16000609, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejh.13835 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Received: 7 April 2022 Revised: 5 July 2022 Accepted: 7 July 2022 DOI: 10.1111/ejh.13835 ORIGINAL ARTICLE Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis Ivan Spicka1 | Philippe Moreau2 | Thomas G. Martin3 | Thierry Facon4 | Gracia Martinez5 | Albert Oriol6 | Youngil Koh7 | Andrew Lim8 | Gabor Mikala9 | Laura Rosiñol10 | Münci Yag ci11 | Michele Cavo12,13 | Marie-Laure Risse14 | Gaëlle Asset15 | Sandrine Macé14 | Helgi van de Velde16 | Kwee Yong17 1 1st Department of Medicine—Department of Hematology, First Faculty of Medicine, Charles University and General Hospital, Prague, Czech Republic 2 University of Nantes, Nantes, France 3 University of California San Francisco, San Francisco, California, USA 4 Department of Haematology, Lille University Hospital, Lille, France 5 Hospital das Clínicas de Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil 6 Hematology Department, Institut Català d'Oncologia and Josep Carreras Institute, Hospital Germans Trias i Pujol, Badalona, Spain 7 Seoul National University Hospital, Seoul, South Korea 8 Austin and Repatriation Medical Center, Heidelberg, Victoria, Australia 9 Department of Hematology and Stem Cell Transplantation, National Institute for Hematology and Infectious Diseases, South Pest Central Hospital, Budapest, Hungary 10 Hospital Clinic, IDIBAPS, Barcelona, Spain 11 Gazi University, Ankara, Turkey 12 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy 13 Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy 14 Sanofi, R&D, Vitry-Sur-Seine, France 15 Sanofi, R&D, Chilly-Mazarin, France 16 Sanofi, Cambridge, Massachusetts, USA 17 Department of Haematology, University College Hospital, London, UK Correspondence Ivan Spicka, 1st Department of Medicine— Abstract Department of Hematology, First Faculty of Introduction: The presence of high-risk chromosomal abnormalities [t(4;14), del(17p), Medicine, Charles University and General Hospital, Prague, Czech Republic, and t(14;16)] has been linked with inferior outcomes in patients with multiple Email: spicka@cesnet.cz myeloma (MM). A prespecified interim analysis of the Phase 3 IKEMA study Funding information (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexametha- Sanofi sone (d; Isa-Kd) significantly improved progression-free survival (PFS) versus Kd in patients with relapsed MM. This prespecified subgroup analysis of IKEMA examined efficacy and safety in patients with high-risk cytogenetics. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd. 504 wileyonlinelibrary.com/journal/ejh Eur J Haematol. 2022;109:504–512. 16000609, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejh.13835 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SPICKA ET AL. 505 Methods: High-risk cytogenetics was assessed by central laboratory and patients were classified as high risk if abnormalities were present in ≥1 of the following: del (17p): 50% cutoff; t(4;14), and/or t(14;16): 30% cutoff. Results: Of the randomized patients, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk chromosomal abnormality. A PFS benefit was seen in favor of Isa-Kd for patients with standard-risk (HR 0.440; 95% CI 0.266–0.728) and high-risk cytogenetics (HR 0.724; 95% CI 0.361–1.451). Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd (85.7%) versus Kd (63.3%) in patients with high-risk cyto- genetics; however, the incidence of serious TEAEs (64.3% vs. 66.7%) was similar. Conclusions: Isa-Kd is a new treatment option for the difficult-to-treat subgroup of patients with relapsed MM and high-risk cytogenetics. KEYWORDS high-risk cytogenetics, isatuximab, multiple myeloma 1 | I N T RO DU CT I O N better (72.6% vs. 56.1%), and complete response ([CR], 39.7% vs. 27.6%) rates, and a manageable safety profile.9–11 Multiple myeloma (MM) is the second most common hematologic This prespecified subgroup analysis of IKEMA examined efficacy malignancy.1,2 For patients with MM, several prognostic factors and safety in patients with high-risk CA [t(4;14), del(17p), and t should be considered for treatment decision-making.3 The presence (14;16)], which is a component of the Revised Multiple Myeloma of high-risk chromosomal abnormalities (CA; defined by the Interna- International Staging System (R-ISS).12 The analysis of gain/ tional Myeloma Working Group consensus as t(4;14), del(17p), and t amplification of 1q21 is increasingly recommended for assessment (14;16)) has been well documented as a negative prognostic factor, of cytogenetic risk but was not part of the prespecified high-risk CA typically leading to poorer outcomes compared with standard-risk definition in the IKEMA protocol, which used CA part of R-ISS. How- patients.4,5 ever, assessment of gain/amplification of 1q21 was part of the Isatuximab (Isa; Sarclisa®, Cambridge, MA, USA) is a monoclo- exploratory endpoints and a detailed analysis will be published nal antibody that binds to a specific epitope of CD38 and exerts separately. 6 anti-MM effects through several modes of action. Based on the Phase 3 ICARIA-MM study, Isa is approved in combination with pomalidomide (P) and dexamethasone (d) for the treatment of 2 | M A T E R I A L S A N D M ET H O D S adult patients with relapsed/refractory MM who have received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor.7 2.1 | Study design and patients Based on the phase III IKEMA study results, Isa in combination with carfilzomib (K) and d is approved in the United States for the The IKEMA study design was previously described.9–11 Patients with treatment of adult patients with relapsed or refractory MM who 1–3 prior lines of therapy were randomized 3:2 to receive Isa-Kd have received 1–3 prior lines of therapy, in the European Union (n = 179) or Kd (n = 123). The Isa-Kd arm received Isa (10 mg/kg intra- for the treatment of adult patients with relapsed MM who have venously) weekly for 4 weeks, then every 2 weeks. Both arms received received ≥1 prior therapy, and in Japan for the treatment of adult K (20 mg/m2 days 1–2; 56 mg/m2 thereafter) twice weekly for 3 of patients with relapsed or refractory MM who have received 1 prior 4 weeks, and d (20 mg) twice weekly. The primary endpoint was PFS, 7,8 treatment. and key secondary endpoints included overall response rate (ORR), IKEMA (NCT03275285) was a randomized, open-label, multina- ≥VGPR rate, MRD negativity rate, CR rate, and overall survival (OS). tional, parallel-group Phase 3 study that investigated Isa in combina- tion with Kd (Isa-Kd, experimental group) versus Kd (control group) in patients with relapsed MM and 1–3 prior lines of therapy.9–11 A pre- 2.2 | Outcomes specified interim efficacy analysis of the IKEMA study showed that Isa-Kd significantly improved progression-free survival (PFS) com- Cytogenetic risk was assessed for all patients by central laboratory pared with Kd in patients with relapsed MM (hazard ratio [HR] 0.531; fluorescence in situ hybridization (FISH) testing after immunomag- 99% confidence interval [CI], 0.318–0.889; one-sided p = 0.0007), netic isolation of CD138+ plasma cells from baseline bone marrow with a clinically meaningful increase in minimal residual disease (MRD) aspirate, interphase chromosome preparation, and hybridization with negativity (29.6% vs. 13.0%), very good partial response (VGPR) or Kreatech FISH probes (11q22.3[ATM]/17p13.1[p53], 4p16.3 16000609, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejh.13835 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 506 SPICKA ET AL. TABLE 1 Baseline characteristics by chromosomal abnormality [del(17p), t(4;14), and/or