by Universidad de Navarra

Genetically heterogeneous mouse models of human-like multiple myeloma. a, Schematic of the genetic screen strategy, whereby transgenic mice were crossed with cγ1-cre or mb1-cre mice. Among 31 genetically heterogeneous mouse lines generated, MI_mb1, MI_cγ1 and BI_cγ1 strains developed MM. GEM, genetically engineered mice; m, months. b, Kaplan–Meier OS curves of MI_mb1, MI_cγ1, BI_cγ1, control (YFP_cγ1 and YFP_mb1) and Vk*MYC mice. c, Representative flow cytometry analysis in the BM of BI_cγ1 mice at the time of death, which shows an increased number of GFP⁺CD138⁺B220⁻sIgM⁻ MM cells. d, Giemsa staining of a representative BM sample in BI_cγ1 mice revealed human-like PCs with expression of acid phosphatase (AP; left). On the right, immunohistochemical examination in BI_cγ1 mice revealed CD138 surface expression by MM cells. e, MM cells show increased surface expression of Bcma, Slamf7 and Taci according to flow cytometry analyses. f, Representative electrophoresis of immunoglobulin secretion in serum samples from MI_mb1, MI_cγ1 and BI_cγ1 mice shows M spikes corresponding to the gamma fraction. g, Quantification of immunoglobulin isotypes in serum samples by ELISA in MI_mb1 (n = 3), MI_cγ1 (n = 2), BI_cγ1 (n = 4) and YFP_cγ1 control (n = 9) mice. h, Kaplan–Meier survival curves of mouse lines that develop MM derived from the BI_cγ1 strain with additional KRAS^G12D mutation, heterozygous Trp53 deletion, or expression of cyclin D1, c-MAF or MMSET. i, Kaplan–Meier survival curves of mouse lines that develop MM derived from MI_cγ1 mice with additional KRAS^G12D mutation, heterozygous Trp53 deletion, c-MAF expression or BCL2 expression. j, Kaplan–Meier survival curves in mice with MMSET/NSD2 expression crossed with lines carrying either IKK2^NF-κB activation or c-MYC expression, which developed MM at old ages. k, Flow cytometry analyses in BI_cγ1 and MI_cγ1 mice revealed that precursor states precede clinically evident MM in genetically heterogeneous mice. l, Analysis of Igh clonality according to RNA-seq of immunoglobulin gene loci and classification by the presence of explicit clonotypes for each sample. B cell receptor (BCR) repertoires and the most expanded clone groups in control, MGUS and MM samples. Log-rank (Mantel–Cox) test was used. *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant. Credit: Nature Medicine (2023). DOI: 10.1038/s41591-022-02178-3

An international group of researchers, led by Dr. José Ángel Martínez-Climent at the Cima University of Navarra, has created mouse avatars of patients with multiple myeloma to study and develop personalized treatments against this blood cancer, the second most frequent hematological cancer and incurable in most cases. These artificial mice can mimic the genetic and immunological diversity of the origin and evolution of this disease in patients. This advance will allow researchers to design more effective and personalized therapies for multiple myeloma.

Nature Medicine has published this study, which opens a pathway for research into other non-curable hematological and solid tumors.

Hospitals, research centers, and biotechnology and pharmaceutical companies from Spain, Switzerland, United States, and Japan have also participated in this multicenter study. The leading researchers of the project are part of the Cancer Center Clínica Universidad de Navarra and belong to the Centro de Investigación Biomédica en Red en Cáncer (CIBERONC) and the Instituto de Investigación Sanitaria de Navarra (IdiSNA)

A multiple myeloma 'catalog' to improve its treatment

Multiple myeloma is a blood cancer that occurs in the bone marrow. It is caused by the proliferation of plasma cells, immune cells responsible for producing antibodies. It is a heterogeneous disease, meaning that it can present in different ways and have different responses to treatment.

To meet the medical need for new treatments to cure the disease, the researchers have used genetic engineering and multi-omic cellular and molecular technologies to analyze more than 500 genetically heterogeneous mice that develop multiple myeloma and tumor cells from more than 1,000 patients with the disease. These samples are from patients attended in the Hematologic Cancer Area of the Cancer Center Clínica Universidad de Navarra.

Thanks to this analysis, "we have generated artificial mice that accurately reflect key aspects of the origin and development of multiple myeloma in humans. This allows us to study the progression of the disease, test therapeutic alternatives and predict the response to combinations of immunotherapy drugs in the clinic," says Marta Larrayoz, a researcher in the Hemato-Oncology Program at Cima University of Navarra and first author of the study.

Significant implications for patients

Researchers must be able to contrast and validate the information provided by preclinical models with patient data to advance laboratory work. "Thanks to our ongoing collaboration with the hematologists at the Cancer Center Clínica Universidad de Navarra, we have identified in our mouse models of multiple myeloma a correlation between the genetic and immunological traits of each tumor and its selective response to preclinical therapies," says José Ángel Martínez-Climent, principal investigator and coordinator of the study, also belongs to the Cima Hemato-Oncology Program.

This research will allow researchers to anticipate treatment outcomes with next-generation immunotherapies and mimic in the laboratory clinical situations associated with the worst outcomes, such as high-risk multiple myeloma, extramedullary disease, or acquired therapeutic resistance. "This scenario offers us opportunities to advance in the investigation of new therapeutic strategies and to optimize the design of future immunotherapy clinical trials," says Martínez-Climent.

"We are testing novel therapies in experimental models at stages of the disease where multiple myeloma cells might be most vulnerable, particularly in early precursor conditions or in the minimal residual disease state (after treatment, when few tumor cells remain). To do this, we have established numerous scientific collaborations with pharmaceutical companies developing clinical trials in this disease to carry out these same trials in our mice," Martínez-Climent adds.

The ultimate goal, say the researchers, "is to transfer the discoveries from the laboratory to the clinic and that research initiatives such as ours can be extrapolated to other hematological malignancies and solid tumors that remain incurable with currently available treatments."

More information: Marta Larrayoz et al, Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma, Nature Medicine (2023). DOI: 10.1038/s41591-022-02178-3

Provided by Universidad de Navarra