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IMWG Revises International Staging System for Multiple Myeloma

December 30, 2021

At this year's International Myeloma Working Group (IMWG) Summit, this large team of myeloma experts released a revised International Staging System (R-ISS) for newly diagnosed multiple myeloma (MM) patients. To better risk-stratify patients with MM, the new system adds genetic information to the standard prognostic tests for MM prognosis.

"The R-ISS staging system is a new risk-stratification algorithm with an improved prognostic power compared with the individual ISS, chromosomal abnormalities, and serum lactate dehydrogenase (LDH) parameters," Antonio Palumbo, MD, chief of the Myeloma Unit in the Department of Oncology at the University of Torino, Italy, and colleagues wrote in the Journal of Clinical Oncology. "It includes simple, reliable, and widely used prognostic markers, and it allows the identification of three different multiple myeloma entities with clearly different outcomes."

To establish these entities, Dr. Palumbo and a panel of 31 international myeloma experts developed an algorithm that adjusted for ISS stage, chromosomal abnormalities, and serum LDH parameters, then validated the algorithm in 3,060 patients from 11 international trials. The distinct MM groups are:

  • R-ISS I: No high-risk chromosomal abnormalities (del17p and/or t[4;14] and/or t[14;16]), normal LDH level (less than the upper limit of normal range); serum β2-microglobulin level <3.5 mg/L and serum albumin level of 3.5 g/dL or greater (n=871; 28%)
  • R-ISS II: All other possible combinations of ISS, chromosomal abnormalities, and LDH (n=1,894; 62%)
  • R-ISS III: Serum β2-microglobulin level >5.5 mg/L and high-risk chromosomal abnormalities (del17p and/or t[4;14] and/or t[14;16]) or high LDH level (n=295; 10%)

Over a median follow-up of 46 months, the rates of five-year overall survival in R-ISS I, R-ISS II, and R-ISS III were respectively: 82, 62, and 40 percent; progression-free survival rates were 55, 36, and 24 percent, respectively.

In a multivariable analysis (adjusting for age at diagnosis, sex, FISH, LDH, ISS stage, and R-ISS stage), the risk of death was significantly increased in patients with revised ISS stage II versus stage I (HR=3.59; 95% CI 2.68-4.80; p<0.001), and stage III versus stage I (HR=9.64; 95% CI 6.24-14.88; p<0.001).

The risk of disease progression was higher among R-ISS stage II patients than stage I patients (HR=1.99; 95% CI 1.61-2.37; p<0.001), and among stage III than stage I patients (HR=3.37; 95% CI 2.54-4.56; p<0.001).

According to Dr. Palumbo and co-authors, one in four patients would have been incorrectly allocated to a good prognosis group if only one of the three factors had been considered.

The previous version of the ISS, which was published in 2005, was a simplified risk-stratification system that only incorporated serum β2-microglobulin level and serum albumin level into risk stratification, without chromosomal abnormalities or serum LDH levels – both of which are key elements to characterize biologic features of MM.

"MM can no longer be considered a single disease, but a mix of different disease entities," the researchers concluded. "The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with newly diagnosed MM effectively with respect to the relative risk to their survival."

The study had some limitations, however, including that the majority of patients enrolled in trials were younger than age 65 and some patients without baseline data were excluded from the ï¬nal analysis. Also, the study "did not include host-related prognostic factors such as age, performance status, and comorbidities, which still play an important role in deï¬ning patient prognosis," the authors noted.


Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33:2863-69.


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