Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3)

a double-blind, randomised, placebo-controlled phase 3 trial

TOURMALINE-MM3 study group

Research output: Contribution to journalArticle

15 Citations (Scopus)

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/m 2 ) 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
Pages (from-to)253-264
Number of pages12
JournalThe Lancet
Volume393
Issue number10168
DOIs
Publication statusPublished - Jan 19 2019

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Stem Cell Transplantation
Placebos
Maintenance
Multiple Myeloma
Disease-Free Survival
Therapeutics
Transplantation
ixazomib
Safety
Eastern Africa
Intention to Treat Analysis
Melphalan
Middle East
Far East
Second Primary Neoplasms
South America
Risk Reduction Behavior
Standard of Care
Random Allocation
North America

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

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

In: The Lancet, Vol. 393, No. 10168, 19.01.2019, p. 253-264.

Research output: Contribution to journalArticle

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title = "Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial",
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/m 2 ) 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.",
author = "{TOURMALINE-MM3 study group} and Dimopoulos, {Meletios A.} and Francesca Gay and Fredrik Schjesvold and Meral Beksac and Roman Hajek and Weisel, {Katja Christina} and Hartmut Goldschmidt and Vladimir Maisnar and Philippe Moreau and Min, {Chang Ki} and Agnieszka Pluta and Chng, {Wee Joo} and Martin Kaiser and Sonja Zweegman and Mateos, {Maria Victoria} and Andrew Spencer and Shinsuke Iida and Gareth Morgan and Kaveri Suryanarayan and Zhaoyang Teng and Tomas Skacel and Antonio Palumbo and Dash, {Ajeeta B.} and Neeraj Gupta and Richard Labotka and Rajkumar, {S. Vincent} and Daniel Bar and Alfredo Basso and Dorotea Fantl and Simon He and Neomi Horvath and Cindy Lee and Phillip Rowlings and Kerry Taylor and Tara Cochrane and Fiona Kwok and Sundreswran Ramanathan and Hermine Agis and Niklas Zojer and Alain Kentos and Fritz Offner and {Van Droogenbroeck}, Jan and Wu, {Ka Lung} and Angelo Maiolino and Gracia Martinez and Karla Zanella and Marcelo Capra and S{\'e}rgio Ara{\'u}jo and Evzen Gregora and Koichi Akashi",
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TY - JOUR

T1 - Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3)

T2 - a double-blind, randomised, placebo-controlled phase 3 trial

AU - TOURMALINE-MM3 study group

AU - Dimopoulos, Meletios A.

AU - Gay, Francesca

AU - Schjesvold, Fredrik

AU - Beksac, Meral

AU - Hajek, Roman

AU - Weisel, Katja Christina

AU - Goldschmidt, Hartmut

AU - Maisnar, Vladimir

AU - Moreau, Philippe

AU - Min, Chang Ki

AU - Pluta, Agnieszka

AU - Chng, Wee Joo

AU - Kaiser, Martin

AU - Zweegman, Sonja

AU - Mateos, Maria Victoria

AU - Spencer, Andrew

AU - Iida, Shinsuke

AU - Morgan, Gareth

AU - Suryanarayan, Kaveri

AU - Teng, Zhaoyang

AU - Skacel, Tomas

AU - Palumbo, Antonio

AU - Dash, Ajeeta B.

AU - Gupta, Neeraj

AU - Labotka, Richard

AU - Rajkumar, S. Vincent

AU - Bar, Daniel

AU - Basso, Alfredo

AU - Fantl, Dorotea

AU - He, Simon

AU - Horvath, Neomi

AU - Lee, Cindy

AU - Rowlings, Phillip

AU - Taylor, Kerry

AU - Cochrane, Tara

AU - Kwok, Fiona

AU - Ramanathan, Sundreswran

AU - Agis, Hermine

AU - Zojer, Niklas

AU - Kentos, Alain

AU - Offner, Fritz

AU - Van Droogenbroeck, Jan

AU - Wu, Ka Lung

AU - Maiolino, Angelo

AU - Martinez, Gracia

AU - Zanella, Karla

AU - Capra, Marcelo

AU - Araújo, Sérgio

AU - Gregora, Evzen

AU - Akashi, Koichi

PY - 2019/1/19

Y1 - 2019/1/19

N2 - 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/m 2 ) 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.

AB - 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/m 2 ) 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.

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U2 - 10.1016/S0140-6736(18)33003-4

DO - 10.1016/S0140-6736(18)33003-4

M3 - Article

VL - 393

SP - 253

EP - 264

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10168

ER -