-Author name in bold denotes the presenting author
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759 Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (Isa-KRd) in Patients with High-Risk Newly Diagnosed Multiple Myeloma: Planned Interim Analysis of the GMMG-Concept TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Risk-adapted Treatment Strategies in Myeloma and Related Conditions
Hematology Disease Topics & Pathways:
clinical trials, Research, adult, Clinical Research, Plasma Cell Disorders, Combination therapy, Diseases, Therapies, Lymphoid Malignancies, Study Population, Human, Minimal Residual Disease
Monday, December 12, 2022: 11:00 AM

Katja C. Weisel, MD1, Britta Besemer, MD2*, Mathias Haenel, MD3*, Raphael Lutz, MD4*, Christoph Mann, MD5*, Markus Munder, MD6*, Martin Goerner, MD7*, Hans Christian Reinhardt, MD8, Axel Nogai, MD9*, Yon-Dschun Ko, MD10*, Maike De Wit, MD11*, Hans Salwender, M.D.12*, Christoph Scheid, MD13*, Ullrich Graeven, MD14*, Rudolf Peceny, MD15, Peter Staib, MD16*, Annette Dieing, MD17*, Anna Jauch, PhD18*, Manola Zago, PhD19*, Axel Benner, PhD20*, Diana Tichy, PhD21*, Carsten Bokemeyer, MD1*, Hartmut Goldschmidt, MD22 and Lisa B. Leypoldt1*

1Department of Oncology, Hematology, BMT with Section of Pneumology; University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2Department of Hematology, Oncology, and Immunology, University of Tuebingen, Tuebingen, Germany
3Department of Hematology, Oncology and Bone Marrow Transplantation, Klinikum Chemnitz, Chemnitz, Germany
4Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
5Department of Hematology, Oncology, Immunology, University Marburg, Marburg, Germany
6Third Department of Medicine, University Medicine Mainz of Johannes Gutenberg University Mainz, Mainz, Germany
7Department of Hematology, Oncology and Palliative Medicine, Klinikum Bielefeld Mitte, Bielefeld, Germany
8Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
9Division of Hematology and Oncology at Campus Benjamin Franklin (CBF), Charité, Berlin, Germany
10Department of Internal Medicine, Hematology and Oncology, Johanniter Krankenhaus Bonn, Bonn, Germany
11Vivantes Klinikum Neukoelln, Berlin, Germany
12Asklepios Tumorzentrum Hamburg, AK Altona and AK St. Georg, Hamburg, Germany
13Leukapheresis and Stem Cell Transplant Unit, Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany
14Dept. of Hematology/Oncology and Gastroenterology, Kliniken Maria Hilf GmbH, Mönchengladbach, Germany
15Klinikum Osnabruck, Osnabruck, Niedersachsen, Germany
16St. Antonius Hospital Eschweiler, Eschweiler, DEU
17Vivantes Klinikum am Urban, Berlin, Germany
18Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
19Center for Clinical Trials, University Hospital of Tuebingen, Tuebingen, Germany
20Division of Biostatistics, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany
21Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
22Department of Medicine V, University Clinic Heidelberg and the National Center for Tumor Diseases, Heidelberg, Germany

Background: High-risk (HR) multiple myeloma (MM) patients (pts) have a significantly disadvantageous prognosis. Emerging data show that achievement of minimal residual disease (MRD) negativity is associated with better outcome in HR pts. Most recently, several clinical trials demonstrated that addition of monoclonal anti CD38 antibodies (i.e. isatuximab) significantly improve MRD negativity, response rate and survival when added to standard of care regimens. Carfilzomib (K), lenalidomide (R) and dexamethasone (d) is one of the most effective and tolerable regimens in newly diagnosed multiple myeloma (NDMM). The phase II CONCEPT trial (NCT03104842) investigates the quadruplet regimen isatuximab plus KRd (Isa-KRd) in HR NDMM in induction and consolidation including high-dose melphalan (HDM) for pts being transplant-eligible (TE). Here, we report for the first time the planned interim analysis (IA) of the primary endpoint MRD negativity after consolidation for TE-patients and the corresponding final analysis of transplant non-eligible (TNE) pts.

