Daratumumab Is an Effective and Safe Salvage Therapy in Relapsed/Refractory Patients with Multiple Myeloma after Allogeneic Stem Cell Transplantation
Authors: Klyuchnikov Evgeny , von Pein Ute-Marie , Ayuk Francis A. , Christopeit Maximilian , Adjalle Raissa , van Randenborgh Andre , Wolschke Christine , Kröger Nicolaus 
Published: October 2019

Abstract
Daratumumab is a human monoclonal antibody that targets CD38, a cell surface protein that is overexpressed on multiple myeloma cells. Some clinical studies have shown encouraging efficacy and acceptable safety profile of daratumumab, so that the drug became the first monoclonal antibody as single agent therapy approved by the FDA for the treatment of multiple myeloma. The role of allo-SCT in myeloma patients remains unclear; nevertheless, the registry study of European Society for Blood and Marrow Transplantation (EBMT) suggests an increasing rate of allografts in Europe in last years. Despite the potentially curative potential of this approach, the increased relapse rate and low PFS remain a central clinical problem. In this single center retrospective analysis, we report on our experience on the use of daratumumab in relapsed/refractory myeloma patients after allo-SCT.
A total of 10 patients (male, n=5) with median age of 59 years (range, 37-69) relapsing after allo-SCTs that had been performed during a period 2008-2015 at the University of Hamburg and received daratumumab as single agent salvage therapy. Before allografting 8 patients received one and 2 patients ≥2 autografts, respectively. All but one patient received at least 1 salvage therapy line prior to the allo-SCT. The allografts were performed from unrelated donors (MUD, n=5; MMUD, n=3) or matched related donors (MRD, n=2). Five patients experienced early relapses (≤12 months) after allo-SCT. The median number of salvage lines post-transplant and prior to first daratumumab infusion was 3 (range, 1-4). The salvage regimens included bortezomib, lenalidomide, pomalidomide and carfilzomib. Daratumumab infusions were started at a median of 21 months (range, 2-30) after relapse/progress. The median number of infusions was 6 (range, 2-12). A total of 10 and 9 patients were available to safety and efficacy evaluation, respectively. The safety was assessed according to the Common Toxicity Criteria (CTC).
A total of 14 adverse events were observed in 9 patients: dyspnea (CTC1, n=2; CTC2, n=1), bronchospasm (CTC2, n=1) shivering (CTC1, n=3), cough (CTC1, n=1; CTC2, n=1), musculoskeletal pain (CTC1, n=2), acute coronary syndrome (CTC3, n=1), skin rush (CTC2, n=1), pressure on eyes (n=1). There were no cases of hematologic toxicity. There were no cases of GvHD. The adverse events appeared in all patients after the first infusion, with improved tolerance of following infusions. There were no cases, where the therapy had to be stopped due to adverse events.
Within a median follow-up of 25 months (range, 3-38) from the relapse/progression 9 of 10 patients remain alive. One patient died due to severe infection after progress of myeloma. A total of 5 of 9 evaluable patients responded (56%), of those 3 of 5 patients with early relapses (PR, n=2; vgPR, n=1). The responses (decrease of paraprotein and/or free light chains; reduction of extramedullary tumor in 1 patient) occurred at a median of 7 days (range, 7-22) after the first administration of daratumumab. The median response duration is 35 days (range, 7-84). All responding and 2 non-responding patients showed clinical improvement of constitutional symptoms. No patients required blood or platelets transfusions during and after the therapy. All responding patients maintain their responses 7, 14, 35, 54 and 84 days after the first administration of daratumumab.
Daratumumab demonstrated encouraging efficacy in relapsed/refractory patients with myeloma after allo-SCT. The administrations of the drug in these heavily pre-treated patients were associated with good safety profile and development in majority of cases non-severe adverse events mostly after the first infusion. Further studies on the use of daratumumab in post-transplant setting are warranted.

Disclosures
Kröger: Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding.