Introduction:

Belantamab Mafodotin (Belamaf) is a BCMA targeted antibody drug conjugate with a multi-modal mechanism of action including direct MMAF induced cellular cytotoxicity as well as immunogenic cell death. Belamaf in combination with bortezomib and dexamethasone (BVd) demonstrated superior progression-free and overall survival for patients with relapsed or refractory multiple myeloma (RRMM) compared to daratumumab, bortezomib and dexamethasone (DREAMM-7 trial) leading to regulatory approvals. However, the mean Belamaf compliance when dosed Q3W in DREAMM-7 was 51%, decreasing as treatment progressed (77% 0-6m, 68% 6-12m, 28% >12m) suggesting that further optimisation of the schedule is possible.

Ocular adverse events with Belamaf mean eye examinations are recommended prior to dosing, adding to the treatment burden for patients and placing additional demands on healthcare resources. The Ocular Surface Disease Index (OSDI), a patient questionnaire, was retrospectively evaluated in the DREAMM-2 trial as a potential surrogate for ocular examinations. Notably, a negative questionnaire was able to rule out grade 3-4 keratopathy in 93.5% of examinations (Popat et al., ASH 2021). This questionnaire was adjusted to a 9-item Visual Related Anamnestic Tool (VRAT) to assess eye symptoms and vision related function. This can be used by healthcare professionals to evaluate ocular side-effects associated with Belamaf, potentially streamlining monitoring and improving patient experience.

Methods

ProMMise is phase I/II muti-centre platform trial investigating Belamaf combinations for patients with RRMM after 1-3 prior lines of therapy. The ProMMise D arm will be conducted in two stages, with a primary objective of determining if BVd can be safely given using the VRAT without the need for mandated eye examinations. Secondary objectives include: to assess the agreement between the VRAT and eye care specialist-led dosing, and to assess treatment compliance and efficacy using a less intensive dosing schedule without eye assessments.

In stage 1, 40 patients will have eye assessments prior to the first 3 doses as well as completing the VRAT. Dosing will be interrupted for ≥ grade 3 events or a positive VRAT. A safety assessment for the use of the VRAT will be performed following this by an independent Safety Review Committee. Thereafter, Stage 2 will enrol 60 patients with no mandated on-treatment eye assessments and ocular adverse events assessed using the VRAT alone prior to each Belamaf dose. If the questionnaire is positive, treatment will be interrupted. A multiple outcome Bayesian monitoring strategy will be used to monitor ocular toxicity in the short-term for participant safety and in the longer-term to assess the suitability of this approach.

Patients will receive BVd in a less intensive schedule to DREAMM-7 based on the trial post-hoc analysis of actual treatment received to improve Belamaf compliance. A weekly bortezomib schedule is used in line with real world practice to reduce peripheral neuropathy, with home administration permissible for patient convenience.

The ProMMise D schedule being evaluated is: Belamaf 2.5mg/kg for cycle 1 then 1.9mg/kg Q8W with bortezomib 1.3mg/m2 s.c. and 40mg dexamethasone weekly for 6 months. Following that, Belamaf monotherapy maintenance will commence Q12W until disease progression or intolerance.

Progress

ProMMise D gained regulatory approval in December 2024. Enrolment is ongoing with results from Stage 1 expected in the first half of 2026.

Conclusions

The ProMMise D trial aims to investigate a patient-centred approach to delivering Belamaf with bortezomib and dexamethasone with less intensive dosing to improve compliance and replacing ocular examinations with a simple questionnaire (VRAT).

Funding

GSK provided funding and Belamaf supply. This study was also supported by Myeloma UK through the UKMRA-MUK- concept and access research programme. Trial registration number: ISRCTN19869915

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2025
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