| minor |
Considering:
- evidence of the superiority of the DARZALEX (daratumumab) + bortezomib + lenalidomide + dexamethasone combination in the induction and consolidation phase followed by the DARZALEX (daratumumab) + lenalidomide combination in the maintenance phase
(D-VRd/D-R protocol) compared to the bortezomib + lenalidomide + dexamethasone combination in the induction and consolidation phase followed by lenalidomide alone in the maintenance phase (VRd/R protocol), in a randomised, open-label phase 3 study, in terms of progression-free survival (PFS) assessed by a computer algorithm, with:
- an HR = 0.42 (CI95% = [0.30; 0.59]; p<0.0001),
- PFS medians not reached in either of the two groups,
- and respective PFS rates at 48 months of 84.3% versus 67.7%, i.e. a difference of 16.6%;
- complete response or better rates (CR + sCR) of 87.9% (CI95% = [84.0; 91.1]) in the D-VRd/D-R group and 70.1% (CI95% = [65.0; 74.8]) in the VRd/R group with an OR = 3.13 ([2.11; 4.65]; p < 0.0001);
- the MRD negativity rate at the 10-5 threshold in patients with a complete response of 75.2% (CI95% = [70.4; 79.6]) in the D-VRd/D-R group and 47.5% (CI95% = [42.2; 52.8]) in the VRd/R group with an OR = 3.40 [2.47; 4.69]; p < 0.0001);
and despite:
- a study objective and design not enabling isolation of the potential therapeutic contribution of the addition of DARZALEX (daratumumab) between the different sequences: induction, transplant and consolidation phase, maintenance phase, given the absence of randomisation before the last phase. In addition, in the maintenance phase context, when treatment may be over the long term, it is important to note that the safety profile of the D-VRd/D-R protocol differs from that of the VRd/R protocol in terms of a numerically higher proportion of serious adverse events (38.8% versus 26.0%). The majority of these SAEs were infections, occurring in 22.7% of patients in the D-VRd/D-R group, versus 13.0% in the VRd group during the maintenance phase;
- the open-label design of the study;
- an amendment deemed to be important to the statistical analysis plan having concerned the hierarchical procedure for the statistical tests (amendment dated 30/08/2023), made after the cut-off date (01/08/2023). These modifications are detrimental to the internal validity of the study, and hence to the quality of the evidence, since they suggest changes in view of the data, hence possibly dictated by said data;
- a possible heterogeneity of effect depending on age: a greater treatment effect is observed in the subgroup of patients under 65 years of age;
- the fact that the comparator (VRd/R) is not the most clinically relevant one in view of current practice, with this comparator actually being little used in routine practice;
- the fact that it is impossible to quantify the contribution of this combination compared to the D-VTd protocol due to concomitant development;
- the absence of any formal conclusion that can be drawn from the descriptive analysis of overall survival, on the basis of currently available data;
- the absence of any formal conclusion that can be drawn for the quality of life data (exploratory endpoint);
the safety profile of the D-VRd/D-R protocol compared to the VRd/R protocol, marked
the Committee deems that DARZALEX 1,800 mg (daratumumab) solution for injection in combination with bortezomib, lenalidomide and dexamethasone as induction and consolidation therapy, followed by maintenance therapy with the DARZALEX (daratumumab) and lenalidomide combination (D-VRd/D-R protocol), provides a minor clinical added value (CAV IV) compared to the combination of bortezomib, lenalidomide and dexamethasone as induction and consolidation therapy, followed by maintenance therapy with lenalidomide alone (VRd/R protocol). |
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