Isatuximab, Lenalidomide, Bortezomib and Dexamethasone Induction Therapy for Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma: Final Progression-Free Survival Analysis of Part 1 of an Open-Label, Multicenter, Randomized, Phase 3 Trial (GMMG-HD7)
Blood, vol. 144, pp. 769
Abstract
Background: In patients (pts) with newly diagnosed multiple myeloma (NDMM), anti-CD38 monoclonal antibodies (CD38-mAb) increase efficacy of standard-of-care regimens. Addition of the CD38-mAb isatuximab (Isa) to lenalidomide, bortezomib, and dexamethasone (RVd) in pts with transplant-eligible NDMM met the primary endpoint of minimal residual disease (MRD) negativity in the bone marrow after induction therapy (Isa-RVd 50% vs. RVd 36%, OR 1.82, 95% CI 1.33-2.48, p<0.001; Goldschmidt H et al., 2022, Lancet Haematol.; NCT03617731). The present analysis compared the effect of induction therapy with Isa-RVd vs. RVd on secondary endpoint of progression-free survival (PFS). Methods: Pts with transplant-eligible NDMM at 67 sites in Germany were stratified by Revised International Staging System (R-ISS; Palumbo A et al., 2015, J Clin Oncol) and equally randomized to receive three 42-day cycles of RVd (lenalidomide 25 mg/d po, d1-14 and d22-35; bortezomib 1.3 mg/m2 SC d1, 4, 8, 11, 22, 25, 29, 32; dexamethasone 20 mg/d po, d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33). In the Isa-RVd arm, Isa was added as follows: 10 mg/kg IV, cycle 1: d 1, 8, 15, 22, 29; cycles 2-3: d 1, 15, 29. Following induction therapy, pts underwent cyclophosphamide-based stem cell collection and subsequently proceeded to high-dose melphalan (200 mg/m2) and autologous hematopoietic stem cell transplant (ASCT). Second ASCT was recommended if pts achieved less than complete response (CR) after first ASCT or in case of high-risk cytogenetics. Pts were then randomized to receive maintenance with either lenalidomide alone (10 mg/d po continuously) or in combination with Isa (10 mg/kg IV, cycle 1: d 1, 8, 15, 22; cycles 2-3: d 1, 15; cycles 4-39: d 1) for up to 36 months. Cytogenetic risk status was defined as presence (high-risk) or absence (standard risk) of deletion17p, t(4;14), and/or t(14;16). PFS was defined as time from first randomization to progression or death from any cause, whichever occurred first. Weighted risk set estimator analyses accounting for second randomization (maintenance therapy) were applied to analyze PFS comparing Isa-RVd with RVd induction followed by lenalidomide maintenance. Data cut-off for the present analysis was January 31, 2024. Results: Between Oct 2018 and Sep 2020, 662 pts were included in the trial. The intention-to-treat analysis comprised 660 pts (Isa-RVd: 331 and RVd: 329). Baseline characteristics were well balanced. 225 (68%)/79 (24%) pts in the Isa-RVd arm and 179 (54%)/99 (30%) pts in the RVd arm received a single or tandem ASCT, respectively. After a median follow up of 47 months (95% CI 46-48), 179 PFS events occurred. Isa-RVd induction therapy significantly prolonged PFS compared with RVd (HR 0.70, 95% CI 0.52-0.94; stratified log-rank p=0.0184). 3-year PFS rates in the Isa-RVd and RVd arms were 83% (95% CI 79-87) and 75% (95% CI 70-80). The PFS benefit for Isa-RVd vs. RVd arm was confirmed on multivariable analysis, including R-ISS, age, sex, performance status, and renal insufficiency (HR 0.64, 95% CI 0.47-0.86; p=0.004). Subgroup analyses found a consistent PFS benefit for Isa-RVd vs. RVd induction among clinically relevant baseline subgroups (female and male sex, good performance status, ISS stages I, II, and III, normal and elevated LDH, standard risk cytogenetics). Patients with poor performance status (WHO grade >1, HR 1.09, 95% CI 0.47-2.52), and high-risk cytogenetics (HR 1.09, 95% CI 0.63-1.91) did not see benefit at this point. Weighted risk set estimator PFS analyses accounting for second randomization confirmed a significant benefit for Isa-RVd vs. RVd induction followed by lenalidomide maintenance (HR 0.63, 95% CI 0.38-1.07; stratified weighted log-rank p=0.016). Estimated, weighted 3-year PFS rates for Isa-RVd and RVd followed by lenalidomide maintenance were 84% (95% CI 79-89) and 73% (95% CI 67-79). OS was not mature with median OS not reached in either arm, and 3-year OS rates of 88% (95% CI 85-92) and 89% (95% CI 86-93) in the Isa-RVd vs. RVd arm. Conclusions: Addition of Isa to RVd during 18 weeks of induction therapy, followed by ASCT, resulted in a significant and clinically meaningful PFS benefit, regardless of the maintenance therapy strategy. The present analysis of the GMMG-HD7 trial supports the MRD negativity benefit reported previously. The trial is ongoing and will evaluate the addition of Isa to lenalidomide during maintenance after a re-randomization (part 2).
