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Abstract
Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG). In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10-6. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial. Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; P < .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; P < .001). Timing of undetectable MRD (after induction v intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%. The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.
Highlights
Assessing measurable residual disease (MRD) has become a standard procedure in many hematologic malignancies,[1,2,3,4] but the lack of effective therapies for multiple myeloma (MM) delayed the interest to perform MRD studies in this disease until the past decade
The International Myeloma Working Group (IMWG) updated the response criteria in 2016 to foster standardized assessment of MRD in prospective trials, which should incorporate MRD-negative definitions based on nextgeneration sequencing (NGS), next-generation flow cytometry (NGF), and positron-emission tomography/computerized tomography (PET/CT).[24]
A few studies have investigated the utility of PET/CT25-30 and NGS27,31-34 in patients treated with novel regimens, and the impressive results obtained with NGS in five trials[31,32,33,34,35] validated the new IMWG sequencing MRD-negative response criterion
Summary
Assessing measurable residual disease (MRD) has become a standard procedure in many hematologic malignancies,[1,2,3,4] but the lack of effective therapies for multiple myeloma (MM) delayed the interest to perform MRD studies in this disease until the past decade. The International Myeloma Working Group (IMWG) updated the response criteria in 2016 to foster standardized assessment of MRD in prospective trials, which should incorporate MRD-negative definitions based on NGS, next-generation flow cytometry (NGF), and positron-emission tomography/computerized tomography (PET/CT).[24] far, a few studies have investigated the utility of PET/CT25-30 and NGS27,31-34 in patients treated with novel regimens, and the impressive results obtained with NGS in five trials[31,32,33,34,35] validated the new IMWG sequencing MRD-negative response criterion. Undetectable MRD by NGF As the New Treatment End Point for Myeloma using NGF in trials have validated the encouraging preliminary results reported by EuroFlow,[36] and many questions about the utility of MRD in patients with MM remain unanswered.[37]
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