Identification of multiple myeloma initiating cells by integrated single-cell multi-omics-based lineage tracing

• Applicants: Dr. Simon Haas, Ph.D.; Professor Dr. Jan Krönke; Dr. Leif Ludwig
• Subject Area: Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514061504

Multiple myeloma is a malignant plasma cell disorder and among the most frequent hematologic malignancies. New treatment approaches like proteasome inhibitors, thalidomide analogs, monoclonal antibodies, and chimeric antigen receptor (CAR) T-cells have improved the outcome of multiple myeloma in the past years. However, even if these therapies are combined with intensive treatment protocols including high-dose chemotherapy and autologous stem cell transplantation, almost all patients eventually relapse due to therapy resistance and succumb to their disease. Large-scale genetic studies have so far identified only few alterations that explain resistance to a specific drug class, implying that resistance is primarily caused by non-genetic mechanisms. Moreover, sensitivity to treatment is highly heterogeneous within the multiple myeloma clone: While the bulk of multiple myeloma cells in treated patients, even those with genetically-defined high-risk disease, respond to therapy, rare, therapy-resistant cells survive the treatment and form the cellular basis for the subsequent relapse. Eradicating these therapy-resistant multiple myeloma cells will therefore require new avenues of treatment to enable the cure of this disease. However, technological hurdles have so far hampered the molecular and cellular characterization of multiple myeloma initiating cells, and therefore the rational design of targeting strategies. In the proposed project, we aim to identify and characterize multiple myeloma initiating cells by analyzing paired primary patient samples obtained before treatment, at remission and at relapse through single cell multi-omics approaches. We will combine readouts of accessible chromatin, transcriptome and surface protein profiling with clonal tracking via immune receptor rearrangements and somatic mitochondrial DNA mutations. Molecular characterization using single cell technologies will provide a basis for refinement of measuring minimal residual disease and develop new therapies against highly resistant myeloma cells and therefore has the potential to improve outcome of multiple myeloma patients.

• DFG Programme: Research Grants