The Biology of Multiple Myeloma
Multiple Myeloma is a cancer of the blood plasma cells. Plasma cells are a type of white blood cell made in the bone marrow that secrete antibodies and play an important role in helping the body fight off invading pathogens such as viruses and bacteria. Multiple myeloma is thought to evolve most commonly from an asymptomatic condition called monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma to symptomatic myeloma.
Multiple myeloma develops from MGUS at a rate of about 1-2% per year. Smoldering myeloma shows a higher conversion to active disease, risk of around 10-20% per year. While studies support a role for both genetic and environmental factors in the development of multiple myeloma and its precursor states, the actual cause of initiation of MGUS or the causes leading to disease progression are unknown.
The symptoms associated with multiple myeloma are in large part a consequence of the uncontrolled growth of the malignant plasma cells. These plasma cells secrete very high levels of protein antibodies and this high protein load can lead to kidney disease and increased blood viscosity. The bone marrow (BM) is the site of disease and the disruption of the bone marrow by the overgrowth of the cancerous plasma cells can lead to anemia, bone disease and in some cases elevated serum levels of calcium. The microenvironment that makes up the bone marrow is composed of a range of cells including stromal cells, osteoclasts, osteoblasts, myeloid cells and lymphoid cells. It is now known that these cells actively support the growth of the myeloma cells and contribute to disease progression and drug resistance.
Given the complexity of the disease, the Grand MMTI research team is advancing our understanding of disease biology and development of novel therapeutics through several lines of investigation. These include identifying factors that contribute the initiation, severity or progression of disease, identifying factors that affect disease response and developing novel therapeutics for disease treatment.
There are several labs involved in projects that approach multiple myeloma treatment by addressing methods that directly kill the multiple myeloma cells. The Ruggero and Shokat labs are studying key regulatory pathways in myeloma cell proliferation and developing therapeutics that interrupt those pathways, causing cell death. The Walter and Toczyski labs are pursuing novel strategies that directly kill multiple myeloma cells by disrupting cell homeostasis. This approach has been validated in the clinic. Velcade works, in part, by disrupting myeloma cell homeostasis. The Taunton lab is taking a different approach. They are developing therapeutics that disrupt the interactions between the malignant myeloma cells and the bone marrow microenvironment nurturing them. There is a great deal of scientific and clinical data supporting this this approach for treating multiple myeloma. Furthermore, in addition to killing the myeloma cells, these therapeutics have the potential to directly reduce the bone disease associated with multiple myeloma.
It has been long understood that the immune system plays a critical role in the prevention and treatment of multiple myeloma. Early on the immune system plays a sentinel role in detecting and destroying pre-cancerous plasma cells before they can become malignant multiple myeloma. However, in certain instances, these pre-cancerous cells evade the immune system and advance to full blown disease. Numerous therapies, both approved and in development, function by boosting the immune system to attack the cancer cells. Two of the Grand MMTI labs (Venstrom & Rubenstein labs) are seeking to better understand the immune response in myeloma treatment and to identify biomarkers predictive of treatment response to immuno-modulatory therapies.
There are 2 additional biomarker programs within the Grand MMTI. The Wells lab has a program to identify biomarkers predictive of treatment response by identifying protein signatures unique multiple myeloma cells undergoing programmed cell death as a result of chemotherapy. It is hoped that these protein signatures will assist doctors in monitoring patients and adjusting their treatment course when necessary. The Ruggero lab is developing biomarkers for predicting which myeloma patients will derive the greatest benefit from therapy with dual acting mTOR inhibitors. This will help identify the right patients for these therapeutics.
Lastly within the research areas for the Grand MMTI, we are involved in research aimed at better understanding the genetics of disease. It is understood that there is a strong genetic basis for multiple myeloma progression and genetic mutations have been identified that are associated with poorer or better prognosis. Nonetheless, the genetic causes leading to MGUS, smoldering myeloma or multiple myeloma are not known, nor have any genes associated with multiple myeloma risk been identified. The Ziv lab is involved in a large program identifying genetic mutations associated with multiple myeloma susceptibility and overall patient survival. It is hoped that these mutations will provide insight to the causes of multiple myeloma and its progression, identify new genes that can be targets for drug discovery or assist with building genetic signatures that doctors can use for designing better treatment regimens.