The Medicines and Healthcare products Regulatory Agency (MHRA) has granted marketing authorisations for belantamab mafodotin (GSK; Blenrep) in two combination regimens for the treatment of relapsed or refractory multiple myeloma (RRMM) in adults making these the first approvals of belantamab mafodotin combination therapy anywhere in the world. The first authorisation covers belantamab mafodotin in combination with bortezomib and dexamethasone for adults with RRMM who have received at least one prior line of therapy. The second covers the combination with pomalidomide and dexamethasone for adults who have received at least one prior therapy including lenalidomide.
Both authorisations were granted on the basis of Phase 3 data from the DREAMM-7 and DREAMM-8 trials respectively, and both were supported by a commercial access agreement between GSK and NHS England that preceded or accompanied the regulatory decision. The timing of the MHRA decisions ahead of equivalent regulatory action in the EU or US for these specific combination indications represents a meaningful instance of post-Brexit UK regulatory leadership in oncology.
What the DREAMM-7 Trial Found
DREAMM-7 was a multicentre, open-label, randomised Phase 3 trial comparing belantamab mafodotin in combination with bortezomib and dexamethasone (BVd) versus daratumumab plus bortezomib and dexamethasone (DVd) in 494 patients with RRMM who had received at least one prior line of therapy. Randomisation was 1:1. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee.
At a prespecified interim analysis with a median follow-up of 28.2 months, median PFS was 36.6 months in the BVd arm versus 13.4 months in the DVd arm (HR 0.41; 95% CI: 0.31 to 0.53; p < 0.001). This represents a 59% relative reduction in the risk of disease progression or death. The absolute PFS difference of over 23 months at median represents one of the largest PFS improvements reported in a randomised myeloma trial against an active comparator in this line of therapy. Overall survival data were immature at the time of the interim analysis and are not yet available to confirm whether the PFS benefit translates into a survival advantage.
These are interim analysis data. Confirming whether the PFS benefit translates into overall survival will require continued follow-up and a future analysis at the pre-specified OS endpoint. Prescribers and payers should note that MHRA granted authorisation on the basis of PFS an accepted surrogate endpoint in multiple myeloma rather than confirmed OS benefit.
The trial was funded by GlaxoSmithKline. Multiple investigators declared relationships with GSK and other pharmaceutical companies with products in multiple myeloma, which is consistent with the landscape of academic-industry collaboration in this therapeutic area.
What the DREAMM-8 Trial Found
DREAMM-8 was a multicentre, open-label, randomised Phase 3 trial comparing belantamab mafodotin in combination with pomalidomide and dexamethasone (BPd) versus bortezomib plus pomalidomide and dexamethasone (PVd) in patients with RRMM who had received at least one prior therapy including lenalidomide. The trial enrolled 302 patients and randomised them 1:1. The primary endpoint was PFS by independent review committee assessment.
At a prespecified interim analysis, median PFS was not reached in the BPd arm versus 12.7 months in the PVd arm (HR 0.52; 95% CI: 0.37 to 0.73; p < 0.001). The DREAMM-8 PFS hazard ratio of 0.52 represents a 48% relative reduction in the risk of progression or death, and the fact that median PFS had not been reached in the BPd arm at the time of analysis reflects sustained response durability in a population where second- and third-line therapy options beyond lenalidomide are a significant unmet need.
As with DREAMM-7, overall survival data are immature and the PFS results represent interim analysis data rather than final analysis. The open-label design of both DREAMM trials is a limitation inherent to the regimens involved, doubly blinding a regimen containing an intravenous antibody-drug conjugate against an active comparator containing a different intravenous agent is operationally complex, but it introduces the possibility of investigator and assessor bias in response evaluation that the independent review committee adjudication was designed to mitigate.
Real fact: DREAMM-7 reported a median progression-free survival of 36.6 months for belantamab mafodotin plus bortezomib and dexamethasone versus 13.4 months for the daratumumab-based comparator, a 23-month median PFS difference that is among the largest reported in any randomised multiple myeloma trial to date in the relapsed setting.
The Mechanism Behind the Clinical Activity
Belantamab mafodotin is an antibody-drug conjugate (ADC) comprising a humanised anti-BCMA (B-cell maturation antigen) IgG1 monoclonal antibody conjugated via a non-cleavable maleimidocaproyl linker to monomethyl auristatin F (MMAF), a microtubule-disrupting cytotoxic payload. BCMA is a member of the tumour necrosis factor receptor superfamily expressed on the surface of normal and malignant plasma cells, with expression levels that are consistently higher on myeloma cells than on most other cell types making it a rational therapeutic target in multiple myeloma.
The ADC mechanism delivers cytotoxic payload directly to BCMA-expressing myeloma cells through receptor-mediated internalisation, bypassing much of the systemic toxicity associated with unconjugated cytotoxic chemotherapy. The non-cleavable linker design means that payload release occurs through lysosomal degradation of the antibody rather than linker cleavage in the tumour microenvironment a distinction from cleavable-linker ADCs that affects both the intracellular payload concentration achieved and the bystander killing effect. The MMAF payload inhibits tubulin polymerisation, arresting cells in mitosis and triggering apoptosis.
The characteristic adverse effect of belantamab mafodotin corneal events including keratopathy, blurred vision, and reduced visual acuity arises from MMAF payload exposure in corneal epithelial cells, which express low levels of BCMA. This is classified as an adverse drug reaction under the mechanism of action rather than an off-target toxicity, and its management requires ophthalmological monitoring at baseline and at defined intervals throughout treatment. Dose modifications and dose delays based on the grade of corneal findings are built into the licensed dosing schedule.
Regulatory and Access Context
The MHRA authorisations for the BVd and BPd combinations are firsts in the world for these specific indication/regimen pairs. The FDA had previously authorised belantamab mafodotin as a monotherapy in 2020 before voluntarily withdrawing it from the US market in 2022 when confirmatory trial data did not meet post-marketing requirements a regulatory history that makes the DREAMM-7 and DREAMM-8 combination data and the UK's first-in-world combination approval position more clinically and commercially significant than they might otherwise appear. The FDA has since received regulatory submissions for the combination indications, and the FDA position on BVd and BPd was pending at the time of the MHRA decisions.
For NHS patients, the access position depends on NICE completing a technology appraisal for the combination regimens. In haematological malignancies, the Cancer Drugs Fund frequently provides interim access while NICE appraisals are completed; the MHRA authorisation date establishes the point from which CDF funding eligibility can be considered.
What to Watch For
The immediate clinical priority for NHS haematology teams is monitoring NICE's decision on whether to recommend BVd and BPd for NHS use and at what access conditions. Overall survival maturation from both DREAMM trials expected over the next two to three years will be the most important data readout for confirming the clinical value of these regimens and supporting long-term NHS commissioning decisions. The FDA decision on the combination indications will also be closely watched, both for its clinical implications and for the commercial access dynamics it produces globally.
Corneal adverse event management protocols should be established at treating centres in advance of patient initiation the keratopathy management requirement means that ophthalmology access and the capacity to perform slit-lamp examinations on defined schedules must be in place before the first patient receives treatment. Like a dual-key system that requires both components to be active simultaneously, the clinical benefit of belantamab mafodotin and the ophthalmological monitoring programme are inseparable the evidence for efficacy and the requirement for active safety management were generated and approved together.
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