Revised-international staging system (R-ISS): A new and simple prognostic assessment for multiple myeloma

Background: Multiple myeloma (MM) is a heterogeneous disease and the thought that there are different diseases with variable outcome led to a definition of prognostic tools. The International Staging System (ISS) is a simple and widely used staging model, but it does not take into account the biology of MM (such as the presence of chromosomal abnormalities) and other important prognostic markers such serum LDH levels. Aims: To evaluate the combined role of three established prognostic factors (ISS, chromosomal abnormalities and serum LDH levels) in newly diagnosed Multiple Myeloma (NDMM) patients. Methods: Data from NDMM patients enrolled in nine international multicenter trials were pooled together and retrospectively analyzed. All patients received new drugs up-front in association with standard chemotherapy or in pretransplant induction and post-transplant maintenance strategies. Patients evaluable for ISS stage, interphase Fluorescence in situ Hybridization (iFISH) and serum LDH levels were included in the analysis. The K-adaptive partitioning was used to identify the ISS/iFISH/LDH groups. Multivariate analyses of OS and PFS were performed. Results: Median age was 63 years; 2159 (60%) patients were younger than 65 years. 1791 (50%) patients received IMIDs, 1370 (38%) proteasome inhibitors and 1606 (45%) underwent autologous stem cell transplantation (ASCT). A total of 2359 patients were evaluable for ISS, iFISH and LDH: 570 (24%) patients presented at baseline with ISS stage III, 612 (26%) had High- Risk (HR) iFISH profile [presence of del(17p) and/or t(4;14) and/or t(14;16)] and 285 (12%) had LDH values higher than the normal limit (LDH high). The recursive partitioning procedure gave an optimal number of 3 ISS/iFISH/LDH groups, defined as revised ISS [R-ISS] stages: R-ISS stage 1 [n=636 (27%)] included patients with ISS I, no HR-iFISH and low LDH; R-ISS stage III [n=246 (11%)] patients with ISS III and HR-iFISH or LDH high; R-ISS stage II included all the other patients [n=1477 (62%)]. After a median follow-up of 4 years, 5- year OS was 81% in the R-ISS I, 62% in the R-ISS II and 39% in the R-ISS III groups. The 5-year PFS was 56% in the R-ISS II, 37% in the R-ISS II and 20% in the R-ISS III groups (median PFS was 65, 41 and 25 months, respectively). Multivariate analyses of OS and PFS confirmed the strong prognostic role of R-ISS. The mortality risk was clearly increased for R-ISS II vs I (HR 3.02), as well as for R-ISS III vs I (HR 7.44). Similarly, the risk of progression was higher for R-ISS II vs I (HR 2.07), as well as for R-ISS Stage III vs I (HR 4.04). Summary and Conclusion: The R-ISS considerably improved the risk assessment in comparison with the individual ISS, iFISH and LDH evaluations. The R-ISS is a new risk model, that includes simple and widely used prognostic markers, it is easily applicable in clinical practice and identifies three different MM entities with clearly different outcomes.