Innovative translational research has been at the core of the UAMS myeloma program since its inception in 1989.
Translational research is research that bridges basic science with developments in clinical care. Breakthroughs in the laboratory are translated rapidly into clinical care applications.
Over the years, the Myeloma Institute’s translational research concept has been to control the growth of myeloma by dissecting and exploiting the molecular and biological consequences of both the myeloma cell and its interaction with the bone marrow microenvironment. Our physician-scientist team has successfully furthered insights in disease biology, genetics, and the development of new diagnostic and staging tools, such as MRI and PET-CT.
The structure of our program has afforded breakthrough discoveries, thanks to our large patient referral base, long-term follow-up, integrated basic-clinical investigation, availability of samples and laboratory correlates in our database, and statistical power to interpret findings in the context of historical patients with comprehensive annotations of the clinical course and therapeutic interventions.
The Myeloma Institute was the first center to achieve truly curative outcomes through our Total Therapy treatment approach. Total Therapy incorporates proven effective agents up front for an “all-out attack” on myeloma. The idea is to knock out the myeloma cells at the outset, even the tough, resistant cells, and give them no opportunity to survive. The goal is eradication of the myeloma and complete molecular cure.
Over the course of the Total Therapy clinical trials, we have discovered that myeloma is not a single disease, but rather a collection of different molecular subgroups with distinct biology, risk status, and clinical outcome. We have shown that our Total Therapy program leads to a cure for a significant proportion of low-risk disease patients. In contrast, outcomes have not significantly improved for high-risk myeloma, which has a poor prognosis and needs innovative therapeutic solutions.
Therefore, a key focus of our current program is on high-risk myeloma, which comprises up to 30 percent of newly diagnosed myeloma cases, with the understanding that lessons learned will be readily applied to low-risk myeloma for even better outcomes in that group.
Our overall research vision encompasses four main paths:
1. Identifying the causes of myeloma.
- Understand the underlying causes of myeloma — environmental, genetic, and other.
- Design strategies to prevent MGUS (monoclonal gammopathy of undetermined significance) and smoldering myeloma from developing into active myeloma.
- Understand how inherited genetic factors interact with cancer cells to affect disease progression, side effects of treatment, and outcome.
2. Myeloma Stem Cell Biology
- Understand how myeloma develops, specifically how MGUS and smoldering myeloma transform into myeloma. γ
- Gain insight into the biology of high-risk myeloma and treatment resistance.
- Design new treatments aimed at the biology of the myeloma stem cell.
3. Targeted Treatment based on Genetics and Epigenetics* of Myeloma
- •Understand the genetic basis of myeloma and use this information to design targeted treatments aimed at switching off the genetic signals that lead to its development.
* Epigenetics refers to the biological mechanisms that switch genes on and off in a stem cell. Epigenetics-based treatments are based on programming cells in order to modify the on-off mechanisms.
4. Total Treatment Approaches to Curing Myeloma
- Harness the immune system to overcome resistance to treatments.
- Target treatment to the molecular lesions
that cause myeloma.
- Reduce treatment toxicity.
- Modify regimens for frailer patient populations.
Overall Theme Moving Forward
With the four basic paths described above as guiding principles, the overall theme for our strategy moving forward is continued therapeutic progress toward growth control and cure of myeloma. This will be accomplished by leveraging the advances we have made during the 26-year history of our Total Therapy program to craft solutions to reverse the poor outcome of high-risk myeloma.
Our goal is to develop a “Precision Medicine” strategy for high-risk disease. To achieve this, we will develop solutions to overcome the problem of intraclonal heterogeneity (diversity within the myeloma cells), which we have shown to be a key mechanism leading to treatment failure and relapse. We will utilize the knowledge we have gained about the clinical behavior and molecular subtypes of myeloma to design therapies that target the genetics underlying the disease process. We will also harness the immune system to target residual disease — cancerous cells that remain after treatment when the patient is in remission and that often cause relapse.
The impact of these advances will be assessed by novel disease-monitoring methods aimed at decreasing the time needed to evaluate the effectiveness of new therapeutic interventions. For example, by using molecular diagnostic tests and functional imaging studies, we can determine if a given treatment is effective. If it is not working as desired, it can be quickly adapted to include different agents.
We will integrate data from next generation sequencing (high-speed technology that enables in-depth study of genomics and molecular biology) into our previous classification systems in order to develop tests that can be used to direct specific therapies. We expect that our new studies, through an increased understanding of myeloma biology and its impact on the bone marrow microenvironment, will lead to improved, individualized treatment plans, minimize treatment-related side effects, and increase patient survival.
In short, we will improve cure rates in high-risk myeloma by rapidly translating preclinical science to innovative therapeutic intervention at relapse and thereby improve the standard of care for newly diagnosed myeloma patients.
Our research strategy is divided into five specific projects that are supported by core services, including biostatistics, clinical trial research coordination, and advanced DNA and RNA technologies.
Project 1, Strategies for Cure in Newly Diagnosed Multiple Myeloma, will implement a clinical trial utilizing single agent anti-CD38* monoclonal antibody for induction and consolidation/maintenance. We will integrate IMiD** drugs in combination with the antibody. We will develop novel molecular endpoints and diagnostics for assessing effectiveness, stratifying cases, and directing therapies.
*CD38 is a surface protein that is expressed by most, if not all, multiple myeloma cells. Anti-CD38 monoclonal antibody is believed to induce tumor cell death through multiple immune-mediated mechanisms of action.
**IMiD stands for immunomodulatory drug. IMiDs are a group of compounds that are analogues of thalidomide and have anti-angiogenic (countering blood vessel development) properties and anti-inflammatory effects.
Project 2, Developmental Therapeutics, will develop expanded natural killer cell and antibody-based combinations aimed at enhancing natural killer cell activity against residual cancer cells that remain after chemotherapy. Additionally, this project will aim to enhance the activity of natural killer cells on a long-term basis and increase our understanding of how resistance develops.
Project 3, Precision Medicine Strategies, will develop an “Umbrella Study” so that novel targeted drugs and combinations of drugs can be quickly evaluated in specific molecular subgroups of myeloma. The Umbrella Study will focus initially on targeting the RAS signaling pathway, which, when permanently activated due to a genetic mutation, drives the proliferation and survival of myeloma cells. Additionally, the Precision Medicine Strategies project will focus on developing biomarkers for targeting specific disease subgroups and a pipeline of agents for entry into the Umbrella Study.
Umbrella studies are designed to test the impact of different drugs on different mutations in a single type of cancer.
Project 4, Targeting the Microenvironment for Growth Control, will investigate the properties of the bone marrow microenvironment cells and the molecular pathways that drive progression of high-risk myeloma cell clones within the microenvironment.
Project 5, The Genetics of High-Risk Myeloma, will characterize the driver genetics and epigenetics of high-risk myeloma and investigate how they can be therapeutically targeted. We will define the mutational basis of disease progression, resistance, and high risk.
The integrated approach of these projects within our research strategy will link clinical and preclinical work and provide a framework through which improvements in laboratory research can be rapidly translated to patient care. Our studies will lead to improved treatment allocation, will reduce treatment-related toxicities, and will increase survival.