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REVIEW ARTICLE - Minimal residual disease in multiple myeloma R. Szalat et al.
early relapse after front-line therapy have also the poor- est outcome.80 Important studies are ongoing to improve treatment strategies in this subgroup of patients. Different results regarding clinical impact of MRD status in high- risk patients have been reported.81,82 While achievement of MRD negativity is associated with clinical improvement in HR MM, it does not overcome its poor prognosis and HR MM may still have early progression. In addition, data from the large phase III trial (Myeloma XI) showed that high-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status.83 BM MRD evaluation only is likely to be insufficient to fully assess MRD, in the context of patchy disease and EMD, as discussed above. Indeed, in a study comparing BM and imaging-based MRD assessment, 12% of patients who achieved BM MRD negativity by flow cytometry had positive PET/CT or whole-body diffusion-weighted MRI (WB-DWI-MRI) and had a shorter PFS in comparison to patients with both BM and imaging MRD negativity.56 Further data are needed to better interpret and use MRD status, especially in high-risk patients and patients with EMD. Sustained MRD and combined BM and imaging-based MRD assessment are important parameters to consider. Both sustained MRD negativity and combined BM and imaging MRD studies (PET/CT or wbMRI) appear to be the most valuable approaches in HR MM patients. Results from randomized trials are expected to address this important question. Similarly, in the context of RR MM, while achieve- ment of MRD negativity is associated with better outcome, most of the patients do experience relapse. This is well illustrated by the KarMMa trial that evaluated the efficacy and safety of Idecabtagene vicleucel (ide-cel) in patients with RR myeloma, for example, in which 26% of the pa- tients achieved MRD negativity, including 79% of patients achieving CR. However, only 40% of patients achieving at least CR were in remission at 20 months of follow-up.84 It seems that sustained MRD negativity combined with WBI will be more relevant in that context.
Should minimal residual disease assessment be made only in patients achieving complete hematologic response?
Another important point relates to which patients should be evaluated for MRD. In clinical trials, MRD investiga- tions were performed either in MM patients achieving CR or stringent CR or at specific timepoints of a given therapeutic protocol (e.g., before SCT, before or during maintenance). It was showed that patients achieving CR with MRD positivity had significantly worse outcome than patients achieving both CR and MRD negativity. However, several studies have reported MRD negative rates in MM patients achieving very good partial response (VGPR), and indeed, up to 25% of patients achieving MRD negativity assessed by either flow cytometry or NGS have persistent positive immunofixation and are, therefore, classified as
VGPR.85 Importantly, retrospective and prospective studies showed that patients with positive IF and MRD negativity have similar outcome to patients with negative IF and MRD negativity. The discrepancy between positive IF and MRD negativity may be related to several reasons, including EM disease, BM sample not representative of full BM or long half-life of the monoclonal immunoglobulin.85 This is further highlighted in studies utilizing MS (the sensitive assay to detect monoclonal immunoglobulin described above). In one study, the monoclonal immunoglobulin was still detectable by matrix-assisted laser desorption/ ionization-time-of-flight mass spectrometer (MALDI-TOF) in 69% of patients who achieved a conventionally defined CR and were BM-based NGF-MRD-negative after 100 days from ASCT.86 Finally, discordant MRD and IF results are frequently observed after CAR T-cell therapy, with low rates of CR observed in patients achieving MRD negativity, particularly in the first six months after treatment, sug- gesting that MRD evaluation which reflects the clearance of myeloma cells in the BM could be an independent prognostic marker in that setting.78 Therefore, assessing MRD in patients achieving at least VGPR or better is very relevant and informative.
Should minimal residual disease status impact therapeutic decision-making?
Minimal residual disease negativity is a very strong and now established prognostic marker. However, its impact on therapeutic decision-making remains to be determined. Several randomized clinical trials are currently ongoing to address this question (Table 3). The goals of these trials are to determine if treatment should be adapted based on MRD status: intensification of treatment in case of MRD positivity, stop maintenance therapy in case of sustained MRD negativity or treatment change in case of MRD status conversion from negativity to positivity. The MASTER trial pioneered this strategy and evaluated the role of BM-based MRD in treatment during consolidation. Patients received combined daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) as induction therapy and BM MRD was performed by NGS at different time points (end of induction, after HDC-SCT, and every 4 cycles of consolidation) to inform the use and duration of treatment with Dara-KRd. Treatment was stopped in patients who achieved 2 consecutive MRD-negative as- sessments. Among 123 included patients, 43% had none, 37% had one, and 20% had 2 high-risk cytogenetic abnor- malities (HRCA), and 96% had BM MRD trackable by NGS. With a median follow-up of 25.1 months, 80% of patients reached MRD negativity (78%, 82%, and 79% for patients with 0, 1, and 2+ HRCA, respectively), including 66% who reached MRD <10-6, and 71% who reached 2 consecutive MRD negative assessments during therapy, entering treat- ment-free surveillance. Two-year PFS was 87% (91%, 97%, and 58% for patients with 0, 1, and 2 HRCA, respectively).
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