Page 42 - Haematologica Vol. 109 - July 2024

REVIEW ARTICLE - Minimal residual disease in multiple myeloma R. Szalat et al.
Cumulative incidence of MRD resurgence or progression 12 months after cessation of therapy was 4%, 0%, and 27% for patients with 0, 1, or 2 HRCA, respectively.82 Similarly, a phase III clinical trial (GEM2012MENOS65) evaluated lenalidomide and dexamethasone maintenance with or without ixazomib in newly diagnosed myeloma patients, with treatment stopping after 24 cycles in case of BM- based MRD-negativity. Patients achieving MRD negativity after 24 months of maintenance therapy had a low pro- gression rate (17.2%) at four years, strongly suggesting that the duration of maintenance therapy can be tailored based on MRD negativity.87 Accordingly, data regarding achievement of MRD negativity and early relapse have been reported but not yet published in high-risk MM patients included in the CASSIOPEIA trial.73 Although longer follow-up is needed, these trials already suggest that cessation of treatment may be feasible in patients with standard risk cytogenetics but not for patients with HRCA. Improving MRD assessment by combining BM and imaging evaluation may be more relevant in high-risk cytogenetic patients in front-line. Another important observation has been reported in a phase II study eval- uating MRD dynamics during lenalidomide maintenance. Patients who lost MRD negativity were more likely to progress than patients with sustained MRD negativity (HR infinite; P<0.0001) as expected, but also and worse than patients with persistent MRD positivity (HR 5.88, 95% CI: 1.18-33.33; P=0.015) at the 2-year landmark. These data suggest that the dynamic of the disease is another very important parameter to consider when evaluating the use of MRD as a therapeutic guide.88
The ongoing MIDAS trial (clinicaltrials.gov 04934475) is designed to evaluate the role of HDC-SCT on the basis of MRD status after induction in newly diagnosed MM pa- tients. In this trial, patients are treated with 6 cycles of quadruplet regimen induction with combined isatuximab, carfilzomib, lenalidomide and dexamethasone (Isa-KRd) and evaluated for BM-based MRD (with a threshold of 10−5 cells) post induction. Patients are next stratified into standard risk (MRD negativity < 10−5) or high risk (MRD positivity> 10−5). Patients achieving MRD negativity fol- lowing induction are randomized to receive 6 additional cycles of Isa-KRd followed by maintenance or HDC-SCT, followed by 2 cycles of Isa-KRd, and maintenance with lenalidomide for three years. High-risk patients defined by MRD positivity post induction are randomly assigned to receive HDC-SCT followed by 2 cycles of Isa-KRd versus tandem HDC-SCT followed by isatuximab-iberdo- mide maintenance for three years. This ambitious trial will address whether MRD status can be used to guide therapy, and if HDC-SCT remains the gold standard in patients achieving early MRD negativity after induction. Several other randomized clinical trials are evaluating
MRD-based treatment decision. The PERSEUS trial (clin- icaltrials.gov 03710603) will evaluate the possibility of stopping daratumumab during maintenance in patients achieving sustained MRD negativity for 12 months and after a minimum of 24 months of maintenance, and the benefit of restarting daratumumab in case of MRD con- version (from negative to positive) or confirmed loss of CR without IMWG disease progression criteria.89 The AURIGA trial (clinicaltrials.gov 03901963), randomly assigns pa- tients who have achieved VGPR but who are MRD-positive to receive daratumumab and lenalidomide versus lena- lidomide maintenance for the primary endpoint of MRD conversion at 12 months from initiation of maintenance. The DRAMMATIC trial (clinicaltrials.gov 04071457) by the Southwest Oncology Group (SWOG; S1803) randomly as- signs patients to receive daratumumab and lenalidomide versus lenalidomide maintenance post HDC-SCT. After two years of maintenance, MRD is assessed to guide further therapy. MRD positive patients will continue with the assigned treatment while MRD negative patients will be further randomized to either continue or discontinue the assigned treatment. The OPTIMUM trial (clinicaltrials.gov 03941860) by the Eastern Cooperative Oncology Group (ECOG; EAA171) will randomly assign MRD positive pa- tients who are receiving lenalidomide maintenance after HDC-SCT to receive ixazomib or placebo in addition to continuing lenalidomide.
In conclusion, MRD assessment methods have significantly improved in the past two decades and allow identification of patients with deep hematologic response. BM-based methods using NGF and NGS are to date the most avail- able, standardized, and sensitive methods. WBI includes wbMRI, and PET/CT are also very interesting, and when combined with BM MRD assessment provide better eval- uation especially in the setting of high-risk cytogenetics and EMD. Achievement of MRD negativity is a very strong prognostic factor that is now an established endpoint in myeloma clinical trials. Persistent or sustained MRD neg- ativity portends better outcome in newly diagnosed and RR disease, including after CAR T-cell therapy in myelo- ma and may allow discontinuation of therapy in patients without high-risk cytogenetics. Several clinical trials are currently ongoing to establish whether MRD can be used to guide therapy and to monitor disease activity.
Disclosures
No conflicts of interest to disclose.
Contributions
All authors made a significant contribution to this article. RES, NCM and KCA took part in the conception of the man- uscript, in drafting, revising and critically reviewing the arti- cle, and gave final approval of the version to be published.
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