Authors 32
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Heidelberg University · University Hospital Heidelberg · National Center for Tumor Diseases
Affiliation as printed
1Internal Medicine V, GMMG - Study Group at University Hospital Heidelberg, Heidelberg, Germany
2National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany
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Heidelberg University · University Hospital Heidelberg · National Center for Tumor Diseases
Affiliation as printed
3National Center for Tumor Diseases Heidelberg, Heidelberg, Germany
4Internal Medicine V, Hematology, Oncology and Rheumatology, GMMG Studygroup, Heidelberg University Hospital, Heidelberg, Germany
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Affiliation as printed
5German Cancer Research Center, Heidelberg, DEU
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Affiliation as printed
6Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Düsseldorf University Hospital · Heinrich Heine University Düsseldorf
Affiliation as printed
7Department of Haematology, Oncology, and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany
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University of Tübingen · Universitätsklinikum Tübingen
Affiliation as printed
8Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany
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Essen University Hospital · University of Duisburg-Essen
Affiliation as printed
9Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer consortium (DKTK partner site Essen), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Universitätsklinikum Knappschaftskrankenhaus Bochum
Affiliation as printed
10Knappschaftskrankenhaus Bochum, University Hospital Bochum, Bochum, Germany
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University Hospital Frankfurt · Goethe University Frankfurt
Affiliation as printed
11Department of Medicine II - Hematology and Oncology, Goethe-University Frankfurt, University Hospital, Frankfurt am Main, Germany
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Affiliation as printed
12Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany
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Philipps University of Marburg
Affiliation as printed
13Department of Haematology, Oncology and Immunology, Philipps-University Marburg, Marburg, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
14University Medical Center Hamburg Eppendorf, Hamburg, Germany
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Krankenhaus Barmherzige Brüder
Affiliation as printed
15Clinic for Oncology and Hematology, Hospital Barmherzige Brueder Regensburg, Regensburg, Germany, Regensburg, DEU
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Heidelberg University · University Hospital Heidelberg
Affiliation as printed
16Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany
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Heidelberg University · University Hospital Heidelberg
Affiliation as printed
18Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
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Affiliation as printed
19Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany
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Charité - Universitätsmedizin Berlin
Affiliation as printed
20Medical Clinic, Charité University Medicine Berlin, Berlin, Germany
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Affiliation as printed
21Coordination Centre for Clinical Trials (KKS), Heidelberg, Germany
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Affiliation as printed
22Department of Hematology, Oncology, Stem Cell Transplantation, Immune and Cell Therapy, Clinical Immunology and Rheumatology, University Hospital Bonn, Bonn, Germany
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University Hospital Carl Gustav Carus
Affiliation as printed
23University Hospital Carl Gustav Carus, Dresden, Germany
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Affiliation as printed
24Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, DEU
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Affiliation as printed
25Clinic for Hematology, Oncology and Palliative Care, Marien Hospital Düsseldorf, Düsseldorf, Germany, Duesseldorf, DEU
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University of Münster · University Hospital Münster
Affiliation as printed
27Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
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Affiliation as printed
28Center for Hematology and Oncology, Bethanien, Frankfurt a.M., Germany, Frankfurt a.M., Germany
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University Medical Center of the Johannes Gutenberg University Mainz
Affiliation as printed
29Department of Internal Medicine III, University Hospital Mainz, Mainz, Germany
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Affiliation as printed
30Medizinische Klinik Schwäbisch-Hall, Schwabisch Hall, DEU
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Affiliation as printed
31Hematology / Oncology Center, Bielefeld, Germany, Bielefeld, Germany
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Affiliation as printed
32Hematology / Oncology Center, Koblenz, Germany, Koblenz, Germany
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Heidelberg University · University Hospital Heidelberg
Affiliation as printed
33Department of Medicine V, Heidelberg Myeloma Center, University Hospital Heidelberg, Heidelberg, Germany
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Affiliation as printed
34Medical Clinic A, Clinic Ludwigshafen, Ludwigshafen, Germany, Ludwigshafen, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
35Department of Oncology, Hematology and BMT, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany
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Asklepios · Asklepios Klinik Altona
Affiliation as printed
36Asklepios Tumorzentrum Hamburg, Asklepios Hospital Hamburg Altona and St. Georg, Hamburg, Germany
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