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753 Isatuximab Plus Carfilzomib and Dexamethasone in Patients with Early Versus Late Relapsed Multiple Myeloma: Ikema Subgroup Analysis

Program: Oral and Poster Abstracts
Type: Oral
Session: 652. Multiple Myeloma and Plasma Cell Dyscrasias: Clinical and Epidemiological: Therapeutic Impact in Multiple Myeloma
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Antibody Therapy, Clinical Research, Diseases, Therapies, Myeloid Malignancies, Monoclonal Antibody Therapy
Monday, December 12, 2022: 11:00 AM

Thierry Facon1*, Philippe Moreau, MD2*, Ross Baker, MBBS, FRACP, FRCPA, BSc3, Ludek Pour, MD, Prof, PhD4*, Chang-Ki Min, MD, PhD5*, Xavier Leleu, MD, PhD6, Mohamad Mohty, MD PhD7, Lionel Karlin8*, Andreea Rawlings9*, Christina Tekle, PhD9*, Sandrine Schwab10*, Marie-Laure Risse10* and Thomas Martin, MD11

1Department of Hematology, Lille University Hospital, Lille, France
2University Hospital Hotel-Dieu, Nantes, France
3Perth Blood Institute, Murdoch University, Perth, Australia
4Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic
5Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul, Korea, Republic of (South)
6Service d'Hématologie et Thérapie Cellulaire, CHU and CIC Inserm 1402, Poitiers, France
7Department of Hematology, Hôpital Saint-Antoine, Sorbonne University, INSERM UMRs 938, Paris, France
8Department of Hematology, Hospices Civils de Lyon, Lyon Sud University Hospital, Pierre Benite, France
9Sanofi, Cambridge, MA
10Sanofi, Vitry-sur-Seine, France
11Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA

Introduction: Patients (pts) with multiple myeloma (MM) frequently relapse requiring successive lines of therapy; those who experience early relapse (within 12 months [mo] of therapy initiation) have worse outcomes. The final progression-free survival (PFS) analysis of the Phase 3 IKEMA study (NCT03275285), performed 2 years after the prespecified interim analysis, confirmed that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d) (Isa-Kd) significantly improved PFS compared with Kd in pts with relapsed MM (median PFS 35.7 [Isa-Kd] vs. 19.2 mo [Kd]; hazard ratio [HR] 0.58; 95.4% CI, 0.42–0.79), with a clinically meaningful increase in minimal residual disease negativity (MRD-) (33.5% vs. 15.4%) and complete response (CR) (44.1% vs. 28.5%) rates in the intent-to treat population, with a manageable safety profile. This subgroup analysis of IKEMA examined updated efficacy and safety of Isa-Kd vs. Kd in pts with MM who experienced early vs. late relapse.

Methods: Pts with 1–3 prior lines of therapy (LOT) were randomized 3:2 to receive Isa-Kd (n=179) or Kd (n=123). Treatment was given until progressive disease or unacceptable toxicity. These longer-term data at a median follow-up of 44 mo are based on a prespecified final PFS analysis of IKEMA; secondary endpoints included CR, MRD-, and safety. Early relapse pts included those who relapsed <12 mo from initiation of the most recent LOT for pts with ≥2 prior LOT, <18 mo for pts with 1 prior LOT, and <12 mo from autologous stem-cell transplantation (ASCT). Late relapse was defined as pts who relapsed ≥12 mo from initiation of the most recent LOT for those with ≥2 prior LOT and ≥18 mo for pts with 1 prior LOT.

