The immediate goal of our research is to improve the treatment and outcomes of patients with multiple myeloma, especially for patients who have developed difficult-to-treat multi-drug resistant disease. Our approach is to utilize primary bone marrow biopsies in developing new therapies, personalizing the application of current drugs, and designing novel drug combinations to treat acquired resistance. In the process, we seek to advance each other’s scientific and professional development within a fun, collaborative environment.
Multiple myeloma is a debilitating blood cancer that afflicts more than 30,000 Americans each year. There is much to be done to improve patients’ lives and finding a cure is achievable. Although the treatment has greatly improved in the past decade, no current therapy is capable of fully eliminating minimal residual disease in most patients. Myeloma is derived from plasma cells, which are responsible for antibody-based immunity. When they become cancerous, myeloma cells secrete monoclonal antibody that causes severe symptoms and also serves as a way to monitor the level of disease. Myeloma cells are susceptible to drugs that exploit their unique attributes, protease inhibitors, and IMiDs.
Myeloma cells under the microscope, crowding out the normal bone marrow cells. Photo credit to Jessica Davis, MD.
Naked antibodies attract components of the immune system, such as macrophages and natural killer (NK) cells to kill myeloma cells. Bispecific antibodies bind both myeloma and T-cells, activating the powerful killing activity of these cells. Antibody-drug conjugates are a targeted delivery system for highly potent chemotherapy directly into the myeloma cells.
Exciting breakthroughs have been made in the development of new immunotherapies for multiple myeloma. Myeloma is readily accessible to antibody-based therapies in the bone marrow and thus an ideal disease for this drug class. Recently, myeloma targeted naked antibodies have shown groundbreaking clinical activity. Now the potential for further improved clinical effects have emerged with antibody-drug conjugates and bispecific antibodies. Our focus is on the development of these antibody-based therapies and optimizing how they are applied, both in terms of finding patient subpopulations that will benefit most and in the rational design of drug combination strategies.
The pipeline for new myeloma drugs is highly active, but completely dependent on cell line models, which don’t accurately reflect the disease in many ways. Thus, a priority for our lab is to bank tissue samples from patients with myeloma at UC Denver. Bone marrow aspirates are obtained clinically at diagnosis and relapse. Donation of an aliquot for research purposes allows us to examine a number of facets of disease biology and optimize its treatment. Among the most important technologies we apply is flow cytometry (aka FACS analysis). This technique allows the isolation of the malignant myeloma population from heterogeneous mixtures of cells for further genetic and phenotypic analyses.
Flow cytometry of a bone marrow sample from a patient with myeloma. (left panel) Bone marrow contains a complex mixture of immune cells and blood cell progenitors that come in all shapes in sizes. (right panel) Differentiating myeloma cells from this mixture requires the use of multiple cell surface markers with known expression patterns on these cells, such as CD38.
Illustration by Gwen Tice
Multiple myeloma cells, like the plasma cells they are derived from, display very high of the protein process required for antibody synthesis. Their dependence on this process causes rapid multiple myeloma cell death upon treatment with protein translation inhibitors, such as omacetaxine.
Currently, no therapy is capable of eliminating minimal residual disease (MRD), preventing cure, and inevitably leading to disease relapse in all patients. As the disease progresses, genetic subclones and subpopulations develop, some of which may underlie the emergence of multi-drug resistance. We believe understanding these developments is key to learning how to better control late-stage myeloma. Ultimately, we hope this type of study will facilitate the development of an approach capable of eliminating MRD, opening the possibility for the cure of this disease.