The International Scoring System (ISS) for Multiple Myeloma Remains a Robust Prognostic Tool Independently of Patients' Renal Function
Authors: Dimopoulos Meletios A. , Kastritis Efstathios , Kyrtsonis Marie-Christine , Meletis John , Michalis Eurydiki , Repoussis Panagiotis , Tsatalas Konstantinos , Michael Michael , Pouli Anastasia , Kartasis Zafiris , Stefanoudaki Ekaterini , Voulgarelis Michael , Delimpasi Sosana , Katodritou Eirini , Symeonidis Argiris , Gavriatopoulou Maria , Koulieris Efstathios , Gika Dimitra , Zomas Athanasios , Roussou Paraskevi , Anagnostopoulos Nikolaos , Economopoulos Theofanis , Konstantopoulos Konstantinos , Parcharidou Agapi , Zervas Konstantinos , Terpos Evangelos 
Published: October 2019

Abstract
Abstract 3036
The ISS introduced by Greipp et al (J Clin Oncol 2005) represents today the most widely used staging system for patients with multiple myeloma (MM) because it is based on two readily available variables: serum albumin and beta2-microglobulin. Serum beta2-microglobulin not only reflects myeloma tumor load but it is also increased in patients with renal dysfunction. Thus, there have been concerns that ISS-3 stage may include MM patients with renal impairment in whom elevated beta2-microglobulin does not reflect tumor burden but rather the degree of renal dysfunction. To address this issue, we assessed the impact of patients' renal function on the prognostic performance of ISS. Our analysis included data from 1516 patients with symptomatic MM that had been entered into the database of the Greek Myeloma Study Group. Renal function was assessed by the estimated GFR (eGFR), which was calculated using the modified MDRD formula (eGFR in mL/min/1.73 m2 = 186 × (Serum Creatinine)−1.154 × (Age)−0.203 × (0.742 if female) × (1.212 if African-American) and the degree of renal dysfunction was staged according to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) classification of chronic kidney disease (CKD) as follows: stage 1 eGFR ≥90 ml/min; stage 2 eGFR of 60–89 ml/min; stage 3 eGFR of 30–59 ml/min; stage 4 eGFR of 15–29 ml/min and stage 5 eGFR <15 ml/min or under dialysis. At the time of treatment initiation, 788 patients had stage 1 or 2 CKD and 728 patients had stage 3–5 CKD. According to ISS, 29% patients had ISS-1, 38% patients had ISS-2 and 33% ISS-3. Renal impairment was significantly more common in ISS-3 patients: 76% of ISS-3 patients had stage 3–5 CKD compared to 42% and 27% for ISS-2 and ISS-1, respectively (p<0.001). Similarly, the incidence of stage 4 or 5 CKD was higher in ISS-3 (23% and 20%, respectively) than in patients with ISS-2 (6% and 1.5%, respectively) or ISS-1 (4% and 1%, p<0.001). In the univariate analysis, which included all patients, stage 3–5 CKD was associated with inferior survival (31 months vs. 51 months for those with stage 1 or 2 CKD, p<0.001). However, CKD stages had not an independent prognostic value in the multivariate analysis. Subsequently, we analyzed the prognostic significance of renal function in each ISS group separately. ISS-1 patients with stage 1 or 2 CKD had a median survival of 76 months vs. 56 months for patients with stage 3–5 CKD (p=0.053). In ISS-2, the respective median survival was 49 months and 29 months for stage 1–2 CKD vs. stage 3–5 CKD (p=0.02). In contrast, in patients with ISS-3 the median survival was similar (30 vs. 24 months, p=0.292) for patients with stage 1–2 CKD and stage 3–5 CKD. Multivariate analysis performed in each ISS subgroup revealed that renal function (either as a dichotomous or as a continuous variable) was not an independent prognostic factor in any of ISS stages: HR=1.031, p=0.873 for ISS-1; HR=0.996, p=0.123 for ISS-2 and HR=1.09, p=0.6 for ISS-3. We conclude that ISS is a simple, yet powerful prognostic staging system. The robustness of ISS remains unaffected by the degree of renal function. In patients with ISS-3, which includes many patients with renal dysfunction, elevated beta2-microglobulin reflects tumor burden, despite its increase due to renal impairment. Our data in a large population of myeloma patients indicate that adjustment for renal function will not improve the prognostic performance across all ISS stages.

Disclosures:
No relevant conflicts of interest to declare.