Single-Center Validation of the Second Revised International Staging System (R2-ISS) in a Population of Transplant-Eligible (TE) Newly-Diagnosed Multiple Myeloma (NDMM) Treated with Bortezomib-Based Regimens
Authors: Mesquita Isabel , Vieira Joana , Martins Helena , Lacerda Joao F. , Esteves Graca 
Published: December 2024

BACKGROUND: the evaluation of prognosis of patients (pts) with NDMM has been recently updated with the R2-ISS score, which combines ISS with LDH level and high-risk cytogenetic abnormalities (HRCA), including for the first time 1q21+ as a poor risk prognostic marker, and excluding the presence of t(14;16) from the score.
AIMS & METHODS: single center retrospective study, including TE-NDMM pts treated with bortezomib(V)-based triplets from 2007 until 2024. The purpose of this study is to validate the R2-ISS score in a real-world population. Furthermore, it aims to compare R2-ISS with R-ISS, identifying R-ISS pts redistribution using the newer score and to assess how this impacts overall survival (OS). End organ damage (EOD) and response evaluation were defined according to the IMWG criteria. Progression-free survival (PFS) was defined as the time from diagnosis until disease progression or all-cause mortality, and OS as the time from diagnosis until death from any cause. The Kaplan-Meier method was used to calculate curves for PFS and OS, and the log-rank test for group comparison. ROC curve was performed to determine the predictive power of each score.
RESULTS: we have analyzed 306 pts, with a median age at diagnosis of 61 years (min-max: 37-73), 56.2% were male and 55.0% had ECOG ≥2. Evaluation of EOD at diagnosis revealed 42.8% anemia, 25.2% kidney failure, 12.5% hypercalcemia, 77.2% bone lesions and 42.5% extramedullary disease. 53.1% were of IgG type. 22.7% presented HRCA, with +1q21 in 29.0%. Prognostic scores: R-ISS stage I in 24.8%, II in 61.9%, III in 13.3%; and R2-ISS stage I in 16.0%, II in 21.6%, III in 48.4% and IV in 13.9%. Of this cohort of pts treated with V-based regimens, 44.1% received a combination containing IMiDs, and 90.5% proceeded to transplant.
The median follow-up was 100.0 months (mo). Median OS (mOS) for the four R2-ISS stages was NR, 159, 86 and 26mo, respectively (p&lt;0.001). 8-year OS rate was 69.6%, 73.6%, 44.9% and 13.6%, respectively. The difference in OS between R2-ISS stages I and II was not statistically significant (p=0.570), but there was a significant difference between stages II vs. III and III vs. IV (p&lt;0.001 for both assessments). There was no difference in PFS or OS according to each treatment regimen within each R2-ISS stage. For pts in the low-risk group, the addition of autologous stem cell transplant did not result in a statistically significant difference in mOS (p=0.744).
We further assessed the redistribution of R-ISS groups according to R2-ISS. 118 pts (41.1%) were reassigned to different risk groups. Within R-ISS II group in which R2-ISS was available (n=166), 42 pts (25.3%) remained as R2-ISS stage II, while 106pts (63.9%) were reclassified as stage III, and 18pts (10.8%) as stage IV. This restaging translated into significantly different OS rates depending on R2-ISS staging (p&lt;0.001), with a mOS for the 3 stages of 159, 85 and 33mo, respectively. Finally, we performed a ROC curve for the prediction of death according to R-ISS vs R2-ISS, with the latter demonstrating a better predictive power for the event death (AUC 0.72 vs 0.645).
DISCUSSION: with this analysis, we were able to validate this new prognostic model in real-world and uniform population of TE-NDMM pts, with a median follow-up of 8 years. Using the R2-ISS score, we were able to stratify our cohort, although it did not reflect differences between stages I vs II in terms of mOS. We have also demonstrated its usefulness in refining prognosis over R-ISS, a score which did not fully discriminate outcomes within the stage II group, enhancing the heterogeneity of pts encompassed in this group.