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

Ehsan Malek (), Priyanka S. Rana, Muthulekha Swamydas, Michael Daunov, Masaru Miyagi, Elena Murphy, James J. Ignatz-Hoover, Leland Metheny, Seong Jin Kim and James J. Driscoll ()
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Ehsan Malek: University Hospitals Cleveland Medical Center
Priyanka S. Rana: University Hospitals Cleveland Medical Center
Muthulekha Swamydas: University Hospitals Cleveland Medical Center
Michael Daunov: University Hospitals Cleveland Medical Center
Masaru Miyagi: Case Western Reserve University
Elena Murphy: Case Western Reserve University School of Medicine
James J. Ignatz-Hoover: University Hospitals Cleveland Medical Center
Leland Metheny: University Hospitals Cleveland Medical Center
Seong Jin Kim: Medpacto Inc.
James J. Driscoll: University Hospitals Cleveland Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51442-2

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