-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

770 Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone (Isa-VRd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): Analyses of Minimal Residual Disease (MRD) Negativity Dynamics in the Phase 3 Imroz Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 654. Multiple Myeloma: Pharmacologic Therapies: Refining the Evidence: Randomized Trials in Multiple Myeloma
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research, Measurable Residual Disease
Monday, December 9, 2024: 10:45 AM

Robert Z. Orlowski, MD, PhD1, Meletios-Athanasios Dimopoulos2, Xavier Leleu3, Zhuogang Liu4*, Tadao Ishida5, Roman Hajek, MD, PhD6, Ivan Špička7*, Joanna Romejko-Jarosinska, MD, PhD8*, Vladimir I. Vorobyev, PhD9*, Britta Besemer, MD10*, Sevgi Beşışık, MD11*, Pawel Robak12*, Hartmut Goldschmidt, MD13, Thomas Martin, MD14, Mohamad Mohty, MD, PhD15, Sandrine Macé, PhD16*, Ercem Kodas, PhD16*, Christina Tekle17*, Andrea Shafer17* and Philippe Moreau, MD, PhD18*

1Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
3Service d'Hématologie et Thérapie Cellulaire, CHU and CIC Inserm 1402, Poitiers, France
4Shengjing Hospital of China Medical University, Shenyang, China
5Japanese Red Cross Medical Center, Tokyo, Japan
6Department of Hemato-Oncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
7Charles University and General Hospital in Prague, Prague, Czech Republic
8Department of Lymphoid Malignancies, Marie Sklowdoska-Curie National Research Institute of Oncology, Warszawa, Poland
9S.P. Botkin Moscow City Clinical Hospital, Moscow, Russian Federation
10Department of Hematology, Oncology, Immunology and Rheumatology, University Hospital of Tuebingen, Tuebingen, Germany
11Department of Internal Medicine, Istanbul Medical Faculty, Istanbul, Turkey
12Department of General Hematology, Copernicus Memorial Hospital, Comprehensive Cancer Center and Traumatology, Łódź, Poland
13Internal Medicine V, Hematology, Oncology and Rheumatology, GMMG Studygroup, Heidelberg University Hospital, Heidelberg, Germany
14Department of Hematology, University of California at San Francisco, San Francisco, CA
15Department of Hematology, Hôpital Saint-Antoine, Sorbonne University and INSERM, Paris, France
16Sanofi, R&D, Vitry-sur-Seine, France
17Sanofi, Cambridge, MA
18University Hospital Hôtel-Dieu, Nantes, France

Introduction:

In the global Phase 3 IMROZ study (NCT03319667), transplant-ineligible patients (pts) with NDMM demonstrated significantly improved progression-free survival (PFS) with Isa-VRd followed by Isa-Rd compared with VRd followed by Rd, along with deep and sustained responses. Pts in the Isa-VRd arm demonstrated a significantly higher overall MRD-negative (MRD-neg) complete response (CR) rate at 10-5 sensitivity threshold vs the VRd arm (56% vs 41%; p=0.003), as well as higher rates of MRD-neg (58% vs 44%) and almost double the rate of sustained MRD-neg (sustMRD-neg) for ≥12 months (47% vs 24%) at any point during the study in the ITT population. The median time to MRD-neg was half as long with Isa-VRd (14.7 months) vs VRd (32.8 months). Here we report further analyses from IMROZ on the dynamics of MRD-neg.

Methods:

In the open-label IMROZ trial, 446 pts were randomized 3:2 to receive Isa-VRd (n=265) in the initiation phase followed by maintenance with Isa-Rd vs VRd (n=181) followed by Rd in pts ≤80 years of age. Pts received Isa (10 mg/kg IV) in the Isa-VRd arm and bortezomib (1.3 mg/m2 SC), lenalidomide (25 mg PO), and dexamethasone (20 mg IV/PO) in both arms. The primary endpoint was PFS. Key secondary endpoints included MRD-neg CR rates assessed by clonoSEQ® next-generation sequencing (NGS) at 10-5 sensitivity threshold in bone marrow aspirates obtained at baseline, and during the initiation (month 6) and maintenance (months 12, 18, 24 and 36) phases from pts with a very good partial response or better. Exploratory analyses included assessments at 10-6 sensitivity threshold and using next-generation flow (NGF).

Results:

MRD dynamics were measured by NGS using 1610 MRD assessments done over 5 years. Of the 306 patients who had an initial MRD assessment during initiation, 50.0% vs 41.1% were MRD-neg in Isa-VRd vs VRd, respectively. MRD-neg deepened over time with an MRD-neg rate of 68.6% and 50.8% for Isa-VRd vs VRd, respectively by month 36. Consistent with the previously published observations of sustMRD-neg for ≥12 months, sustMRD-neg rates at ≥24 and ≥36 months were higher with Isa-VRd than VRd (36.0% vs 13.3% and 25.7% vs 7.2%, respectively); similar observations of sustMRD-neg rates were seen at 10-6 sensitivity threshold. Looking at MRD status during maintenance at month 12, 18, 24 and 36 revealed that a higher proportion of Isa-VRd vs VRd pts converted from MRD positivity during initiation to MRD-neg during maintenance, and this positive-to-negative conversion rate increased over the maintenance period (month 12: 20.8% vs 16.3%; month 18: 22.7% vs 18.8%; month 24: 35.0% vs 18.0%; month 36: 47.2% vs 32.3%, respectively). Correlation of MRD status change and of time to first MRD-neg status with PFS benefit will be presented.

