Evaluation of the Revised International Staging System in 400 Patients with Symptomatic Myeloma in a Japanese Clinical Setting
Authors: Abe Yoshiaki , Takeshi Yamashita , Mikio Ueda , Sunami Kazutaka , Narita Kentaro , Kobayashi Hiroki , Takamatsu Hiroyuki , Kitadate Akihiro , Takeuchi Masami , Matsue Kosei 
Published: October 2019

Abstract
Background:In 2015, the International Myeloma Working Group (IMWG) developed the Revised International Staging System (R-ISS), which combined the ISS with the status of high-risk cytogenetic abnormalities (CAs) and serum levels of lactate dehydrogenase to identify three multiple myeloma (MM) entities with clearly different outcomes. However, although MM tends to affect older adults, the original and validation studies of the R-ISS included relatively younger patients. Furthermore, although studies report that bortezomib-containing therapies can reverse the unfavorable prognostic impact of the t(4;14) CA,most original and validation studies of the R-ISS included few patients who had been treated with bortezomib. Therefore, the results of these studies are less applicable to patients in the era of novel targeted agents.
Methods: This study retrospectively analyzed the data of 400 consecutive patients who were newly diagnosed with MM and treated with chemotherapy between January 2006 and December 2017 at Kameda Medical Center, Kamogowa-shi, Japan; Keiju Kanazawa Hospital, Ishikawa, Japan and National Hospital Organization Okayama Medical Center, Okayama, Japan. We included only patients who had been treated with novel agents (e.g., immunomodulatory agents or proteasome inhibitors) to reduce the prognostic impact of heterogeneity in chemotherapy.
Results: The 400 included patients had a median age of 72 years (interquartile range [IQR]: 64-79 years). The median observation period was 37.9 months (IQR: 16.4-67.9 months). Ninety-eight (24.5%), 121 (30.2%) and 181 (45.2%) patients were classified as ISS stages I, II, and III, respectively, while 66 (16.5%), 243 (60.8%), and 91 (22.8%) patients were classified as R-ISS stages I, II, and III, respectively. Additionally, 384 (96.0%) patients were treated with bortezomib. R-ISS stages II and III differed significantly in terms of age, with the former including significantly older patients than the latter (median age: 74 and 70 years, respectively; P=0.001). The Kaplan-Meier overall survival (OS) curves according to the ISS and R-ISS stages are shown in Figure 1A and 1B, respectively. The three groups of patients categorized by ISS stage differed significantly in terms of survival duration. By contrast, no significant differences in OS were observed between R-ISS stages II and III (median OS: 63.4 and 54.7 months, respectively; P=0.32).Furthermore, receiver operating characteristic (ROC) curves were developed tocompare the prognostic performances of the ISS and R-ISS. Notably, the area under curve (AUC) was significantly greater for the ISS than for the R-ISS (0.659 vs. 0.608, respectively; P=0.029, Figure 2A). ISS stage III patients recategorized to R-ISS stage III were significantly younger than those recategorized to R-ISS stage II (median age, 70 vs. 77 years; P<0.001) and had a relatively more favorable OS (Figure 3). Patients with high-risk cytogenetic abnormality t(4;14) were significantly younger than the others and also had an improved OS (Figure 4), which was attributed to young age and bortezomib therapy.We again divided the patients into three groups using a modified R-ISS (mR-ISS) categorization in which only t(14;16) and del(17p) were included as high-risk CAs.The three groups categorized by mR-ISS stage exhibited significant differences in survival (Figure 1C).We additionally developed a ROC curve for the mR-ISS, and the resulting AUC value was significantly greater than that obtained for the R-ISS (0.657 vs. 0.608, respectively; P=0.001, Figure 2B).
Conclusions: Our study is the first to suggest that the performance of the R-ISS may be somewhat limited when applied to patients with MM who are treated with novel agents in ageing societies. Furthermore, we suggest that this limitation may be attributed to the inclusion of t(4;14) as a high-risk CA in the R-ISS categorization strategy. This potential limitation suggests that the R-ISS should be carefully interpreted on an individual basis when applied to patients in a real-world setting. Our findings are of particular interest because many developed countries, including Western countries, are approaching a period of super-ageing such as that observed currently in Japan.

Disclosures
Sunami: Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Merck Sharp and Dohme: Research Funding; Takeda: Research Funding; AbbVie: Research Funding; Sanofi: Research Funding. Takamatsu:Janssen: Honoraria; Bristol-Myers Squibb: Research Funding; Ono: Research Funding; Celgene: Honoraria, Research Funding.