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301 Maintenance Therapy with the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 Tourmaline-MM3 Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Novel Targeted Combinations in Myeloma
Hematology Disease Topics & Pathways:
Adult, Diseases, Study Population, Clinically relevant, Myeloid Malignancies
Sunday, December 2, 2018: 7:30 AM
Grand Ballroom 7 (Marriott Marquis San Diego Marina)

Meletios A Dimopoulos, MD1, Francesca Gay, MD, PhD2, Fredrik H. Schjesvold, MD PhD3, Meral Beksac, MD4*, Roman Hajek5, Katja Weisel, MD6*, Hartmut Goldschmidt, MD7, Vladimir Maisnar, MD8*, Philippe Moreau9*, Chang-Ki Min, MD10*, Agnieszka Pluta, MD11*, Wee Joo Chng, MB ChB, PhD, FRCP(UK), FRCPath, FAMS12, Martin Kaiser, MD13, Sonja Zweegman, MD, PhD14, Maria-Victoria Mateos, MD, PhD15, Andrew Spencer, MBBS, FRACP, FRCPA, DM16, Shinsuke Iida, MD, PhD17, Gareth Morgan, MD18, Zhaoyang Teng, PhD19*, Kaveri Suryanarayan19*, Tomas Skacel, MD, PhD19*, Ajeeta B Dash, PhD19*, Richard Labotka, MD19* and S. Vincent Rajkumar, MD20

1Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
2Department of Oncology and Hematology, Azienda Ospedaliero City of Health and Science of Turin, Turin, Italy
3Oslo Myeloma Center, Oslo University Hospital, Oslo, Norway
4Department of Hematology, Ankara University, Ankara, Turkey
5Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
6Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany
7Department of Internal Medicine V, University Hospital Heidelberg and National Center of Tumor Diseases, Heidelberg, Germany
8Fourth Department of Medicine - Hematology, FN and LF UK Hradec Králové, Hradec Králové, Czech Republic
9University Hospital Hôtel-Dieu, Nantes, France
10Department of Internal Medicine, Seoul St. Mary’s Hospital, Seoul, Korea, Republic of (South)
11Department of Hematology, Medical University of Lodz, Multidisciplinary Provincial Centre of Traumatology and Oncology Nicolas Copernicus in Lodz, Lodz, Poland
12Department of Haematology-Oncology, National University Cancer Institute, National University Health System, and Cancer Science Institute of Singapore, Singapore, Singapore
13Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
14Department of Hematology, Cancer Cancer Amsterdam, VUMC, Amsterdam, Netherlands
15Hematology, Hospital Universitario de Salamanca, CIC, IBMCC (USAL-CSIC), Salamanca, Spain
16Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, Canada
17Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
18University of Arkansas for Medical Sciences, Little Rock, AR
19Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA
20Division of Hematology, Mayo Clinic, Rochester, MN

Introduction

Maintenance therapy has been extensively explored as a strategy for prolonging the duration of disease control and potentially survival following ASCT. To date, only lenalidomide has been approved for this indication. However, lenalidomide maintenance is associated with the development of second primary malignancies and tolerability issues. PIs are a backbone of MM treatment, and bortezomib-based maintenance has shown promising activity post-ASCT, yet the benefit of PI-based maintenance has not been demonstrated in a phase 3 trial vs placebo. Moreover, the feasibility of bortezomib maintenance in routine clinical practice is limited due to tolerability and the need for regular parenteral administration. There is a need for an oral PI maintenance therapy that can be administered for a prolonged period, improve depth of response without cumulative or late-onset toxicity, and improve convenience for patients.

Methods

The phase 3, double-blind, placebo-controlled, multicenter TOURMALINE-MM3 study (NCT02181413) compared weekly ixazomib vs placebo maintenance in NDMM patients who had at least a partial response (≥PR) to induction therapy with a PI and/or immunomodulatory drug (IMiD) followed by single ASCT. Patients were randomized (3:2) to receive ixazomib or matched placebo on days 1, 8, and 15 of 28-day cycles for up to 2 years or until progressive disease (PD) or unacceptable toxicity. Randomization was stratified by induction regimen (PI without IMiD vs IMiD without PI vs PI+IMiD), pre-induction ISS stage (I vs II or III), and post-ASCT response (complete response [CR] or very good partial response [VGPR] vs PR). Patients were ineligible if they had received post-ASCT consolidation or tandem ASCT. The ixazomib dose was 3.0 mg during cycles 1–4, increasing to 4 mg from cycle 5 if tolerated during cycles 1–4. The primary endpoint was PFS per independent review committee (IRC), who were blinded to treatment assignment. The key secondary endpoint was OS. Here, we report data from the final analysis for PFS (data cut-off: April 16, 2018).

