Multiple Myeloma

"One of our lines of research focuses on identifying biomarkers of resistance and potential therapeutic targets for multiple myeloma."

DR. JESÚS SAN MIGUEL
SENIOR RESEARCHER. MULTIPLE MYELOMA RESEARCH GROUP

The Cima Multiple Myeloma Group is made up of internationally renowned clinical hematologists and research experts.

Multiple myeloma is the second most common hematological malignancy and, despite therapeutic advances in the last decade, remains incurable for most patients.

It represents a unique cancer model to investigate mechanisms that regulate malignant transformation from a benign stage, termed "monoclonal gammopathy of uncertain significance (MGUS)" to an indolent stage that precedes the most advanced and active form of the disease: symptomatic multiple myeloma.

Multiple myeloma is a unique model in which different clinical stages have a common denominator: the clonal plasma cell. This same common denominator is shared with other monoclonal gammopathies such as primary systemic amyloidosis and is characterized by the expansion of a small clone of aberrant plasma cells that secrete a monoclonal immunoglobulin whose variable portion of the light chain constitutes the precursor protein of amyloid fibrils.

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Objectives of the Research Group
in Multiple Myeloma

We cover the study of multiple myeloma and other monoclonal gammopathies through a cross-sectional investigation.

To understand the mechanisms involved in the transformation of healthy plasma cells into pre-malignant and cancerous cells.

 

Identify the plasma cell clone responsible for dissemination, resistance, and relapse, by studying circulating tumor cells (CTC) and minimal residual disease (MRD).

Identify extreme phenotypes: cure vs. resistance

To develop animal models of multiple myeloma that reproduce its complexity and heterogeneity and allow the design of new treatments.

Identification of metabolic vulnerabilities in these diseases.

To define the role of the immune system and the microenvironment in the pathogenesis of multiple myeloma and acute leukemia, and in their drug resistance.

Developing strategies to reverse tumor resistance and finding highly accurate biomarkers to monitor treatment efficacy.

To develop clinical trials that can improve the treatment of multiple myeloma (CAR-T therapies).

To understand the implication of alterations in the transcriptome and epigenome in the development and progression of multiple myeloma and acute leukemia.

To develop new compounds directed against epigenetic mechanisms with activity in multiple myeloma cells.

 

THE TARGET OF MULTIPLE MYELOMA

New therapeutic alternatives for the treatment of multiple myeloma

Proteosome inhibitors, which induce cell death; immunomodulators that stimulate our immune system and monoclonal antibodies that are able to detect an antigen of the tumor cell in order to destroy it, are the main lines of our research.

Lines of research

PI: Bruno Paiva

Objectives:

  1. To develop a complete immunophenotypic characterization of tumor cell precursors (including single cell level analysis) in healthy individuals of advanced age and in premalignant stages of MM (MGUS and smoldering MM) and AL to discover new markers involved in malignant transformation.
  2. To study the role of circulating tumor cells (CTCs) and common progenitor cells (CPCs) in the dissemination from benign to malignant stages.
  3. To discover the role of the immune system as a driver and Achilles heel of malignant transformation.

PI: Patricia Maiso

Objectives: 

  • To compare the genomic profile of bone marrow mesenchymal stromal cells (MSCs) from healthy donors with those at diagnosis (in AL and MM).
  • To investigate the genomic profile and biomarkers of BMMSCs at the time of diagnosis (AL and MM), at the time of MRD and at the time of relapse in both diseases.

PI: Xabier Agirre

Our general objective is to study and to know in depth both the complete transcriptome (especially the one referring to long non-coding RNAs (lncRNAs)), the altered epigenome and the aberrant metabolism of tumor plasma cells of monoclonal gammopathy of uncertain significance and multiple myeloma. This objective pursues the aim to better understand the biology of the disease and to detect new targets for the development of new therapeutic strategies for the treatment and improvement of the quality of life of these patients.

Objectives:

  • Analysis of the complete transcriptome of lncRNAs of multiple myeloma tumor cells, in the context of the humoral immune response, and functional study of lncRNAs altered in this disease.
  • Design and validate new RNA-based therapeutic strategies for the treatment of multiple myeloma.
  • Analysis of the epigenome of the tumor plasma cell of monoclonal gammopathy of uncertain significance and multiple myeloma, both in mouse models and primary samples, and the functional study of its alteration in this disease.
  • Detection and functional studies on essential and synthetic lethal metabolic genes in multiple myeloma.
  • Synthesize and validate new small molecules directed against genetic and metabolic targets for the treatment of multiple myeloma.

PI: Bruno Paiva

Objectives:

  • Define the genome and proteome of MRD vs diagnostic clones to understand the molecular signature of ultra-chemoresistant cells that allow them to resist therapy.
  • To understand the relevance of molecular and immunological signatures of MRD clones on patient survival.
  • Optimize MRD and liquid biopsy strategies to monitor treatment efficacy: i) is sustained MRD negativity a surrogate for operational cure; ii) role of immune surveillance in MRD+ patients; iii) role of immune surveillance in MRD+ patients.

PI: Bruno Paiva y Patricia Maiso

Objectives:

  • Analyze the mechanisms of action and synergy of efficacy in tumor cells and immune system.
  • Implement new generation biomarkers to monitor clinical trials.

PI: José Ángel Martínez Climent

Objectives:

We have generated a series of experimental models in genetically modified mice that recapitulate the main biological and clinical features of multiple myeloma (MM), including the progressive development of a precursor phase of the disease in the bone marrow (resembling monoclonal gammopathy of uncertain significance MGUS) that eventually progresses to clinically symptomatic MM.

These experimental models include the main genetic lesions detected in patients with MM, allowing them to be sub-classified into genetic risk groups (standard, intermediate, and high). Our preliminary data show that malignant plasma cells in mice are very similar to cells from patients with the disease, both phenotypically and molecularly, in the different genetic risk subgroups.

We also observed that the bone marrow microenvironment in which disease develops in mice includes a progressive increase in infiltrating CD8 T lymphocytes, with effector phenotype and PD-1 expression. In this context, depletion of these T subpopulations accelerates the development of MM, suggesting a role of the immune system in the development of the disease.

The overall objective of the present project is to define the immune biology and the response to immunotherapy strategies in the different genetic risk subgroups in MM, and is based on the preliminary results obtained through the development and characterization of experimental murine models.

In the present project we will continue the study of such models using high resolution cellular and molecular analysis techniques, which have been developed in our hemato-oncology department, and the results will be analyzed with integrative methods of computational biology.

The specific objectives are the following:

  1. Determine the molecular mechanisms that converge to promote the progressive transformation of plasma cells in the different experimental models.
  2. Characterize the role of the immune system in the progressive transition between MGUS and MM phase in different experimental models.
  3. To evaluate the response to different combinations of targeted therapeutic agents and immunotherapy in the experimental models.
  4. Characterize the mechanisms of therapeutic response and resistance to immunotherapy in the tumor plasma cell and bone marrow microenvironment.
  5. The mouse results will be analyzed in the context of human pathology, with the aim of defining the immune biology of MM development with unprecedented resolution, which will hopefully contribute to the experimental design of future clinical trials of MM patients.

Meet the research team

Scientific activity of the
Multiple Myeloma Research Group