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Daratumumab, Vaccines in Multiple Myeloma

Panelists:Ivan Marques Borello, MD, Johns Hopkinsk; Myron S. Czuczman, MD, Roswell Park; Madhav V. Dhodapkar, MBBS, Yale; Dan Douer, MD, MSK
Published: Tuesday, Aug 25, 2015


The monoclonal antibody daratumumab, which targets CD38, is being explored as a treatment for patients with multiple myeloma. The investigational molecule has single-agent activity, including in patients who have failed multiple lines of therapy, such as bortezomib and lenalidomide.

In a pivotal phase II study, daratumumab demonstrated a 65% one-year overall survival rate and a 29.2% objective response rate in patients with double refractory heavily pretreated multiple myeloma. Based on these findings, the company that develops the drug initiated a rolling submission of data to the FDA for potential regulatory approval.

Toxicities associated with daratumumab include infusion reactions, says Madhav Dhodapkar, MD, which usually occur during the initial cycle of therapy and improve with subsequent treatment. The most common all-grade adverse events with daratumumab include fatigue (39.6%), anemia (33%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), and cough (20.8%).

In addition to monoclonal antibodies, vaccines are also being developed for patients with hematologic malignancies, states Ivan Marques Borrello, MD. Historically, an idiotype vaccine has been explored; although, these vaccines have been less successful in myeloma than in lymphoma, says Borrello. The idiotype in lymphoma is expressed on the lymphoma cell, whereas it is mostly secreted in myeloma, making it difficult to prime the immune system against something that is in circulation rather than attached to a tumor.

A Clinical Trials Network (CTN) study is assessing the use of a vaccine approach in patients with multiple myeloma using patient-derived myeloma cells that have been fused with autologous dendritic cells. Fusing a tumor cell with a dendritic cell allows for more effective antigen presentation, explains Borrello. The need to refer patients at the time of diagnosis to an academic center in order to manufacturing the vaccine is a potential limitation facing this approach. Future studies will examine the use of allogeneic cells, which would avoid this issue, Borrello notes.
 
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The monoclonal antibody daratumumab, which targets CD38, is being explored as a treatment for patients with multiple myeloma. The investigational molecule has single-agent activity, including in patients who have failed multiple lines of therapy, such as bortezomib and lenalidomide.

In a pivotal phase II study, daratumumab demonstrated a 65% one-year overall survival rate and a 29.2% objective response rate in patients with double refractory heavily pretreated multiple myeloma. Based on these findings, the company that develops the drug initiated a rolling submission of data to the FDA for potential regulatory approval.

Toxicities associated with daratumumab include infusion reactions, says Madhav Dhodapkar, MD, which usually occur during the initial cycle of therapy and improve with subsequent treatment. The most common all-grade adverse events with daratumumab include fatigue (39.6%), anemia (33%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), and cough (20.8%).

In addition to monoclonal antibodies, vaccines are also being developed for patients with hematologic malignancies, states Ivan Marques Borrello, MD. Historically, an idiotype vaccine has been explored; although, these vaccines have been less successful in myeloma than in lymphoma, says Borrello. The idiotype in lymphoma is expressed on the lymphoma cell, whereas it is mostly secreted in myeloma, making it difficult to prime the immune system against something that is in circulation rather than attached to a tumor.

A Clinical Trials Network (CTN) study is assessing the use of a vaccine approach in patients with multiple myeloma using patient-derived myeloma cells that have been fused with autologous dendritic cells. Fusing a tumor cell with a dendritic cell allows for more effective antigen presentation, explains Borrello. The need to refer patients at the time of diagnosis to an academic center in order to manufacturing the vaccine is a potential limitation facing this approach. Future studies will examine the use of allogeneic cells, which would avoid this issue, Borrello notes.
 
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