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Consultant in Hematology
Department of Hematology, Clínica Universidad de Navarra
University of Navarra
Paula Rodriquez-Otero, MD, PhD, has disclosed that she has received consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Kite, Oncopeptides, and Sanofi and fees for non-CME/CE services from Amgen, Bristol-Myers Squibb, and Celgene.
Although there are numerous therapies available for relapsed/refractory (R/R) multiple myeloma (MM), patients who are refractory to the 3 main classes of agents used—anti-CD38 antibodies, proteasome inhibitors, and immunomodulatory agents—have limited treatment options and poor outcomes. The median OS is approximately 9 months and the median PFS is 3-4 months for patients who are triple refractory. Targeting the B-cell maturation antigen (BCMA) is one novel therapeutic strategy. BCMA plays a role in B-cell maturation and differentiation, and BCMA expression is restricted to plasma cells, including myeloma plasma cells. Belantamab mafodotin is a BCMA-targeted antibody–drug conjugate with monomethyl auristatin F as the cytotoxic agent.
On August 5, 2020, the FDA granted accelerated approval to belantamab mafodotin-blmf for use in adult patients with R/R MM after 4 or more previous therapies. Previous therapies must include an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. The recommended dosing of belantamab mafodotin is 2.5 mg/kg every 3 weeks given via IV infusion over 30 minutes.
Efficacy and Safety of Belantamab Mafodotin
The phase II DREAMM-2 study enrolled patients with MM who were refractory to lenalidomide, proteasome inhibitors, and anti-CD38 monoclonal antibodies after 3 or more lines of therapy. Patients in this study were heavily pretreated with a median of 6-7 previous lines of therapy depending on the cohort. The study used 2 doses of belantamab mafodotin—2.5 mg/kg and 3.4 mg/kg—and the ORR was 31% and 35%, respectively. Even though the ORR is not very high, in my opinion, a key result is that responses are durable, with a median duration of response of 11 months at the 2.5-mg/kg dose, which is a long time in this setting. The median PFS with this dose was 2.8 months and median OS was 13.7 months.
Regarding safety, we know that there are 2 important adverse events associated with belantamab mafodotin. The first is corneal events and keratopathy that was present in 73% to 77% of the patients treated at the 2 different doses, with grade ≥ 3 events reported in 42% to 45% of the patients. Keratopathy was reversible and manageable with ophthalmic care. The second common adverse event associated with belantamab mafodotin is thrombocytopenia that was reported in 38% of the patients treated with the 2.5-mg/kg dose and was grade ≥ 3 in 22% of the patients.
Integrating Belantamab Mafodotin Into the Clinic
One of the key things to be aware of with belantamab mafodotin is the high frequency of ocular adverse events. The accelerated approval of belantamab mafodotin carries a boxed warning about changes in the corneal epithelium that may result in vision changes. Ophthalmologist examinations are required at baseline and after each dose. Patients need regular ophthalmology examinations, especially during the first 4 months of therapy. Of note, there is a discrepancy between ocular findings and patient-reported symptoms. Only approximately 25% of patients report ocular-related symptoms, such as dry eye and vision changes, whereas ocular findings occur in approximately 75% of the patients. It is important to note that dry eye or other ocular problems may play a role in ocular toxicity associated with therapy, and a differential diagnosis is required. Patients with glaucoma, dry eye, diabetes, or other ocular problems are at higher risk for this toxicity and need to be monitored carefully. The underlying mechanism is the formation of cysts that begin in the periphery of the cornea but may move to the center of the cornea, resulting in symptoms. If cysts are detected upon ophthalmologic examination, the dose of belantamab mafodotin should the decreased or dose delayed to prevent further damage in the cornea. In the DREAMM-2 trial, responses were maintained in patients with dose decreases or dose delay.
Ongoing Studies of Belantamab Mafodotin
Despite continuous improvement in survival and the incorporation of several new treatments, patients with MM continue to relapse and additional therapies are needed, particularly for patients with triple‑class‑refractory disease. BCMA has proven to be a good target, resulting in the approval of the new therapy belantamab mafodotin for patients with R/R MM. Additional clinical trials of belantamab mafodotin alone or in combination with other therapies for R/R MM are currently underway. Preliminary results from the phase II DREAMM-6 trial (NCT03544281) of belantamab mafodotin plus bortezomib/dexamethasone showed no unexpected safety signals and a promising ORR of 78%. Key phase III studies with this agent include the DREAMM-3 trial (NCT04162210) comparing belantamab mafodotin vs pomalidomide/dexamethasone; the DREAMM-8 trial (NCT04484623) comparing belantamab mafodotin plus pomalidomide/dexamethasone vs bortezomib plus pomalidomide/dexamethasone; and the DREAMM-7 trial (NCT04246047) comparing bortezomib/dexamethasone plus either belantamab mafodotin or daratumumab. We await results from these trials with hope for better outcomes for patients with R/R MM.
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