The second revision of the International Staging System (R2‐ISS) stratifies progression‐free and overall survival in multiple myeloma: Real world data results in an Australian and New Zealand Population

To evaluate the performance of the second revision of the International Staging System 2 (R2ISS) in a realworld cohort, we applied the scoring system to patients with newlydiagnosed multiple myeloma (NDMM) in the Myeloma and Related Diseases Registry (MRDR). Our analysis establishes the validity of this risk scoring system in a realworld setting, in addition to being able to further riskstratify the Revised International Staging System (RISS) group II category. The R2ISS is a recently described update to the established RISS for NDMM patients. In addition to β2microglobulin, albumin, lactate dehydrogenase (LDH), del17p, and t(4;14) by fluorescenceinsitu hybridisation (FISH) included in the RISS, the R2ISS additionally considers gain of chromosome 1q (1q+), and adds additional weight when more than one highrisk cytogenetic abnormality is present. The cytogenetic abnormality t(14;16) is no longer included in the R2ISS. The impetus for this revision was poor discrimination within the intermediate risk stage (stage II) by the RISS, which categorises more than 50% of patients within this one group despite heterogeneous disease outcomes. The R2ISS stratifies patients by assigning a score value (in square brackets) to the included prognostic variables: ISS II [1], ISS III [1.5], del(17p) [1], high LDH [1], t(4;14) [1], and 1q+ [0.5]. The sum of these scores determines the risk group: I low (0), II low/intermediate (0.5– 1), III intermediate/high (1.5– 2.5) and IV high. 5 A limitation of the creation of this system was its derivation from a platform that exclusively enrolled clinicaltrial participants. Such participants are highly selected based on trial eligibility criteria and receive myeloma therapy that by definition deviates from current standards of care. Thus, prior to widespread adoption, there is a need to validate this risk stratification system within a nonclinicaltrial ‘realworld’ population. To assess its realworld value, we retrospectively applied R2ISS scoring to patients in the MRDR, that prospectively collects data on NDMM patients from 56 Australian and New Zealand centres. All NDMM patients at each participating site are invited to join the registry, and their data are included unless they opt off, which is rare. Progressionfree survival (PFS) was defined as the time from diagnosis until disease progression or allcause mortality. Overall survival (OS) was defined as the time from diagnosis until death from any cause. FISH for del17p, (4;14) and 1q+ was performed at the designated central reference laboratory for each state/country on CD138+ enriched cells. The cutoff for FISH positivity differs between sites, ranging from 10% to 15% for IgH translocations and from 10% to 20% for numerical aberrations. The Kaplan– Meier method was used to calculate curves for PFS and OS, with groups compared using the logrank test. Of the 3483 patients diagnosed from January 2012 to February 2022, complete staging data (ISS, LDH and FISH) was evaluable for 1289 (37%) patients. Disease progression and survival data were available for 1272 (36.5%) and 1275 (36.7%) patients respectively. Median followup was 32 months. Patient demographic and clinical characteristics are described in Table 1. R2ISS scorestratified PFS is shown in Figure 1. Median PFS in R2ISS group I was 40.2months [95% confidence interval (95% CI) 34.5– 51.5 months], in group II it was 42.3 months (95% CI 36.1– 50.6 months), in group III it was 24.0 months (95% CI 21.6– 27.4 months), and in group IV it was 21.0 months (95% CI 14.1– 25.4 months). There was a significant difference in PFS between R2ISS risk groups I versus III [hazard ratio (HR) 2.0 (95% CI 1.5– 2.6), p < 0.001] and groups I versus IV [HR 2.9 (95% CI 2.0– 4.1), p < 0.001], but not group I versus II [HR 1.0 (95% CI 0.8– 1.4), p = 0.761]. R2ISS scorestratified OS is shown in Figure 1B. Median OS was not reached (NR) by 84 months in groups I and II (95% CI 73.4– NR months and 90.8– NR months respectively), in group III it was 51.3 months (95% CI 45.4– 67.0 months), and in group IV it was 48.5 months (95% CI 41.9NR months). There was a significant difference in OS of R2ISS risk groups I versus III [HR 2.9 (95% CI 2.0– 4.2), p < 0.001] and of groups I versus IV [HR 3.5 (95% CI 2.1– 5.7), p <0.001], but not of groups I versus II [HR 1.1 (95% CI 0.8– 1.7), p = 0.526]. We further assessed the redistribution of RISS groups following R2ISS recategorisation. Of the patient cohort, 873 (67.7%) were categorised as RISS stage II. When recategorised by R2ISS these patients were redistributed across DOI: 10.1111/bjh.18536