Contributions
Abstract: EP1025
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
The armamentarium of treatment for newly diagnosed multiple myeloma (NDMM) has recently expanded. Yet MM remains largely incurable and all patients inevitably relapse or fail treatment. Progression-free survival (PFS) is a common primary endpoint in NDMM trials; however, demonstrating improvements in PFS requires a larger sample size and longer follow-up compared with other endpoints.
Aims
Endpoints such as overall response rate (ORR), complete response (CR), stringent complete response (sCR), and minimal residual disease (MRD) may be clinically relevant surrogate endpoints; this study investigated their role as surrogates for PFS in NDMM.
Methods
Medline, Embase, and Cochrane databases were systematically searched for randomized controlled trials (RCT) studies published from 2010 to July 2020. Additionally, relevant congress abstracts from 2018 to 2020 were reviewed. Studies that reported ORR, CR, sCR, or MRD and median PFS were extracted. The correlations between PFS and ORR, CR, sCR, or MRD were estimated using Pearson’s correlation weighted by sample size in each study arm. Surrogacy for PFS was evaluated using unadjusted and adjusted weighted linear regression models to estimate the gain in median PFS associated with each surrogate. Factors considered for adjustment included study year, age, sex, International Staging System risk stage, eligibility for transplant, and treatment type (lenalidomide/bortezomib [LEN/BOR] vs other). Optimal adjusted models were selected based on model fit statistics. Separately, a review of real-world evidence (RWE) studies was conducted following similar parameters to further investigate the association of MRD with survival.
Results
Seventy-five RCTs studies were identified with 101 study arms reporting median PFS. Final analysis datasets were developed that included study arms with valid pairs of median PFS with ORR (N=89), CR (N=87), sCR (N=20), and MRD (N=14). Moderate-to-strong significant correlations were observed for PFS with ORR (Pearson r=0.59), CR (r=0.48), sCR (r=0.68), and MRD (r=0.69). The unadjusted analysis models estimated an average increase of 0.50 (95% confidence interval [CI]: 0.36, 0.64), 0.42 (95% CI: 0.25, 0.58), 1.05 (95% CI: 0.58, 1.52), and 0.35 (95% CI: 0.12, 0.58) months of median PFS per percentage point increase in ORR, CR, sCR, and MRD, respectively (Figure 1). Following adjustment for age, and treatment type in the ORR model, and ISS risk stage in the CR model, the associations remained significant but were attenuated to 0.35 (95% CI: 0.21, 0.49) and 0.29 (95% CI: 0.16, 0.41) months of median PFS for each point of ORR and CR, respectively. Adjusted models could not be constructed for sCR or MRD models due to small sample size. The systematic review of RWE revealed 20 studies investigating the association between survival and MRD; 12 found significant (p < 0.05) survival benefit associated with MRD-negativity.
Conclusion
We demonstrated significant associations of PFS with ORR, CR, sCR, and MRD in NDMM, which may justify their use as surrogate endpoints to estimate PFS benefit in this population. Adjusted models estimate a 10% increase in ORR or CR is associated with 3.5 and 2.9-month increases in median PFS, respectively. The results of the exploratory MRD analyses of this study and RWE complement recent publications which have suggested that MRD-negativity is a viable surrogate endpoint for PFS in MM. The accumulation of evidence from multiple methodologies strengthens the argument that MRD is a suitable surrogate for PFS in NDMM.
Keyword(s): Multiple myeloma, Survival
Abstract: EP1025
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
The armamentarium of treatment for newly diagnosed multiple myeloma (NDMM) has recently expanded. Yet MM remains largely incurable and all patients inevitably relapse or fail treatment. Progression-free survival (PFS) is a common primary endpoint in NDMM trials; however, demonstrating improvements in PFS requires a larger sample size and longer follow-up compared with other endpoints.
Aims
Endpoints such as overall response rate (ORR), complete response (CR), stringent complete response (sCR), and minimal residual disease (MRD) may be clinically relevant surrogate endpoints; this study investigated their role as surrogates for PFS in NDMM.
Methods
Medline, Embase, and Cochrane databases were systematically searched for randomized controlled trials (RCT) studies published from 2010 to July 2020. Additionally, relevant congress abstracts from 2018 to 2020 were reviewed. Studies that reported ORR, CR, sCR, or MRD and median PFS were extracted. The correlations between PFS and ORR, CR, sCR, or MRD were estimated using Pearson’s correlation weighted by sample size in each study arm. Surrogacy for PFS was evaluated using unadjusted and adjusted weighted linear regression models to estimate the gain in median PFS associated with each surrogate. Factors considered for adjustment included study year, age, sex, International Staging System risk stage, eligibility for transplant, and treatment type (lenalidomide/bortezomib [LEN/BOR] vs other). Optimal adjusted models were selected based on model fit statistics. Separately, a review of real-world evidence (RWE) studies was conducted following similar parameters to further investigate the association of MRD with survival.
Results
Seventy-five RCTs studies were identified with 101 study arms reporting median PFS. Final analysis datasets were developed that included study arms with valid pairs of median PFS with ORR (N=89), CR (N=87), sCR (N=20), and MRD (N=14). Moderate-to-strong significant correlations were observed for PFS with ORR (Pearson r=0.59), CR (r=0.48), sCR (r=0.68), and MRD (r=0.69). The unadjusted analysis models estimated an average increase of 0.50 (95% confidence interval [CI]: 0.36, 0.64), 0.42 (95% CI: 0.25, 0.58), 1.05 (95% CI: 0.58, 1.52), and 0.35 (95% CI: 0.12, 0.58) months of median PFS per percentage point increase in ORR, CR, sCR, and MRD, respectively (Figure 1). Following adjustment for age, and treatment type in the ORR model, and ISS risk stage in the CR model, the associations remained significant but were attenuated to 0.35 (95% CI: 0.21, 0.49) and 0.29 (95% CI: 0.16, 0.41) months of median PFS for each point of ORR and CR, respectively. Adjusted models could not be constructed for sCR or MRD models due to small sample size. The systematic review of RWE revealed 20 studies investigating the association between survival and MRD; 12 found significant (p < 0.05) survival benefit associated with MRD-negativity.
Conclusion
We demonstrated significant associations of PFS with ORR, CR, sCR, and MRD in NDMM, which may justify their use as surrogate endpoints to estimate PFS benefit in this population. Adjusted models estimate a 10% increase in ORR or CR is associated with 3.5 and 2.9-month increases in median PFS, respectively. The results of the exploratory MRD analyses of this study and RWE complement recent publications which have suggested that MRD-negativity is a viable surrogate endpoint for PFS in MM. The accumulation of evidence from multiple methodologies strengthens the argument that MRD is a suitable surrogate for PFS in NDMM.
Keyword(s): Multiple myeloma, Survival