International Staging System (ISS) Is Superior to Durie-Salmon (DS) Staging in Predicting Overall Mortality in Multiple Myeloma (MM)
Authors: Ailawadhi Sikander , Sher Taimur , Patel Mehul , Derby Lyudmyla , Mashtare Terry , Wilding Gregory E. , Miller Kena , Mohr Alice , Lee Kelvin , Chanan-Khan Asher A. 
Published: April 2020

Abstract
Background: Despite recent therapeutic advancements, multiple myeloma (MM) remains an incurable disorder. Disease stage is the most commonly used parameter to determine tumor burden, need for treatment initiation and survival outcome. In this context the International Staging System (ISS) proposed in 2005 is considered a good predictor of overall survival (OS) and is reported to be more objective than the previous Durie-Salmon staging system (DSS). To date there has been no direct comparison to determine which of these is superior in predicting OS or mortality. Furthermore, ISS was defined prior to the routine availability of novel agents and primarily included MM patients who had undergone autologous stem cell transplant. Whether ISS has similar predictive value in non-transplant patients has not been reported. We investigated the ability to predict OS and mortality of these two staging systems in non-transplant patients with MM.
Methods: All MM patients seen at RPCI between January 2004 and June 2007 were included in the analysis. Clinical staging was done as per the DSS and ISS in all patients. Descriptive baseline demographic data and survival data were collected. A 0.05 nominal significance level was used in all hypothesis testing.
Results: A total of 170 consecutive patients were evaluated. None of the patients had undergone a stem cell transplant for their MM diagnosis. Survival data was available on 144 patients which are reported in this analysis. Of these 48% (n=69) were females and 52% (n=75) were males, with a median age of 60 years (range 35–83). The DSS revealed a distribution as follows: stage IA (21; 14.6%), stage IB (1; 0.7%), stage IIA (23; 16%), stage IIB (1; 0.7%), stage IIIA (81; 56.2%) and stage IIIB (17; 11.8%). The distribution as per ISS was stage I (76; 52.8%), stage II (31; 21.5%) and stage III (37; 25.7%). A Cox proportional hazards model was fit to compute a generalized R-square (Gen R2) statistic for the two staging systems and to compute hazard ratios (HR). The Gen R2 for DSS was 0.0259, while for ISS was 0.0461. Thus, by themselves, the two staging systems were not particularly predictive of OS. Comparison was then made by separating stage III (advanced stage disease) from stage I and II for both DSS and ISS. The estimated hazard of death for DSS I/II patients was not significantly different from the estimated hazard of death for DSS III patients (HR=0.48; 95% CI 0.2,1.14; p=0.09), while the estimated hazard of death for ISS I/II patients was significantly different from that for ISS III patients (HR=0.43; 95% CI 0.21,0.85; p=0.01). Exact odds ratios (OR) were computed between dichotomized DSS or ISS stage with patient status at years 1, 2 and 3 of follow up. Survival analysis at 1-year, 2-year and 3-year time point included 112, 93 and 77 patients, respectively. At 1-year, the sample odds of death for stage I/II patients were significantly different from the sample odds of death for stage III patients in both, the DSS (OR=0.32; 95% CI 0.1,0.93; p=0.02) and ISS (OR=0.25; 95% CI 0.08,0.25; p=0.005). At 2-year as well, this difference was significant for both, DSS (OR=0.32; 95% CI 0.1,0.98; p=0.03) and ISS (OR=0.18; 95% CI 0.06,0.63; p=0.002). At 3-year though, the DSS was no longer able to predict a significant difference in the sample odds of death between stage I/II and stage III patients (OR=0.4; 95% CI 0.11,1.34; p=0.11), while the sample odds of death as per the ISS were still significantly different (OR=0.21; 95% CI 0.04, 0.78; p=0.01).
Conclusions: Our data from a prospective large cohort of non-transplant MM patients suggests that ISS is more predictive of overall mortality than the DSS. Furthermore, when comparing advanced stage disease (stage III) with early-stage disease (stage I/II), the DSS may only be able to predict short-term survival, while ISS is able to effectively predict survival over a prolonged period.
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