Less Is More: Deciphering the Association between Ocular Adverse Events and Clinical Activity of Belantamab Mafodotin in Multiple Myeloma

Introduction Belantamab mafodotin (belamaf; GSK2857916) has demonstrated important efficacy and tolerability in patients (pts) with relapsed/refractory multiple myeloma (MM). Ocular adverse events (OAEs; best corrected visual acuity [BCVA] change from baseline and keratopathy) are the most common adverse events (AEs) observed with belamaf and the main reason for dose holds and delays. However, the effect of OAE-related dose modifications on treatment efficacy has not been investigated. Herein, we present data from the BelaRd study, evaluating belamaf plus lenalidomide/dexamethasone (Rd) in transplant-ineligible pts with newly diagnosed MM, that offer insights on the association between OAEs and belamaf's clinical activity. Methods The ongoing phase 1/2 BelaRd study (NCT04808037) comprises 2 Parts. Part 1 evaluates the safety/tolerability of three different belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd and established the recommended phase 2 dose (RP2D) of 1.9 mg/kg Q8W/Q12W. Part 2 assesses the safety/efficacy of RP2D in Groups A and B and evaluates two belamaf dosing guidelines for managing OAEs. In this trial, belamaf is initially administered Q8W and, depending on OAEs, dosing may be adjusted to Q12W. Ocular exams are performed by an ophthalmologist and include Snellen BCVA and slit-lamp corneal evaluation, while OAEs are graded with the Keratopathy Visual Acuity scale. In Part 1 and in Group A, belamaf dosing is permitted when OAEs are Gr0-1, while dosing is held at OAEs Gr2-4, until their resolution to Gr ≤1. In Group B, dosing is determined by the novel Vision-Related Anamnestic tool and the presence of Gr ≥3 OAEs identified in an ophthalmic exam. We present safety/efficacy results over an extensive follow-up period for both Parts (cut-off date 15/05/24). Results This analysis includes all pts from both Parts of the trial who have completed three cycles of treatment (n=65; median age: 74.0 years; male: 38 [58.5%]), of whom 49 (75.4%) are still on treatment and 16 (24.6%) discontinued (11 [16.9%] fatal events; 3 [4.6%] consent withdrawal; 2 [3.1%] progressive disease). By the clinical cut-off (CCO) date of this analysis, 52/65 (80%) pts have switched to the Q12W dosing schedule. The interval between the first belamaf dose and the first manifestation of a Gr≥2 OAE varied greatly among pts and can be used to divide them into two hypothetical groups. The first group consists of pts who had a Gr2-4 OAE within the first three months of treatment (Group 1; 19/65, 29.2%). The second group consists of pts who only had Gr0-1 OAEs during this time (Group 2; 46/65, 70.8%). By the CCO date, 68.4% of Group 1 pts had achieved a ≥CR response, while the respective proportion in Group 2 was 37.0%. Importantly, this trend was observed across all three dose levels of this analysis. The proportions of ≥CR responses were 100%, 57.2% and 100.0% for Group 1 and 57.2%, 28.6% and 45.5% for Group 2 for the dose levels of 2.5, 1.9 and 1.4 mg/kg, respectively. Additionally, for Groups 1 and 2, the median (range) from the 3-month landmark time to CR in months was 11.76 (4.37-13.90) and 23.29 (8.67-NR), respectively. The median (Q1-Q3) duration of the interval between belamaf doses was 13.1 (10.3-18.6)/11.9 (8.0-13.3) weeks for Groups 1 and 2, respectively, while the respective belamaf cumulative dose intensities were 0.543/0.625 mg/month. Finally, at a median follow-up of 19.8 months, all pts who achieved a ≥CR response had previously manifested Gr2-4 OAEs, while pts who only had Gr0-1 OAEs achieved ≤VGPR. Conclusions Our analyses highlight the complex association between OAEs and clinical activity, indicating the idiosyncratic nature of a patient's response to belamaf in terms of ocular toxicity and efficacy. Indeed, our data reveal that early manifestation of at least moderately severe OAEs (Gr≥2) correspond to early deep responses, a phenomenon observed across all dose levels. Additionally, dose intensity (DI) does not have a linear association with hematologic response, as pts with lower cumulative DI manifested deeper responses. Furthermore, an extended dosing interval due to OAEs is also a hallmark of better efficacy. Conclusively, OAEs, the most common AEs of belamaf that are responsible for dose modifications, may have a predictive and, potentially, also a prognostic role. Moving forward, the association between OAEs and efficacy warrants further investigation in larger sample sizes.