Exploring Alternative Dosing Regimens of Single-Agent Belantamab Mafodotin on Safety and Efficacy in Patients with Relapsed or Refractory Multiple Myeloma: DREAMM-14

Introduction: Belantamab mafodotin is a first-in-class, monomethyl auristatin F (MMAF)-containing, B-cell maturation antigen (BCMA)-directed antibody-drug conjugate (ADC) that is approved in the United States and European Union for adult patients with relapsed/refractory multiple myeloma (RRMM). In the pivotal Phase II DREAMM-2 study, single-agent belantamab mafodotin (2.5 mg/kg administered intravenously every 3 weeks [Q3W]) demonstrated an objective response rate of 32% with a manageable safety profile in triple-class refractory adult patients with RRMM (Lonial et al. Lancet Oncol. 2020). At 13 months of follow-up, responses were durable, with a median duration of response of 11 months and an overall survival of 13.7 months (Lonial et al. ASH 2020, Poster 1417).

Corneal events are common and expected with belantamab mafodotin and other MMAF-containing ADCs. In DREAMM-2, keratopathy (a pathological eye exam finding) presented as superficial punctate keratopathy and/or microcyst-like epithelial changes. Ocular symptoms, such as decline in best-corrected visual acuity or patient-reported adverse events (eg, blurred vision or dry eye), were also common during treatment. Corneal events with or without symptoms were managed with dose modifications (delays and reductions), and clinically meaningful responses were observed even with prolonged treatment-free intervals; this suggests that alternative dosing regimens of belantamab mafodotin may lower rates of corneal events without compromising efficacy.

The goal of the DREAMM-14 study is to investigate whether an improved overall benefit/risk profile of single-agent belantamab mafodotin can be achieved by modifying the belantamab mafodotin dose, schedule, or both relative to the approved dosing regimen (2.5 mg/kg Q3W).

Methods: This Phase II, 5-arm, randomized, parallel, open-label multicenter study will include patients with RRMM who have received at least 3 prior lines of therapy including an anti-CD38 monoclonal antibody (mAb), an immunomodulatory agent, and a proteasome inhibitor. Patients aged ≥18 years with Eastern Cooperative Oncology Group Performance Status ≤2 and who provide informed consent will be eligible. Patients with corneal epithelial disease (except mild punctate keratopathy) or prior exposure to BCMA-targeted therapies or ADCs will be excluded.

Patients will be randomized into Arms A to D (n=40 each) and arm E (n=20) in parallel and stratified by the International Staging System (ISS) for MM (I vs II vs III) and prior lines of therapy (3 vs ≥4). Single-agent belantamab mafodotin will be administered at doses and schedules as follows-Arm A: 2.5 mg/kg Q3W (control); Arm B: 1.9 mg/kg Q3W; Arm C: 2.5 mg/kg Q6W; Arm D: 1.9 mg/kg Q6W; Arm E: 1.9 mg/kg Q6W with dose modifications based on oncology staff assessment of ocular symptoms (patient-reported symptoms using the Ocular Surface Disease Index) and visual acuity. Participants in all arms will have Q3W response assessments and Q3W ophthalmic examinations and monitoring by qualified eye care specialists. Ocular event-related dose modifications for all arms except Arm E will be guided by the Keratopathy and Visual Acuity (KVA) scale. Participants in all arms will be treated until progressive disease, unacceptable toxicity, or death.

The primary endpoint will be incidence of Grade ≥2 ocular adverse events according to the KVA scale. Key secondary endpoints include ocular safety and tolerability, pharmacokinetics, and efficacy outcomes of belantamab mafodotin in all arms. Follow-up for progression-free survival will be Q3W until progressive disease, start of new anticancer therapy, withdrawal of consent, end of study, or death. Follow-up for overall survival will be Q12W from treatment discontinuation. The duration of this study will be approximately 22 months. The study is planned to start in the first quarter of 2022.

Funding: GSK (Study 209628); drug linker technology licensed from Seagen; mAb produced using POTELLIGENT Technology licensed from BioWa.