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CAR-T cell therapy for MM: EMN consensus statement
the normal and malignant plasma cells and B lympho- cytes.4 BCMA is also expressed on myeloma cell lines.5 Considering the strong and fairly homogeneous expres- sion of the BCMA receptor on malignant plasma cells and its important mechanism of action, BCMA represent an ideal therapeutic target for CAR-T cell therapy.6 Indeed, the majority of CAR-T cell programs currently being test- ed in clinical trials are targeting BCMA. Other targets on MM cells are under early preclinical development. The first 'in human' clinical trial of CAR-T cells targeting BCMA that showed anti-myeloma activity was published in 2016.7 Several recent phase I / II trials show promising preliminary results in MM patients progressing on protea- some inhibitors, immunomodulatory drugs (IMiD) and monoclonal antibodies targeting CD38.8-9 In this situation of unmet medical need, high response rates and minimal residual disease (MRD) negativity are achieved, and the median progression-free survival (PFS) in responding patients is >15 months.5,8,9 Nevertheless, no plateau has been observed on PFS curves, indicating the low probabil- ity for cure, at least in these heavily pretreated patients. CAR-T cell therapy is a potentially life-threatening strate- gy that that can only be administered in experienced cen- ters. The major toxicity in MM patients is the cytokine release syndrome (CRS) that may require short hospital- ization in intensive care units.5,6,10 Neurotoxicity seems far less frequent and severe when compared to CAR-T cell therapy for B-ALL and DLBCL.5-6,10 Overall, fewer than 100 patients with RRMM treated with CAR-T cells targeting BCMA have been reported. These patients were highly selected, had refractory disease at the time of entry into clinical trials, while still having good clinical status, and were able to remain without any therapeutic intervention for 4-5 weeks during the manufacturing process of CAR- T cells.
CAR-T cell therapy is by far one of the most expensive therapies for hematologic malignancies.
Practical considerations
Once CAR-T cell therapy is approved in RRMM, it will become one of the most important indications for this strategy in Europe and world-wide.
For the moment, CAR-T cell therapy for MM is still experimental.7-8 Clinical programs need to be developed under the scientific guidance of the disease experts and co- operative groups in selected centers.
The results of large company-sponsored phase II trials using CAR-T cells infused at the optimal dose are expect- ed at the end of 2019. Several phase III trials have just started (2019), testing CAR-T cells either in very advanced patients or earlier in the course of the disease, especially in high-risk patients. Very few academic trials using CAR-T cell therapy are currently ongoing. The CAR-T cell thera- py is different from allogeneic stem cell transplantation (allo-SCT).5-6 There is no scientific reason to support the experience on allo-SCT as the only prerequisite for the identification / selection of centers accredited for CAR-T cell therapy. Toxicity of CAR-T cells is different from that of allo-SCT: the use of a protected environment is not needed, graft-versus-host disease (GvHD) is by definition absent. Given this, one of the most common links between allo-SCT and the CAR-T programs is the aphere- sis process that will require pertinent accreditations and/or
certifications. Experience in hematopoietic transplantation (allo and/or auto) is very important, and expertise in cell therapy manipulation is critical. CAR-T therapy should be performed by a team of experts in MM and in cellular therapy, which curently includes experts in the specific disease and in autologous and/or allogeneic transplanta- tion, in close collaboration with, among others, intensive care specialists and neurologists, together with a well trained nursing team.
CAR-T cell therapy for MM will potentially become a highly-specialized medication, associated with very high costs. Indications for the use of CAR-T therapy should be clearly defined by experts in MM, if possible through international guidelines. A European consensus, defined by co-operative groups, national societies of hematology, the European Myeloma Network (EMN) and the European Hematology Association (EHA) should be pro- posed to national and European authorities.
The creation of a list of centers of excellence in each European country, certified for CAR-T cell therapy and other advanced immunotherapies, based on disease area and expertise is of the utmost importance. This list may be drawn up by national societies and national health authorities, in the overarching framework of the main European societies, including the specific myeloma groups in each country as well as the European Myeloma Network and EHA.
A specific European registry for the follow up of patients receiving CAR-T cell therapy including treatment indications, response data, previous and subsequent lines of therapy and treatments, safety and long-term follow up (e.g. to monitor for insertion mutagenesis after genetic modification of T cells) must be compiled. As all data from patients treated with CAR-T cells will be registered on the database of the European Group for Blood and Marrow Transplantation (EBMT), it will be mandatory to build a working group combining myeloma experts and national co-operative groups to ensure the accuracy of the data submitted. The presence of disease experts in this group is key to generate scientific knowledge and to propose new studies. This registry should also collect data from other types of innovative and expensive immunotherapies in order to compare their safety and efficacy.
Important issues in the near future
CAR-T cell therapy is still an experimental therapy, mainly developed by pharmaceutical companies. Academic research programs are urgently needed to improve efficacy and safety, either working with biotech companies or big pharma or independently. A particular focus should be to improve persistence of CAR-T cells, avoid antigen loss and reduce CRS/neurotoxicity.10,11 This is nothing new in myeloma, a disease in which the close collaboration between the pharmaceutical companies and the European co-operative group has led to an improve- ment in outcomes.
The definition of the optimal use of CAR-T cells, includ- ing very precise indications and approval, requires the guidance of myeloma experts. For example, when is a patient to be considered a candidate for CAR-T cell thera- py? What is the optimal bridging therapy? Does this also depend on renal function? What are the alternative treat- ment options? Such questions clearly indicate that the
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