Results

656 patients were randomized (395 ixazomib; 261 placebo). Patient demographics were balanced between groups; overall median age was 57 years (range, 24–73), 37% vs 63% had ISS I vs II or III, 59%/11%/30% had received PI without IMiD / IMiD without PI / PI+IMiD induction therapy, 34%/45%/21% had achieved CR / VGPR / PR following induction/ASCT, and 18% had high-risk cytogenetics [del(17p), t(4;14), or t(14;16)]. After a median follow-up of 31 months with 54% of PFS events, there was a 28% reduction in the risk of progression/death, corresponding to a 39% improvement in PFS with ixazomib vs placebo (median 26.5 vs 21.3 months; hazard ratio [HR] 0.72; 95% CI: 0.582, 0.890; p=0.002; Figure). In a landmark analysis from ASCT, PFS was 30.7 vs 24.9 months (HR 0.684; 95% CI: 0.551, 0.848; p<0.001). Median PFS2 and OS have not yet been reached in either arm. Ixazomib maintenance led to higher rates of deepened response compared with placebo (relative risk 1.41; 95% CI: 1.10, 1.80; p=0.004). Conversion from documented MRD positivity at study entry to MRD negativity occurred at a higher rate with ixazomib compared with placebo (12% vs 7%). PFS benefit was seen broadly across subgroups, including ISS III (HR 0.661), PI-exposed (HR 0.750), PI-naïve (HR 0.497), and patients with high-risk cytogenetics (HR 0.625). Discontinuation due to AEs was low (7% ixazomib vs 5% placebo). With ixazomib vs placebo, 42% vs 26% of patients had grade ≥3 AEs; 27% vs 20% had serious AEs; and 1 patient vs 0 died on treatment. Common grade ≥3 AEs were infections (15% vs 8%) including pneumonia (6% vs 4%), gastrointestinal disorders (6% vs 1%), neutropenia (5% vs 3%), and thrombocytopenia (5% vs <1%). Peripheral neuropathy rates were 19% vs 15% (<1% vs 0 grade 3). Rate of second primary malignancies was 3% in both arms. Global Quality of Life scores (EORTC QLQ-C30) on ixazomib were similar to placebo.

Conclusions

This study demonstrated a 28% reduction in the risk of progression/death, corresponding to a 39% improvement in PFS with ixazomib maintenance, with deepening of responses and increased conversions to MRD negativity over control, as well as a favorable safety profile, including an absence of risk of second primary malignancies and low rates of peripheral neuropathy, supporting ixazomib as a valuable option for maintenance therapy in responding patients post-ASCT.

Disclosures: Dimopoulos: Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Gay: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Takeda Celgene, Amgen, BMS, and Roche: Other: Advisor; Janssen, Amgen, Takeda, Celgene, BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Schjesvold: Oncopeptides: Consultancy; Abbvie: Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Beksac: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hajek: Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Weisel: Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Takeda: Consultancy, Honoraria; Angeb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Bristol Myers SquibbMS: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Goldschmidt: Adaptive Biotechnology: Consultancy, Membership on an entity's Board of Directors or advisory committees; ArtTempi: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Research Funding; Chugai: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Maisnar: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Moreau: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chng: Merck: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Aslan: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding. Kaiser: Janssen: Consultancy, Honoraria; Takeda: Consultancy, Other: Travel Support; Bristol-Myers Squibb: Consultancy, Other: Travel support; Chugai: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Zweegman: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mateos: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Spencer: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Iida: Janssen: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Astellas: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Toyama Chemical: Research Funding; MSD: Research Funding; Gilead: Research Funding; Teijin Pharma: Research Funding; Sanofi: Consultancy. Morgan: Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria. Teng: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Suryanarayan: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Skacel: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Department of Hematology, Charles University General Hospital, Prague, Czech Republic: Other: Affiliation. Dash: Takeda Pharmaceuticals International Co.: Employment. Labotka: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

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*signifies non-member of ASH