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 MM patients. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase Fluorescence In Situ Hybridization (iFISH) after CD138 plasma cells purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). Methods Clinical and laboratory data from 4445 NDMM patients enrolled in eleven 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 3060/4445 patients. We defined three groups: revised ISS (R-ISS) I (N=871), including ISS I (serum β2-microglobulin level <3.5mg/L and serum albumin level ≥3.5g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)] and normal LDH level (below the upper limit of normal range); R-ISS III (N=295), including ISS III (serum β2-microglobulin level >5.5mg/L) and high-risk CA or high LDH level; R-ISS II (N=1894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS 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 was 55%, 36% and 24%, respectively. Conclusions The R-ISS is a simple and powerful prognostic staging system and we recommend its use in future clinical studies to stratify NDMM patients effectively with respect to the relative risk to their survival.

Validation of multiple myeloma risk stratification indices in routine clinical practice: Analysis of data from the Czech Myeloma Group Registry of Monoclonal Gammopathies

“…As part of its development, the original ISS was tested and found to be effective in patients from different geographic regions (North America, Europe, and Asia), patients of different ages (<65 and ≥65 years), patients receiving different treatments (standard therapy or autologous stem cell transplantation [ASCT]), and patients at different study sites (single sites and cooperative groups) 10. In the same way, the R‐ISS was tested in patients of different ages (≤65 and >65 years) and in patients receiving different treatments (ASCT, proteasome inhibitors [PIs], or immunomodulatory drugs [IMiDs]) 1. Although the ISS risk stratification tool has been evaluated outside of a clinical trial framework,14 the majority of patients (69.1%) on which the system was based were participating in a clinical trial10; similarly, the R‐ISS was based wholly on patients enrolled in experimental trials 1.…”

“…As we were not able to obtain +1q data (these were not uniformly reported since the beginning of the registry), we simplified the analysis of IMWG score as high risk vs others. Cytogenetic data were obtained from multiple laboratories with various cutoffs for positivity reporting; depending on the threshold defined by each local laboratory, patients were considered positive for a translocation when it was present in a percentage ranging from 5% to 20% (with the most frequently reported cutoff value being 20%, as used in previous research) 1. High LDH was defined as a serum level greater than the upper limit of normal.…”

“…Multiple myeloma (MM) is a clinically heterogeneous disease, as evidenced by considerable variation in rates of response to treatment and overall survival (OS); indeed, OS in patients with MM has been shown to range from a few months to more than a decade 1. Much of the clinical heterogeneity of MM is thought to arise from multiple genomic events that result in tumor development and progression 2.…”

“…Several groups have worked to develop systems that use prognostic markers to stratify patients with MM into homogeneous survival subgroups 1, 6, 7, 8, 9. Risk stratification facilitates prognostication, allowing patients to be categorized as having lower risk (ie, longer OS) or higher risk (ie, shorter OS) disease.…”

“…With the IMWG system, patients are categorized as low risk (ISS Stage I/II and the absence of t(4;14), del(17p), and 1q21 and age <55 years), intermediate risk (neither low risk nor high risk), or high risk (ISS Stage II/III and t(4;14) or del(17p)). In 2015, a revised version of the ISS (R‐ISS) was presented,1 which incorporated chromosomal abnormalities detected by interphase fluorescent in situ hybridization (iFISH) and serum lactate dehydrogenase (LDH). With the R‐ISS, patients are categorized as Stage I (ISS Stage I and standard‐risk chromosomal abnormalities by iFISH and normal LDH), Stage II (neither Stage I nor Stage III), or Stage III (ISS Stage III and either high‐risk chromosomal abnormalities [del(17p) and/or t(4;14) and/or t(14;16)] by iFISH or high LDH).…”