Results of the Phase III Randomized Iskia Trial: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone As Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients
Author:
Gay Francesca12, Roeloffzen Wilfried3, Dimopoulos Meletios A.4, Rosiñol Laura5, van der Klift Marjolein6, Mina Roberto12, Rocafiguera Albert Oriol7, Katodritou Eirini8, Wu Ka Lung9, Rodriguez Otero Paula10, Hajek Roman1112, Antonioli Elisabetta13, van Duin Mark14, D'Agostino Mattia21, Martinez-Lopez Joaquin15, van Leeuwen-Segarceanu Elena M.16, Tacchetti Paola17, van de Donk Niels W.C.J.18, Weisel Katja19, Pour Luděk20, Radocha Jakub21, Belotti Angelo22, Schjesvold Fredrik2324, Bladé Joan25, Einsele Hermann26, Sonneveld Pieter14, Boccadoro Mario27, Broijl Annemiek14
Affiliation:
1. 1Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy 2. 2Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy 3. 3Department of Hematology, University Medical Center Groningen, Groningen, Netherlands 4. 4Hematology and Medical Oncology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece 5. 5Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain 6. 6Department of Internal Medicine, Amphia Hospital, Breda, Netherlands 7. 7Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain 8. 8Department of Hematology, Theagenion Cancer Hospital, Thessaloniki, Greece 9. 9ZNA Stuivenberg, Antwerp, Belgium 10. 10Clínica Universidad de Navarra, Pamplona, Spain 11. 11Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic 12. 12Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic 13. 13Hematology Unit, AOU Careggi, Florence, Italy 14. 14Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands 15. 15Hematology Department, Hospital Universitario 12 de Octubre, Medicine Department Complutense University, CNIO, Madrid, Spain 16. 16Department of Hematology, St. Antonius Hospital, Nieuwegein, Netherlands 17. 17IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy 18. 18Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Hematology, Cancer Center Amsterdam, Amsterdam, Netherlands 19. 19Department of Oncology, Hematology and BMT, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany 20. 20Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic 21. 214th Department of Internal Medicine-Hematology, University Hospital Hradec Kralove, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic 22. 22Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy 23. 23Oslo Myeloma Center, Department of Hematology, Oslo University Hospital, Oslo, Norway 24. 24KG Jebsen Center for B cell malignancies, University of Oslo, Oslo, Norway 25. 25Hematology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain 26. 26Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany 27. 27European Myeloma Network, EMN, Italy
Abstract
OffLabel Disclosure:
Background. The current standard treatment for transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM) consists of quadruplet induction with proteasome inhibitors, immunomodulatory agents, dexamethasone and anti-CD38 monoclonal antibody followed by high-dose melphalan and autologous stem-cell transplant (MEL200-ASCT), with subsequent consolidation. The phase III IsKia trial assessed efficacy and safety of isatuximab-carfilzomib-lenalidomide-dexamethasone (IsaKRd) as pre-ASCT induction and post-ASCT consolidation vs KRd.
Methods. TE NDMM pts aged <70 years were enrolled and randomized. IsaKRd pts received 4 28-day cycles of Isa: 10 mg/kg IV days 1, 8, 15, 22 cycle 1, followed by 10 mg/kg days 1, 15 cycles 2-4; K: 20 mg/m 2 IV day 1 cycle 1, followed by 56 mg/m 2 IV days 8, 15 cycle 1 and days 1, 8, 15 cycles 2-4; R: 25 mg PO daily days 1-21; d: 40 mg PO days 1, 8, 15, 22; MEL200-ASCT and 4 consolidation cycles with IsaKRd at the same schedule. KRd pts received 4 KRd induction cycles; MEL200-ASCT and 4 KRd consolidation cycles (K, R and d at the same schedule as in the IsaKRd arm). The primary endpoint was the rate of minimal residual disease (MRD) negativity by next-generation sequencing (NGS; 10 -5) after consolidation in the intention-to-treat (ITT) population. MRD was tested in all pts who achieved at least a very good partial response (≥VGPR). Key secondary endpoints were the rate of NGS MRD negativity (10 -5) after induction and PFS. MRD rates were evaluated in an ITT analysis (pts with missing MRD data or who achieved ≤PR were considered as MRD positive). The data cut-off for the analysis was May 22, 2023.
