Development of a Low-dose Percutaneous Delivery System of Lenalidomide for Hematologic Malignancies: The Journey from Ideation to Phase 2

This presentation explores the scientific rationale, preclinical validation, and early clinical translation of STAR-LLD—a novel, continuous low-dose percutaneous lenalidomide delivery system for hematologic malignancies, with a focus on multiple myeloma (MM). Conventional oral lenalidomide regimens are constrained by rapid drug clearance, high peak plasma concentrations, and dose-limiting hematologic toxicities. STAR-LLD leverages subcutaneous infusion technology to maintain plasma concentrations above the minimum effective threshold for immune activation (≥0.04–0.1 µM/L), targeting sustained Ikaros/Aiolos protein degradation and optimal immunomodulatory activity.

Key preclinical studies in murine xenograft MM models demonstrated that continuous subcutaneous lenalidomide at 144 µg/day achieved superior tumor control (81% reduction in tumor volume) and prolonged time to treatment failure compared to standard daily bolus dosing, with no dose-limiting toxicities or significant hematologic suppression. Chronic dosing in healthy mice confirmed the absence of neutropenia, thrombocytopenia, or local tissue toxicity, supporting a favorable safety profile.

Phase 1 clinical data in relapsed/refractory MM patients revealed that continuous subcutaneous STAR-LLD at 400 µg/h (9.6 mg/day) achieved >92% bioavailability, stable plasma concentrations above the biologically active range, and a >90% reduction in Cmax and ~57% lower AUC versus oral dosing. Notably, no Grade 3–4 hematologic toxicities were observed, and all patients achieved an objective response (1 CR, 5 PR), suggesting an improved therapeutic index and reduced risk of treatment-limiting cytopenias.

Learning Objectives:

• Understand the rationale and scientific basis for continuous low-dose lenalidomide delivery in hematologic malignancies, including the pharmacokinetic and pharmacodynamic advantages over conventional oral dosing.
• Evaluate preclinical and early clinical data supporting the efficacy and safety of STAR-LLD, and recognize the implications for patient outcomes and future therapeutic strategies.
• Identify the translational steps and regulatory considerations involved in advancing STAR-LLD from preclinical models to Phase 2 clinical trials.

This session is ideal for clinicians, researchers, and industry professionals interested in drug delivery innovation, myeloma therapeutics, and translational oncology.