In addition, key subgroup analyses by MRD-neg status at 10-5 and 10-6 demonstrated a benefit and a shorter median time to MRD-neg with Isa-VRd vs VRd. Good concordance was shown between NGS and NGF for MRD-neg (10-5) pts (70.4%) and MRD-neg CR pts (75.9%).

Conclusions:

Isa-VRd followed by Isa-Rd led to greater depth of response of MRD-neg over time, with higher rates of MRD-neg at both the end of initiation and during maintenance compared with the control arm. Results from these analyses continue to demonstrate higher rates of sustMRD-neg over time at 10-5 and 10-6 sensitivity thresholds, and more pts retained MRD-neg status through maintenance phase. More pts had positive-to-negative conversions with Isa-VRd vs VRd, with conversion events increasing over the maintenance period. These data support the benefit of Isa in addition to VRd as initiation therapy, as well as the addition of Isa to Rd during maintenance in transplant-ineligible pts with NDMM.

Clinical trial registration: NCT03319667. Funding: Sanofi.

Disclosures: Orlowski: Bristol Myers Squibb, CARsgen Therapeutics, Exelixis Inc, Heidelberg Pharma, Janssen Biotech Inc, Sanofi, Takeda Pharmaceuticals USA Inc; Laboratory Research Funding: Asylia Therapeutics Inc, BioTheryX Inc, Heidelberg Pharma: Research Funding; AbbVie Inc, Adaptive Biotechnologies Corporation, Asylia Therapeutics Inc, BioTheryX Inc, Bristol Myers Squibb, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Nanjing IASO Biotherapeutics, Neoleukin Therapeutics, Oncopeptides, Pf: Membership on an entity's Board of Directors or advisory committees; DEM BioPharma, Inc., Karyopharm Therapeutics, Lytica Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Myeloma 360, Nanjing IASO Biotherapeutics, Neoleukin Corporation, Oncopeptides AB, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sporos Bio: Membership on an entity's Board of Directors or advisory committees; Asylia Therapeutics Inc.: Current equity holder in private company, Patents & Royalties; BioTheryX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi, Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos: AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees; SANOFI: Honoraria; REGENERON: Honoraria; MENARINI: Honoraria; TAKEDA: Honoraria; GSK: Honoraria; BMS: Honoraria; JANSSEN: Honoraria; BEIGENE: Honoraria; SWIXX: Honoraria; ASTRA ZENECA: Honoraria. Leleu: Kite, A Gilead Company: Consultancy, Honoraria. Hajek: Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; BMS: Consultancy, Honoraria, Research Funding; PharmaMar: Consultancy, Honoraria; Novartis: Consultancy, Research Funding. Špička: Charles University and General University Hospital in Prague, Czech republic: Current Employment; BMS: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Takeda: 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; GSK: Honoraria; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Romejko-Jarosinska: AstraZeneca, Gilead, Roche, Janssen, Celgene, Sanofi, Takeda: Honoraria, Speakers Bureau; Gilead, Roche, Takeda: Other: Support for attending meetings and/or travel; Swixx: Other: Participation on a Data Safety Monitoring Board or advisory board. Besemer: Oncopeptides: Honoraria; GlaxoSmithKline: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AMGEN: Honoraria; Pfizer: Honoraria. Goldschmidt: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; grants and/or provision of Investigational Medicinal Product, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; Karyopharm: Research Funding; Incyte Corporation: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product; support for attending meetings and/or travel, Research Funding; Hoffmann-La Roche: Research Funding; Heidelberg Pharma: Research Funding; GlycoMimetics Inc.: Research Funding; GlaxoSmithKline (GSK): Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product; Celgene: Research Funding; Merck Sharp and Dohme (MSD): Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Molecular Partners: Research Funding; MorphoSys AG: Research Funding; Novartis: Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Pfizer: Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product; support for attending meetings and/or travel, Research Funding; Takeda: Research Funding; Array Biopharma/Pfizer: Other: Grants and/or provision of Investigational Medicinal Product; Bristol Myers Squibb/Celgene: Other: Grants and/or provision of Investigational Medicinal Product; Dietmar Hopp Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Mundipharma GmbH: Other: Grants and/or provision of Investigational Medicinal Product. Martin: BMS: Research Funding; Pfizer: Honoraria; GSK: Honoraria; Roche: Honoraria; Janssen: Research Funding; Sanofi: Research Funding; AMGEN: Research Funding. Mohty: GSK: Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria; Stemline Menarini: Honoraria; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; Takeda: Honoraria; Pfizer: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive: Honoraria; MaaT Pharma: Current equity holder in publicly-traded company. Macé: Sanofi: Current Employment, Current equity holder in publicly-traded company. Kodas: Sanofi: Current Employment. Tekle: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Shafer: Sanofi: Current Employment. Moreau: Celgene, Janssen, Takeda, Amgen, Pfizer, AbbVie, Sanofi: Honoraria; Celgene, Janssen, Takeda, Amgen, Pfizer, AbbVie, Sanofi: Other: Participation on a Data Safety Monitoring Board or advisory board ; Celgene, Janssen, Takeda, Amgen, Pfizer, AbbVie, Sanofi: Consultancy.

*signifies non-member of ASH