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Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial

MA. Dimopoulos, I. Špička, H. Quach, A. Oriol, R. Hájek, M. Garg, M. Beksac, S. Bringhen, E. Katodritou, WJ. Chng, X. Leleu, S. Iida, MV. Mateos, G. Morgan, A. Vorog, R. Labotka, B. Wang, A. Palumbo, S. Lonial, TOURMALINE-MM4 study group

. 2020 ; 38 (34) : 4030-4041. [pub] 20201006

Language English Country United States

Document type Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21019739

PURPOSE: Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation (ASCT) but has generally been limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed. PATIENTS AND METHODS: The phase III, double-blind, placebo-controlled TOURMALINE-MM4 study randomly assigned (3:2) patients with NDMM not undergoing ASCT who achieved better than or equal to partial response after 6-12 months of standard induction therapy to receive the oral proteasome inhibitor (PI) ixazomib or placebo on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. The primary endpoint was PFS since time of randomization. RESULTS: Patients were randomly assigned to receive ixazomib (n = 425) or placebo (n = 281). TOURMALINE-MM4 met its primary endpoint with a 34.1% reduction in risk of progression or death with ixazomib versus placebo (median PFS since randomization, 17.4 v 9.4 months; hazard ratio [HR], 0.659; 95% CI, 0.542 to 0.801; P < .001; median follow-up, 21.1 months). Ixazomib significantly benefitted patients who achieved complete or very good partial response postinduction (median PFS, 25.6 v 12.9 months; HR, 0.586; P < .001). With ixazomib versus placebo, 36.6% versus 23.2% of patients had grade ≥ 3 treatment-emergent adverse events (TEAEs); 12.9% versus 8.0% discontinued treatment because of TEAEs. Common any-grade TEAEs included nausea (26.8% v 8.0%), vomiting (24.2% v 4.3%), and diarrhea (23.2% v 12.3%). There was no increase in new primary malignancies (5.2% v 6.2%); rates of on-study deaths were 2.6% versus 2.2%. CONCLUSION: Ixazomib maintenance prolongs PFS with no unexpected toxicity in patients with NDMM not undergoing ASCT. To our knowledge, this is the first PI demonstrated in a randomized clinical trial to have single-agent efficacy for maintenance and is the first oral PI option in this patient population.

1st Department of Medicine Department of Hematology 1st Faculty of Medicine Charles University and General Hospital Prague Prague Czech Republic

Department of Hemato oncology University Hospital Ostrava University of Ostrava and Faculty of Medicine Ostrava Czech Republic

Department of Hematology and Medical Oncology Winship Cancer Institute of Emory University Atlanta GA

Department of Hematology and Oncology Nagoya City University Graduate School of Medical Sciences Nagoya Japan

Department of Hematology Ankara University Ankara Turkey

Department of Hematology Oncology National University Cancer Institute National University Health System and Yong Loo Lin School of Medicine and Cancer Science Institute of Singapore National University of Singapore Singapore

Department of Hematology Theagenion Cancer Hospital Thessaloniki Greece

Department of Hematology University of Melbourne St Vincent's Hospital Melbourne Victoria Australia

Division of Hematology University of Torino Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino Torino Italy

Hematology and Medical Oncology Department of Clinical Therapeutics National and Kapodistrian University of Athens School of Medicine Athens Greece

Hematology Hospital Universitario de Salamanca University Hospital of Salamanca Centro de Investigación del Cáncer Instituto de Biología Molecular y Celular del Cáncer Salamanca Spain

Hematology Leicester Royal Infirmary University Hospitals of Leicester NHS Trust Leicester United Kingdom

Institut d'Investigació contra la Leucèmia Josep Carreras and Institut Català d'Oncologia Hospital Germans Trias i Pujol Badalona Spain

Millennium Pharmaceuticals Inc a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Cambridge MA

Perlmutter Cancer Center NYU Langone Health New York NY

Pôle Régional de Cancérologie Department of Haematology Centre Hospitalier Universitaire La Milétrie Poitiers Poitiers France

References provided by Crossref.org

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$a PURPOSE: Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation (ASCT) but has generally been limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed. PATIENTS AND METHODS: The phase III, double-blind, placebo-controlled TOURMALINE-MM4 study randomly assigned (3:2) patients with NDMM not undergoing ASCT who achieved better than or equal to partial response after 6-12 months of standard induction therapy to receive the oral proteasome inhibitor (PI) ixazomib or placebo on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. The primary endpoint was PFS since time of randomization. RESULTS: Patients were randomly assigned to receive ixazomib (n = 425) or placebo (n = 281). TOURMALINE-MM4 met its primary endpoint with a 34.1% reduction in risk of progression or death with ixazomib versus placebo (median PFS since randomization, 17.4 v 9.4 months; hazard ratio [HR], 0.659; 95% CI, 0.542 to 0.801; P < .001; median follow-up, 21.1 months). Ixazomib significantly benefitted patients who achieved complete or very good partial response postinduction (median PFS, 25.6 v 12.9 months; HR, 0.586; P < .001). With ixazomib versus placebo, 36.6% versus 23.2% of patients had grade ≥ 3 treatment-emergent adverse events (TEAEs); 12.9% versus 8.0% discontinued treatment because of TEAEs. Common any-grade TEAEs included nausea (26.8% v 8.0%), vomiting (24.2% v 4.3%), and diarrhea (23.2% v 12.3%). There was no increase in new primary malignancies (5.2% v 6.2%); rates of on-study deaths were 2.6% versus 2.2%. CONCLUSION: Ixazomib maintenance prolongs PFS with no unexpected toxicity in patients with NDMM not undergoing ASCT. To our knowledge, this is the first PI demonstrated in a randomized clinical trial to have single-agent efficacy for maintenance and is the first oral PI option in this patient population.
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