Modification of belantamab mafodotin dosing to balance efficacy and tolerability in the DREAMM-7 and DREAMM-8 trials

Abstract

Belantamab mafodotin (belamaf) combined with standard therapies demonstrated significant progression-free survival (PFS) and overall survival benefits in DREAMM-7 and PFS benefit in DREAMM-8 in relapsed/refractory multiple myeloma. Belamaf dose modifications managed adverse events, including belamaf-related ocular events. Ocular events included ocular adverse reactions (eg, dry eyes, photophobia, eye irritation) and protocol-mandated ophthalmic examination findings. Protocol-recommended dose modifications for ocular events were driven by ophthalmic examination findings and included belamaf dose delays until resolution and reductions. We used descriptive analyses to evaluate the impact of dose modifications on managing ocular events and treatment efficacy. In patients with normal baseline vision who were receiving treatment, dose modifications extended belamaf dosing intervals to a median of 8 to 12 weeks by 9 months; the prevalences of reduced vision to bilateral 20/50 or worse and ocular adverse reactions were highest in the first 3 months and remained low at later time points. The median time to resolution after grade ≥2 ophthalmic examination findings was 12 weeks. Rates of belamaf discontinuations due to ocular events were low. Almost all responders (partial response or better) required dose modifications. Most patients achieved a response before an extended (>2 cycles) dose delay; most who had not, subsequently achieved or deepened their response. In DREAMM-7 and DREAMM-8, the median PFS in patients with ≥1 dose delay of ≥12 weeks was 36.6 months and not reached, respectively. Ocular events were common but effectively managed with dose modifications, allowing for patients to remain on treatment and derive robust efficacy benefit. The trials were registered at www.clinicaltrials.gov as #NCT04246047 (DREAMM-7) and #NCT04484623 (DREAMM-8).

Graphical abstract

Figure 1.

Ocular event management. (A-B) Ocular ARs and OEFs were used to assess ocular events (A) and OEFs drove protocol-recommended belamaf dose modification (B). ∗Examination findings were reported as AEs before implementation of KVA scale. ^†Dose modification should be based on the most severe finding. If eyes differ in severity, the dose modification guideline should be applied based on the more severe eye. ^‡Corneal ulcer is defined as an epithelial defect with underlying stromal infiltration. ^§Changes in visual acuity due to treatment-related corneal findings. CTCAE, Common Terminology Criteria for Adverse Events; NA, not applicable; Q3W, every 3 weeks.

Figure 2.

Reading and driving in patients with normal baseline BCVA (20/25 or better in ≥1 eye) who received BVd in DREAMM-7 and BPd in DREAMM-8. Post hoc pooled analysis (BVd and BPd) of reading (A) and driving (B) in patients who had BCVA of 20/25 or better in ≥1 eye at baseline by time intervals since the first belamaf dose. (C) Summary of patients who stopped reading and driving. ∗Patients who could read with little or no difficulty or read with some difficulty at baseline, mainly due to eyesight issues, were considered, whereas those who stopped reading due to other reasons during follow-up were excluded. ^†The first 2.5 years of treatment are shown due to the limited number of patients at risk beyond this time point. ^‡Patients who could drive with little or no difficulty or drive with some difficulty at baseline, mainly due to eyesight issues, were considered, whereas those who stopped driving due to other reasons during follow-up were excluded. ^§Occurrences before the treatment end date are considered. ^||Time not being able to read/drive is the sum of days from when the patient stopped reading/driving to reading/driving with no, little, or some difficulty or the end of belamaf treatment, whichever is earlier, divided by the duration of belamaf treatment. EOT, end of treatment; IQR, interquartile range.

Figure 3.

Median dosing interval and ocular events. (A-B) Post hoc analyses that included only treated patients who had BCVA of 20/25 or better in ≥1 eye at baseline in DREAMM-7 (n = 211; A) and DREAMM-8 (n = 137; B). The graph only shows the occurrence of bilateral 20/50 or worse BCVA changes, overall median of the average time between belamaf doses, and discontinuation of belamaf due to ocular events in each time interval while patients remained on belamaf treatment. The incidence rate at each time point is based on the number of patients who remained on treatment at that time point and does not reflect the overall risk of developing bilateral worsening of 20/50 or greater or discontinuing due to an ocular event at any time during belamaf treatment. The increased time between doses is due to AEs, including ocular events, and other non–AE-related reasons. This graph does not detail any efficacy parameter over time. ∗Median of average days between doses for each patient per interval was used and converted to weeks. ^†For DREAMM-7, events during the initial 2.5 years of treatment are shown due to limited number of patients at risk beyond this time point. ^‡For DREAMM-8, the first 2 years of treatment are shown due to limited number of patients at risk beyond this time point. CTCAE, Common Terminology Criteria for Adverse Events; IQR, interquartile range.

Figure 4.

Summary of best response after the first extended dose delay of belamaf. (A-B) Post hoc analysis of DREAMM-7 (A) and DREAMM-8 (B) evaluating best response in patients on treatment before the first extended dose delay and after the first extended dose delay at any time (left graph) or after 1 to 2 doses (right graph). The first extended dose delay was defined as lasting >2 cycles, which in DREAMM-7 was >42 days and in DREAMM-8 was >56 days. CR, complete response; MR, minimal response; NE, not evaluable; PD, progressive disease; sCR, stringent complete response; SD, stable disease; VGPR, very good PR.

Figure 5.

PFS in patients with ≥1 extended belamaf dose delay of ≥12 weeks. (A-B) Post hoc analysis evaluating patients who had ≥1 belamaf dose delay of ≥12 weeks in (A) DREAMM-7 (BVd, n = 146) and (B) DREAMM-8 (BPd, n = 98). NR, not reached.