Methods: 153 pts with HR NDMM were included into the open-label, academic, multicentre phase II clinical trial, an extension cohort of TE pts is currently recruiting. According to the trial design, 99 of 127 TE pts in study arm A (TE-ITT) were included in the intention-to-treat population (ITT) of the planned IA (TE-ITT-IA); results of the 26 TNE pts in study arm B (TNE-ITT) are finally reported. HR MM was defined by the presence of del17p or t(4;14) or t(14;16) or > 3 copies 1q21 in combination with ISS 2 or 3 stage disease. Pts could be included after a maximum of 1 cycle of MM treatment. Pts received 6 cycles of Isa-KRd induction, followed by HDM for TE pts or 2 Isa-KRd cycles for TNE pts, 4 cycles Isa-KRd consolidation and Isa-KR maintenance. Primary endpoint is MRD negativity at end of consolidation measured by next-generation flow at the minimum sensitivity threshold of 10-5 (H0: MRD-neg-rate ≤ 50% (TE) and ≤ 30% (TNE), tested by one-sided binomial test), this planned IA reports on. Secondary endpoint is progression-free survival (PFS), tertiary endpoints include overall response rate (ORR) and safety.

Results: 125 pts (99 TE-ITT-IA, 26 TNE-ITT) were included from August 2017 to April 2020 in the IA population in 17 German Centres. No bias arose in the reduction of the TE-ITT population to the TE-ITT-IA population. Based on inclusion criteria, all pts had cytogenetic HR disease including del17p in 55 pts (44.0%), t(4;14) in 48 (38.4%), t(14;16) in 19 (15.2%) and > 3 copies 1q21 in 45 pts (36.0%). 38 pts (30.4%) had ≥ 2 HR aberrations. 66 pts (52.8%) had ISS 2 and 58 (46.4%) ISS 3 disease. Median age (range) was 58 (35-73) years in the TE-ITT-IA and 74 (64-87) years in the TNE-ITT. The design of the study provides for the MRD-analysis to be performed on 93 patients in the TE-ITT-IA and 24 patients in the TNE-IA. At the end of consolidation, in the TE-ITT-IA population 67.7% (n=63) of pts were MRD negative, 3.2% (n=3) MRD positive, 24.7% (n=23) timepoint not reached, 4.3% (n=4) missing (4 pts not assessable, 2 did not start). In the TNE-ITT population 54.2% (n=13) of pts were MRD negative, 0% MRD positive, 45.8% (n=11) timepoint not reached. The primary endpoint was significantly reached in both study arms (p = 0.0004 for TE-ITT-IA and p=0.012 for TNE-ITT). ORR (best response to treatment) in the TE-ITT-IA was 94.9% (n=94) with 72.7% showing complete remission (CR) or better (n=72), 18.2% (n=18) very good partial remission (VGPR), 4% (n=4) partial remission (PR), 1% (n=1) progressive disease (PD) and 4% (n=4) timepoint not reached. In the TNE-ITT, 57.7% (n=15) showed CR or better 30.8% (n=8) VGPR, 3.8% (n=1) were unknown and 7.7% (n=2) timepoint not reached. Updated PFS data will be shown. Safety-population consists of 122 pts. In total, 85.2% (n=104) developed ≥ grade 3 treatment-emergent adverse events (TEAEs). Serious TEAEs occurred in 64.8% (n=79) of pts. TEAEs leading to discontinuation of study treatment occurred in 5 pts.

Conclusions: The CONCEPT trial is the first trial investigating Isa-KRd for HR NDMM in TE and TNE patients. Isa-KRd in induction and consolidation leads to high MRD negativity rates after consolidation in this difficult-to-treat population. Toxicity was consistent with expectations and no new safety signals occurred in this IA. In our view, our data underline the importance of optimized quadruplet treatment in NDMM, especially in HR disease.

