Evaluating Minimal Residual Disease Negativity As a Surrogate Endpoint for Treatment Efficacy in Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials
Authors: Ntanasis-Stathopoulos Ioannis , Filippatos Charalampos , Ntanasis-Stathopoulos Anastasios , Malandrakis Panagiotis , Kastritis Efstathios , Dimopoulos Meletios A. , Terpos Evangelos , Gavriatopoulou Maria 
Published: December 2024

Background
Evaluating survival endpoints in multiple myeloma (MM) clinical trials is challenging due to improved patient outcomes from novel therapies. Timely approval of breakthrough treatments is crucial for patients requiring salvage therapy, thus identifying early surrogate endpoints predictive of long-term efficacy is essential. Minimal residual disease (MRD) negativity has shown prognostic value in MM trials. This meta-analysis assesses the association between MRD negativity and clinical outcomes in MM patients enrolled in Randomized Controlled Trials (RCTs).
Methods
A systematic database search (end-of-search: June 2nd, 2024) identified RCTs evaluating MM treatments that reported MRD status and clinical outcomes. Pooled odds ratios (OR), hazard ratios (HR), and 95% confidence intervals (CI) were calculated using random-effects models. Subsequently, univariate meta-analytic regressions examined the impact of MRD negativity on clinical outcomes. Subgroup and meta-regression analyses addressed heterogeneity and potential associations between varying factors and reported outcomes.
Results
In total, 35 records reporting results from varying follow-ups of 29 RCTs enrolling 15635 MM patients were included. In the base case, longest follow-up analysis, patients enrolled in treatment arms had higher odds of exhibiting MRD negativity [OR 2.84, 95% CI (2.15, 3.75)] along with favorable PFS [HR 0.54, 95% CI (0.47, 0.61)] and OS [HR 0.80, 95% (0.71, 0.91)] when compared to those of reference arms. There was a significant, negative and strong association between MRD negativity ORs and the survival outcomes (meta-analytic framework regression slopes [β_PFS = -0.35 p&lt;0.001, R2=0.79 and β_OS = -0.21 (p&lt;0.001, R2=1]. These associations for MRD negativity ORs and PFS HRs are further validated for NDMM patients (β_PFS =-0.35, p&lt;0.001, R2=0.79), while for RRMM results were consistent but not significant (β_PFS =-0.17, R2 = 0.17, p = 0.121).
At 1-year follow-up periods, patients in treatment arms had increased odds for MRD negativity [OR = 2.82, 95% CI (1.77, 4.49)] and reduced hazard rates for disease progression or death (PFS) [HR = 0.54, 95% CI (0.42, 0.69)], when compared to the reference arms [β_PFS = -0.42 (p&lt;0.001, R2=0.72)].
In the subgroup of 2-year follow up, patients in treatment arms had increased odds for MRD negative status [OR = 2.98, 95% CI (1.73, 5.14)] and reduced hazard rates for disease progression or death (PFS) [HR = 0.55, 95% CI (0.43, 0.70)], with these being significantly strongly and negatively associated [β_PFS = -0.21 (p&lt;0.001, R2=0.62)].
For the longer, 3-year and 4-year follow-up periods, patients in treatment arms exhibited increased odds for MRD negative status [OR(3-year) = 2.94, 95% CI (1.55, 5.59), OR(4-year) = 3.64, 95% CI (2.47, 5.37)] and lower PFS hazard rates [HR(3-year) = 0.48, 95% CI (0.36, 0.64), HR(4-year) = 0.51, 95% CI (0.42, 0.61)] when compared to those of reference arms.
Furthermore, 10 records annunciated outcomes for 12-month sustained MRD negativity. Patients enrolled in treatment arms had increased odds to sustain MRD negativity for a year [OR = 2.68, 95% CI (1.67, 4.31)] while also exhibiting lower hazard rates for disease progression or death [PFS HR = 0.52, 95% CI (0.43, 0.63)] (Figures S70 and S73). Meta-analytic oriented regression revealed a strong statistically significant and negative association [β_PFS = -0.30 (p&lt;0.001, R2=0.91)].
Six records from the total sample reported Time to Next Treatment (TTNT) outcomes in terms of HRs between arms. Patients in the treatment arms exhibited a pooled 59% lower hazard rate for needing a next treatment regimen at any given time of the follow-up period [HR = 0.41, 95% CI (0.31, 0.54)] when compared to those of the reference arms while also having increased odds of MRD negative status [OR = 0.41, 95% CI (0.31, 0.54)].
Conclusion
In conclusion, this comprehensive meta-analysis of 29 RCTs enrolling 15635 MM patients demonstrates that patient groups which exhibited higher odds of MRD negativity also had favorable survival outcomes compared to others. These findings support the implementation of MRD negativity status as a potent surrogate endpoint for treatment efficacy in terms of survival outcomes in patients with MM.