t(14;16)]—randomized population High risk Standard risk Patient characteristic Isa-Kd (n = 42) Kd (n = 31) Isa-Kd (n = 114) Kd (n = 77) Age in years, median (range) 62.5 (37–83) 63.0 (38–80) 65.0 (38–86) 64.0 (33–90) <65 23 (54.8) 17 (54.8) 54 (47.4) 41 (53.2) ≥65 to <75 15 (35.7) 10 (32.3) 50 (43.9) 30 (39.0) ≥75 4 (9.5) 4 (12.9) 10 (8.8) 6 (7.8) ECOG PS, n (%) 0 18 (42.9) 20 (64.5) 64 (56.1) 43 (55.8) 1 22 (52.4) 9 (29.0) 44 (38.6) 31 (40.3) 2 2 (4.8) 2 (6.5) 5 (4.4) 3 (3.9) 3 0 0 1 (0.9) 0 ISS stage at study entry, n (%) Stage I 20 (47.6) 20 (64.5) 61 (53.5) 41 (53.2) Stage II 15 (35.7) 6 (19.4) 37 (32.5) 21 (27.3) Stage III 7 (16.7) 5 (16.1) 16 (14.0) 14 (18.2) Unknown 0 0 0 1 (1.3) R-ISS stage at study entry, n (%) Stage I 0 0 45 (39.5) 33 (42.9) Stage II 35 (83.3) 26 (83.9) 60 (52.6) 39 (50.6) Stage III 7 (16.7) 5 (16.1) 8 (7.0) 3 (3.9) Not classified 0 0 1 (0.9) 2 (2.6) Cytogenetic riska at study entry, n (%) del(17p) Present 18 (42.9) 16 (51.6) 0 0 t(4;14) Present 22 (52.4) 20 (64.5) 0 0 t(14;16) Present 6 (14.3) 0 0 0 Prior lines of therapy, median (range) 1 (1–3) 2 (1–3) 2 (1–4) 2 (1–4) Patients with soft tissue plasmacytoma as per IRC, n (%) 4 (9.5) 0 7 (6.2) 4 (5.2) Patients refractory to treatment, n (%) Refractory to IMiD agent 16 (38.1) 13 (41.9) 52 (45.6) 37 (48.1) Refractory to PI 14 (33.3) 12 (38.7) 34 (29.8) 25 (32.5) Refractory to IMiD agent and PI 6 (14.3) 5 (16.1) 24 (21.1) 17 (22.1) Refractory to last regimen 20 (47.6) 18 (58.1) 59 (51.8) 43 (55.8) Abbreviations: d, dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; IMiD, immunomodulatory drug; IRC, Independent Review Committee; Isa, isatuximab; ISS, International Staging System; K, carfilzomib; PI, proteasome inhibitor; R-ISS, Revised International Staging System. a High-risk status was defined as presence of del(17p), t(4;14), and/or t(14;16) by FISH. Cytogenetics was performed by a central laboratory with cutoff 50% for del(17p), 30% for t(4;14) and t(14;16). [FGFR3]; 14q32.3[IGH]; 16q23.2[MAF]). Patients were classified in 2.3 | Statistical analyses the high-risk CA subgroup if at least 1 of the following CA (part of the R-ISS parameters) was detected by central laboratory with the Statistical procedures for the IKEMA study have been described previ- following prespecified cutoffs: del(17p): 50% cutoff; t(4;14) and/or t ously.11 Median PFS and corresponding CIs were calculated by the 13 (14;16): 30% cutoff. Adverse events (AEs) were graded per the Kaplan–Meier method. HR estimates by subgroup were determined National Cancer Institute—Common Terminology Criteria for AEs using a nonstratified Cox proportional hazard model with terms for version 4.03. the factor, treatment, and their interaction. 16000609, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejh.13835 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SPICKA ET AL. 507 Isa-Kd Median Kd Median Group PFS Group PFS Subgroup (n/N) (95% CI) (n/N) (95% CI) Hazard ratio (95% CI) All patients 48/179 NR (NR–NR) 55/123 19.154 (15.770–NR) 0.531 (0.359–0.786) High-risk chromosomal abnormality* At least one 17/42 NR (13.076–NR) 15/31 18.201 (8.674–NR) 0.724 (0.361–1.451) None 27/114 NR (NR–NR) 35/77 19.450 (15.376–NR) 0.440 (0.266–0.728) del(17p) Present 6/18 NR (9.232–NR) 7/16 19.154 (8.674–NR) 0.837 (0.281–2.496) Absent 39/143 NR (NR–NR) 43/96 19.450 (15.376–NR) 0.510 (0.330–0.788 t(4;14) Present 10/22 NR (11.433–NR) 11/20 0.549 (0.232–1.301) Absent 34/137 NR (NR–NR) 39/89 19.450 (15.770–NR) 0.491 (0.310–0.778) t(14;16) Present 4/6 7.129 (2.530–NR) 0/0 NC NC Absent 41/153 NR (NR–NR) 50/111 19.154 (15.770–NR) 0.501 (0.331–0.757) 0.0 0.5 1.0 1.5 2.0 2.5 Isa-Kd better Kd better F I G U R E 1 Progression-free survival across cytogenetic risk subgroups. *High-risk cytogenetics defined as the presence of del(17p), t(4;14), and/or t(14;16). CI, confidence interval; d, dexamethasone; Isa, isatuximab; K, carfilzomib; NC, not calculable; NR, not reached; PFS, progression- free survival. 3 | RESULTS 95% CI: 0.232–1.301; median PFS was NR [95% CI: 11.433–NR] with Isa-Kd vs. 11.138 [95% CI: 4.830–NR] with Kd), whereas PFS benefit 3.1 | Patient baseline characteristics was less pronounced in patients with del(17p) (HR 0.837; 95% CI: 0.281–2.496; median PFS was NR [95% CI: 9.232–NR] with Isa-Kd Of the randomized patients, 23.5% (n = 42/179; Isa-Kd) and 25.2% vs. 19.154 months [95% CI: 8.674–NR] with Kd) (Figure 2). Due to (n = 31/123; Kd) had ≥1 high-risk CA; approximately 10% of patients the small number of patients with t(14;16), no efficacy analyses were had missing cytogenetics data (13%, Isa-Kd; 11%, Kd). At the interim conducted separately. analysis, more patients remained on Isa-Kd versus Kd among those with ≥1 high-risk CA (45.2% [19/42] vs. 25.8% [8/31], respectively). This was also true among standard-risk patients, where 55.3% 3.3 | Efficacy: Depth of response (63/114) of patients remained on Isa-Kd versus 31.2% (24/77) who remained on Kd. The addition of isatuximab to Kd led to improved depth of response Baseline characteristics of patients are presented in Table 1. More compared with Kd alone in patients with standard-risk CA, with higher patients with high-risk CA receiving Kd had an Eastern Cooperative ≥VGPR (78.9% vs. 54.5%) (Figure 3A), MRD negativity (36.0% Oncology Group performance status of 0 (42.9% Isa-Kd vs. 64.5% Kd) vs. 11.7%; Figure 3B), and CR rates (46.5% vs. 26.0%; Figure 3C). Sim- and were classified as ISS Stage I (47.6% Isa-Kd vs. 64.5% Kd), ilar ≥VGPR (57.1% vs. 54.8%), MRD negativity (21.4% vs. 22.6%), and whereas there was a similar proportion of patients with ISS Stage III in CR (23.8% vs. 22.6%) rates were observed between arms in patients the 2 arms (16.7% Isa-Kd vs. 16.1% Kd). No high-risk patients receiv- with high-risk CA. A greater percentage of patients with t(4;14) ing Kd had soft-tissue plasmacytomas compared with 10% of patients receiving Isa-Kd exhibited improved ≥VGPR (72.7% vs. 50.0%), MRD receiving Isa-Kd. The median numbers of prior lines were 1 (Isa-Kd) negativity (31.8% vs. 25.0%), and CR (36.4% vs. 20.0%) rates, which and 2 (Kd). Other baseline characteristics were well balanced. was similar to that observed in standard-risk patients. Patients with del(17p) did not experience improved depth of response with Isa-Kd. Due to small patient numbers, those with (14;16) were not included in 3.2 | Efficacy: PFS the analysis. The addition of isatuximab to Kd improved PFS for patients with ≥1 high-risk CA (HR 0.724; 95% CI: 0.361–1.451; median PFS was not 3.4 | Safety reached [NR; 95% CI: 13.076–NR] with Isa-Kd versus 18.201 months [95% CI: 8.674–NR] with Kd), and standard-risk patients (HR 0.440; The median duration of exposure was higher for patients receiving Isa- 95% CI: 0.266–0.728; median PFS was NR [95% CI: NR–NR] with Isa- Kd versus Kd among those with high-risk CA (74.0 vs. 48.0 weeks) and Kd vs. 19.450 months [95% CI: 15.376–NR] with Kd) (Figure 1). standard risk (81.0 vs. 63.0 weeks). Isa-Kd had a manageable safety Patients with t(4;14) exhibited improved PFS with Isa-Kd (HR 0.549; profile in both subgroups (Table 2). Most patients with high- (100% Isa- 16000609, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejh.13835 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 508 SPICKA ET AL. 1.0 F I G U R E 2 Progression-free 0.9 survival is prolonged for patients 0.8 with certain chromosomal Kaplan-Meier estimate abnormalities receiving Isa-Kd. 0.7 Patients with t(4;14) exhibited 0.6 prolonged progression-free 0.5 survival (A), whereas patients 0.4 with del(17p) had a less pronounced benefit (B). d, 0.3 Kd - t(4,14) Kd - No t(4,14) dexamethasone; Isa, 0.2 Isa-Kd–t(4,14) isatuximab; K, carfilzomib. 