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The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial

Author

Listed:
  • Ehsan Malek

    (University Hospitals Cleveland Medical Center
    Case Western Reserve University School of Medicine
    Case Western Reserve University)

  • Priyanka S. Rana

    (University Hospitals Cleveland Medical Center
    Case Western Reserve University School of Medicine
    Case Western Reserve University)

  • Muthulekha Swamydas

    (University Hospitals Cleveland Medical Center
    Case Western Reserve University School of Medicine
    Case Western Reserve University)

  • Michael Daunov

    (University Hospitals Cleveland Medical Center
    Case Western Reserve University School of Medicine
    Case Western Reserve University)

  • Masaru Miyagi

    (Case Western Reserve University
    Case Western Reserve University School of Medicine
    Case Western Reserve University School of Medicine)

  • Elena Murphy

    (Case Western Reserve University School of Medicine)

  • James J. Ignatz-Hoover

    (University Hospitals Cleveland Medical Center
    Case Western Reserve University School of Medicine
    Case Western Reserve University)

  • Leland Metheny

    (University Hospitals Cleveland Medical Center
    Case Western Reserve University School of Medicine
    Case Western Reserve University)

  • Seong Jin Kim

    (Medpacto Inc.)

  • James J. Driscoll

    (University Hospitals Cleveland Medical Center
    Case Western Reserve University School of Medicine
    Case Western Reserve University)

Abstract

Functional blockade of the transforming growth factor-beta (TGFβ) signalling pathway improves the efficacy of cytotoxic and immunotherapies. Here, we conducted a phase 1b study (ClinicalTrials.gov., NCT03143985) to determine the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/or refractory multiple myeloma (RRMM) patients who had received ≥2 lines of chemoimmunotherapy. Secondary endpoints demonstrated sustained clinical responses, favorable pharmacokinetic parameters and a 6-month progression-free survival of 82%. Vactosertib combined with pomalidomide was well-tolerated at all dose levels and displayed a manageable adverse event profile. Exploratory analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFβ levels in patient bone marrow as well as the level of CD8+ T-cells that expressed the immunoinhibitory marker PD-1. In vitro experiments indicated that vactosertib+pomalidomide co-treatment decreased the viability of MM cell lines and patient tumor cells, and increased CD8+ T-cell cytotoxic activity. Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.

Suggested Citation

  • Ehsan Malek & Priyanka S. Rana & Muthulekha Swamydas & Michael Daunov & Masaru Miyagi & Elena Murphy & James J. Ignatz-Hoover & Leland Metheny & Seong Jin Kim & James J. Driscoll, 2024. "The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51442-2
    DOI: 10.1038/s41467-024-51442-2
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