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551 The Phase 3 TOURMALINE-MM2 Trial: Oral Ixazomib, Lenalidomide, and Dexamethasone (IRd) Vs Placebo-Rd for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma/Amyloidosis: Therapy, excluding Transplantation: Initial Therapy
Hematology Disease Topics & Pathways:
multiple myeloma, Diseases, Elderly, Technology and Procedures, Plasma Cell Disorders, cytogenetics, Lymphoid Malignancies, Study Population
Monday, December 7, 2020: 7:45 AM

Thierry Facon, MD1*, Christopher P. Venner2*, Nizar Bahlis, MD3, Fritz Offner, MD, PhD4, Darrell J White, MD5, Lotfi Benboubker, MD6*, Sophie Rigaudeau, MD7*, Philippe Rodon, MD8, Sung-Soo Yoon, MD, PhD9, Kenshi Suzuki, MD, PhD10, Hirohiko Shibayama, MD, PhD11, Xiaoquan Zhang, MD12*, Godwin Yung12*, Robert M. Rifkin, MD13, Philippe Moreau14*, Sagar Lonial, MD15, Shaji K. Kumar, MD16, Paul G. Richardson, MD17 and S. Vincent Rajkumar, MD18

1Centre Hospitalier Universitaire (CHU) Lille, Service des Maladies du Sang, University of Lille, Lille, France
2Division of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
3Division of Hematology and Oncology, Charbonneau Cancer Research Institute, University of Calgary, Calgary, AB, Canada
4Hematology, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium
5QEII Health Sciences Center and Dalhousie University, Halifax, NS, Canada
6Service d'Hématologie et Thérapie Cellulaire, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire (CHRU), Tours, France
7Department of Clinical Hematology, Centre Hospitalier Versailles, Le Chesnay, France
8Unite d'Hematologie et d'Oncologie, Centre Hospitalier Périgueux, Périgueux, France
9Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of (South)
10Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
11Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
12Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA
13Rocky Mountain Cancer Center, Denver, CO
14Department of Hematology, University Hospital of Nantes, Nantes, France
15Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
16Division of Hematology, Mayo Clinic, Rochester, MN
17Dana-Farber Cancer Institute, Boston, MA
18Mayo Clinic Rochester, Division of Hematology, Rochester, MN

Background

Continuous Rd-based regimens are among the standards of care in transplant-ineligible NDMM patients. These patients are diverse, ranging from fit 70-plus-year-olds to elderly and/or frail patients with poor performance status, requiring treatment to be adapted to individual patient settings. The use of proteasome inhibitors (PIs) in a continuous fashion or to higher cumulative doses leads to improved long-term outcomes; however, long-term administration of injectable PIs may present challenges associated with treatment burden and tolerability. An all-oral PI-Rd triplet may be useful for patients who do not want to or cannot travel to the clinic frequently. The oral PI ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. The multicenter, double-blind, placebo-controlled TOURMALINE-MM2 trial compared IRd vs placebo-Rd in transplant-ineligible NDMM patients.

Methods

Transplant-ineligible NDMM adult patients were randomized (1:1) to ixazomib 4 mg (n=351) or matching placebo (n=354) on days 1, 8, and 15 of 28-day cycles, plus lenalidomide 25 mg on days 1–21 (10 mg for patients with renal impairment), and dexamethasone 40 mg on days 1, 8, 15, and 22 (20 mg for patients aged >75 years). After 18 cycles, dexamethasone was discontinued and treatment continued using ixazomib 3 mg and lenalidomide 10 mg until progression or toxicity. Randomization was stratified by age (<75 vs ≥75 years), International Staging System (ISS) stage (I or II vs III), and Brief Pain Inventory-Short Form (BPI-SF) worst pain score (<4 vs ≥4) at screening. The primary endpoint was progression-free survival (PFS) assessed by an Independent Review Committee (IRC); key secondary endpoints included overall survival (OS), complete response (CR) rate, and pain response rate. Other secondary endpoints included overall response rate (ORR), time to response (TTR), time to progression (TTP), and safety. Sample size was determined to provide 80% power for OS and 92% power for PFS. PFS was tested in the intent-to-treat (ITT) population (alpha=0.04) and 3 prespecified subgroups in parallel (total alpha=0.01), including patients with expanded high-risk cytogenetics [t(4;14), t(14;16), del(17p), amp(1q21)], patients aged <75 years, and patients with a creatinine clearance (CrCl) >60 mL/min. We report data from the final analysis for PFS.

