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 - Rouvio, Ory
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
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/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.
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/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.
UR - http://www.scopus.com/inward/record.url?scp=85060020572&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(18)33003-4
DO - 10.1016/S0140-6736(18)33003-4
M3 - Article
AN - SCOPUS:85060020572
SN - 0140-6736
VL - 393
SP - 253
EP - 264
JO - The Lancet
JF - The Lancet
IS - 10168
ER -