Total Therapy 2 (TT2) for Multiple Myeloma (MM): Contributions to Survival Outcomes of Dosing of Thalidomide (T), Dexamethasone (D) and Interferon (I) Maintenance Components.

Abstract

AbstractAbstract 1356 Background:We have previously reported on the roles of VTD (bortezomib, thalidomide, dexamethasone) maintenance components in Total Therapy 3 (TT3), noting the important contributions of cumulative dosing of VTD components for overall survival (OS) and, especially, a detrimental effect of pre-mature drug discontinuation (PMDD) in the case of V (van Rhee et al: Blood 2010). Here we examine in a similar fashion the roles of T, D and I in TT2 toward OS. Patients and Methods:TT2 accrued a total of 668 patients, of whom 323 were randomized to the T arm and the remainder to the control arm. The cumulative dosing effects of T and D during induction, transplantation, consolidation and maintenance phases were evaluated while, in the case of I, its contribution in the maintenance phase only was examined. We also examined outcomes according to the number of induction and consolidation cycles applied prior to and after transplantation and according to the number and timeliness of administering both transplant interventions. In order to utilize the entire patient population, post-baseline treatment interventions and responses were treated as time-dependent variables. Multivariate analyses were performed to examine the collective impact on OS and EFS of baseline characteristics, treatment compliance and type of and time to salvage therapy. Results:Randomization to T prolonged both OS and EFS, as did timely completion of second transplant and first cycle of consolidation chemotherapy. During most protocol steps, cumulative dosing of both D and T benefited OS or EFS while pre-mature discontinuation of D shortened both OS and EFS; this was upheld in multivariate analyses, whether or not GEP data were included and also when time to salvage therapy was considered. D dosing prior to relapse was an independently favorable variable for post-relapse survival, which also was longer when disease progression did not occur within 2 years. D's dosing role was apparent only in the subset of patients presenting with lowest tertile gene expression levels of the glucocorticoid receptor gene, NR3C1. Conclusion:In addition to confirming well-established variables (beta-2-microgobulin, lactate dehydrogenase, cytogenetic abnormalities, gene expression profiling [GEP]-derived risk and molecular subgroups), randomization to T and timely applications of second transplantation consolidation and maintenance phases favorably affected outcomes. We conclude that D dosing, especially in low NR3C1-level myeloma, is an important treatment component that favorably affects global survival.Multivariate Analysis (both arms combined, including GEP data)Overall Survival from EnrollmentEvent-Free Survival from EnrollmentVariablen/N (%)HR (95% CI)P-valueHR (95% CI)P-valueAlbumin < 3.5 g/dL118/655 (18%)1.33 (1.00,1.75)0.0481.31 (1.02,1.67)0.033B2M > 5.5 mg/L118/655 (18%)1.41 (1.07,1.86)0.0151.42 (1.11,1.81)0.005LDH > 190 U/L202/655 (31%)1.47 (1.15,1.88)0.0021.27 (1.03,1.57)0.025Cytogenetic abnormalities197/655 (30%)1.81 (1.43,2.30)<.0011.63 (1.33,2.00)<.001Randomization to thalidomide319/655 (49%)0.77 (0.61,0.97)0.0240.69 (0.57,0.84)<.001Completed transplant 2*0.63 (0.49,0.81)<.0010.80 (0.64,1.00)0.048Discontinued dexamethasone*2.50 (1.97,3.16)<.0011.85 (1.49,2.29)<.001Multivariate Analysis (both arms combined, including GEP data)Overall Survival from EnrollmentEvent-Free Survival from EnrollmentVariablen/N (%)HR (95% CI)P-valueHR (95% CI)P-valueB2M > 5.5 mg/L72/347 (21%)1.54 (1.05,2.28)0.0281.64 (1.19,2.27)0.003CRP ≥ 8 mg/L124/347 (36%)0.87 (0.61,1.25)0.4510.70 (0.52,0.94)0.018LDH ≥ 190 U/L117/347 (34%)1.64 (1.15,2.34)0.0071.19 (0.89,1.59)0.241Cytogenetic abnormalities110/347 (32%)1.80 (1.26,2.56)0.0011.62 (1.22,2.16)<.001GEP high-risk45/347 (13%)2.60 (1.69,3.98)<.0012.31 (1.57,3.38)<.001GEP MS subgroup43/347 (12%)2.07 (1.37,3.12)<.0011.79 (1.23,2.60)0.002GEP TP53 deletion34/347 (10%)2.14 (1.36,3.39)0.0011.90 (1.26,2.87)0.002Randomization to thalidomide173/347 (50%)0.71 (0.51,1.00)0.0500.62 (0.47,0.81)<.001Discontinued dexamethasone*3.23 (2.30,4.55)<.0011.71 (1.26,2.31)<.001 Disclosures:No relevant conflicts of interest to declare.