Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis.

person Ivan Spicka Clinical Department of Hematology, 1st Medical Department, Charles University, Prague, Czech Republic info_outline Ivan Spicka, Philippe Moreau, Thomas G. Martin, Thierry Facon, Gracia Martinez, Albert Oriol, Youngil Koh, Andrew Lim, Gabor Mikala, Laura Rosiñol, Münci Yağci, Michele Cavo, Marie-Laure Risse, Gaëlle Asset, Sandrine Macé, Helgi Van De Velde, Kwee Yong

Authors person Ivan Spicka Clinical Department of Hematology, 1st Medical Department, Charles University, Prague, Czech Republic info_outline Ivan Spicka, Philippe Moreau, Thomas G. Martin, Thierry Facon, Gracia Martinez, Albert Oriol, Youngil Koh, Andrew Lim, Gabor Mikala, Laura Rosiñol, Münci Yağci, Michele Cavo, Marie-Laure Risse, Gaëlle Asset, Sandrine Macé, Helgi Van De Velde, Kwee Yong Organizations Clinical Department of Hematology, 1st Medical Department, Charles University, Prague, Czech Republic, University of Nantes, Nantes, France, University of California, San Francisco, San Francisco, CA, Department of Haematology, Lille University Hospital, Lille, France, Hospital das Clínicas de São Paulo, São Paulo, Brazil, Institut Català d’Oncologia and Josep Carreras Institute, Hospital Germans Trias i Pujol, Barcelona, Spain, Seoul National University Hospital, Seoul, South Korea, Austin & Repatriation Medical Center, Heidelberg, Victoria, Australia, National Institute for Hematology and Infectious Diseases, South Pest Central Hospital, Budapest, Hungary, Hospital Clinic, IDIBAPS, Barcelona, Spain, Gazi University, Ankara, Turkey, Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy, Sanofi R&D, Vitry-Alfortville, France, Sanofi R&D, Chilly-Mazarin, France, Sanofi R&D, TMED, Vitry-Sur-Seine, France, Sanofi Oncology, Cambridge, MA, University College Hospital, London, United Kingdom Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Sanofi Background: A prespecified interim efficacy analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d) (Isa-Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (HR 0.531; 99% CI, 0.318–0.889; P = 0.0007), with a clinically meaningful increase in minimal residual disease negativity (MRD-) (29.6% vs 13.0%) and complete response (CR) (39.7% vs 27.6%) rates, and a manageable safety profile. This subgroup analysis of IKEMA examined efficacy and safety in pts with high-risk cytogenetics [t(4;14), del(17p), and t(14;16)] and/or gain(1q21). Methods: Pts with 1–3 prior lines of therapy were randomized 3:2 to receive Isa-Kd (n = 179) or Kd (n = 123). High-risk cytogenetics was assessed by central laboratory analysis and defined as ≥1 of the following: del(17p): 50% cutoff; t(4;14) or t(14;16): 30% cutoff. Assessment of gain(1q21) was prespecified as ≥3 copies: 30% cutoff. Results: Of the randomized pts, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk cytogenetic abnormality (CA); 26.3% (Isa-Kd) and 25.2% (Kd) had isolated gain(1q21). The addition of Isa to Kd improved PFS for pts with ≥1 high-risk CA and standard-risk pts (Table); pts with t(4;14) (HR 0.549; 95% CI, 0.232–1.301) had a more pronounced treatment effect than pts with del(17p) (HR 0.837; 95% CI, 0.281–2.496). A clear PFS benefit with Isa-Kd was also seen for pts with isolated gain(1q21) and gain(1q21) combined with other high-risk CA (Table). The trend toward improved CR, ≥very good partial response (VGPR), and MRD- rates with the addition of Isa was more pronounced in pts with gain(1q21) than in pts with high-risk CA alone. Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd vs Kd, but the incidence of serious and fatal TEAEs was similar with both arms for high-risk pts (Table). Conclusions: The addition of Isa to Kd improved PFS in pts with high-risk CA and disease response in pts with gain(1q21) isolated or combined with high-risk CA, with a manageable safety profile, consistent with the benefit observed in the overall IKEMA population. Isa-Kd is a potential new treatment option for the difficult-to-treat subgroup of pts with RMM and high-risk cytogenetics. Funding: Sanofi. Clinical trial information: NCT03275285 % High Risk Standard Risk Isolated Gain(1q21) Gain(1q21) + High-Risk CA Isa-Kd n = 42 Kd n = 31 Isa-Kd n = 114 Kd n = 77 Isa-Kd n = 47 Kd n = 31 Isa-Kd n = 25 Kd n = 19 PFS HR vs Kd (95% CI) 0.724 (0.361–1.451) 0.440 (0.266–0.728) 0.462 (0.219–0.972) 0.678 (0.299–1.537) CR 23.8 22.6 46.5 26.0 46.8 22.6 32.0 26.3 ≥VGPR 57.1 54.8 78.9 54.5 80.9 51.6 64.0 52.6 MRD- 21.4 22.6 36.0 11.7 36.2 9.7 28.0 21.1 Grade ≥3 TEAEs 85.7 63.3 76.1 76.6 78.3 67.7 88.0 66.7 Serious TEAEs 64.3 66.7 57.5 59.7 63.0 51.6 60.0 66.7 Fatal TEAEs 0 0 4.4 5.2 6.5 3.2 0 0 TEAEs leading to definitive discontinuation 4.8 10.0 9.7 18.2 10.9 19.4 0 0