Impact of Long-Term Treatment with Belantamab Mafodotin on Safety and Efficacy Outcomes in Patients with Relapsed/Refractory Multiple Myeloma in DREAMM-3
Authors: Hungria Vania T.M , Weisel Katja , Radinoff Atanas , Delimpasi Sosana , Mikala Gabor , Masszi Tamas , Li Jian , Capra Marcelo , Maiolino Angelo , Pappa Vasiliki , Chraniuk Dominik , Osipov Iurii , Leleu Xavier , Low Michael , Matsumoto Morio , Li Mary , Sule Neal , Polinkovsky Margaret , Davis Randy , Bright Shelley , McKeown Astrid , Opalinska Joanna , Dimopoulos Meletios Athanasios 
Published: December 2023

Introduction: DREAMM-3 (NCT04162210) is a randomized study comparing single-agent belantamab mafodotin, a first-in-class antibody-drug conjugate targeting B-cell maturation antigen, to a standard-of-care regimen, pomalidomide plus dexamethasone (Pd). This post-hoc analysis from the DREAMM-3 trial evaluated the safety and efficacy of long-term treatment (≥52 weeks) with belantamab mafodotin compared with Pd, as well as the effects of dose modifications, in adult patients with relapsed/refractory multiple myeloma (RRMM) at third line of therapy or later.

Methods: Patients were randomized (2:1) to belantamab mafodotin 2.5 mg/kg intravenously once every 3 weeks (Q3W; 21-day cycle) or pomalidomide 4 mg orally once daily (Days 1-21) and dexamethasone 40 mg (20 mg if &gt;75 years) orally once weekly (28-day cycle). Belantamab mafodotin dose reductions or delays were permitted to manage treatment-related Grade 3-4 adverse events (AEs), or Grade 2 AEs that were worsening or had symptoms lasting &gt;7 days. Following AE resolution to Grade ≤1, belantamab mafodotin treatment could resume with or without dose reduction (to 1.9 mg/kg). If no dose delays occurred, patients could receive a maximum of 17 cycles in 52 weeks, hence 17 cycles was used as a threshold to assess long term safety. Ocular exams were performed prior to dosing belantamab mafodotin Q3W up to Cycle 6, then every 3 months if no significant ocular events were reported. Treatment-related ocular AEs were graded per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5 and per the Keratopathy Visual Acuity (KVA) scale. The KVA scale incorporates corneal examination findings and changes in Snellen-equivalent best corrected visual acuity (BCVA) into a composite grade. Ocular AEs are reported as worst-case post-baseline. Efficacy responses (per 2016 International Myeloma Working Group criteria) were assessed Q3W, regardless of treatment delays.

Results: As of September 12, 2022, 50/218 (23%) patients were treated with belantamab mafodotin for ≥52 weeks. AEs were reported in all patients treated with belantamab mafodotin for ≥52 weeks. Grade ≥3 AEs occurred in 82% (n=41); the most frequent were reduced visual acuity (24%), thrombocytopenia (18%), and neutropenia (16%). The majority of AEs reported occurred at or before cycle 17. For the most common (&gt;40%) AEs (any grade), few additional events occurred after cycle 17 (1 new occurrence each of dry eye, reduced visual acuity, eye irritation, and thrombocytopenia after cycle 17). Few infections (any grade) occurred after cycle 17 (COVID-19, n=5; viral infection, n=1; pneumonia influenzal, n=1). No patients permanently discontinued treatment due to AEs considered related to belantamab mafodotin. Ocular AEs were reported in 94% (n=47) of patients treated with belantamab mafodotin for ≥52 weeks. The majority of ocular AEs (n=487) were of Grade 1 or 2 severity (88%) and no ocular AEs led to study treatment discontinuation. At the time of data cutoff, 95% (n=41) of patients experiencing Grade ≥2 KVA events had recovered prior to the end of study treatment exposure (defined as last dose + 20 days). Most patients had a dose modification, and no loss of efficacy was observed. The clinical benefit rate (≥minimal response) in these patients was 90% (45/50) and the median time to best response was 6.3 months (range 0.8-18.8). Median duration of response was not reached (NR; 95% CI 17.9, NR) in the subset of patients treated for ≥52 weeks. At the time of data cutoff, 94% (n=47) patients were alive.

Conclusions: In patients who received long-term treatment (≥52 weeks), the safety profile of belantamab mafodotin was consistent with previous reports. Despite the need for belantamab mafodotin dose delays and reductions, no patients discontinued study treatment due to belantamab mafodotin-related AEs. During dose delays, clinical responses were maintained or deepened in most cases, demonstrating that management of AEs using dose modifications did not impact clinical activity. Together, this suggests that dose modifications are highly effective in the management of emerging AEs while allowing for sustained clinical benefit.

Funding: GSK (207495). Drug linker technology licensed from Seagen Inc.; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.