0.1 Isa-Kd–No t(4,14) Censor 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (Months) Number at Risk Kd - t(4,14) 20 13 6 5 0 Kd - No t(4,14) 89 74 58 38 5 I Kd - t(4,14) 22 18 15 10 0 I Kd - No t(4,14) 137 118 99 82 5 1.0 0.9 0.8 Kaplan-Meier estimate 0.7 0.6 0.5 0.4 0.3 Kd - del(17p) Kd - No del(17p) 0.2 IKd - del(17p) 0.1 IKd - No del(17p) Censor 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (Months) Number at Risk Kd - del(17p) 16 12 11 9 1 Kd - No del(17p) 96 79 57 38 5 I Kd - del(17p) 18 15 10 9 0 I Kd - No del(17p) 143 122 104 83 5 Kd; 93.3% Kd) and standard-risk CA (95.6% Isa-Kd; 100% Kd) experi- in the overall population was similar (20.3% [Isa-Kd] vs. 19.7% [Kd]). enced ≥1 treatment-emergent adverse event (TEAE). Grade ≥3 TEAEs The incidence of infusion reactions was consistent with that of the were more common with Isa-Kd versus Kd in patients with high-risk overall population. CA (85.7% vs. 63.3%); however, the incidence of serious TEAEs (64.3% vs. 66.7%) and TEAEs with fatal outcome during study treatment (0% vs. 0%) was similar in both arms for patients with high-risk CA. Fewer 4 | DI SCU SSION patients treated with Isa-Kd experienced TEAEs leading to definitive discontinuation among all cytogenetic risk groups, consistent with the In this IKEMA subgroup analysis, the addition of Isa to Kd led to results reported for the overall population. improved PFS in patients with high-risk CA, supporting the benefit of Selected TEAEs are shown in Table 3. Patients with high-risk CA Isa-Kd in patients with relapsed MM reported in the overall popula- had higher rates of infection (all-grade and Grade ≥ 3) with Isa-Kd tion, and including those with high-risk cytogenetics.13 Patients with t vs. Kd. The difference in all-grade TEAEs was driven by upper respira- (4;14) exhibited improved depth of response following treatment with tory tract infections and nasopharyngitis. A similar incidence of all- Isa-Kd; however, the benefit was less pronounced in patients with del grade pneumonia was seen with Isa-Kd (28.6%) versus Kd (26.7%), (17p). In a subgroup analysis of the Phase 3 ICARIA-MM study, but the incidence of Grade ≥ 3 pneumonia was higher with Isa-Kd patients with relapsed/refractory MM and high-risk cytogenetics who (16.7% vs. 6.7%). Grade ≥ 3 hypertension was reported more fre- received Isa-Pd had improved ORR and PFS compared with those quently with Isa-Kd (21.4%) versus Kd (6.7%); however, the incidence who received Pd.14 Together, results from ICARIA-MM and IKEMA 16000609, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejh.13835 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SPICKA ET AL. 509 F I G U R E 3 Improved depth of response with Isa-Kd versus Kd across cytogenetic risk groups. d, 90.0 78.9 dexamethasone; Isa, 80.0 72.7 isatuximab; K, carfilzomib; MRD, minimal residual disease; VGPR, 70.0 62.5 Incidence (%) very good partial response 60.0 54.5 57.1 54.8 50.0 50.0 44.4 40.0 30.0 20.0 10.0 0.0 Standard Risk High Risk t(4;14) del(17p) Isa-Kd Kd MRD- 40.0 36.0 35.0 31.8 30.0 Incidence (%) 25.0 25.0 25.0 22.6 21.4 20.0 15.0 11.7 11.1 10.0 5.0 0.0 Standard Risk High Risk t(4;14) del(17p) Isa-Kd Kd Complete Response 50.0 46.5 45.0 40.0 36.4 35.0 31.3 Incidence (%) 30.0 26.0 23.8 22.6 25.0 22.2 20.0 20.0 15.0 10.0 5.0 0.0 Standard Risk High Risk t(4;14) del(17p) Isa-Kd Kd 16000609, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejh.13835 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 510 SPICKA ET AL. TABLE 2 Safety summary High riska Standard riskb Isa-Kd (n = 42) Kd (n = 30) Isa-Kd (n = 113) Kd (n = 77) Patients with any TEAE 42 (100) 28 (93.3) 108 (95.6) 77 (100) Patients with any Grade ≥3 TEAE 36 (85.7) 19 (63.3) 86 (76.1) 59 (76.6) c Patients with any Grade 5 TEAE 0 0 5 (4.4) 4 (5.2) Patients with any serious TEAE 