Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group

Abstract

Purpose: The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM).

Patients and methods: Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival.

Results: ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum β2-microglobulin level > 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively.

Conclusion: The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival.

Fig 1.

(A) Overall survival (OS) in patients with multiple myeloma stratified by revised International Staging System (R-ISS) algorithm. Median OS was not reached for patients included in R-ISS stage I, whereas it was 83 months for R-ISS stage II and 43 months for R-ISS stage III. (B) Univariable analysis of OS. CA, chromosomal abnormalities; F, female; HR, hazard ratio; LDH, lactate dehydrogenase; M, male; NR, not reached.

Fig 2.

(A) Progression-free survival (PFS) in patients with multiple myeloma stratified by revised International Staging System (R-ISS) algorithm. Median PFS was 66 months for patients with R-ISS stage I, 42 months for patients with R-ISS stage II, and 29 months for patients with R-ISS stage III. (B) Univariable analysis of PFS. CA, chromosomal abnormalities; F, female; HR, hazard ratio; LDH, lactate dehydrogenase; M, male; NR, not reached.

Fig 3.

Revised International Staging System (R-ISS) and overall survival (OS) by type of treatment. (A) OS in regimens non–transplantation-based regimens. (B) OS in transplantation-based regimens. (C) OS in immunomodulatory-based regimens. (D) OS in proteasome inhibitor–based regimens. NR, not reached.

Fig A1.

Revised International Staging System (R-ISS) and survival by age. (A) Overall survival (OS) in patients ≤ 65 years of age. (B) OS in patients older than age 65 years. (C) Progression-free survival (PFS) in patients ≤ 65 years old. (D) PFS in patients older than age 65 years. NR, not reached.