Skip to main content
IMS Events Main banner

    MRD and Biomarkers

    (OA-25) High Accuracy of Next-Generation Flow (NGF) in Predicting Measurable Residual Disease by Next-Generation Sequencing (NGS) in the 10−6 Range: A Prospective Comparison Within the Phase III IsKia Trial

    Saturday, September 20, 2025
    08:20 - 08:30 East Coast USA Time
    Location: Room 718

      Abstract Presenter(s)

    • Mattia D'Agostino, MD

      Investigator
      Division of Hematology, AOU Città della Salute e della Scienza di Torino, University of Torino and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
      Torino, Piemonte, Italy

    Introduction:

    Measurable residual disease (MRD) negativity is the strongest predictor of long-term remission in multiple myeloma (MM). NGS is approved in the US for monitoring MRD in MM, whereas NGF is an alternative technique. In the randomized, phase III IsKia trial, a pre-planned, prospective comparison of NGF and NGS was conducted to assess their concordance.

    Methods:

    Patients (pts) received isatuximab-carfilzomib-lenalidomide-dexamethasone induction, HDM-ASCT, consolidation and light consolidation vs the same treatment without isatuximab. MRD was assessed by NGF and NGS after induction, ASCT, consolidation and light consolidation in all pts achieving ≥VGPR. Samples were centralized in Torino (IT) and Rotterdam (NL) laboratories. NGS was performed by clonoSEQ® (Adaptive Biotechnologies, Seattle) and was prioritized, as MRD negativity by NGS was the trial primary endpoint. NGF was performed by IT and NL following EuroFlow standardized protocols. Concordance between NGF and NGS was evaluated quantitatively – using positive cells per million in paired samples at the same sensitivity – and qualitatively (negative vs positive) by calculating concordant over total samples. Cohen's κ coefficient (κ) was used to evaluate the strength of concordance.

    Results:

    After a median follow-up of 35 months (IQR 32–38), 843 bone marrow (BM) samples were analyzed by NGF. A median number of 6.95 million (IQR 3.51–10) total nucleated cells were analyzed with a median limit of detection of 0.0003% (IQR 0.0002%–0.0006%) per sample. In the ITT population, the MRD negativity rates detected by NGF after each time point were superimposable to those detected by NGS. 692/843 (82%) samples were evaluable at the 10-5 sensitivity by both NGF and NGS. At 10-5, concordance was 89% (κ 0.70). A regression analysis showed a strong positive correlation (Spearman’s rank [R] 0.76; p< 0.0001). Using NGS as standard, the NGF positive predictive value (PPV) was 98%, and the negative (N)PV 65%. Since NGS was prioritized, the maximum sensitivity by NGF (2*10-6) was reached in 319/843 (38%) samples, among which 289/319 (91%) were evaluable at the maximum sensitivity of both techniques (2*10-6 by NGF; 10-6 by NGS). At the maximum sensitivity of both techniques, concordance was 88% (κ 0.75). A regression analysis showed a R of 0.85 (p< 0.0001). The NGF PPV and NPV in predicting the NGS MRD status were 96% and 82%. Analyzing both NGF and NGS at a sensitivity of 2*10-6, concordance was 90% (κ 0.80). NGF PPV and NPV in predicting the NGS MRD status were 96% and 86%. No differences were observed grouping samples by clinical phase or exposure to anti-CD38 mAbs.

    Conclusions:

    NGF and NGS showed highly concordant results (up to 90% at 2*10-6), suggesting that both may be used to evaluate MRD in the BM in clinical practice. NGF performance was not affected by clinical phase or pt exposure to anti-CD38 mAbs. A higher NPV of NGF in predicting NGS was found when a 2*10-6 sensitivity was reached with NGF.