27 (64.3) 20 (66.7) 65 (57.5) 46 (59.7) Patients with any TEAE leading to definitive discontinuation 2 (4.8) 3 (10.0) 11 (9.7) 14 (18.2) Abbreviations: D, dexamethasone; FISH, fluorescence in situ hybridization; Isa, isatuximab; K, carfilzomib; TEAE, treatment-emergent adverse event. a High-risk status was defined as presence of del(17p), t(4;14), and/or t(14;16) by FISH. Cytogenetics was performed by a central laboratory with cut-off 50% for del(17p), 30% for t(4;14) and t(14;16). b Standard-risk status was defined as absence of del(17p), t(4;14), and t(14;16) by FISH. c TEAE with fatal outcome during the treatment period. TABLE 3 Selected TEAEs—safety population High riska Standard riskb Isa-Kd (n = 42) Kd (n = 30) Isa-Kd (n = 113) Kd (n = 77) Selected TEAEs by SOC or SMQ or PT, Any Any Any Any n (%) grade Grade ≥3 grade Grade ≥3 grade Grade ≥3 grade Grade ≥3 Infections and infestations (SOC) 35 (83.3) 15 (35.7) 23 (76.7) 8 (26.7) 98 (86.7) 46 (40.7) 67 (87.0) 24 (31.2) Upper respiratory tract infection 16 (38.1) 2 (4.8) 2 (6.7) 1 (3.3) 41 (36.3) 4 (3.5) 23 (29.9) 1 (1.3) Pneumonia 12 (28.6) 7 (16.7) 8 (26.7) 2 (6.7) 25 (22.1) 19 (16.8) 12 (15.6) 11 (14.3) Bronchitis 9 (21.4) 0 6 (20.0) 0 26 (23.0) 4 (3.5) 7 (9.1) 0 Nasopharyngitis 8 (19.0) 0 2 (6.7) 0 18 (15.9) 0 11 (14.3) 0 Others Infusion-related reaction 23 (54.8) 1 (2.4) 0 0 44 (38.9) 0 4 (5.2) 0 Hypertension 13 (31.0) 9 (21.4) 6 (20.0) 2 (6.7) 45 (39.8) 25 (22.1) 31 (40.3) 22 (28.6) Diarrhea 14 (33.3) 3 (7.1) 8 (26.7) 1 (3.3) 41 (36.3) 1 (0.9) 25 (32.5) 2 (2.6) Insomnia 13 (31.0) 2 (4.8) 8 (26.7) 1 (3.3) 26 (23.0) 6 (5.3) 20 (26.0) 2 (2.6) Fatigue 13 (31.0) 0 5 (16.7) 0 32 (28.3) 4 (3.5) 18 (23.4) 1 (1.3) Asthenia 7 (16.7) 1 (2.4) 3 (10.0) 0 21 (18.6) 1 (0.9) 16 (20.8) 3 (3.9) Abbreviations: d, dexamethasone; Isa, isatuximab; K, carfilzomib; PT, MedDRA preferred term; SMQ, standardized MedDRA query; SOC, system organ class; TEAE, treatment-emergent adverse event. a High-risk status was defined as presence of del(17p), t(4;14), and/or t(14;16) by FISH. Cytogenetics was performed by a central laboratory with cut-off 50% for del(17p), 30% for t(4;14) and t(14;16). b Standard-risk status was defined as absence of del(17p), t(4;14), and t(14;16) by FISH. suggest that Isa provides clinical benefit to patients with high-risk In CASTOR and POLLUX, cytogenetic status was assessed by cytogenetics. local laboratories, and definitions of cytogenetic status varied by In CANDOR, which investigated the addition of daratumumab study site. Similar to CANDOR, cytogenetic status was unknown in a (another anti-CD38 monoclonal antibody) to Kd, cytogenetic status was high percentage of patients (30% CASTOR; 20% POLLUX).16–18 assessed by central laboratory but was unknown in approximately 50% Results in this subgroup were published at the 3-year follow-up for of patients, and 16% of all patients had high-risk CA.15 Compared with both studies. Patients with high-risk CA treated with daratumumab, IKEMA, a similar PFS benefit was reported with daratumumab plus Kd bortezomib, and dexamethasone exhibited prolonged PFS (HR: 0.41; versus Kd alone among patients with high-risk CA (HR: 0.70; 95% CI: 95% CI: 0.21–0.83) with a median of 12.6 versus 6.2 months.18 0.36–1.40); however, the high percentage of patients with unknown Patients with high-risk CA treated with daratumumab, lenalidomide, cytogenetic status makes these results less robust. To date, other out- and dexamethasone also exhibited prolonged PFS (HR: 0.34; 95% CI: comes such as ORR, ≥VGPR, CR, and MRD rates in patients with high- 0.16–0.72) and higher rates of MRD negativity (26% vs. 0%, respec- risk CA have not been published for daratumumab plus Kd. tively) compared with patients treated with lenalidomide and d.17 16000609, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejh.13835 