Bortezomib added to SoC improves 10-year survival in newly diagnosed multiple myeloma
Bortezomib in combination with thalidomide plus dexamethasone (VTD) significantly improves progression-free survival (PFS) and overall survival (OS) vs thalidomide plus dexamethasone (TD) alone in patients with newly diagnosed multiple myeloma (MM) undergoing double autologous stem cell transplantation (ASCT), 10-year results of the GIMEMA-MMY-3006 trial have shown.
“The long-term PFS and OS benefits of VTD were maintained even in patients predicted to have adverse prognosis based on high-risk cytogenetic abnormalities [HRCA], International Staging System [ISS] stage II/III disease, and/or failure to achieve complete response [CR] to therapy,” said investigator Dr Paola Tacchetti of the Bologna University School of Medicine, Bologna, Italy. [Tacchetti P, et al, ASH 2018, abstract 125]
In the trial, 474 patients with newly diagnosed MM were randomized to receive VTD or TD as induction therapy before and consolidation therapy after double ASCT. In both treatment arms, induction therapy was given in three 21-day cycles, while consolidation therapy was given in two 35-day cycles. Results after a median follow-up of 36 months demonstrated a significant improvement in PFS with VTD vs TD (hazard ratio [HR], 0.63; p=0.0061). [Lancet 2010;376:2075-2085]
“After a median follow-up of 124.1 months, PFS rate was 34 percent in the VTD arm vs 17 percent in the TD arm, with a median PFS of 59.6 months vs 40.7 months, representing a significant 38 percent reduction in the risk of disease progression or death [HR, 0.62; 95 percent CI, 0.50 to 0.77; p<0.0001],” reported Tacchetti.
“The 10-year OS rate was 60 percent in the VTD arm vs 46 percent in the TD arm, and median OS was not reached in the VTD arm vs 110 months in the TD arm, representing a significant 32 percent reduction in the risk of death [HR, 0.68; 95 percent CI, 0.51 to 0.90; p=0.007],” she continued.
The PFS and OS benefits of VTD were maintained in prespecified patient subgroups, including in patients with the HRCA feature of t(4;14) and/or del(17p) positivity (PFS rate, 17 percent vs 3 percent with TD; median PFS, 44 months vs 25 months; HR, 0.45; 95 percent CI, 0.30 to 0.69; p<0.001) (OS rate, 42 percent vs 22 percent; median OS, 102 months vs 56 months; HR, 0.54; 95 percent CI, 0.34 to 0.88; p=0.011).
“On multivariate Cox regression analysis, randomization to the VTD arm was found to be an independent predictor of both prolonged PFS [HR, 0.599; 95 percent CI, 0.475 to 0.756; p<0.001] and prolonged OS [HR 0.675; 95 percent CI, 0.501 to 0.910; p=0.010],” said Tacchetti.
Specific multivariate regression analysis not including therapy showed that presence of HRCA (HR, 1.857; 95 percent CI, 1.452 to 2.375; p<0.001), ISS stage II/III disease (HR, 1.384; 95 percent CI, 1.099 to 2.743; p=0.006), and failure to achieve CR (HR, 2.006; 95 percent CI, 1.593 to 2.526; p<0.001) were leading factors adversely affecting PFS.
Using these three adverse variables to build a prognostic scoring system, patients in the study were stratified into three risk groups with divergent outcomes: a low-risk group with none of the adverse variables (22 percent of patients), with a 10-year PFS rate of 44 percent and 10-year OS rate of 76 percent; an intermediate-risk group with one adverse variable (39 percent of patients), with 10-year PFS and OS rates of 28 percent and 58 percent, respectively; and a high-risk group with 2–3 adverse variables (39 percent of patients), with 10-year PFS and OS rates of 9 percent and 32 percent, respectively.
“VTD demonstrated significant PFS and OS benefits vs TD among patients in the high-risk group. In this group of patients, 10-year PFS rate was 13 percent for VTD vs 7 percent for TD [HR, 0.66; 95 percent CI, 0.47 to 0.92; p=0.015], while 10-year OS rate was 43 percent vs 23 percent [HR, 0.65; 95 percent CI, 0.43 to 0.97; p=0.033],” said Tacchetti.
In the intermediate-risk group, VTD demonstrated a significant benefit in PFS (10-year PFS rate, 41 percent vs 15 percent; HR, 0.50; 95 percent CI, 0.34 to 0.73; p<0.001), and a numerical improvement in OS (10-year OS rate, 62 percent vs 52 percent; HR, 0.73; 95 percent CI, 0.45 to 1.20; p=0.218).
In the low-risk group, improvements in PFS and OS with VTD vs TD did not reach statistical significance (10-year PFS rate, 51 percent vs 36 percent; HR, 0.75; 95 percent CI, 0.43 to 1.28; p=0.285) (10-year OS rate, 79 percent vs 72 percent; HR, 0.76; 95 percent CI, 0.32 to 1.75; p=0.517).
“A PFS time of 78 months predicted long-term survival outcomes in both the intermediate-risk and low-risk groups, according to results of assessment of conditional survival,” said Tacchetti. “After 78 months, conditional PFS became superimposable for the intermediate-risk and low-risk groups [86 percent and 87 percent, respectively], but was significantly lower in the high-risk group [63 percent].”“Our results demonstrated persistent PFS benefit that translated into extended OS with VTD vs TD, with significant benefit observed in both high-risk and intermediate-risk groups,” she concluded.