Allocation and validation of the second revision of the International Staging System in the ICARIA-MM and IKEMA studies

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: The International Staging System (ISS) underwent revision to include high-risk chromosomal abnormalities (R-ISS), and recently, to assign a score for each risk feature, including 1q21+ (R2-ISS), providing better discrimination in patients (pts) with intermediate-risk multiple myeloma (MM) Aims: To validate R2-ISS in pts with relapsed/refractory MM (RRMM) and in pts treated with anti-CD38 monoclonal antibodies (mAb) using Phase 3 ICARIA-MM and IKEMA study data. Methods: Pts from the treatment (triplet) and control (doublet) arms were pooled for both the ICARIA-MM (isatuximab–pomalidomide–dexamethasone; Isa-Pd vs Pd) and IKEMA (Isa–carfilzomib–d; Isa-Kd vs Kd) studies. Pts were classified based on R2-ISS, where a score of 0 = Stage I; 0.5–1.0 = Stage 2; 1.5–2.5 is Stage3; and > 3.0 = Stage 4. Hazard ratios (HR) and corresponding confidence intervals (CI) were estimated using the Cox proportional hazards model. Results: Of 609 pts, 68 were classified as Stage 1; 136, Stage 2; 204, Stage 3; 55, Stage 4; and 146 were not classified. Progression-free survival (PFS) decreased with increasing stage (Stage 2, median [m]PFS 21.2 months [HR 1.52; 95% CI:0.979–2.358]; Stage 3, mPFS 12.2 months [HR 2.59; 95% CI: 1.709–3.923]; and Stage 4, mPFS 7.0 months [HR 3.51; 95% CI: 2.124–5.784] vs Stage 1, mPFS38.8 months). Pts receiving Isa-based triplet therapy had longer PFS vs those receiving doublet therapy (mPFS 23.9 vs 11.8 months [HR 0.544; 95% CI: 0.436–0.680]), which was seen for all R2-ISS stages (Table). In an exploratory overall survival (OS) analysis including final ICARIA-MM and immature IKEMA data, OS also decreased with increasing stage (Stage 2, mOS not reached [NR; HR 1.3;95% CI 0.78–2.18]; Stage 3, mOS 27.5 months [HR 2.77; 95% CI: 1.730–4.450]; and Stage 4, mOS 11.3 months [HR 4.25; 95% CI: 2.480–7.269] vs Stage 1, mOS NR). Summary/Conclusion: For the first time, these data independently validate the prognostic value of the R2-ISS staging system in pts with RRMM, and in pts treated with anti-CD38 mAb. Isa-based triplet therapy led to improved PFS regardless of R2-ISS stage vs the doublet.Keywords: Multiple myeloma, Chromosomal abnormality, CD38, Monoclonal antibody