Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial

TOURMALINE-MM3 study group

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63 Scopus citations

Abstract

Background: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. Methods: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. Findings: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. Interpretation: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. Funding: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

Original languageEnglish (US)
Pages (from-to)253-264
Number of pages12
JournalThe Lancet
Volume393
Issue number10168
DOIs
StatePublished - Jan 19 2019

Bibliographical note

Funding Information:
MAD is a consultant for Amgen, Celgene, Takeda, Janssen, and Bristol-Myers Squibb; has received honoraria from Amgen, Celgene, Takeda, and Janssen; and has participated in speaker bureaus for Amgen, Celgene, Takeda, and Janssen. FG has received honoraria from Amgen, Celgene, Takeda, Janssen, and Bristol-Myers Squibb and is a member of the advisory committee for Celgene, Takeda, Seattle Genetics, and Roche. FS has participated in speaker bureaus for Amgen, Celgene, Takeda, Abbvie, and Janssen and is a member of advisory boards for Amgen, Celgene, Takeda, Janssen, Bristol-Myers Squibb, Bayer, Adaptive, and Oncopeptides. MB has been a member on advisory boards for Janssen Cilag, Takeda, Amgen, and Sanofi and has participated in speaker bureaus for Janssen Cilag, Celgene, Takeda, and Amgen. RH provides consultancy for Takeda, Bristol-Myers Squibb, Amgen, Janssen, and Celgene; has received research funding from Takeda, Amgen, Janssen, and Novartis; and has received honoraria from Takeda, Bristol-Myers Squibb, Amgen, Janssen, and Celgene. KCW has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda and research funding from Amgen, Celgene, Janssen, and Sanofi. HG has participated in advisory boards for Adaptive Biotechnology, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Sanofi, and Takeda; has received research funding from Amgen, Bristol-Myers Squibb, Celgene, Chugai, Janssen, Sanofi, Mundipharma, Takeda, and Novartis; and has received honoraria from ArtTempi, Bristol-Myers Squibb, Celgene, Chugai, Janssen, and Novartis. PM has participated in advisory boards for and received honoraria from Celgene, Amgen, Janssen, and Abbvie. W-JC has received honoraria from Takeda. MK provides consultancy for Amgen, Janssen, Takeda, and Celgene and has received research funding from Celgene and travel support from Takeda. SZ has received research funding from and participated in advisory boards for Takeda, Celgene, and Janssen. M-VM has received personal fees from Takeda, Janssen, Amgen, Celgene, GlaxoSmithKline, and Abbvie. AS provides consultancy for Specialised Therapeutics Australia; has received honoraria from Takeda, Celgene, Janssen, and Amgen; has participated in speaker bureaus for Takeda, Celgene, and Janssen; and has received research funding from Takeda, Celgene, Janssen, and GlaxoSmithKline. SI has received research funding from Takeda, Ono, Janssen, Celgene, Novartis, Chugai, Abbvie, Bristol-Myers Squibb, Kyowa-Hakko Kirin, Merck Sharp & Dohme, Daiichi Sankyo, Gilead, Teijin Pharma, and Astellas, and has received honoraria from Takeda, Janssen, Celgene, Ono, and Bristol-Myers Squibb. TS, KS, ZT, ABD, NG, and RL are employed by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. TS is also affiliated with the Department of Hematology, Charles University General Hospital, Prague, Czech Republic. APa is employed by and has ownership interests (stock options) in Millennium Pharmaceuticals; he is a consultant for and has received honoraria from Amgen, Novartis, Bristol-Myers Squibb, Genmab, Celgene, Janssen-Cilag, Takeda, Sanofi Aventis, and Merck; has received research funding from Amgen, Novartis, Bristol-Myers Squibb, Genmab, Celgene, Janssen-Cilag, Takeda, Sanofi Aventis, Merck and Binding Site; and has participated in a speakers bureau for Bristol-Myers Squibb. SVR declares no competing interests; their employer, the Mayo Clinic, received research funding for this clinical trial. VM, CKM, APl, and GM declare no competing interests.

Funding Information:
This study was sponsored by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. We thank the participants and their families, as well as the physicians, nurses, study coordinators, and research staff for participation in the trial; Renda Ferrari and Janice Ahn of Millennium Pharmaceuticals for editorial assistance; and Laura Webb of FireKite, an Ashfield company, part of UDG Healthcare, for professional medical writing assistance, which was funded by Millennium Pharmaceuticals.

Publisher Copyright:
© 2019 Elsevier Ltd

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