The TGFβ Type I Receptor Kinase Inhibitor Vactosertib Improves T-Cell Fitness in Relapsed/Refractory Multiple Myeloma: A Phase 1b Trial
Authors: Malek Ehsan , Ignatz-Hoover James J , Rana Priyanka S. , Driscoll James J. 
Published: December 2024

Background: Multiple myeloma (MM) is the second most frequent hematologic malignancy and is characterized by the expansion of monoclonal plasma cells within a tumor-permissive bone marrow milieu. The emergence of relapsed and/or refractory MM (RRMM) is provoked through the clonal evolution of malignant plasma cells that harbor genomic, metabolic and proteomic perturbations. For most patients, relapsed disease remains a major cause of overall mortality. Hence, despite therapeutic advances, MM remains incurable in the vast majority of patients and novel strategies to improve patient outcome represent an urgent, unmet clinical need. Transforming growth factors (TGFs) are systemic cytokines that exert pleiotropic effects and regulate myelomagenesis as well as the emergence of drug resistance in MM cells. TGF-β modulates numerous cell types present with the tumor microenvironment (TME), including many immune cell types. MM cells leverage TGFβ to reshape the TME and escape mechanisms of immune surveillance.
Results: 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 potent, orally-available TGFβ type I receptor kinase inhibitor vactosertib in RRMM patients who had received &gt;2 lines of chemoimmunotherapy. Secondary endpoints demonstrated sustained clinical responses, favorable pharmacokinetic parameters and a six-month progression-free survival (PFS-6) of 82%. Vactosertib combined with pomalidomide was well-tolerated at all dose levels, displayed a manageable adverse event profile and induced durable responses. Exploratory analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFβ levels in patient bone marrow samples 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 MM cell line and patient tumor cell viability and increased CD8+ T-cell cytotoxic activity. Taken together, our results indicate that vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and overcomes immunosuppressive challenges within the TME to reinvigorate T-cell fitness.
Conclusions: Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents. An improved understanding of the roles of TGFβ in regulating adaptive and innate immune systems in MM has led to the development of a novel immune-based therapies. Functional blockade of the TGFβ signaling pathway improves the efficacy of cytotoxic and immunotherapies. Since the administration of TGFβ inhibitors as monotherapy in clinical trials has not demonstrated significant responses, the development of TGFβ blockade therapy is primarily oriented toward TGFβ inhibitor combinations. Current studies are focused on defining the antimyeloma effects of vactosertib in combination with immune checkpoint inhibitors, autologous and allogeneic chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers. Accumulating evidence suggests that functional blockade of the TGF pathway offers promise to optimize CAR-T-cell therapy for hematologic and solid tumors, albeit with efficacy anticipated restricted to specific populations.