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SPICKA ET AL. 511 In IKEMA, approximately 90% of patients had conclusive central Helgi van de Velde, are employed by Sanofi and may have stock and/or laboratory assessment, with a stringent and clear definition of positivity, stock options in the company. Kwee Yong: Nothing to disclose. enabling the definitive demonstration of the benefit of Isa. The sub- group analysis in high-risk CA patients of these studies and the IKEMA DATA AVAILABILITY STAT EMEN T study support that the combination of an anti-CD38 monoclonal anti- Qualified researchers can request access to patient-level data and body with a proteasome inhibitor and corticosteroid results in a supe- related study documents including the clinical study report, study proto- rior outcome in patients with RRMM and high-risk CA; however, this col with any amendments, blank case report forms, statistical analysis benefit is not to the same extent as that seen in patients with standard plan, and dataset specifications. Patient-level data will be anonymized, risk. Because of the limited sample size of subgroup analyses, larger and study documents will be redacted to protect the privacy of trial par- studies with additional follow-up are needed to further support the ticipants. Further details on Sanofi's data-sharing criteria, eligible stud- benefit of Isa-Kd in the subgroup of patients with high-risk CA. ies, and process for requesting access are at: https://www.vivli.org. The addition of Isa to Kd improved PFS in patients with high-risk CA, improved PFS and depth of response in patients with t(4;14), and OR CID led to a less pronounced PFS benefit in patients with del(17p), with a Philippe Moreau https://orcid.org/0000-0003-1780-8746 manageable safety profile, which was consistent with the benefit Albert Oriol https://orcid.org/0000-0001-6804-2221 observed in the overall IKEMA population. Isa-Kd represents a new treatment option for the difficult-to-treat subgroup of patients with RE FE RE NCE S relapsed MM and high-risk cytogenetics. 1. Kazandjian D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol. 2016;43(6):676-681. 2. Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. AUTHOR CONTRIBUTIONS Mayo Clin Proc. 2016;91(1):101-119. Ivan Spicka, Philippe Moreau, Thomas G. Martin, Thierry Facon, 3. Biran N, Jagannath S, Chari A. Risk stratification in multiple myeloma, Gracia Martinez, Albert Oriol, Youngil Koh, Andrew Lim, Gabor Mikala, part 1: characterization of high-risk disease. Clin Adv Hematol Oncol. Laura Rosiñol, Münci Ya gci, Michele Cavo, and Kwee Yong contributed to 2013;11(8):489-503. data acquisition and data interpretation; Gaëlle Asset contributed to statisti- 4. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the interna- cal analysis; Sandrine Macé contributed to data analysis and data interpre- tional myeloma working group. Blood. 2016 Jun 16;127(24):2955- tation; Marie-Laure Risse, contributed to data analysis and data 2962. interpretation; Helgi van de Velde contributed to study design, data analysis 5. Lancman G, Tremblay D, Barley K, et al. The effect of novel therapies and interpretation. All authors contributed to critical revision and final in high-molecular-risk multiple myeloma. Clin Adv Hematol Oncol. approval of the manuscript. 2017;15(11):870-879. 6. Jiang H, Acharya C, An G, et al. SAR650984 directly induces multiple mye- loma cell death via lysosomal-associated and apoptotic pathways, which is ACKNOWLEDGMENTS further enhanced by pomalidomide. Leukemia. 2016;30(2):399-408. The IKEMA study was sponsored by Sanofi. The authors would like to 7. Sarclisa® (isatuximab-irfc). Prescribing information. Sanofi-Aventis thank the participating patients and their families, as well as the study U.S. LLC; 2021. centers and investigators for their contributions to the study. Medical 8. Sarclisa® (isatuximab). Prescribing information. Sanofi Co, Ltd; 2021. 