Results

At data cutoff (Dec 2, 2019), in the IRd vs placebo-Rd arms, median age was 73 vs 74 years (43% vs 44% ≥75 years), 16% vs 17% had ISS stage III MM, and 54% of patients in each arm had a BPI-SF worst pain score of ≥4. At a median follow-up of 53.3 vs 55.8 months, there was an obvious positive trend in PFS favoring IRd; with 169 vs 209 patients having progressed or died in the IRd vs placebo-Rd arms, median PFS was 35.3 vs 21.8 months (hazard ratio [HR] 0.830; p=0.073; Figure). Median PFS in the 3 prespecified subgroups of patients with expanded high-risk cytogenetics, patients aged <75 years, and patients with CrCl >60 mL/min are shown in the Table. ORRs were similar between arms, but depth of response was greater with IRd vs placebo-Rd (Table). Median TTR and TTP for IRd and placebo-Rd are shown in the Table. Median OS was not reached in either arm (HR 0.998) after a median follow-up of ~58 months and with 136 and 148 patients having died in the IRd and placebo-Rd arms, respectively. Treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With IRd vs placebo-Rd, 88% vs 81% of patients had grade ≥3 TEAEs; the most common grade ≥3 events (≥5% difference) included neutropenia (17% vs 27%), rash (17% vs 7%), thrombocytopenia (13% vs 5%), and diarrhea (10% vs 2%); 66% vs 62% had serious TEAEs, 35% vs 27% had TEAEs resulting in discontinuation of the full regimen, and 8% vs 6% of patients died on study.

Conclusions

Addition of ixazomib to Rd led to a clinically meaningful, obvious positive trend in PFS, with a 13.5-month improvement in the median in transplant-ineligible NDMM patients. Improvements in TTP and CR rate were also observed. In line with TOURMALINE-MM1 (Avet-Loiseau Blood 2017), IRd improved the poor PFS associated with expanded high-risk cytogenetics vs placebo-Rd. Safety findings were generally consistent with the well-characterized, tolerable, and manageable toxicity profile of ixazomib/IRd. IRd is a feasible treatment option for certain patients who could benefit from an all-oral triplet combination.

Disclosures: Facon: Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Venner: Takeda, Amgen, Celgene, Johnson & Johnson and Sanofi, GSK, Janssen: Honoraria. Bahlis: Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; GSK: Consultancy, Honoraria. White: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria. Rigaudeau: Takeda, Celgene: Honoraria, Other: Data monitoring board member for Takeda. Yoon: F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; YuhanPharma: Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy; Amgen: Consultancy, Honoraria; Kyowahako Kirin: Research Funding. Suzuki: Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Shibayama: Otsuka: Honoraria; Fujimoto: Honoraria; Pfizer: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria, Research Funding; Merck Sharp & Dohme: Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Research Funding; Shionogi: Research Funding; Teijin: Research Funding; Astellas: Research Funding; Bristol-Myers Squibb: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Mundi Pharma: Honoraria; Kyowa Kirin: Honoraria. Zhang: Takeda: Current Employment. Yung: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Ended employment in the past 24 months. Rifkin: McKesson: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other: Stock ownership; Takeda, Amgen, Celgene, BMS, Mylan, Coherus BioSciences, Fresenius: Consultancy; Takeda, Amgen, BMS (Celgene): Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Investigator in AbbVie sponsored clinical trials. Moreau: Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Honoraria; Takeda: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Lonial: Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria; Onyx: Honoraria; JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy. Kumar: Genecentrix: Consultancy; Cellectar: Other; Carsgen: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; MedImmune: Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Karyopharm: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding. Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib in newly diagnosed multiple myeloma patients who are ineligible for transplant

*signifies non-member of ASH