P983: dreamm-20: a study to investigate the safety and efficacy of belantamab for the treatment of multiple myeloma when used as monotherapy and in combination treatments

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Multiple myeloma (MM) is an incurable malignant clonal plasma cell disorder and accounts for 1% of all cancers and 10% of all hematologic malignancies globally. Treatments for MM include combinations of proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies, alkylating agents, and corticosteroids, as well as the newer chimeric antigen receptor (CAR) T-cell therapies, antibody-drug conjugates (ADCs), and bispecific antibodies. As relapse usually occurs, there is a high unmet need for new effective treatments with better safety profiles, given the toxicity of current standards of care and emerging treatments. B-cell maturation antigen (BCMA), a cell surface receptor expressed on B-lymphocytes and plasma cells, is upregulated on MM cells. BCMA has been clinically validated as a target for treatment of MM. Belantamab (GSK2857914) is a humanized afucosylated IgG1 monoclonal antibody targeting BCMA. Belantamab shares the same monoclonal antibody structure as the ADC belantamab mafodotin but without the conjugated monomethyl auristatin-F payload. Based on preclinical data, the mechanism of action of belantamab is antibody-dependent cellular cytotoxicity through increased FcγRIII binding, antibody-dependent cellular phagocytosis, and blocking of BCMA-mediated pro-survival and proliferative signaling. Belantamab is active in vitro against MM cell lines and primary patient samples, and in mouse xenografts; preclinical evidence supports clinical investigation for MM. Aims: To evaluate the safety, tolerability, and antitumor activity of belantamab monotherapy and combination treatments in adults with MM. Methods: Part 1 of DREAMM-20 is a phase 1, open-label, multicenter, dose-escalation study of patients with relapsed or refractory MM to determine the safety, tolerability, and recommended Part 2 dose for belantamab. Inclusion criteria include patients aged ≥18 years with confirmed MM (defined by the International Myeloma Working Group [IMWG]), measurable disease, Eastern Cooperative Oncology Group performance status of 0-2, and adequate organ system function. Patients must have received at least 3 prior lines of therapy, which included an immunomodulatory agent, PI, and an anti-CD38 antibody (unless contraindicated or unavailable). Prior receipt of BCMA-targeted agents is allowed. Key exclusion criteria include current corneal epithelial disease except nonconfluent superficial punctate keratitis, signs of meningeal or CNS involvement with MM, and evidence of cardiovascular risks. Patients must provide informed consent to participate. Patients will receive belantamab via intravenous infusion on days 1 and 15 of 28-day cycles. Dose-escalation is conducted using the modified toxicity probability interval method. The primary endpoint is the incidence of adverse events, including dose-limiting toxicities, which will be assessed using National Cancer Institute-Common Toxicity Criteria for Adverse Events v5.0. Secondary endpoints include pharmacokinetics, incidence of anti-drug antibodies, and overall response rate (assessed per the 2016 IMWG criteria). Exploratory endpoints include pharmacodynamics and quality of life, longitudinal soluble BCMA and M-protein levels, along with other biomarker assessments. Biomarker and pharmacokinetic evaluations will be performed on peripheral blood and bone marrow. Results: The data from Part 1 will be used to inform the dose(s), schedule, and potential combination partners for subsequent study Parts. Summary/Conclusion: The trial is sponsored by GSK and registered at clinicaltrials.gov (NCT05714839). Keywords: Phase I, relapsed/refractory, Multiple myeloma, B-cell maturation antigen