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      A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis

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          Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light-chain amyloidosis (AL). We report the results of a prospective multicenter phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) >50 mg/L were included in 15 centers between September of 2016 and April of 2018. Patients received 6 28-day cycles of IV daratumumab, every week for cycles 1 and 2 and every 2 weeks for cycles 3 through 6. Median age was 69 years (range, 45-83). Twenty-six patients had ≥2 organs involved, with heart in 24 and kidney in 26. Median time from diagnosis to enrollment was 23 months (interquartile range, 4-122), with a median of 3 prior therapies (range, 1-5). At data cutoff (September of 2019), all patients discontinued therapy; 33 received the planned 6 cycles. Overall, 22 patients had hematological response, and 19 patients (47.5%) achieved very good partial response (dFLC <40 mg/L) or better. Median time to hematological response was 1 week. Patients with no response after 4 doses were unlikely to respond further. Renal and cardiac responses occurred in 8 and 7 patients, respectively. Daratumumab was well tolerated, with no unexpected adverse events. With a median follow-up of 26 months, the 2-year overall survival rate was 74% (95% confidence interval, 62-81). Daratumumab monotherapy is associated with deep and rapid hematological responses in previously treated AL patients, with a good safety profile. Further studies of daratumumab in combination regimens are warranted.

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          Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.

          Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy.
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            Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma.

            Daratumumab targets CD38-expressing myeloma cells through a variety of immune-mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with crosslinking. These mechanisms may also target nonplasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from 2 daratumumab monotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cells and myeloid-derived suppressor cells, previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified. These Tregs were more immunosuppressive in vitro than CD38-negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab induced significant increases in CD8(+):CD4(+) and CD8(+):Treg ratios, and increased memory T cells while decreasing naïve T cells. The majority of patients demonstrated these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T-cell increases, elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCR clonality positively correlated with increased CD8(+) PB T-cell counts. Depletion of CD38(+) immunosuppressive cells, which is associated with an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and TCR clonality, represents possible additional mechanisms of action for daratumumab and deserves further exploration.
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              Is Open Access

              Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

              Daratumumab (DARA) is a human CD38-specific IgG1 antibody that is in clinical development for the treatment of multiple myeloma (MM). The potential for IgG1 antibodies to induce macrophage-mediated phagocytosis, in combination with the known presence of macrophages in the tumor microenvironment in MM and other hematological tumors, led us to investigate the contribution of antibody-dependent, macrophage-mediated phagocytosis to DARA's mechanism of action. Live cell imaging revealed that DARA efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly and sequentially engulfed multiple tumor cells. DARA-dependent phagocytosis by mouse and human macrophages was also observed in an in vitro flow cytometry assay, using a range of MM and Burkitt's lymphoma cell lines. Phagocytosis contributed to DARA's anti-tumor activity in vivo, in both a subcutaneous and an intravenous leukemic xenograft mouse model. Finally, DARA was shown to induce macrophage-mediated phagocytosis of MM cells isolated from 11 of 12 MM patients that showed variable levels of CD38 expression. In summary, we demonstrate that phagocytosis is a fast, potent and clinically relevant mechanism of action that may contribute to the therapeutic activity of DARA in multiple myeloma and potentially other hematological tumors.

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                American Society of Hematology
                April 30 2020
                April 30 2020
                : 135
                : 18
                : 1531-1540
                [1 ]Hématologie Clinique, IUC Oncopole, Toulouse, France;
                [2 ]Amyloidosis Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
                [3 ]Department of Molecular Medicine, University of Pavia, Pavia, Italy;
                [4 ]U1153 Centre de Recherche en Épidémiologie et Statistiques (CRESS), Equipe de Recherche en Biostatistiques et Epidémiologie Clinique (ECSTRRA),
                [5 ]Service d'Immuno-Hématologie Clinique, Hôpital Saint Louis, Assistance Publique–Hôpitaux de Paris (AP–HP), Université de Paris, Paris, France;
                [6 ]Service d’Hématologie, Institut Paoli Calmette, Marseille, France;
                [7 ]Service d’Hématologie Clinique, Centre Hospitalier Universitaire (CHU) Nancy, Nancy, France;
                [8 ]Service d’Hématologie, Hôpital Sud, CHU Lyon, Lyon, France;
                [9 ]Service Néphrologie et Transplantation d’Organes, Hôpital Rangueil, CHU Toulouse, Toulouse, France;
                [10 ]Institut d'Hématologie de Basse-Normandie, CHU Caen, Caen, France;
                [11 ]Service Hématologie Clinique et Thérapies Cellulaires, CHU Amiens, Amiens, France;
                [12 ]Service d’Hématologie Adultes Hôpital Necker, AP–HP Paris, Paris, France;
                [13 ]Service d’Hématologie, CHU Nantes, Nantes, France;
                [14 ]Service des Maladies du Sang, Centre Hospitalier Régional Universitaire (CHRU) Lille, Lille, France;
                [15 ]Service d’Hématologie, CH Metz, France;
                [16 ]Unité Hémopathies Lymphoïdes, Hôpital Henri-Mondor, AP–HP Créteil, Créteil, France;
                [17 ]Centre de Référence pour l'Amylose AL et autres Maladies de Dépôts d'Immunoglobulines Monoclonales and
                [18 ]Service d’Hématologie Clinique et de Thérapie Cellulaire, CHU Limoges, Limoges, France; and
                [19 ]Service de Néphrologie, Hémodialyse et Transplantation Rénale, Centre d'Investigation Clinique (CIC) INSERM 1402, CHU Poitiers, Poitiers, France
                © 2020


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