Results: There were 107 early relapse pts (61/179 [34.1%] Isa-Kd, 46/123 [37.4%] Kd) and 176 late relapse pts (104 [58.1%] Isa-Kd, 72 [58.5%] Kd. Among early relapse pts, the Isa-Kd arm had a higher proportion of pts who had renal impairment (31.0% vs. 15.4%) and lower incidence of pts with ISS Stage I (31.1% vs. 54.3%) compared with the Kd arm. The median number of prior LOT was 2 for both treatment arms in early relapse pts and in the late relapse Kd arm; late relapse Isa-Kd arm had a median of 1 prior LOT (55.8% had 1 prior LOT with Isa-Kd vs. 48.6% pts with Kd). In late relapse, more pts had the chromosomal abnormality 1q21+ with Isa-Kd (44.2%) vs. Kd (33.3%). At data cut-off, the median PFS was longer for pts treated with Isa-Kd vs. Kd in both early relapse (24.7 vs. 17.2 mo; HR 0.662 [95.4% CI, 0.404–1.087]) and late relapse (42.7 vs. 21.9 mo; HR, 0.542 [95.4% CI, 0.353–0.833]) pts (Figures 1 and 2). The overall response rates were 82.0% vs. 82.6% in early relapse pts, and 90.4% vs. 86.1% in late relapse pts with Isa-Kd vs. Kd, respectively. More pts achieved very good partial response or better (early relapse: 67.2% vs. 52.2%; late relapse: 76.0% vs. 58.3%), MRD- (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), and MRD- CR rates (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) with Isa-Kd vs. Kd, respectively. Grade ≥3 and serious treatment-emergent adverse events (TEAEs) were similar in both treatment arms in early relapse pts, but were higher in the Isa-Kd arm in late relapse pts; however, rates of TEAEs leading to definitive discontinuation or death were similar in both treatment arms across both early and late relapse pts. All-grade TEAEs reported more frequently with Isa-Kd (≥10% difference vs. Kd) included infusion reactions in early relapse (41.0% vs. 6.5%) and late relapse pts (50.0% vs. 1.4%), upper respiratory tract infection (38.2% vs. 26.8%), fatigue (32.4% vs.19.7%), dyspnea (36.3% vs. 22.5%), bronchitis (30.4% vs. 12.7%), cough (23.5% vs. 11.3%), and gastroenteritis (14.7% vs. 4.2%) in late relapse pts. Hematologic laboratory abnormalities reported more frequently (≥5%) in the Isa-Kd arm included Grade 3 anemia (42.6% vs. 30.4%), Grade 3 neutropenia (18.0% vs. 4.3% ), and Grade 3 and 4 thrombocytopenia (21.3% vs.15.2% and 18.0% vs 13.0%) in early relapse pts and Grade 3 neutropenia (13.7% vs. 8.5%) in late relapse pts with Isa-Kd vs. Kd, respectively.

Conclusions: The addition of Isa to Kd improved PFS and depth of response, with a manageable safety profile in both early and late relapse pts, consistent with the benefit observed in the overall IKEMA study population. These results support Isa-Kd as a standard of care in pts with relapsed and/or refractory MM regardless of early or late relapse.

Funding: Sanofi

Disclosures: Moreau: AbbVie, Amgen, Celgene, Janssen, Oncopeptides, Sanofi: Honoraria. Baker: AbbVie: Research Funding; Acerta Pharma: Research Funding; Alexion: Research Funding; Amgen: Research Funding; Bayer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; CSL Behring: Research Funding; Daiichi Sankyo: Research Funding; Jansen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; Pfizer: Research Funding; Portola: Research Funding; Rigel Pharmaceuticals: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Pharmaxis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biegene: Research Funding; Technoclone: Research Funding; Cardinal Health: Honoraria. Leleu: Janssen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Amgen, Merck, BMS, GSK, Janssen, Oncopeptide, Takeda, Roche, Novartis, AbbVie, Sanofi, Gilead, Pfizer, Harpoon Therapeutic, Regeneron, Iteos: Consultancy, Honoraria; BMS: Honoraria; Amgen, BMS/Celgene, Janssen, Takeda, Novartis, Sanofi, Merck, Oncopeptide, Karyopharm, Roche, Abbvie, Carsgen, GSK, and Harpoon Therapeutics: Honoraria. Mohty: GSK: Honoraria; Gilead: Honoraria; Pfizer,: Honoraria; Oncopeptides: Honoraria; Astellas: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Karlin: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees. Rawlings: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Tekle: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Risse: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Martin: Amgen, Johnson & Johnson / Janssen, Sanofi, and Seattle Genetics: Research Funding; GlaxoSmithKline and Legend Biotech: Consultancy; Legend Biotech: Consultancy.

*signifies non-member of ASH