Ερευνητικό υλικό ΕΚΠΑ

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

Αγγλικά

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. © 2019 Elsevier Ltd

2019

Dimopoulos, M.A.
Gay, F.
Schjesvold, F.
Beksac, M.
Hajek, R.
Weisel, K.C.
Goldschmidt, H.
Maisnar, V.
Moreau, P.
Min, C.K.
Pluta, A.
Chng, W.-J.
Kaiser, M.
Zweegman, S.
Mateos, M.-V.
Spencer, A.
Iida, S.
Morgan, G.
Suryanarayan, K.
Teng, Z.
Skacel, T.
Palumbo, A.
Dash, A.B.
Gupta, N.
Labotka, R.
Rajkumar, S.V.
Bar, D.
Basso, A.
Fantl, D.
He, S.
Horvath, N.
Lee, C.
Rowlings, P.
Taylor, K.
Cochrane, T.
Kwok, F.
Ramanathan, S.
Agis, H.
Zojer, N.
Kentos, A.
Offner, F.
Van Droogenbroeck, J.
Wu, K.L.
Maiolino, A.
Martinez, G.
Zanella, K.
Capra, M.
Araújo, S.
Gregora, E.
Pour, L.
Scudla, V.
Spicka, I.
Abildgaard, N.
Andersen, N.
Jensen, B.A.
Helleberg, C.
Plesner, T.
Salomo, M.
Svirskaite, A.
Delarue, R.
Blau, I.
Schieferdecker, A.
Teleanu, V.
Munder, M.
Röllig, C.
Salwender, H.-J.
Fuhrmann, S.
Weisel, K.
Duerig, J.
Zeis, M.
Klein, S.
Reimer, P.
Schmidt, C.
Scheid, C.
Mayer, K.
Hoffmann, M.
Sosada, M.
Dimopoulos, A.
Delimpasi, S.
Kyrtsonis, M.-C.
Anagnostopoulos, A.
Nagy, Z.
Illés, Á.
Egyed, M.
Borbényi, Z.
Mikala, G.
Dally, N.
Horowitz, N.
Gutwein, O.
Nemets, A.
Vaxman, I.
Shvetz, O.
Trestman, S.
Ruchlemer, R.
Nagler, A.
Tadmor, T.
Rouvio, O.
Preis, M.
Cavo, M.
De Rosa, L.
Musto, P.
Cafro, A.
Tosi, P.
Offidani, M.
Corso, A.
Rossi, G.
Liberati, A.M.
Bosi, A.
Suzuki, K.
Nakaseko, C.
Ishikawa, T.
Matsumoto, M.
Nagai, H.
Sunami, K.
Chou, T.
Akashi, K.
Takezako, N.
Hagiwara, S.
Eom, H.S.
Jo, D.-Y.
Kim, J.S.
Lee, J.H.
Yoon, S.S.
Yoon, D.H.
Kim, K.
Levin, M.-D.
Vellenga, E.
Minnema, M.
Waage, A.
Haukås, E.
Grosicki, S.
Pluta, A.
Robak, T.
Marques, H.
Bergantim, R.
Campilho, F.
Chng, W.J.
Goh, Y.T.
McDonald, A.
Rapoport, B.
Álvarez Rivas, M.A.
De Arriba de La Fuente, F.
González Montes, Y.
Martin Sanchez, J.
Mateos, M.V.
Oriol Rocafiguera, A.
Rosinol, L.
San Miguel, J.
Pérez de Oteyza, J.
Encinas, C.
Alegre-Amor, A.
López-Guía, A.
Axelsson, P.
Carlson, K.
Stromberg, O.
Hansson, M.
Hveding Blimark, C.
Mueller, R.
Chen, C.-C.
Liu, T.-C.
Huang, S.-Y.
Wang, P.-N.
Na Nakorn, T.
Prayongratana, K.
Unal, A.
Goker, H.
Sonmez, M.
Korenkova, S.
Chaidos, A.
Oakervee, H.
Sati, H.
Benjamin, R.
Wechalekar, A.
Garg, M.
Ramasamy, K.
Cook, G.
Chantry, A.
Jenner, M.
Buadi, F.
Berryman, R.
Janakiram, M.
TOURMALINE-MM3 study group

The Lancet Neurology

The Lancet Publishing Group

393

10168

253-264

ixazomib; melphalan; placebo; antineoplastic agent; boron derivative; glycine; ixazomib, adult; aged; anemia; Article; autologous stem cell transplantation; cardiovascular disease; chromosome 14; chromosome 16; chromosome 17p; chromosome 4; chromosome deletion; chromosome translocation; controlled study; diarrhea; disease severity; double blind procedure; drug dose increase; drug fatality; drug megadose; drug safety; drug tolerability; female; gastrointestinal disease; herpes zoster; high risk patient; human; infection; intention to treat analysis; maintenance therapy; major clinical study; male; median survival time; mortality risk; multiple cycle treatment; multiple myeloma; nausea; neutropenia; overall survival; patient-reported outcome; peripheral neuropathy; priority journal; progression free survival; quality of life; randomized controlled trial; rash; thrombocytopenia; vomiting; analogs and derivatives; autotransplantation; clinical trial; disease exacerbation; middle aged; multicenter study; multiple myeloma; oral drug administration; phase 3 clinical trial; stem cell transplantation; time factor; treatment outcome, Administration, Oral; Antineoplastic Agents; Boron Compounds; Disease Progression; Double-Blind Method; Female; Glycine; Humans; Male; Middle Aged; Multiple Myeloma; Stem Cell Transplantation; Time Factors; Transplantation, Autologous; Treatment Outcome

https://doi.org/10.1016/S0140-6736(18)33003-4

10.1016/S0140-6736(18)33003-4

https://pergamos.lib.uoa.gr/uoa/dl/object/3106326