The antibody drug conjugate belantamab mafodotin recently became the first BCMA-directed agent to receive EMA registration and as from January 1 2022 also reimbursement in Belgium as monotherapy for the treatment of adult multiple myeloma (MM) patients, who received at least four prior therapies and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.1 According to Prof. Michel Delforge (University Hospitals Leuven), this is a notoriously difficult to treat population for whom we don’t have many therapeutic options. As such, the registration and reimbursement of this agent, which has a completely different mode of action than all other antimyeloma drugs, offers heavily pretreated MM patients a truly alternative treatment option.
The current backbone of the treatment for MM patients is made up of proteasome inhibitors (PIs), immunomodulatory agents (IMIDs) and monoclonal antibodies directed against CD38. Throughout the treatment course, different combinations of these drug classes are being used resulting in an unprecedented survival benefit for patients with MM. However, the depth and the duration of response in patients diminish with every subsequent therapy and a proportion of patients ultimately becomes refractory to PIs, IMIDs, and monoclonal antibodies. Therapeutic options for these patients are limited and they face a very dismal prognosis, underscoring the need for new treatment options with an alternative mode of action.2 One of the better studied alternative treatment strategies consists of targeting BCMA, a cell-membrane receptor that is abundantly expressed on malignant plasma cells.
In this light, the phase II DREAMM-2 trial evaluated the anti-BCMA antibody drug conjugate (ADC) belantamab mafodotin in RRMM and disease progression after ≥3 lines of therapy.3,4 To be eligible for the study, patients had to be refractory to IMIDs and PIs, and be refractory or intolerant to an anti-CD38 monoclonal antibody. In total, 97 patients were included in the approved dosing arm of 2.5 mg/kg. In this cohort, an overall response rate of 32% was reported, with a median duration of response of 11 months at 13 months follow-up.4 According to Prof. Delforge, this excellent response durability is the most important clinical benefit of belantamab mafodotin. “This finding is also very much in line with my personal experience with this agent. In fact, all patients that I treated with belantamab mafodotin and responded are currently still on treatment and continue to be in remission.” The median overall and progression-free survival of patients treated with 2.5 mg/kg of belantamab mafodotin were reported at 13.7 and 2.8 months, respectively.3,4 Among patients who obtained a partial response or better (representing 58% of responders), the 1-year estimated OS rate was 87%. Response rates to belantamab mafodotin were consistent across investigated subgroups, including patients with mild or moderate renal impairment (ORR: 33%) and patients with high-risk cytogenetics (ORR: 29%).3,4
Overall, 84% of patients treated with belantamab mafodotin experienced a grade ≥3 adverse event (AE).3 The most common of these grade ≥3 AEs consists of keratopathy (46%). Prof Delforge: “Keratopathy is indeed common with this agent, but it is relatively easy to manage through dose modifications or treatment interruptions and rarely requires permanent treatment discontinuation. Also prolonging the dosing interval from 3 to 4 weeks is effective in dealing with this AE. To monitor patients for keratopathy every patient needs to see an ophthalmologist prior to at least the first 3 belantamab mafodotin infusion cycles and all patients also receive prophylactic eye drops to prevent them from developing dry eyes. Finally, we also give them a vasoconstrictor and a cold eye mask during the infusion to minimize the uptake of the drug in the eyes.”
Although dose modifications (delays [54%] or reductions [33%]) to manage AEs were common in DREAMM-2, these modifications did not have an impact on responses to belantamab mafodotin. In fact, a high proportion of patients (88%) with a clinical response who had prolonged dose interruptions continued to have clinical benefit after their first delay. In addition, clinical responses were generally also maintained in patients who had >1 prolonged dose delay. The rate of permanent treatment discontinuation was low at only 9%.
In brief, the anti-BCMA ADC belantamab mafodotin induces durable clinical responses in about a third of patients with RRMM with refractoriness to IMIDs and PIs, and refractoriness or intolerance to an anti-CD38 antibody. The agent comes with a tolerable safety profile that can easily be managed by dose modifications. As such, belantamab mafodotin monotherapy represents a well-tolerated and effective new treatment option for this difficult-to-treat patient population.
References
This article has been realised with the contribution of GlaxoSmithKline
PM-BE-BLM-ADVR-210002 – December 2021
SmPC: https://www.e-compendium.be/nl/bijsluiters/wetenschappelijk/7919/18882
Please report adverse events to the Belgian Centre for Pharmacovigilance for medicines for Human use of the Federal Agency for Medicines and Health Products adversedrugreactions@afmps.be or via the ‘yellow card’ available on www.fagg-afmps.be or to GlaxoSmithKline Pharmaceuticals s.a./n.v. 010/ 85 85 00.
