Dreamm-3: A Phase 3, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin (GSK2857916) Monotherapy Compared with Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Participants with Relapsed/Refractory Multiple Myeloma (RRMM)

Background: Belantamab mafodotin is a humanized, afucosylated, anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Upon binding to BCMA on the surface of plasma cells, it is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released, antibody-dependent cellular cytotoxicity is enhanced, and immunogenic cell death occurs. In vitro and in vivo cytotoxic activity against both myeloma cell lines and primary patient cells has been demonstrated in preclinical studies. In the first-in-human phase 1 study (DREAMM-1/BMA117159, NCT02064387), belantamab mafodotin had a manageable safety profile and demonstrated a rapid, deep, and durable clinical response as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). In a cohort of 35 heavily pretreated patients with RRMM (57% with ≥5 lines of prior therapy) who received belantamab mafodotin 3.4 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1, 76.1) was demonstrated. The median progression-free survival (PFS) was 12.0 months (95% CI: 3.1, not estimable [NE]) and the median duration of response (DoR) was 14.3 months (95% CI: 10.6, NE). Belantamab mafodotin monotherapy in patients with RRMM is being further evaluated against the standard-of-care pomalidomide/dexamethasone (Pom/Dex) regimen in the DREAMM-3 study.

Methods: The phase 3, multicenter, randomized, open-label DREAMM-3 study will evaluate the efficacy and safety of belantamab mafodotin monotherapy compared with Pom/Dex, an established standard-of-care regimen in RRMM. In this global study, patients treated with ≥2 prior lines of therapy, including ≥2 consecutive cycles of both lenalidomide and a proteasome inhibitor, and refractory to the last line of treatment, will be eligible for inclusion. Participants with prior allogeneic transplant will be excluded, as will those with prior exposure to BCMA-targeted therapies and Pom. Approximately 320 participants will be randomized (2:1) to receive either belantamab mafodotin or Pom/Dex and will be stratified by age, exposure to anti-CD38 therapy, and number of prior lines of treatment. Belantamab mafodotin will be administered IV Q3W, at the dose confirmed in the ongoing DREAMM-2 study (NCT03525678). Pom will be administered orally at 4 mg on Days 1-21 of each 28-day cycle, with Dex 40 or 20 mg (depending on age) on Days 1, 8, 15, and 22. Treatment in both arms will continue until progressive disease, unacceptable toxicity, or death. The primary endpoint is PFS, and overall survival is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, minimal residual disease negativity rate (10^-5 threshold assessed by next-generation sequencing), DoR, safety, and health-related quality of life. Bone marrow and blood samples will be collected for biomarker research. The study is planned to start in late 2019.

Acknowledgments: Editorial assistance was provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd, UK, and funded by GlaxoSmithKline.

Study is funded by GlaxoSmithKline (ID: 207495); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa.