Page 237 - Haematologica April 2020

First-line therapy in elderly MM patients
del(17p), t(4;14) and t(14;16), consistently with the IMWG recommendations. Major advantages of this study are the number of patients with available cytogenetic data and the fact that all FISH analyses were performed at one central- ized facility only.
In our analysis, VMP resulted in a 45% reduction in the risk of death or progression, as compared to that achieved with Rd-R (HR=0.54), in the high-risk group, with the PFS benefit being confirmed across the single cytogenetic abnormalities, whereas no significant difference in PFS was found in the standard-risk group (HR=0.96, interaction P=0.03). Furthermore, high-risk patients treated with VMP had a reduced risk of death (HR: 0.73), confirmed across all cytogenetic subgroups, in comparison with patients treat- ed with Rd-R, while no difference was noted between patients treated with VMP or Rd-R within the standard- risk group (HR=1.08). However, we could not distinguish the role of melphalan from that of bortezomib in improv- ing the outcome of high-risk patients.
The PFS benefit for VMP over Rd-R in high-risk patients was seen in both younger (≤75 years; HR=0.75) and older patients (>75 years; HR=0.19), while in older, standard-risk patients VMP and Rd-R had similar effects on outcomes (HR=0.96). Similarly, while the OS benefit among high-risk patients was independent of age (patients ≤75 years, HR=0.75; patients >75 years, HR=0.65), older patients with standard-risk cytogenetics benefited less from VMP (patients >75 years, HR=1.81) than they did from Rd-R.
No data about the patients’ frailty at diagnosis were available in the GIMEMA-MM-03-05 trial, and chronolog- ical age was the only parameter that could be evaluated in the two trials included in this analysis.
In order to better assess the efficacy of approved upfront regimens according to cytogenetic risk, we restricted our analysis to patients randomized to the VMP arm of the GIMEMA-MM-03-05 trial and the Rd-R arm of the EMN01 trial, since both VMP and Rd are approved combi- nations for patients with newly diagnosed MM who are ineligible for transplantation. Of note, in the EMN01-trial patients in the Rd-R arm received nine cycles of Rd fol- lowed by lenalidomide maintenance or lenalidomide-pred- nisone maintenance until progression (lenalidomide 10 mg/day), whereas in the standard approved regimen, Rd is administered continuously until progression.15 This could in part explain the inferior PFS in the EMN01 trial (21 months) as compared to that in the FIRST trial (26
Table 3. Multivariate Cox models with three-way interaction between treatment type, age and cytogenetics, adjusted for International Staging System stage, Karnofsky Performance Status, extramedullary disease and age as a continu- ous variable.
months).7,15 On the other hand, we recently presented, at an American Society of Hematology meeting, preliminary results of a randomized phase III study comparing stan- dard Rd to Rd-R in older, intermediate fit patients, defined by the IMWG frailty score,19 showing no difference between continuous Rd and Rd-R in terms of PFS (HR=0.93, 95% CI: 0.64-1.34; P=0.681) and OS (HR=0.73, 95% CI: 0.40-1.33; P=0.306).20
In the VISTA trial, bortezomib was given twice weekly during cycles 1 to 4 and once weekly thereafter, while in the GIMEMA-MM-03-05-trial half of the patients in the VMP arm (n=191, 51%) received once-weekly borte- zomib. However, we had previously shown that the once weekly schedule was equally effective as the twice week- ly one in a subgroup analysis of the GIMEMA-MM-03-05 study, potentially due to a more tolerable safety profile of once weekly bortezomib.13,14 This might explain a some- what more favorable median PFS with VMP in the GIMEMA-MM-03-05 study (median, 24.8 months) as compared to the PFS reported in the VISTA trial (median, 21.7 months).4
The major limitation of this unplanned cross-trial com- parison is the absence of randomization between the two treatments, so the results should be interpreted with par- ticular caution. Despite similar eligibility criteria and a comparable follow-up of more than 5 years, there were some significant differences between the two populations. In fact, patients treated with Rd-R were significantly older and patients treated with VMP had a significantly higher creatinine level. Another limitation is that patients enrolled in the two source trials had to meet strict inclusion and exclusion criteria.
Despite these caveats, a head-to-head comparison between VMP and Rd is currently lacking, as is a prospec- tive evaluation of the different treatments in high-risk and standard-risk MM patients. To the best of our knowledge, this is the first study that has pooled together and analyzed a large series of transplant-ineligible patients with NDMM treated with either a bortezomib- or lenalidomide-based combination, with the aim of providing an answer to the burning question of the optimal upfront treatment for NDMM patients according to their cytogenetic risk.
Our results suggest that the doublet regimen Rd may be a suboptimal option for patients with high-risk cytogenet- ics, further supporting the 2016 IMWG recommendations that a triplet regimen containing an IMiD and a PI should be used in this setting.9 In this light, a major step forward has been made with the results of the Southwest Oncology Group (SWOG) S0777, which showed superior response rate, PFS and OS with the triplet regimen borte- zomib-lenalidomide-dexamethasone (VRD) than with Rd in NDMM without intention to immediate transplanta- tion.21 Of note, the longest PFS in high-risk patients was obtained with VRD (38 months). Nevertheless, the analy- sis was based on only 44 high-risk patients.
The selection of treatment in elderly patients should also consider the risk of toxicity and the capability to tolerate treatment, since advanced age and the occurrence of severe adverse events may negatively affect survival.22 In our analysis, this was particularly evident in standard-risk patients, in whom no difference was found between VMP and Rd-R and the benefit of Rd-R was more evident in patients over 75 years. In this context, the presence of spe- cific comorbidities (such as peripheral neuropathy or renal insufficiency), older age (>75 years) or the presence of
Main analysis
Standard-risk cytogenetics - age ≤75 Standard-risk cytogenetics - age >75 High-risk cytogenetics - age ≤75 High-risk cytogenetics - age >75 3-way interaction-P
2-way cytogenetics interaction-P 2-way age interaction-P
PFS HR* (95% CI)
0.92 (0.67 - 1.27)
0.96 (0.56 - 1.66) 0.75 (0.45 - 1.26) 0.19 (0.07 - 0.52) 0.03
0.03
0.85
OS
HR* (95% CI)
0.83 (0.53 - 1.29)
1.81 (0.94 - 3.49) 0.75 (0.39 - 1.43) 0.65 (0.21 - 2.04) 0.23
0.23
0.04
PFS: progression-free survival; OS: overall survival; HR: hazard ratio; 95% CI: 95% confidence interval.
haematologica | 2020; 105(4)
1079