Phase 2 Randomized Dose‑Optimization Study of GSK5764227 with CyBorD Combination Therapy in Adults with Newly Diagnosed Light‑Chain (AL) Amyloidosis

The primary objective is to assess the efficacy of belantamab mafodotin in combination with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in adults with newly diagnosed amyloid light chain amyloidosis, with the aim of determining its therapeutic benefit in this high‑risk population.

Secondary objectives include:

• Evaluation of the safety profile of belantamab mafodotin combined with CyBorD.
• Further assessment of efficacy of the combination regimen.
• Characterization of the pharmacokinetic properties of belantamab mafodotin when administered with CyBorD.
• Assessment of the immunogenic potential of belantamab mafodotin in this patient cohort.

Forty‑three participants (both females and males) aged 18 years or older were enrolled. All individuals had histologically confirmed newly diagnosed amyloid light chain amyloidosis with systemic involvement of at least one organ, positive Congo‑red staining, and evidence of a monoclonal plasma‑cell disorder. Eligibility required measurable clonal disease (serum monoclonal protein ≥ 0.5 g/dL or involved serum free light chain ≥ 5.0 mg/dL with abnormal ratio), an ECOG performance status of 0‑2, and adequate organ function (ANC ≥ 1.0 × 10⁹/L, platelets ≥ 75 × 10⁹/L, bilirubin ≤ 1.5 × ULN, ALT ≤ 2.5‑3 × ULN, eGFR ≥ 30 mL/min/1.73 m²). Participants were not candidates for high‑dose chemotherapy with autologous stem‑cell transplantation as first‑line therapy. Contraception requirements applied to both sexes, including abstinence or use of highly effective barrier methods, and restrictions on semen or oocyte donation during and after treatment. Selection was based on the defined diagnostic and laboratory criteria, performance status, and organ‑function thresholds, ensuring a population with relatively preserved functional status suitable for the combination regimen.

The study is a Phase 2, open‑label, randomized dose‑optimization trial evaluating belantamab mafodotin in combination with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in adult participants with newly diagnosed amyloid light chain amyloidosis. Eligible individuals undergo a screening visit to confirm diagnosis, assess eligibility criteria, and obtain baseline laboratory and ophthalmic assessments. After randomization to predefined dose cohorts, participants receive the investigational regimen on a defined schedule and attend regular follow‑up visits for safety monitoring, response assessment, and pharmacokinetic sampling. The trial continues until the end‑of‑study visit, which includes final efficacy and safety evaluations. Participant involvement spans from the screening visit through the end‑of‑study visit, covering the entire treatment and follow‑up period. The overall study timeline extends from the anticipated recruitment start on 21 July 2026 to an estimated completion date of 1 August 2033.

The study evaluates the investigational monoclonal antibody‑drug conjugate belantamab mafodotin (GSK5764227) supplied as a powder for solution for infusion for intravenous administration at a dose of 1.9 mg/kg given on day 1 of each 28‑day treatment cycle.

Dexamethasone is provided as Fortecortin® 2 mg tablets and Dexamethason 8 mg GALEN® tablets, both oral tablets containing 40 mg dexamethasone per dose. The corticosteroid is administered orally once weekly throughout the treatment cycles.

Cyclophosphamide is supplied as Endoxan® and ENDOXAN 50 mg film‑coated tablets, each containing 500 mg cyclophosphamide. The agent is taken orally on day 1 of each cycle.

Bortezomib is provided as VELCADE 3.5 mg powder for solution for injection and Bortezomib Hikma 3.5 mg powder for solution for injection, both intended for subcutaneous injection at a dose of 1.3 mg/m². The proteasome inhibitor is administered subcutaneously on days 1, 8, and 15 of each cycle.

All oral medications are dispensed in blister packs with dose‑specific labeling, and administration times are recorded in the study drug diary. Intravenous and subcutaneous injections are performed by qualified personnel, and infusion rates are documented in the electronic case report form. Compliance is monitored by pill count at each visit, review of the drug diary, and verification of administration records for injectable agents.

Efficacy will be evaluated primarily by the Overall Complete Hematologic Response (CHR) rate, defined as the proportion of participants who achieve a CHR according to the consensus guidelines for AL amyloidosis during or after study treatment initiation. Secondary efficacy assessments include the organ response rate (organ response rate (OrRR)) for kidney, heart, and liver, the duration of CHR measured from the date of initial CHR documentation to the first evidence of hematologic progressive disease, and pharmacokinetic parameters (e.g., Cmax, AUC) for belantamab mafodotin and cys‑mcMMAF. Additional secondary measures comprise the incidence and titers of anti‑drug antibodies and the incidence, severity, duration, and resolution of ocular findings assessed by ophthalmic examination, including changes in Best corrected visual acuity (BCVA).

Assessment of hematologic response will be performed by laboratory evaluation of serum free light chains and immunofixation, applying the established AL amyloidosis response criteria. Organ responses will be determined using organ‑specific biomarkers and imaging studies as defined in the consensus guidelines. Ocular assessments will be conducted by standardized corneal examination and BCVA testing at predefined study visits. All efficacy parameters will be collected at baseline and at scheduled follow‑up visits throughout the treatment period, with data analyzed using descriptive statistics to calculate response rates and time‑to‑event outcomes.