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Clinical Trial
. 2021 Aug 1;39(22):2430-2442.
doi: 10.1200/JCO.21.00972. Epub 2021 Jun 11.

Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Paul G Richardson  1 , Shaji K Kumar  2 , Tamás Masszi  3 , Norbert Grzasko  4   5 , Nizar J Bahlis  6 , Markus Hansson  7   8 , Luděk Pour  9 , Irwindeep Sandhu  10 , Peter Ganly  11 , Bartrum W Baker  12 , Sharon R Jackson  13 , Anne-Marie Stoppa  14 , Peter Gimsing  15 , Laurent Garderet  16 , Cyrille Touzeau  17 , Francis K Buadi  2 , Jacob P Laubach  1 , Michele Cavo  18 , Mohamed Darif  19 , Richard Labotka  19 , Deborah Berg  19 , Philippe Moreau  17
Affiliations
Clinical Trial

Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Paul G Richardson et al. J Clin Oncol. .

Abstract

Purpose: The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS).

Patients and methods: Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point.

Results: With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns.

Conclusion: Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.

Trial registration: ClinicalTrials.gov NCT01564537.

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Conflict of interest statement

Paul G. RichardsonConsulting or Advisory Role: Celgene, Janssen, Takeda, Karyopharm Therapeutics, Oncopeptides, Sanofi, Jazz Pharmaceuticals, Secura BioResearch Funding: Celgene, Takeda, Bristol Myers Squibb, Oncopeptides Shaji K. KumarConsulting or Advisory Role: Takeda, Janssen Oncology, Amgen, AbbVie, Merck, Celgene, Genentech/Roche, Oncopeptides, Kite (a Gilead company), Genecentrix, Molecular Partners, Bluebird Bio, CellectarResearch Funding: Celgene, Takeda, AbbVie, Novartis, Sanofi, Janssen Oncology, Merck, Kite (a Gilead company), MedImmune, Roche/Genentech, TeneoBio, CARsgen Therapeutics Tamas MassziConsulting or Advisory Role: AbbVie, Bristol Myers Squibb, Janssen-Cilag, Novartis, Pfizer, Takeda Norbert GrzaskoHonoraria: Molteni Farmaceutici, Celgene, Amgen Nizar J. BahlisHonoraria: Celgene, Janssen, AbbVie, Amgen, Sanofi, Takeda, Karyopharm Therapeutics, GlaxoSmithKline, Genentech/RocheConsulting or Advisory Role: Janssen, Celgene, Amgen, Sanofi, Takeda, Pfizer, Karyopharm TherapeuticsResearch Funding: Janssen, Celgene Markus HanssonConsulting or Advisory Role: Amgen, Celgene, Takeda, Janssen, Sanofi Irwindeep SandhuStock and Other Ownership Interests: illumiSonicsHonoraria: Janssen, Amgen, Gilead Sciences, Takeda, Celgene/Bristol Myers Squibb, Sanofi, BeiGeneConsulting or Advisory Role: Janssen, Amgen, Takeda, Gilead Sciences, Celgene/Bristol Myers Squibb, Sanofi, BeiGene Sharon R. JacksonHonoraria: AbbVie NZConsulting or Advisory Role: AbbVie NZSpeakers' Bureau: AbbVie NZTravel, Accommodations, Expenses: Roche NZ Anne-Marie StoppaConsulting or Advisory Role: Sanofi, Janssen, TakedaTravel, Accommodations, Expenses: Janssen Laurent GarderetConsulting or Advisory Role: Amgen, Takeda, Novartis, Bristol Myers Squibb, Janssen, SanofiTravel, Accommodations, Expenses: Bristol Myers Squibb, Amgen Cyrille TouzeauHonoraria: AbbVie, Celgene, Amgen, Takeda, Janssen, Sanofi, Novartis, GlaxoSmithKlineConsulting or Advisory Role: Novartis, Amgen, Celgene, AbbVie, Takeda, Janssen, GlaxoSmithKlineResearch Funding: AbbVie Michele CavoHonoraria: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesConsulting or Advisory Role: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesSpeakers' Bureau: Janssen, Celgene Mohamed DarifEmployment: TakedaConsulting or Advisory Role: Takeda Richard LabotkaEmployment: Takeda Deborah BergEmployment: TakedaStock and Other Ownership Interests: TakedaPatents, Royalties, Other Intellectual Property: Takeda Philippe MoreauHonoraria: Celgene, Janssen-Cilag, Amgen, GlaxoSmithKline, AbbVie, SanofiConsulting or Advisory Role: Celgene, Janssen, Amgen, GlaxoSmithKline, Sanofi, AbbVieNo other potential conflicts of interest were reported.

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