The most widely used multiple myeloma (MM) staging system, the Revised International Staging System (R-ISS), is based on lactate dehydrogenase (LDH), albumin, high-risk genetic markers by FISH, and beta-2 microglobulin (B2M). However, it does not account for additional risk impacted by multiple genetic abnormalities, or the risk imparted by presence of gain of chromosome 1q, and most patients are staged as R-ISS Stage 2.

Two new staging systems, the Mayo Additive Staging System (MASS), and the Second Revision of the International Staging System (R2-ISS) have been recently proposed. A comparison of the performance of these two systems has not previously been done. We aimed to externally demonstrate the application of these staging systems and compare their performances in a large, contemporary cohort of patients in the United States.

We conducted a retrospective cohort study using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, comprising de-identified patient-level structured and unstructured data, curated via technology-enabled abstraction and originating from approximately 280 US cancer clinics (~800 sites of care). The study included newly diagnosed MM patients initiating treatment between January 1, 2016 and October 1, 2022. We used the Kaplan-Meier method to evaluate real-world overall survival (rwOS) and patients were followed from first-line treatment initiation (index date) until the first of death, end of the study period or last recorded activity. The log-rank test to compare survival curves across derived stages. Multivariable analysis was conducted using stratified Cox models to account for non-proportional hazards by age with covariate adjustment for race/ethnicity, sex, practice type (academic or community) and diagnosis year (2016-2019 vs 2020-2022). Discrimination and calibration were evaluated in crude models using Harrell's c-index and the Hosmer-Lemeshow goodness-of-fit test, respectively.

There were 497 patients with MM included. Patient characteristics are listed in Panel A. The distribution of patients across R-ISS stages were as follows, 24%, 63% and 13% for Stage 1, 2 and 3 respectively. rwOS differed across R-ISS stage (log-rank p = 0.0006) and the median OS (OS) was not reached (NR), 63, and 37 months for R-ISS stage 1, 2, and 3, respectively.

34%, 35% and 31% for MASS 1, 2, and 3, respectively. The corresponding survival curves were significantly different (p < 0.0001), with associated mOS of 77, 61 and 45 months for MASS stages 1, 2, and 3, respectively.

R2-ISS includes four risk categories (stages I-IV) and in our cohort, 20% (n = 100) were stage I (low), 126 (25%) were stage II (low-intermediate), 229 (46%) were stage III (intermediate), and 42 (9%) were stage IV (high). Survival across stages were significantly different (p<0.0001), though the survival curves for low and low-intermediate, and intermediate-high and high, were clustered, suggesting comparable outcomes in stages I-II and stages III-IV. mOS for R2-ISS stages I, II, III, and IV was NR, 69, 50 and 51 months respectively (Panel B).

In fully adjusted analyses, as compared to MASS I, the hazards of death were 2.0 (95% CI 1.3-3.2) for MASS II and 2.7 (1.7-4.2) for MASS III. The hazards of death were similar for R2-ISS low and low-int (HR for low-int vs low: 1.2 [0.7, 2.3]). As compared to R2-ISS low, the hazards of death were similarly higher for int-high and high (HRs: 2.4 [1.4, 4.1] and 2.6 [1.3, 5.2], respectively). Discrimination and calibration were similar across all staging systems (c = 0.6, and Hosmer-Lemeshow p>0.05 for all three staging systems).

Application of contemporary MM staging systems in a large cohort of US patients shows that they are prognostic for OS in MM. MASS demonstrated a greater separation for OS across stages, whereas R2-ISS intermediate-high and high were largely overlapping. Although our results demonstrate similar accuracy and reliability of MASS and R2-ISS, the discrimination of patients across different stages seen with the newer staging systems, as opposed to R-ISS, calls for greater use of these newer staging systems in routine clinical practice.

Fonseca:Antegene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Millenium: Consultancy; Binding Site: Consultancy; Janssen: Consultancy; Juno: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Aztrazenica: Consultancy; Kite: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; BMS (Celgene): Consultancy; Takeda: Consultancy; AMGEN: Consultancy; FISH: Patents & Royalties: FISH; AZBio: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Pharmacyclics: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Calip:Flatiron: Current Employment; Roche: Current equity holder in publicly-traded company. Wang:Flatiron: Current Employment; Roche: Current equity holder in publicly-traded company. Parrinello:Flatiron Health: Consultancy; Clue by Biowink: Consultancy; Evidation Health: Consultancy; EQRx: Consultancy; Roche: Current equity holder in publicly-traded company; Medicus Economics: Consultancy; Jazz Pharmaceuticals: Consultancy; Omada Health: Consultancy; Plinth: Consultancy; TTI Health: Consultancy. Sborov:Gilead: Research Funding; Arcellx: Consultancy, Research Funding; Bioline: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy; Abbvie: Consultancy; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Research Funding; GSK: Consultancy, Research Funding; Cantex: Research Funding; RocheX: Research Funding.

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2023
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