Líneas de investigación
CAR-T cells against BCMA in multiple myeloma: prognostic factors related to their activity and development of a new generation of chimeric receptors
Despite the available number of treatments for multiple myeloma, the majority of patients end up presenting refractoriness to all available therapeutic lines and some strategies of immunotherapy, such as CAR-T cells, are under evaluation. CAR-T cell therapy is based on the administration of autologous T lymphocytes genetically modified to redirect their specificity against the antigen of interest. The introduction of this therapy in multiple myeloma is being evaluated through the use of CAR-T directed against the BCMA antigen (B-cell maturation antigen), present on the tumor cells. Even with these therapies, many patients will relapse. Some questions have emerged when using CAR-T cells in myeloma, such as the role of soluble BCMA, the degree of BCMA expression in plasma cells, its role in the eradication of extramedullary disease or the likelihood of BCMA-negative relapse. In addition, one of the limitations of the use of this therapy is the difficulty to maintain the effectiveness of CAR-T cells over time. Therefore, the possibility of developing a complete new generation of CAR-T is being actively studied.
Extramedullary involvement in multiple myeloma
The extramedullary involvement in multiple myeloma is associated with a poor response to therapy and to a shortened survival. Our group is largely interested in extramedullary disease, focused on the definition, assessment, incidence and prognostic impact of this involvement, both at diagnosis and at relapse, as well as the biological aspects related to this escape of the tumor cells outside the bone marrow.
Our group has developed new diagnostic criteria for the plasma cell leukemia, the most aggressive form of malignant monoclonal gammopathy that will have an impact on response and survival
Mechanisms of immune control involved in the progression of monoclonal gammopathies
Many patients with asymptomatic monoclonal gammopathies are stable for years but some can progress to myeloma, macroglobulinemia or amyloidosis. After treatment, some of them can remain in complete remission for a long period of time while others show only transient responses. Our objective is to identify immunoregulatory molecules in the microenvironment as well as genomic and clinical features involved on progression. A better understanding of their functional roles will contribute to the development of new therapeutic strategies. We are investigating gene and protein expression in bone marrow plasma cells from patients with monoclonal gammopathy of undetermined significance, macroglobulinemia and multiple myeloma in different disease stages. Based on our lab findings, we will evaluate therapeutic approaches against relevant targets in bone marrow culture assays.
Cardiac involvement and targeted treatments in amyloidosis
The degree of cardiac involvement is the critical prognostic marker in AL amyloidosis. Our institution is a reference center for this disease and our research, apart from clinical trials, is devoted to the study of cardiac involvement. We prospectively studied the consecutive patients diagnosed at our institution including cardiac biomarkers, echocardiography, cardiac magnetic resonance and endomyocardial biopsy. The impact of new drugs for the two-hit strategy in this disease is under evaluation: the use of drugs against the bone marrow plasma cells, similar to those used on multiple myeloma, in combination with drugs targeting the amyloid already deposited in the involved organs, such as heart and kidney.
Clinical trials and real life studies
We are developing a number of clinical trials with new drugs and new drug combinations in multiple myeloma, macroglobulinemia and AL amyloidosis. Some of them are part of the Spanish Myeloma Group/PETHEMA network and others are sponsored by pharmaceutical companies, including confirmatory phase III trials. We are also involved in phase I and II trials investigating novel molecules, including immunotherapy with bi-specific antibodies and CAR-T cells. In our database, we have included all patients diagnosed and followed at our institution since 1970 with myeloma, amyloidosis, macroglobulinemia and other gammopathies. We are analyzing survival outcomes overtime, the treatment practice with the number of patients receiving second and subsequent lines of rescue therapy, the proportion of patients included in clinical trials and the causes of exclusion. Finally, cost/efficacy analysis will be performed.