Preclinical and clinical evaluation of belantamab mafodotin based immunotherapy combinations in multiple myeloma
Mauro Lorenzo Mohamed
Centro de Investigación del Cáncer. Universidad de Salamanca - CSIC
Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal proliferation of malignant plasma cells within the bone marrow. Despite advances in therapy, most patients eventually relapse, highlighting the need for novel strategies that enhance anti-MM immunity. In this work, we explore the combination of belantamab mafodotin (belamaf), an anti-BCMA antibody-drug conjugate, with treatments approved for MM, including daratumumab, an anti-CD38 monoclonal antibody, and the triplet of bortezomib + lenalidomide + dexamethasone (VRd), as a strategy to potentiate immune-mediated cytotoxicity.
Our preclinical data show that belamaf monotherapy is effective at inducing cell death in MM models. When combined with daratumumab, we observe a synergistic increase in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), particularly at low doses of both drugs. This synergy was confirmed in a humanized NSG-CD34+ mouse model with a complete tumor eradication upon combination treatment accompanied by an enhanced immune profile, with an increase in effector immune cell populations in mice treated with the combination.
To further explore the immunological impact of belamaf in a clinical setting, we analyzed immune profiles from patients enrolled in the GEM-Bela-VRd clinical trial, which investigates the addition of belamaf to the standard VRd regimen in newly diagnosed transplant-eligible MM patients. Using a double-platform immunophenotyping strategy, we characterized immune responses at key treatment timepoints (screening, cycle 3, and end of induction). We observed a trend toward a more exhausted immune phenotype over time, particularly within T cells, while exhausted NK populations remained unchanged. Exploratory analyses also showed a progressive reduction in malignant plasma cells and increased expression of markers associated with immunogenic cell death. Absolute counts of CD8+ T cells and NK cells at screening emerged as potential biomarkers of response, with higher counts associated with deeper responses, both at early and late stages.
Together, these findings provide a strong preclinical rationale for the clinical development of the daratumumab and belamaf combination. In parallel, our immunomonitoring analyses within the GEM-Bela-VRd clinical trial highlight the relevance of tracking immune profiles before and during treatment, offering potential biomarkers to guide response assessment in multiple myeloma.