Page 36 - Haematologica Vol. 109 - July 2024

REVIEW ARTICLE - Minimal residual disease in multiple myeloma R. Szalat et al.
number of malignant plasma cells during or after treat- ment was adopted in the International Myeloma Working Group (IMWG) consensus criteria in 2015 to provide more accurate hematologic response assessment. Since then, MRD evaluation has been shown to significantly improve hematologic response evaluation and to improve prognostic stratification after therapy in newly diagnosed transplant eligible and transplant non-eligible patients and in relapsed disease. The prognostic role of MRD is now well documented and has been demonstrated in several retrospective and prospective studies, and MRD negativity is now an estab- lished criteria in MM clinical trials. However, the impact of MRD assessment on treatment decisions remains to be determined and is currently under in-depth investigation in several randomized clinical trials.6-16 In addition to BM- based MRD evaluation, novel techniques utilizing whole body imaging (WBI) and blood-based evaluation have been developed and will likely improve MRD evaluation in MM patients. Here, we describe the different methods available to assess MRD, and discuss the clinical applications and challenges of using MRD in clinical practice.
Bone marrow-based minimal residual disease assessment
Next-generation flow cytometry
First MRD evaluation was performed by multiparametric flow cytometry (MFC), a technique available worldwide able to identify monotypic plasma cells in the BM even if present at a low level.17,18 Conventional MFC MRD approach- es usually use 4-10 cell markers (colors) but are limited by relatively low sensitivity, absence of standardization, and lack of reproducibility. Therefore, next-generation flow cy- tometry (NGF), a more sensitive method, was developed and standardized by EuroFlow to overcome most of the conventional MFC limitations.19-21 NGF is based on a more efficient sample preparation protocol for acquisition of up to 10 million BM cells and uses 8-12 colors characterizing most cellular subtypes and normal plasma cells (CD138 and CD38) and aberrant plasma cell markers (CD20, CD56, CD19, CD45, CD27, CD28, CD33, and CD117). Additionally, intra-cy- toplasmic markers for κ or λ immunoglobulin light chains are used to confirm monotypic or clonal cells. Importantly, NGF high sensibility allows detecting one abnormal plasma cell out of 10^-6 cells and does not require a sample at the time of diagnosis.21 It is also adapted to patients receiving anti-CD38 therapy, despite the potential interference with plasma cell detection.21 Standardized data analysis methods allow for an increased sensitivity and reliability. The clinical impact of high-sensitivity MRD detection by NGF has been validated in randomized clinical trials and in real-world pa- tients with MM.19,22 In the GEM/PETHEMA trials, only 7% of patients achieving MRD-negativity (MRD <2 10^-6 cells) were
reported to have disease progression with half of those patients progressing with extra-medullary disease (EMD). Achievement of MRD negativity was associated with an 82% and 88% reduction in the risk of progression and death (Hazard Ratios [HR] of 0.18 and 0.12; P<0.001), respectively. Importantly, MRD negativity overcame the poor prognostic value of high-risk cytogenetics at diagnosis.19 The EuroFlow NGF approach has now been validated by the IMWG as the reference flow cytometry method to evaluate MRD negativity after therapy.5 The EuroFlow process, which uses 2-tube 8-color methodology, is widely used in Europe, Asia and the US. However, several groups, especially in the US, have developed other methods, using single-tube, 10- or 12-color methods that are similarly efficient, more cost-effective, and conform to the IMWG and National Comprehensive Cancer Network guidelines.23
Next-generation sequencing
High-throughput DNA sequencing methods developed to study B- or T-cell receptor repertoire have been applied to MM. These methods can identify one malignant cell in 1 million analyzed cells (10^-6). The Adaptive Biotechnologies (clonoSEQ) NGS assay is currently the only assay cleared by the FDA for MRD evaluation in BM from patients with MM. NGS can detect clonotypes that are defined by shar- ing identical immunoglobulin gene sequence reads with a frequency ≥5%. This strategy requires an initial BM sample to identify the predominant clone, and allows the myeloma clone to be detected in 90-92% of myeloma patients.16 The prognosis value of achieving NGS-based MRD negativity has been demonstrated in several randomized trials. In the Intergroupe Francophone du Myélome 2009 trial, MRD neg- ativity was a strong prognostic factor for both PFS (adjusted HR: 0.22; 95% Confidence Interval [CI]: 0.15-0.34; P<0.001) and OS (adjusted HR: 0.24; 95% CI: 0.11-0.54; P=0.001). Pa- tients who were MRD negative had a higher probability of prolonged PFS than patients with MRD-positive disease and a cytogenetic risk profile, regardless of the treatment arm or International Staging System disease stage at diagnosis. The level of MRD correlated with outcome, and the deeper the level of MRD (<10^-6), the better the prognosis.16 A pooled analysis searching for associations between patients achiev- ing CR or better (≥CR) with MRD-negative status and PFS from 4 randomized clinical trials, confirmed that relapsed/ refractory MM (RRMM) and transplant ineligible newly di- agnosed MM (TIE NDMM) patients achieving ≥CR with MRD negativity had a significant PFS benefit (NDMM and RRMM HR: 0.20; P<0.0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P<0.0001).14 Remarkably, achievement of MRD negativity is, independently of the study arm, associated with best and similar outcome in newly diagnosed MM patients who are transplant eligible and transplant ineligible, as well as in relapse refractory disease.14,15 These data strongly support the concept that achieving MRD negativity may be more important than how it was actually achieved.
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