Abstract
Background
Studies investigating thalidomide consolidation/maintenance strategies post ASCT in patients with MM have consistently demonstrated improvement in duration of myeloma control, however not consistently shown improvements in overall survival. Cost effectiveness of thalidomide in the post-ASCT consolidation/maintenance setting in Australian clinical practice has not been previously established
Aim
To determine whether progression free survival (PFS) and overall survival (OS) advantages for thalidomide consolidation post ASCT at 3 years post randomisation in the ALLG MM6 study are durable at later follow-up. To compare overall response rate (ORR) to salvage therapy and incidence of second primary malignancy (SPM). To investigate the cost-effectiveness of thalidomide in the post-ASCT consolidation setting.
Methods
Phase III, randomised, multi-centre, open label study. 243 newly diagnosed MM patients 6 weeks following a single MEL200 ASCT as part of their first-line therapy were randomly assigned to receive indefinite prednisolone maintenance (50mg alternate days) alone (CA = 129 patients, 1 patient withdrew consent) or in combination with 12 months of thalidomide consolidation (100mg/d increasing to 200mg/d after 2/52) (TA = 114 patients). This was a post hoc analysis, PFS and OS were measured from date of randomization; these endpoints were compared using intention-to-treat analyses. Data for ORR to salvage therapy was collected retrospectively for 96 of 187 relapsed/progressed patients only (TA = 42/81 relapsed, CA = 54/109 relapsed), as was data for SPM (207/238 patients, TA = 104/112, CA = 103/126). All statistical analyses were performed using SPSS version 19.
Economic analysis incorporated treatment exposure (primary drug and co-therapies), the use of ongoing medical and diagnostic services, occurrence of SAEs and use of therapies to treat those events, post progression therapy and duration of survival, and was represented as incremental cost per discounted mean life year gained (LYG) – incremental cost effectiveness ration (ICER). All costs and outcomes beyond 12 months were discounted at 5% per annum, and were calculated in Australian dollars.
Results
After a median follow-up of 5.4 years post randomization, 2 patients per arm were lost to follow-up (TA = 112, CA = 126). Post randomization estimated 5 year PFS rates were 27% versus 15% (p=0.005; hazard ratio [HR] 0.16: 95% CI 0.044 to 0.582) and OS rates were 66% versus 47% (p=0.007; HR 0.12: 95% CI 0.028 to 0.558) in TA and CA respectively. Thalidomide remained beneficial irrespective of pre-ASCT B2m level <4mg/L (p=0.002) and ≥4mg/L (p=0.049), however TA patients who achieved VGPR/CR post ASCT no longer had a PFS advantage over CA patients who achieved VGPR/CR. Patients required at least 8 months of thalidomide exposure to gain a PFS and OS advantage (p<0.001). Landmark analysis confirmed that PFS/OS benefit was gained within the first 8-12m of therapy. There was no difference in ORR to salvage therapy (62% versus 69%, p=0.5), survival post-progression or incidence of SPM for TA versus CA.
Discounted mean LYG for TA patients was 0.92 years (95%CI 0.32 to 1.52), and estimated treatment for TA patients cost $67,911 compared to $42,999 for CA patients, with a resultant incremental cost of $24,912 for TA compared with CA. ICER was $26,996 per mean LYG for TA versus CA. Cost of thalidomide accounted for 56% of the overall incremental cost difference between TA and CA, post-progression therapy 21%, and SAEs contributed the least to estimated difference in costs (3%).
Conclusion
PFS and OS advantages ascribed to thalidomide consolidation post ASCT remain highly significant at 5 years. At least 8 months of thalidomide exposure was required to attain the PFS/OS benefit. Further recapitulating previous findings, thalidomide did not impact on ORR to salvage therapy or survival following relapse in the context of salvage with alternate novel therapies. Thalidomide consolidation is cost effective in terms of ICER, with cost of thalidomide the key contributor to the cost difference.
Disclosures:
Spencer: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.
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