Page 38 - Haematologica Vol. 109 - July 2024

REVIEW ARTICLE - Minimal residual disease in multiple myeloma R. Szalat et al.
of BM MRD negativity detected by serum immunofixation or MS has been reported in different studies and may be related to the immunoglobulin half-life rather than to an MRD-positive disease. Therefore, incorporation of MS needs to be clarified.
Whole-body imaging and minimal residual disease assessment
While imaging studies do not allow the detection of active disease at the single cell resolution, relatively novel WBI techniques including positron emission tomography with computed tomography (PET/CT) and magnetic resonance imaging (MRI) allow a better characterization of bone lesions and EMD. PET/CT and whole-body MRI have been evaluated to assess residual disease after therapy.48-51 Both methods are very sensitive and have been shown to complement BM-based MRD assessment considering the patchy nature of MM and its spatial heterogeneity. Patients presenting with EM lesions or with para-medullary plasmacytomas are at higher risk of developing EMD even in the context of BM MRD-negativity.52 18Fluorodeoxyglucose (18F-FDG)- PET is a very sensitive method to identify active disease, and several studies showed that PET-positive lesions after completion of therapy is associated with poorer outcome, while FDG-PET/CT negativity after autologous stem cell transplantation (ASCT) in patients achieving CR predicts a lower risk of progression or death.53-56 Patients obtaining PET/CT normalization upon therapy have comparable prog- nosis to patients without baseline increased metabolism, suggesting the value of treating until suppression of glu- cose metabolism.56 In the FORTE trial, a high concordance between PET/CT and NGS (84%) and between PET/CT and MFC (93%) at 10^−5 in the identification of BM residual dis- ease was reported. By contrast, there was a discrepancy in the assessment of MRD in patients with focal lesions in approximately 33-37% of cases, suggesting that PET/ CT alone might not be accurate enough.57 Similarly, in the CASSIOPET study, a significant concordance between BM and PET/CT-based MRD assessment was reported in 109 patients, but the data suggested a higher sensitivity for the BM-based MRD method.58 A standardized definition of PET/CT complete metabolic response has been proposed considering the uptake of the liver as threshold and is currently under confirmation in independent prospec- tive series of patients.48 A significant challenge related to 18FDG PET/CT relates to the 10-15% of MM patients with no FDG-avid lesions due to lack of hexokinase enzyme, which is responsible for FDG trapping in the myeloma cells or to the absence of identified lesions.59 New PET/CT tracers including CD38, radiolabeled antibodies and VLA-4 (clin- icaltrials.gov 03804424) represent new, potentially more sensitive methods that are under investigation.13,60,61 Along these lines, conjugating daratumumab with the positron emitting radioisotopes Copper-64 (64Cu) and Zirconium-89 (89Zr) has allowed for the creation of immunoPET tracers.
89Zr-Daratumumab has demonstrated an ability to detect MM cells or lesions when not detected by 18FDG-PET/CT and other clinically standard imaging methods.62,63 However, the lesser availability of these newer tracers, interpatient heterogeneity regarding specific targets, and lack of pro- spective data remain important challenges to be addressed. Similar to PET/CT, presence of residual lesions after high- dose chemotherapy followed by autologous stem cell transplant (HDC-SCT) identified by whole body MRI (wbM- RI) is associated with adverse prognostic significance.64-66 MRI seems to be more sensitive in diagnostic methods to identify myeloma lesions than PET/CT. In a prospective study comparing PET/CT and wbMRI in 60 patients, wb- MRI showed significantly higher detection of focal lesions at all anatomic sites (except ribs, scapulae, and clavicles) and of diffuse disease at all sites. However, MRI is not able to differentiate between vital and necrotic tissue within pre-existing osteolytic lesions64 and therefore PET/CT pos- itivity may be more accurate to assess MRD and to predict patient outcome.67-69 A more sensitive MRI-based method called diffusion weighted imaging (DWI) is a promising al- ternative allowing more accurate detection of active lesions and is under investigation.70,71 Whether MRD is assessed with PET/CT or wbMRI, the complementary role of imaging studies to BM-based MRD evaluations is significant and strategies to include both are being evaluated.
Based on the increasing amount of MRD data, and the availability, reproducibility and standardization of MRD methods, MRD assessment has become an important and validated criterion in clinical trials. MRD assessment is now used for patient selection, risk stratification or enrichment of clinical trial subgroups, and as an endpoint. MRD assess- ment will likely contribute to expedite drug development.13 However, using MRD assessment to guide therapy and MRD incorporation in clinical practice is not yet validated. We here discuss some of the most significant challenges that have been or need to be addressed.
Which minimal residual disease method to use?
As discussed above, MRD assessment using BM-based methods remains the gold standard with increasing data regarding WBI. Availability, cost, prognostic power, and consistency are important factors to consider. Regard- ing BM-based MRD, NFC and NGS are the 2 methods of choice to evaluate BM MRD and both have been shown to constitute a strong prognostic marker in MM. Table 1 summarizes the main characteristics of these methods. Comparison between flow cytometry and NGS methods has been performed in randomized clinical trials. In the phase II multicenter randomized FORTE trial, 86% of cor- relation with MRD at a sensitivity of 10^−5 in patients ≥CR was reported.72 In the phase III CASSIOPEIA trial, MFC and NGS were consistent in 83.5% with a sensitivity of 10^−5.73 A direct comparison between NGF and NGS (not Clono- seq platform) was also reported in a study of 106 patients
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