Disclosures: Weisel: GSK: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria; Karyopharm: Consultancy, Honoraria; Stemline: Honoraria; Pfizer: Honoraria; AstraZeneca: Honoraria; BeiGene: Consultancy, Honoraria. Besemer: Sanofi: Honoraria; Janssen: Honoraria; GSK: Honoraria; Amgen: Honoraria. Haenel: GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Honoraria; JAZZ: Consultancy, Honoraria. Mann: BMS: Honoraria; Celgene: Honoraria; Sanofi: Honoraria. Munder: Janssen: Honoraria; Amgen: Honoraria; Incyte: Research Funding; BMS: Honoraria; GSK: Honoraria; Takeda: Honoraria. Reinhardt: Gilead: Research Funding; Merck: Honoraria; Abbvie: Honoraria; CDL Therapeutics GmbH: Other. Nogai: Takeda: Honoraria, Other: non-financial support; Amgen: Other: non-financial support; Alexion: Honoraria; Janssen: Honoraria, Other: non-financial support; BMS: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Roche: Honoraria; Celgene: Honoraria. De Wit: Janssen: Honoraria. Salwender: Sanofi: Honoraria; Takeda: Honoraria; Oncopeptides: Honoraria; GSK: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; BMS: Honoraria. Scheid: Sanofi: Honoraria. Graeven: Amgen: Honoraria; Boehringer Ingelheim: Honoraria; Daichi Sankyo: Honoraria; Servier: Honoraria; Celgene/BMS: Honoraria; AstraZeneca: Honoraria; Johnson&Johnson: Honoraria; Merck: Other: non-financial support; MSD: Honoraria; BMS: Honoraria. Peceny: Sanofi Genzyme: Honoraria, Research Funding; Novartis: Research Funding; DRK Blutspendedienst NSTOB: Research Funding; Boehringer Ingelheim Pharma GmbH & Co KG: Research Funding; Celgene/BMS: Research Funding. Staib: Abbvie: Honoraria, Other: non-financial support, Research Funding; Amgen: Honoraria, Other: non-financial support , Research Funding; Celgene/BMS: Honoraria, Other: non-financial support , Research Funding; Janssen-Cilag: Honoraria, Other: non-financial support , Research Funding; Novartis: Honoraria, Other: non-financial support , Research Funding; Gilead: Honoraria, Other: non-financial support , Research Funding; Pfizer: Honoraria, Other: non-financial support , Research Funding; Roche: Honoraria, Other, Research Funding. Bokemeyer: Bayer: Honoraria; Berlin Chemie: Honoraria; Janssen: Honoraria; GSO Research: Honoraria; Astra Zeneca: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Merck Serono: Honoraria; BMS: Honoraria; med update: Honoraria; AOK Germany: Honoraria; Merck Sharp Dohme: Honoraria; Novartis: Honoraria. Goldschmidt: Merck Sharp and Dohme (MSD): Research Funding; Mundipharma GmbH: Research Funding; Takeda: Research Funding; Novartis: Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Incyte: Research Funding; Molecular Partners: Research Funding; SANOFI: Consultancy, Honoraria, Other: Grants, Research Funding; Chugai: Honoraria, Other: grants, Research Funding; Janssen: Consultancy, Honoraria, Other: Grants, Research Funding; Amgen, BMS, Celgene, Chugai, Dietmar-Hopp-Foundation, Janssen, Johns Hopkins University, Sanofi: Other: Grants and/or provision of Investigational Medicinal Product; GlaxoSmithKline (GSK): Honoraria; Celgene: Consultancy, Honoraria, Other: Grants, Research Funding; Amgen, BMS, Celgene, Chugai, Janssen, Incyte, Molecular Partners, Merck Sharp and Dohme, Sanofi, Mundipharma GmbH, Takeda, Novartis: Research Funding; Amgen, BMS, Janssen, Sanofi, Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Other: Grants, Research Funding; AMGEN: Consultancy, Honoraria, Other: Grants, Research Funding; Amgen, BMS, Chugai, GlaxoSmithKline, Janssen, Novartis, Sanofi, Pfizer: Honoraria; Amgen, BMS, GlaxoSmithKline, Janssen, Novartis, Sanofi, Pfizer: Other: Support for attending meetings and/or travel; Array Biopharma: Research Funding; Dietmar-Hopp-Foundation: Research Funding. Leypoldt: Celgene/BMS: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Janssen-Cilag: Honoraria; Abbvie: Honoraria, Research Funding.

OffLabel Disclosure: Combination treatment of Isatuximab, Carfilzomib, Lenalidomide and dexamethasone is being investigated in this clinical study for treatment of newly diagnosed high risk multiple myeloma. This treatment combination is not approved in this indication.

*signifies non-member of ASH