A retrospective analysis from the University of Catania, Italy has demonstrated that Pepaxti (melphalan flufenamide or melflufen), in combination with dexamethasone, shows effectiveness and tolerability in heavily pretreated patients with relapsed, refractory multiple myeloma (RRMM).
The single-center study, presented at the 6th European Myeloma Network Meeting in Athens, Greece, included eight patients with triple-class refractory RRMM who had received a median of 3.5 prior lines of therapy. Despite this extensive treatment history, Pepaxti achieved an overall response rate of 37.5%, with three patients achieving partial responses.
"Our experience adds to the growing body of real-world evidence on melflufen in relapsed and refractory myeloma. Even in a high-risk patient cohort, we observed encouraging disease control with a manageable safety profile," said Dr. Etta Conticello from the Division of Haematology at Azienda Policlinico-S. Marco, University of Catania.
Patient Characteristics and Treatment Response
The study population had a median age of 68.5 years (range 56-81), with three patients aged 70 or older. Four patients presented with extramedullary disease, including two with intracranial involvement, one with hepatic, and one with paraosseus disease. One patient had plasmacellular leukemia.
All patients were triple-class refractory, having previously received treatments including proteasome inhibitors, immunomodulatory drugs (lenalidomide and pomalidomide), and anti-CD38 monoclonal antibodies. Four patients had undergone prior autologous transplantation.
Beyond the three partial responses, one patient achieved minimal response and two maintained stable disease. Only two patients experienced disease progression. The median overall survival was not reached, with a predicted 8-month overall survival rate of 87%.
Safety Profile and Management
The primary adverse events were hematologic toxicities, including grade ≥3 anemia (two patients), grade ≥3 thrombocytopenia (three patients), and grade ≥3 neutropenia (two patients). These side effects were managed through dose delays, reductions, and supportive care measures such as transfusions and growth factors.
Three patients required a 50% dose reduction, and one patient needed a treatment delay of approximately two months due to hematologic toxicity. There was one patient death attributed to pneumonia.
Regulatory Status and Clinical Implications
Pepaxti is currently approved in Europe for RRMM patients who have received at least three prior lines of therapy and whose disease has progressed on or after their last treatment. However, in the United States, the FDA withdrew its approval for the drug (marketed as Pepaxto) in February 2024.
Stefan Norin, Chief Medical Officer at Oncopeptides, the developer of Pepaxti, commented: "These real-world findings provide further support for Pepaxti's potential benefit in heavily pretreated patients, including those with aggressive disease phenotypes."
Bruno Bolognese, Head of European Medical Affairs at Oncopeptides, added: "It is truly encouraging to see how real-world clinical experience continues to confirm the potential of Pepaxti in treating patients with advanced multiple myeloma. Close collaboration with the medical community is essential as we work to address the significant unmet needs of patients with limited treatment options."
Multiple Myeloma Treatment Landscape
Multiple myeloma remains an incurable blood cancer characterized by the abnormal proliferation of plasma cells in the bone marrow. Despite advances in treatment, patients who become refractory to established therapies including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies face limited options.
The findings from this real-world study align with results from the HORIZON trial, further supporting Pepaxti's role in addressing the significant unmet needs of heavily pretreated RRMM patients. The ability to achieve responses even in patients with high-risk features such as extramedullary disease is particularly noteworthy, as these patients typically have poor outcomes with conventional therapies.
As the treatment landscape for multiple myeloma continues to evolve, real-world evidence becomes increasingly important in understanding how novel therapies perform outside the controlled environment of clinical trials, particularly in patients with advanced disease and limited therapeutic options.
