The Revised International Staging System (R-ISS) is a powerful tool for risk stratification of newly diagnosed MM patients 

The revised international staging system (R-ISS) was established in order to provide improved risk/prognosis stratification of patients over the standard International Staging System (ISS). This was achieved by incorporating data for the presence of chromosomal abnormalities (a reflection of the myeloma clone) with levels of serum lactate dehydrogenase (LDH) (a measure of tumor activity). Efstathios Kastritis and colleagues from the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens, evaluated the R-ISS using an independent cohort of unselected patients, since it was originally devised using only data from patients enrolled on clinical trials. Their findings were published in Haematologica (Journal of the European Hematology Association) in March 2017.

Study Design 

• Pts (n = 475) were selected (from those treated at a single center) according to ISS stage, cytogenetics (by iFISH for del17p, t(4;14) and t(14;16)), and serum LDH, between 2007 and 2014
• Median age = 67 years (range, 27–91 years); 53% >65 years, 25% >75 years vs. 32% >65 yrs in the International Myeloma Working Group (IMWG) cohort used for R-ISS formulation
• Pts with low estimated glomerular filtration rate (eGFR) and those on dialysis were included, unlike IMWG cohort 
• Distribution according to ISS: ISS-1 = 24%, ISS-2 = 34% and ISS-3 = 42%; high-risk cytogenetics [t(4;14), del17p or t(14;16)] = 23.5%; elevated LDH = 15% versus IMWG cohort: ISS-1 = 38%, ISS-2 = 38% and ISS-3 = 24%; high-risk cytogenetics = 24% and LDH = 13%
• Distribution according to R-ISS: R ISS-1 = 18%, R-ISS3 = 18%, R-ISS2 = 64.5% versus IMWG cohort: R-ISS-1 = 28%, R-ISS-2 = 62%, R-ISS-3 = 10%

Key Findings

• Disease progression or death of entire cohort = 57%; 63% remain alive
• Median PFS of entire cohort = 27 months; estimated median OS = 63 months. All data are given as: R-ISS-1, R-ISS-2 and R-ISS-3, respectively:
• Median PFS via R-ISS: 34, 28 and 17 months (P<0.001)
• Probability of OS at 3 years: 83%, 69% and 45%  and at 5 years: 77%, 53% and 19% (P<0.001)
• Five-year OS rate by age: ≤65 yrs = 50%, 66–75 yrs = 32% and >75 yrs = 21%
• Five-year OS by age and stratified by R-ISS:
  • ≤65 yrs = 84%, 71% and 29% (P<0.001)
  • 66–75 yrs = 73%, 43% and 18% (P=0.001)
  • >75 yrs = 59%, 33% and 0% (P=0.122)
• Five-year probability of OS by treatment and stratified by R-ISS:
  • not treated with high-dose melphalan (HDM) and autologous stem cell transplant (ASCT): 64%, 41% and 13%, (P<0.001)
  • pts treated with HDM and ASCT:  93%, 77% and 32%, (P<0.001)
  • bortezomib-based upfront therapy: 95%, 69% and 18%, (P<0.001)
  • immunomodulatory drugs: 68%, 41% and 23%, (P=0.002).
• R-ISS in patients with different degrees of renal dysfunction:
  • eGFR ≥30 mL/min/1.73 m², 5-year OS: 76%, 56% and 28% (P<0.001)
  • eGFR <30 mL/min/1.73 m², no patients had R-ISS-1 disease and median OS for R-ISS-2 vs. R-ISS-3 = 42 vs. 32 months (P=0.354); probability of 5-year OS = 40% vs. 8% (although pt number insufficient for statistical significance)
• Multivariate analysis indicated that R-ISS stage was an independent prognostic factor associated with survival:
  • R-ISS-2 vs. R-ISS-1: HR = 1.68
  • R-ISS-3 vs. R-ISS-1: HR = 3.8

This study illustrated the ability of the R-ISS to identify groups of patients with distinct outcomes. Specifically, distinctions could be made among patients according to age (pts >75 years of age were shown to have a favorable prognosis), those treated with or without HDM and ASCT, and those treated with either bortezomib-based or IMiD-based primary therapy. These findings provide a positive endorsement for the use of the R-ISS as a robust tool for patient stratification.

Table: R-ISS classifications

iFISH, interphase fluorescence in situ hybridization; LDH, lactate dehydrogenase; R-ISS, revised-International Staging System
R-ISS-1	pts with ISS-1 (serum β2-microblobulin level <3.5 mg/L and serum albumin level ≥3.5 g/dL), no high-risk cytogenetic abnormalities in iFISH [such as del(17p) and/or t(4;14) and/or t(14;16)] and normal LDH levels (below the upper limit of normal)
R-ISS-3	pts with ISS-3 (serum β2-microglobulin level >5.5 mg/L) and either high-risk cytogenetic abnormalities in iFISH or elevated LDH levels;
R-ISS-2	all the other possible combinations