA with CloneSight, a highly sensitive ( >10^-4) next-generation sequencing (NGS) method based on patient-specific multiplexed amplicon mini-panels targeting somatic mutations identified at diagnosis. Additionally, two cases employed PhasED-Seq, which uses multiple somatic mutations within individual DNA fragments and 67 new BM-MRD positive samples have been included to enhance ctDNA detection sensitivity. In all cases, PB-MRD was then evaluated using BloodFlow, another high-sensitive method (10^-7) that combines immunomagnetic enrichment with NGF.

Results: CloneSight was performed in a total of 83 patients, of whom 9 could not be studied due to the absence of suitable somatic mutations for PB-MRD tracking (88% applicability). A total of 194 longitudinal samples were studied, of which 12 (6%) were PB-MRD positive, from 9 of the 74 (12%) patients. In 166 of the 194 samples, BM- MRD was simultaneously analyzed using NGF. The concordance between PB-MRD using CloneSight and BM-MRD using NGF was 67% (62% double negative and 5% double positive MRD results). The frequency of CloneSight-/NGF+ and CloneSight+/NGF- discordant assessments was 31% and 2%, respectively. Of note, only 3 of the 74 (4%) MRD negative patients relapsed thus far. Upon analyzing PB- MRD with both methods described above, another 4/74 patients were CloneSight- /BloodFlow+, of whom 1 progressed. Of note, the only case (1/74) being CloneSight+/BloodFlow- relapsed. The negative predictive value (NPV) of double negative MRD detection in PB using BloodFlow was about 80%. CloneSight also offered a high positive predictive value (PPV) of 100%. The landmark median PFS of patients with negative vs positive PB-MRD using CloneSight was NR vs 14 months, respectively (HR:11.7, P< .001).

Conclusions:





Our inquiry revealed that CloneSight and BloodFlow effectively detect PB-MRD with high sensitivity detecting ctDNA and circulating tumor cells (CTCs), respectively. In addition, the presence of mutations and CTCs was consistently related to inferior progression-free survival (PFS). These methods also demonstrated a high PPV, suggesting that the identification of such events in the group of BM-MRD-positive patients could stratify those at immediate risk of relapse.

NB, AMM, YRH, ML, LN and CG contributed equally to this work as co-authors.
JML, BP and NP contributed equally to this work as senior co-authors.