Results. 302 pts were enrolled and randomized (151 in both the IsaKRd and KRd arms). Pt characteristics were well balanced between the two arms: median age was 61 vs 60 years, respectively; 18% vs 19% of pts had high-risk (HiR) cytogenetic abnormalities (CA) [del(17p) and/or t(4;14) and/or t(14;16)]; 9% vs 8% had ≥2 HiR CA [double hit; including del(17p), t(4;14), t(14;16) and gain/amp(1q)]. In ITT analysis, the rates of MRD negativity at the 10 -5 cut-off after consolidation (primary endpoint) were 77% vs 67% (OR 1.67; p=0.049) with IsaKRd vs KRd; the respective rates of MRD negativity at the 10 -6 cut-off were 67% vs 48% (OR 2.29; p<0.001); consistent MRD results were detected by next-generation flow. ≥VGPR after consolidation was 94% in both arms; ≥CR 74% vs 72% and sCR 64% vs 67% in the IsaKRd vs KRd arms. The MRD negativity advantage, both at 10 -5 and 10 -6, was retained in all subgroups analyzed ( Figure), with similar benefit in pts with standard-risk (SR) and HiR features. In particular, the 10 -5 MRD negativity rates with IsaKRd were 76% in HiR and 77% in double-hit pts, comparable to the one in SR pts (79%). In the KRd arm, the 10 -5 MRD negativity rates were 58% in HiR and 53% in double-hit pts, inferior to the one in SR pts (70%). The 10 -6 MRD negativity rates with IsaKRd were 72% in HiR, 77% in double-hit pts and 67% in SR pts. The MRD negativity rate after induction (first key secondary endpoint) was also significantly higher with IsaKRd vs KRd (10 -5: 45% vs 26%, OR 2.34, p<0.001; 10 -6: 27% vs 14%, OR 2.36, p=0.004), with a consistent benefit in all subgroups. After induction, the MRD negativity rates in HiR and double-hit pts treated with IsaKRd were: 10 -5, HiR 60%, double-hit 54%; 10 -6, HiR 40%, double-hit 31%. The MRD negativity rates after ASCT were also significantly better with IsaKRd vs KRd (10 -5: 64% vs 49%, OR 1.93, p=0.006; 10 -6: 52% vs 27%, OR 3.01, p<0.001), with a consistent advantage in all subgroups. At the current follow-up (median, 20 months, IQR 18-23), there was no difference in PFS (95% at 1 year in both arms). 55% of pts had ≥1 hematologic adverse events (AEs) with IsaKRd vs 43% with KRd; main grade 3-4 hematologic AEs in IsaKRd vs KRd were neutropenia (37% vs 22%) and thrombocytopenia (15% vs 17%). 41% of pts had ≥1 non-hematologic AEs with IsaKRd vs 37% with KRd, including infections (16% vs 12%), gastrointestinal (7% vs 5%), vascular (2% vs 7%) and cardiac events (1% vs 4%). Discontinuation for toxicity was 6% in IsaKRd vs 5% in KRd arms; treatment-related deaths were 4 with IsaKRd (2 COVID, 1 pneumonia, 1 pulmonary embolism) and 1 with KRd (septic shock).
Conclusion. In TE NDMM pts, the addition of isatuximab to KRd induction and consolidation significantly increased MRD negativity rates in every treatment phase as compared to KRd, with no new safety concerns. This benefit was retained in HiR pts.
Gay: Pfizer: Honoraria, Other: Advisory board; Amgen: Honoraria, Other: Advisory board; Takeda: Honoraria, Other: Advisory board; Sanofi: Honoraria, Other: Advisory board; Bristol Myers Squibb/Celgene: Honoraria, Other: Advisory board; Oncopeptides: Other: Advisory board; Janssen: Honoraria, Other: Advisory board; Roche: Other: Advisory board; GlaxoSmithKline: Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board. Roeloffzen:Amgen: Other: Travel grants, honoraria or advisory board (not personal); Sanofi: Other: Travel grants, honoraria or advisory board (not personal); AbbVie: Other: Travel grants, honoraria or advisory board (not personal); Bristol Myers Squibb: Other: Travel grants, honoraria or advisory board (not personal); Janssen: Other: Travel grants, honoraria or advisory board (not personal). Dimopoulos:AbbVie: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees; BeiGene Inc: Honoraria, Membership on an entity’s Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Menarini: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Rosiñol:Amgen: Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures; GlaxoSmithKline: Other: Honoraria for lectures; Sanofi: Other: Honoraria for lectures; Bristol Myers Squibb/Celgene: Other: Honoraria for lectures; Janssen: Other: Honoraria for lectures. Mina:Pfizer: Honoraria; Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Rocafiguera:Oncopeptides: Membership on an entity’s Board of Directors or advisory committees; GSK: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Menarini: Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Katodritou:Janssen Cilag, Amgen, Abbvie, Pfizer, GSK, Takeda, Sanofi, Karyopharm: Honoraria, Research Funding. Rodriguez Otero:AbbVie: Consultancy, Membership on an entity’s Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees, Other: Honoraria for lectures; Pfizer: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Other: Travel grants; Amgen: Other: Honoraria for lectures; Regeneron: Other: Honoraria for lectures; Oncopeptides: Membership on an entity’s Board of Directors or advisory committees; Roche: Consultancy; Sanofi: Membership on an entity’s Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Other: Honoraria for lectures; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Other: Honoraria for lectures. Hajek:Amgen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; Celgene: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; Sanofi: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity’s Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees; AbbVie: Consultancy; PharmaMar: Consultancy, Honoraria. D’Agostino:Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Janssen: Other: Honoraria for lectures; Sanofi: Membership on an entity’s Board of Directors or advisory committees, Other: Honoraria for lectures; GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees, Other: Honoraria for lectures. Tacchetti:Takeda: Honoraria; Amgen: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria; Janssen: Honoraria. van de Donk:Bristol Myers Squibb: Other: Advisory boards (all paid to institution), Research Funding; Servier: Other: Advisory boards (all paid to institution); Adaptive: Other: Advisory boards (all paid to institution); Pfizer: Other: Advisory boards (all paid to institution); Roche: Other: Advisory boards (all paid to institution); Novartis: Other: Advisory boards (all paid to institution); Janssen Pharmaceuticals: Other: Advisory boards (all paid to institution), Research Funding; Amgen: Other: Advisory boards (all paid to institution), Research Funding; Bayer: Other: Advisory boards (all paid to institution); Novartis: Research Funding; AbbVie: Other: Advisory boards (all paid to institution); Takeda: Other: Advisory boards (all paid to institution); Celgene: Other: Advisory boards (all paid to institution), Research Funding; Cellectis: Research Funding. Weisel:Amgen: Consultancy, Honoraria, Other: Research grant to institution; Adaptive Biotech: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Research grant to institution; Janssen: Consultancy, Honoraria, Other: Research grant to institution; GlaxoSmithKline: Consultancy, Honoraria, Other: Research grant to institution; AstraZeneca: Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Other: Research grant to institution; Takeda: Consultancy, Honoraria, Other: Research grant; Sanofi: Consultancy, Honoraria, Other: Research grant to institution; Stemline: Honoraria; Oncopeptides: Consultancy, Honoraria; Novartis: Honoraria; Roche Pharma: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria. Radocha:Sanofi: Consultancy, Honoraria, Other: Travel expenses; Janssen: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel expenses. Belotti:Janssen: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Schjesvold:Pfizer: Other: Honoraria for lectures and educational material; Daiichi Sankyo: Other: Honoraria for lectures and educational material; Skylite DX: Other: Honoraria for lectures and educational material; Novartis: Other: Honoraria for lectures and educational material; Targovax: Research Funding; Oncopeptides: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; Celgene: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; Abbvie: Consultancy, Other: Honoraria for lectures and educational material; Bristol Myers Squibb: Consultancy, Other: Honoraria for lectures and educational material; Sanofi: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Other: Honoraria for lectures and educational material; Janssen-Cilag: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; Amgen: Other: Honoraria for lectures and educational material; Schain: Other: Honoraria for lectures and educational material. Bladé:Sanofi: Other: Honoraria for lectures; Janssen: Other: Honoraria for lectures; Amgen: Other: Honoraria for lectures; Celgene/Bristol Myers Squibb: Other: Honoraria for lectures. Einsele:Janssen: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Takeda: Honoraria, Other: Consulting or advisory role, Travel support; Amgen: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Novartis: Honoraria, Other: Consulting or advisory role, Travel support; GlaxoSmithKline: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Sanofi: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding. Sonneveld:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Karyopharm: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Boccadoro:Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees; AbbVie: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Broijl:Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees.
This presentation includes information or discussion of the off-label use of a drug or drugs for the treatment of multiple myeloma: isatuximab, carfilzomib, lenalidomide, and dexamethasone.
Figure 1
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Cited by
25 articles.
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