Longitudinal minimal residual disease assessment in multiple myeloma patients in complete remission - results from the NMSG flow-MRD substudy within the EMN02/HO95 MM trial

Alexander Schmitz, Rasmus Froberg Brøndum, Hans Erik Johnsen, Ulf-Henrik Mellqvist, Anders Waage, Peter Gimsing, Davine Hofste Op Bruinink, Vincent van der Velden, Bronno van der Holt, Markus Hansson, Niels Frost Andersen, Ulf Christian Frølund, Carsten Helleberg, Fredrik H Schjesvold, Lucia Ahlberg, Nina Gulbrandsen, Bjorn Andreasson, Birgitta Lauri, Einar Haukas, Julie Støve Bødker, Anne Stidsholt Roug, Martin Bøgsted, Marianne T Severinsen, Henrik Gregersen, Niels Abildgaard, Pieter Sonneveld, Karen Dybkær, Alexander Schmitz, Rasmus Froberg Brøndum, Hans Erik Johnsen, Ulf-Henrik Mellqvist, Anders Waage, Peter Gimsing, Davine Hofste Op Bruinink, Vincent van der Velden, Bronno van der Holt, Markus Hansson, Niels Frost Andersen, Ulf Christian Frølund, Carsten Helleberg, Fredrik H Schjesvold, Lucia Ahlberg, Nina Gulbrandsen, Bjorn Andreasson, Birgitta Lauri, Einar Haukas, Julie Støve Bødker, Anne Stidsholt Roug, Martin Bøgsted, Marianne T Severinsen, Henrik Gregersen, Niels Abildgaard, Pieter Sonneveld, Karen Dybkær

Abstract

Background: Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments.

Methods: Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression.

Results: Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with ≥3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4-2.3 months). Minimal malignant plasma cells detection limit was 4 × 10-5.

Conclusions: Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression.

Trial registration: NCT01208766.

Keywords: Flow cytometry; Minimal residual disease; Multiple myeloma.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
1st Flow-RA of bone marrow sample received from patients at response evaluation. X-axis: Patients with response status of CR and sCR are aligned according to PID number and flow-MRD status. Y-axis: Cell Counts/sFLCr values (log scale). (*1): sFLCr was close to normal range (0.24) and became normal with the next sFLCr measurement (1.58). (*2): sFLCr was taken 27 days after MFC date, previous sFLCr measurement (> 27 days before MFC date) displayed normal ratio. Abbreviations: CR: Complete response. SCR: Stringent complete response. Patient ID / PID: Patient identification number. SFLCr: Serum free light chain ratio. MFC: Multiparamteric flow cytometry. mPC: Malignant plasma cells. nPC: normal polyclonal plasma cells
Fig. 2
Fig. 2
Flow-MRD monitoring of patients reaching CR/sCR during their course, identifies flow-MRD positive patients over time before progression is clinically observed, while flow-MRD negative maintain progression-free regardless their initial RS status. Data points for longitudinal flow-MRD assessment (circles) after inclusion from 20 patients with ≥3 flow-MRD BM samples (inclusive 1st RA), analysed until clinical progression or until date of last clinical contact are lined up over time. Inclusion, RS, progression and date of last contact (until censoring) are indicated. Abbreviations: PR: Partial response. VGPR: Very good PR. CR: Complete response. SCR: stringent CR. INCL: Date of inclusion into the MRD-study. PROG: Date of clinical progression. Flow-MRD: MRD assessment using MFC. RA = Response assessment. RS: Response status (clinical). Patient ID: Patient identification number. SFLCr: Serum free light chain ratio. MFC: Multiparamteric flow cytometry. mPC: Malignant plasma cells. DLC: Date of last contact or censoring date. (*): Patients progressed with extramedullary disease. n.d.: 1st RA BM sample not received or flow-MRD status not determined
Fig. 3
Fig. 3
Monitoring the quantity of flow-MRD until clinical progression across six patients with clinical progression reveals, that flow-MRD positivity precedes substantial changes in clinical monitored values for sFLCr, SPEP and IF, and subsequent clinical progression. Time from inclusion to measured flow-MRD positivity varied from 5.9–64.4 month (Mean 19.1 month). MRD positivity was detected with a mean of 12.6 month (range 9.6–26.6) before clinical progression (according to IMWG standard) was recorded. Median mPC doubling time was calculated to 1.8 month (1.4–2.3) across the six patients, fitting a log-linear model for mPC concentration (mPC/ × 106 events) versus time to clinical progression. X-axis: Timeline (months to clinical progression). Y-axis: mPC frequency. Achieved flow-MRD detection limit for the MRD+ patient group is shown as a dotted horizontal line. Abbreviations: MRD: Minimal residual disease. PID: Patient identification ID. SCR: Stringent complete response. SFLCr: Serum free light chain ratio (abnormal/normal). IF: Immunofixation (positive/negative) SPEP: Serum protein electrophoresis (positive/negative). Lin: Linear. Log: Logarithmic. nd: not determined. “0”: Flow-MRD negative

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