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MULTIPLE MYELOMA, GAMMOPATHIES

Ixazomib, lenalidomide and dexamethasone consolidation with randomized ixazomib or lenalidomide maintenance after autologous transplant in newly diagnosed multiple myeloma

Leukemia volume 36, pages 2917–2921 (2022)Cite this article

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In eligible patients with newly diagnosed multiple myeloma (NDMM), frontline autologous stem cell transplant (ASCT) is standard of care [1]. However, the use of consolidation after ASCT remains controversial, with landmark trials yielding conflicting results [2,3,4]. There is interest in consolidation regimens that are efficacious yet less toxic and more convenient. A potential candidate is the all-oral triplet of ixazomib, lenalidomide and dexamethasone (IRd), which reduces required healthcare visits relative to other proteasome inhibitor (PI)-based regimens [5]. A second unresolved aspect of post-ASCT therapy is the optimal maintenance strategy. Lenalidomide maintenance is standard of care, but is associated with significant toxicities, leading to a discontinuation rate of approximately 50% at 2 years [6]. Two years of post-ASCT maintenance ixazomib was demonstrated to improve PFS relative to placebo, with a toxicity profile comparable to the control arm [7]. However, randomized data comparing lenalidomide and ixazomib is lacking.

Consequently, we conducted a phase II multicenter trial with two stages. First, patients were enrolled after restaging at day + 100 following frontline ASCT and received four cycles of IRd consolidation (Data Supplement). The trial was formally powered for this stage and sample size was calculated to detect a 10% improvement in measurable residual disease (MRD) negativity rate following consolidation as determined by next generation sequencing (NGS) with a stringent <1 × 10−6 cutoff (Data Supplement). Second, patients without disease progression during consolidation were randomized (1:1) to open-label maintenance with ixazomib or lenalidomide until disease progression or intolerance. No formal power calculation was performed for this stage, but the trial had adequate sample size to determine non-inferiority of ixazomib with a pre-specified margin of 1.3 (Data Supplement). Randomization was stratified by MRD-status following consolidation. Patients unable to tolerate lenalidomide or ixazomib during consolidation were excluded from the analysis and received the alternate maintenance arm.

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Fig. 1: Disease response and progression free survival (PFS).

Data availability

Requests for de-identified patient level data should be directed to the senior author and will be evaluated on a case-by-case basis.

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Acknowledgements

We would like to thank the patients and their families who agreed to participate in this trial; the nurses, physicians, study coordinators and research coordinators for their care and participation in this trial; Multiple Myeloma Research Consortium members and administrators for their support of this trial; Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core which provided protocol development services; Heidi Simmons and Allison Jacob from Adaptive Biotechnologies for technical assistance regarding assay interpretation.

Funding

The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842. MS was supported by the National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number TL1TR002344. MPR was supported by an NCI Research Specialist Award (R50CA211466). This study was also supported (in part) by research funding from Takeda, who provided ixazomib and material support for the trial, and Adaptive Biotechnologies, who performed clonoSEQ analysis at no charge.

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Authors and Affiliations

  1. Washington University School of Medicine, St. Louis, MO, USA

    Michael Slade, Mark A. Fiala, Michael P. Rettig, Feng Gao & Ravi Vij

  2. University of California- San Francisco, San Francisco, CA, USA

    Thomas G. Martin

  3. Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Nitya Nathwani

  4. Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Abhinav Deol

  5. Mayo Clinic, Rochester, MN, USA

    Francis K. Buadi

  6. Emory University, Atlanta, GA, USA

    Jonathan L. Kaufman & Craig C. Hofmeister

  7. Sarah Cannon Research Institute, Denver, CO, USA

    Tara K. Gregory

  8. Sarah Cannon Research Institute, Nashville, TN, USA

    Jesus Berdeja

  9. Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    Ajai Chari

  10. Ohio State University, Columbus, OH, USA

    Ashley Rosko

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  1. Michael Slade
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Contributions

MS and MAF wrote the first version of this manuscript. MS, MAF and RV wrote the subsequent versions. MS and MPR designed, performed and analyzed the correlative studies. FG and MAF performed the statistical analysis. MS, TGM, NN, MAF, AD, FKB, FLK, CCH, TKG, JB, AC, AR and RV participated in the design of the study and contributed data. All authors evaluated and critically revised the manuscript and approved the final version. All authors have access to the full dataset. No professional medical writers were involved in the drafting of this manuscript.

Corresponding author

Correspondence to Ravi Vij.

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Competing interests

MS receives research funding from SecuraBio. RV receives grant support from Takeda, BMS, and Sanofi, serves on the advisory boards of Takeda, BMS, Sanofi, Legend, Biegene, Oncopeptides. Adaptive, GSK, and Pfizer and serves as a consultant for Harpoon. CCH receives research funds as principal investigator from BMS/Celgene, Nektar, Oncolytic therapeutics and Sanofi, serves on the advisory boards of Janssen, BMS, GlaxoSmithKline, Oncopeptides, Sanofi and BlueBirdBio and receives patent funds from Recursion pharmaceuticals. JB reports institutional research support from Abbvie, Acetylon, Amgen, Bluebird bio, BMS, Celgene, Celularity, CRISPR Therapeutics, EMD Sorono, Genentech, GSK, Ichnos Sciences, Incyte, Janssen, Lilly, Novartis, Poseida, Sanofi, Takeda, and Teva and receive consultancy payments from Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, and Takeda. MAF, FG, FKB, TKG, AR, NN, TGM, AD, JLK, AC and MPR declare no relevant conflicts of interest.

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Slade, M., Martin, T.G., Nathwani, N. et al. Ixazomib, lenalidomide and dexamethasone consolidation with randomized ixazomib or lenalidomide maintenance after autologous transplant in newly diagnosed multiple myeloma. Leukemia 36, 2917–2921 (2022). https://doi.org/10.1038/s41375-022-01691-1

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