A Revised International Staging System of Multiple Myeloma in the Era of Novel Agents and Autologous Stem Cell Transplantation in Japan: A Multicenter Retrospective Collaborative Study of the Japanese Society of Myeloma

Survival outcomes of patients with multiple myeloma (MM) vary considerably depending on the presence or absence of disease-related risk factors [i.e., advanced ISS (International Staging System) stage, CAs (cytogenetic abnormalities), etc.], patient-related risk factors, and/or treatment-related risk factors. ISS, developed in 2006 by the IMWG (International Myeloma Working Group), has been considered an important disease-related baseline prognostication model and has been used in routine clinical practice worldwide. However, it is solely determined by the serum biochemistry data without taking account of CAs which are currently identified as the most powerful prognostic indicator for MM. Recently, a Revised ISS (R-ISS) scoring system which is accounting the presence or absence of serum LDH abnormality as well as CAs such as t(4;14), t(14;16), or del(17p) in addition to the ISS stage has been proposed (Oliva S, et al. EHA 2014, #S1289). In the present study, we applied the R-ISS to the Japanese MM patients diagnosed between 2001 and 2012 and compared the clinical relevance of the R-ISS with that of the original ISS in the era of novel agents and autologous stem cell transplantation (ASCT). Clinical data of 3,270 patients were collected from 38 centers; however, ISS and R-ISS were only applicable to 2,998 and 788 patients, respectively. Patient characteristics including age, gender, type of M protein, Durie and Salmon stage, ISS stage, and chromosomal abnormalities were not significantly different between the patients to which ISS and R-ISS were applied. In the 788 patients evaluable for the R-ISS analysis, distribution of the patients according to the ISS stages I, II, and III were 31.4%, 35.8%, and 32.8%, respectively, whereas that of the R-ISS stages were 22.2%, 67.6%, and 10.2%, respectively. Median overall survival (OS) for the ISS stages I, II, and III were 100.7, 65.2, and 50.9 months, respectively, and that of R-ISS stages I, II, and III were 152.8, 62.4, and 40.5 months, respectively. Accordingly, the difference of survival time between the stages seemed more distinct in R-ISS compared with the performance of the original ISS. According to the analysis by the ISS, there were no significant difference in the median OS between the patients whether initially treated with novel agents or with conventional chemotherapy (stage I, 91.2 vs 84.6 months, p=0.054; stage II, 64.1 vs 62.5 months, p=0.18; and stage III, 41.2 vs 37.2 months, p=0.24). In contrast, the analysis by the R-ISS disclosed a beneficial effect of novel therapy than with conventional chemotherapy, particularly in patients with stage I disease (stage I, not reached vs 87.6 months, p=0.018; stage II, 78.8 vs 61.7 months, p=0.075; and stage III, 37.5 vs 45.3 months, p=0.87). As for ASCT, both ISS and R-ISS stages showed a significant difference in the median OS between the patients treated with ASCT and those without ASCT (ISS stages: stage I, 101.3 vs 78.8 months, p=0.40; stage II, 83.8 vs 52.4 months, p=0.0002; stage III, 67.5 vs 31.7 months, p=0.0004; and R-ISS stages: stage I, not reached vs 90.7 months, p=0.21; stage II, 74.2 vs 56.5 months, p<0.00001; stage III, 73.8 vs 37.5 months, p=0.11). Thus, our results have demonstrated that R-ISS is a useful model for the risk assessment of Japanese patients with MM. Notably, the outcome of MM patients with R-ISS stage I showed a dramatic improvement by the initial treatment with novel agents and ASCT. However, the survival benefit remained unmet in patients with advanced stages of R-ISS even in the era of novel agents and ASCT, and further development of therapeutic strategies is needed in high-risk patients with MM.