9. Moreau P, Dimopoulos M, Mikhael J, et al. Isatuximab plus carfilzomib writing support was provided by Erin Burns-Tidmore, PhD, of Elevate and dexamethasone vs carfilzomib and dexamethasone in Medical Affairs, contracted by Sanofi for publication support services. relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study. 2020 European Hematology CONF LICT OF IN TE RE ST Association Congress Virtual; 2020. Ivan Spicka: Honoraria—Amgen, Celgene, Janssen-Cilag, Bristol Myers 10. Moreau P, Dimopoulos MA, Yong K, et al. Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in Squibb, Takeda, Novartis. Philippe Moreau: Honoraria—Sanofi, Cel- patients with relapsed/refractory multiple myeloma: IKEMA phase III gene, Amgen, Janssen. Thomas G. Martin: Research support—Sanofi, study design. Future Oncol. 2020 Jan;16(2):4347-4358. Amgen. Thierry Facon: Honoraria—Sanofi, Amgen, Janssen, Celgene, 11. Moreau P, Dimopoulos M, Mikhael J, et al. Isatuximab combined with Takeda, Karyopharm, Oncopeptides, Roche; Speakers Bureau— carfilzomib and dexamethasone versus carfilzomib with dexametha- sone in patients with relapsed multiple myeloma: interim analysis of Takeda, Janssen. Gracia Martinez: Nothing to disclose. Albert Oriol: the IKEMA phase 3 study. Lancet. 2021;397(10292):2361-2371. doi: Honoraria—BMS/Celgene, Sanofi, Amgen, GSK. Youngil Koh: Nothing 10.1016/S0140-6736(21)00592-4 to disclose. Andrew Lim: Consultant—Celgene; Research funding— 12. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international Celgene; Honoraria—Celgene. Gabor Mikala: Honoraria—AbbVie, staging system for multiple myeloma: a report from international Amgen, Celgene, Janssen, Novartis, Takeda. Laura Rosiñol: Honoraria— myeloma working group. J Clin Oncol. 2015 Sep 10;33(26):2863- 2869. ci: Nothing to dis- Janssen, Celgene, Amgen, Takeda, Sanofi. Münci Yag 13. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, close. Michele Cavo: Honoraria—AbbVie, Amgen, Bristol Myers Squibb, and dexamethasone in relapsed multiple myeloma (IKEMA): a multi- Adaptive Biotechnologies, Celgene, Janssen China R&D, GlaxoSmithK- centre, open-label, randomised phase 3 trial. Lancet. 2021; line, Takeda. Marie-Laure Risse, Gaëlle Asset, Sandrine Macé, and 397(10292):2361-2371. 16000609, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejh.13835 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 512 SPICKA ET AL. 14. Harrison SJ, Perrot A, Alegre A, et al. Subgroup analysis of ICARIA- 18. Mateos MV, Sonneveld P, Hungria V, et al. Daratumumab, Bortezo- MM study in relapsed/refractory multiple myeloma patients with mib, and dexamethasone versus Bortezomib and dexamethasone in high-risk cytogenetics. Br J Haematol. 2021;194:120-131. patients with previously treated multiple myeloma: three-year follow- 15. Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexametha- up of CASTOR. Clin Lymphoma Myeloma Leuk. 2020 Aug;20(8): sone, and daratumumab versus carfilzomib and dexamethasone for 509-518. patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197. 16. Weisel K, Spencer A, Lentzsch S, et al. Daratumumab, bortezomib, How to cite this article: Spicka I, Moreau P, Martin TG, et al. and dexamethasone in relapsed or refractory multiple myeloma: sub- group analysis of CASTOR based on cytogenetic risk. J Hematol Isatuximab plus carfilzomib and dexamethasone in relapsed Oncol. 2020 Aug 20;13(1):115. multiple myeloma patients with high-risk cytogenetics: IKEMA 17. Kaufman JL, Dimopoulos MA, White D, et al. Daratumumab, lenalido- subgroup analysis. Eur J Haematol. 2022;109(5):504‐512. mide, and dexamethasone in relapsed/refractory myeloma: a cytoge- doi:10.1111/ejh.13835 netic subgroup analysis of POLLUX. Blood Cancer J. 2020 Nov 3; 10(11):111.