Abstract

Background: Thalidomide (T) and bortezomib (B) in combination with melphalan-prednisone (MP) were both shown to be superior to treatment with MP. However, head-to-head comparison of these regimens is lacking. When direct comparison is not available, indirect meta-analysis of randomized controlled trials (RCTs) can be performed. Such an analysis preserves the original randomization and therefore is considered to be more reliable than comparison based on non-RCT data.

Methods: Previously described methods for adjusted indirect comparisons developed by Bucher et al and Glenny et al were used. We created the following chain of inference: we first pooled RCTs that compared MPT with MP, and BMP vs. MP. We then compared the pooled estimate to obtain the unbiased estimate in treatment differences between BMP vs. MPT.

Results: 4 RCTs compared MPT vs. MP and 1 BMP vs. MP. Data from RCT by Waage et.al. were not available. The results for all comparisons are summarized in the table. Meta-analysis of 3 RCTs comparing MPT vs. MP showed no difference in overall survival (OS), and treatment-related mortality (TRM). However, event-free survival (EFS), partial response (PR), complete response (CR) and very good partial response (VGPR) were significantly better with MPT, but at the risk of significant grade III-IV adverse events (AE), and deep-vein thrombosis (DVT). OS, EFS, CR and VGPR was significantly better with BMP vs MP in 1 RCT, but at significant risk for grade III-IV AE. There was no difference between BMP and MP in terms of TRM, DVT, and PR. Comparison of BMP versus MPT showed no difference in OS, EFS, TRM, DVT, and PR. However BMP is associated with significantly less grade III-IV AE and better CR.

Conclusion: There was no difference in OS, EFS, or TRM between BMP and MPT. However, treatment with BMP results in improved complete response, while grade III-IV AE were more common in MPT arm. The lack of statistical difference is likely due to insufficient power (absence of evidence) rather than true differences of no effect (evidence of absence). Since the power of this indirect meta-analysis was low, direct head-to-head comparison between these competing regimens is warranted.

Table.

Outcome Comparisons 
 MPT versus MP (3 RCT; N= 852) Conclusion BMP versus MP (1 RCT; N=682) Conclusion BMP versus MPT Conclusion 
OS HR=0.747 (95%CI 0.534, 0.046); p=0.089 No difference HR=0.607 (95%CI 0.425, 0.866); p=0.006 BMP better HR=0.812 (95%CI 0.498, 1.325); p=0.405 No difference 
EFS HR=0.569 (95%CI 0.484, 0.668); p=0 MPT better HR=0.483 (95%CI 0.37, 0.63); p=0 BMP better HR=0.85 (95%CI 0.623, 1.159); p=0.304 No difference 
TRM Risk ratio (RR)=0.976 (95%CI 0.469, 2.031); p=0.949 No difference RR=0.566 (95%CI 0.167, 1.917); p=0.361 No difference RR=0.58 (95%CI 0.14, 2.405); p=0.453 No difference 
DVT RR=3.586 (95%CI 2.021, 6.632); p=0.00 MP better RR=0.991 (95%CI 0.243, 4.041); p=0.99 No difference RR=0.276 (95%CI 0.61, 1.261); p=0.0971 No difference 
Grade III-IV AE RR=4.257 (95%CI 3.402, 5.327); p=0.0 MP better RR=1.512 (95%CI 1.255, 1.814); p=0.0 MP better RR=0.355 95%CI 0.265, 0.474; p=0.00 BMP better 
CR RR=0.911 (95%CI 0.875, 0.948); p=0.00 MPT better RR=0.728 (95%CI 0.676, 0.783); p=0 BMP better RR=0.799 (95%CI 0.735, 0.869); p=0.00 BMP better 
VGPR RR=0.778 (95%CI 0.720, 0.840); p=0.005 MPT better RR=0.947 (95%CI 0.907, .990); p=0.016 BMP better RR=1.219 (95%CI 1.115, 1.331); p=0.00 MPT better 
PR RR=0.885 (95%CI 0.794, 0.986); p=0.027 MPT better RR=0.914 (95%CI 0.821, 1.018); p=0.101 No difference RR=1.033 (95%CI 0.887, 1.203); p=0.675 No difference 
Outcome Comparisons 
 MPT versus MP (3 RCT; N= 852) Conclusion BMP versus MP (1 RCT; N=682) Conclusion BMP versus MPT Conclusion 
OS HR=0.747 (95%CI 0.534, 0.046); p=0.089 No difference HR=0.607 (95%CI 0.425, 0.866); p=0.006 BMP better HR=0.812 (95%CI 0.498, 1.325); p=0.405 No difference 
EFS HR=0.569 (95%CI 0.484, 0.668); p=0 MPT better HR=0.483 (95%CI 0.37, 0.63); p=0 BMP better HR=0.85 (95%CI 0.623, 1.159); p=0.304 No difference 
TRM Risk ratio (RR)=0.976 (95%CI 0.469, 2.031); p=0.949 No difference RR=0.566 (95%CI 0.167, 1.917); p=0.361 No difference RR=0.58 (95%CI 0.14, 2.405); p=0.453 No difference 
DVT RR=3.586 (95%CI 2.021, 6.632); p=0.00 MP better RR=0.991 (95%CI 0.243, 4.041); p=0.99 No difference RR=0.276 (95%CI 0.61, 1.261); p=0.0971 No difference 
Grade III-IV AE RR=4.257 (95%CI 3.402, 5.327); p=0.0 MP better RR=1.512 (95%CI 1.255, 1.814); p=0.0 MP better RR=0.355 95%CI 0.265, 0.474; p=0.00 BMP better 
CR RR=0.911 (95%CI 0.875, 0.948); p=0.00 MPT better RR=0.728 (95%CI 0.676, 0.783); p=0 BMP better RR=0.799 (95%CI 0.735, 0.869); p=0.00 BMP better 
VGPR RR=0.778 (95%CI 0.720, 0.840); p=0.005 MPT better RR=0.947 (95%CI 0.907, .990); p=0.016 BMP better RR=1.219 (95%CI 1.115, 1.331); p=0.00 MPT better 
PR RR=0.885 (95%CI 0.794, 0.986); p=0.027 MPT better RR=0.914 (95%CI 0.821, 1.018); p=0.101 No difference RR=1.033 (95%CI 0.887, 1.203); p=0.675 No difference 

Disclosures: No relevant conflicts of interest to declare.

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