Page 236 - Haematologica April 2020

A. Larocca et al.
and ISS stage data. No difference in PFS was observed between the groups treated with VMP or Rd-R (HR=0.85, 95% CI: 0.69-1.04); subgroup analysis confirmed the pre- vious results for cytogenetics, with no difference for stan- dard-risk patients (HR=1.01, 95% CI: 0.78-1.30); while, in high-risk patients, there was a significant benefit from VMP treatment in comparison with Rd-R treatment (HR=0.53, 95% CI: 0.34-0.82; interaction P=0.02) (Online Supplementary Figure S3). No difference in OS was observed between the groups treated with VMP or Rd-R (HR=0.86, 95% CI: 0.66-1.13); subgroup analysis revealed that VMP was more beneficial than Rd-R for patients ≤75 years (HR=0.72, 95% CI: 0.52-0.99), whereas patients >75 years benefited more from Rd-R (HR=1.29, 95% CI: 0. 79- 2.08; interaction P=0.05) (Online Supplementary Figure S4).
Multivariate Cox models with the three-way interaction confirmed the results for PFS and OS (Online Supplementary Table S1).
Discussion
In this pooled analysis of 474 transplant-ineligible patients with newly diagnosed MM, we evaluated the impact on survival outcomes of initial treatment, consist- ing of either a bortezomib-based regimen (VMP) or a lenalidomide-based one (Rd-R), in different subgroups of patients, focusing on groups with different cytogenetic risk profiles, as determined by FISH. We found no difference between VMP and Rd-R among standard-risk patients, whereas, among high-risk patients, VMP improved PFS (HR=0.54) and OS (HR=0.73) as compared to Rd-R.
Risk assessment and stratification have long been per-
formed in MM, taking into consideration both the aggres- siveness of the disease at presentation, based on ISS stage, and its cytogenetic features, determined by either FISH or gene expression profile. Many prognostic factors have been identified in myeloma, the most important ones being chronological and biological age, defined by frailty status in elderly patients, and the presence of chromosomal abnormalities identified by FISH.11
Although risk assessment had limited impact on thera- peutic choices in the past, with the expanding armamen- tarium of treatments for MM and the growing evidence of effect modification, it is likely to become a fundamental factor in selecting and tailoring treatment. The International Myeloma Working Group (IMWG) guide- lines recommend that all newly diagnosed (ND)MM patients be screened by FISH for chromosomal abnormali- ties, including del(17p), t(4;14) and t(14;16), and that all older patients undergo a geriatric assessment for the evalu- ation of frailty.19 Despite these recommendations, to date no trial has prospectively evaluated the efficacy of standard therapies according to patients’ risk status, either based on chromosomal abnormalities identified by FISH or on frailty status. Hence, very limited data are available about the efficacy of current standards of care, such as VMP and Rd, for NDMM patients with high-risk cytogenetics. The VISTA trial did not find any difference between high-risk and standard-risk patients treated with VMP.4,5 In the FIRST trial, there was no evidence that lenalidomide improved outcome of patients with high-risk cytogenetics.7 However, the small number of high-risk patients in both trials makes it difficult to draw definitive conclusions.
In our study, we defined high-risk patients as those car- rying at least one cytogenetic abnormality, including
Figure 2. Subgroup analysis of overall survival in the intention-to-treat population for patients treated with VMP or Rd-R. VMP: bortezomib-melphalan-prednisone; Rd-R: lenalidomide-dexamethasone followed by lenalidomide maintenance; HR: hazard ratio; 95% CI: 95% confidence interval; ISS: International Staging System.
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