Oct. 27, 2016 | Sean Murray of Kimberling City, Missouri, was working a stressful job in November 2008.
His project list was long and deadlines were coming due. So, yes, he noticed the pain in the upper middle part of his back. But the 49-year-old figured it was a pinched nerve or a pulled muscle and decided it was just another annoyance he’d have to deal with.
Ten days after the pain started, it became too big to ignore. At this point, Murray had been sleeping in a recliner because it hurt to lay down. He dragged himself to his primary care physician who ordered x-rays and referred him to an orthopaedic surgeon.
“I had a feeling I was in good hands. The surgeon had the same name as an actor who plays Superman. He was, in my mind, Dr. Superman,” Murray said.
Results from an MRI and CT scan led the surgeon to suspect Murray had an advanced case of multiple myeloma.
Murray was asleep when the doctor called that evening. Karen, his wife, answered the phone.
“He told her he was going to refer me to one of the best places in the world that treats multiple myeloma. She automatically started to think of well-known hospitals like MD Anderson or the Mayo Clinic,” Murray said.
He says his wife’s first reaction to the doctor was “Are you kidding?” when he recommended a facility in Little Rock.
“There isn’t another institute like it in the world,” said Gareth Morgan, M.D, Ph.D., professor and director of the UAMS Myeloma Institute. “We have lots of patients, half of which come from outside of Arkansas. We were the first people who could make the claim that we can cure myeloma.”
Morgan says the survival rates are twice as good at UAMS as they are in other myeloma treatment centers. Over a ten-year period, 50 to 60 percent of UAMS myeloma patients are alive and well, compared to 20 to 30 percent in other comparable facilities.
Morgan attributes it to the use of a combination of different classes of drugs: one that enhances the immune system, one that targets the proteosome and antibody therapy. Morgan describes the antibodies as silver bullets that target only cancer cells, leaving healthy parts alone and limiting side effects.
“It’s an interesting example of how taking science and genetics into the clinic has allowed us to first understand the disease, then target treatment to the genetics of the disease and improve survival,” Morgan said. “Focusing on that is what we believe gives us success.”
For his treatment, Murray moved to Little Rock for ten months. It was a challenging time, he said. His wife was with him whenever possible. She was an elementary school music teacher, in graduate school at night, and was taking care of their two daughters, Katie and Elizabeth, who were 11 and 5 at the time. He was happy to have a close network of family and friends from all over the country helped him when his wife was with the children in Missouri.
When Murray went home and began his three-year chemotherapy maintenance period, he started a blog to keep his friends and loved ones updated without having to repeat his story several times. He called it Myeloma Youreloma.
“It began as a place where people could check in to see how I was doing and what my thoughts were,” Murray said.
His blog caught the attention of editors at The Myeloma Beacon. Since then, Murray had the opportunity to write a patient perspective on their website. He’s written more than 75 entries. Murray says his goal is to encourage other myeloma patients to not give up hope.
“This disease is willing to take everything away from you if you let it,” Murray said. “It’s as if the sun stops shining and you lose passion for things you once cared about. It’s an all-consuming disease, if you allow it to be.”
Murray says during his darkest times, his wife and two children are his motivators to beat his illness. He and Karen adopted their daughters from China. Katie had been left alone on the steps of a Buddhist temple. Liz had been left in a factory courtyard before they were taken to orphanages.
“One thing that keeps me going when I want to give up is the sad thought of leaving my daughters. I don’t want them to be abandoned again. I tell myself, ‘I may not be able to do this for Sean Murray. But I would do anything for Kate and Liz’s dad and Karen’s husband.’ Thanks to UAMS, I am still here with my family.”
This video was filmed in 2011 when David Fajgenbaum was in in his third year of medical school. Since then, Fajgenbaum has had two more life-threatening relapses, but he is currently in his longest remission since becoming ill with HHV-8-negative multicentric Castleman disease.
Fajgenbaum, MD, MBA, MSc, is now an assistant professor of Medicine in the Division of Translational Medicine & Human Genetics at the University of Pennsylvania, the executive director of the Castleman Disease Collaborative Network (CDCN), and the associate director of Patient Impact of the University of Pennsylvania’s Orphan Disease Center. https://www.med.upenn.edu/apps/faculty/index.php/g348/p8205911
Fajgenbaum co-founded the CDCN in 2012 to accelerate research and treatments for Castleman Disease through global collaboration, strategic investment in high impact research, and patient engagement.
Fajgenbaum is also the co-founder and former board chair of the National Students of AMF (Actively Moving Forward) Support Network, a non-profit organization dedicated to supporting grieving college students. AMF has reached 3,000+ students on 200+ college campuses throughout the U.S.
Fajgenbaum completed his MBA at the Wharton School of the University of Pennsylvania. He earned his MD from the Raymond & Ruth Perelman School of Medicine at the University of Pennsylvania and a BS in Human Sciences from Georgetown University.
Fajgenbaum is married to the love of his life, Caitlin Prazenica.
The world of myeloma research is undergoing exciting advances that are changing the landscape of diagnosis and therapeutic interventions.
With new drug development, creative combinations of drugs, increased understanding of how the body’s immune system can be harnessed, and the ability to define each patient’s disease at the molecular level, we can now offer treatments that specifically target cancer cells while sparing healthy cells. In short, we can move away from the toxic treatments of old to more easily-tolerated and more effective regimens that produce even better outcomes.
The Myeloma Institute’s team of experts is at the forefront of these promising developments. We are pushing the science along avenues that are leading to increased cure rates for more and more patients.
As you read this inaugural issue of Myeloma, I invite you to embrace both the reality and further prospect of a cure that our work, along with the work of our colleagues, is bringing to patients throughout the world.
Cheers and kind regards,
Gareth Morgan, M.D., Ph.D
Director, UAMS Myeloma Institute
The goal of Myeloma is to provide timely updates about progress in clinical treatment and research advances, as well as stories and information of general interest.
As a world leader in myeloma and related diseases, we are committed to ensuring that patients and those involved in their care — family, friends, physicians and other medical professionals — are well equipped to make informed decisions that support the best possible health for each individual. We hope the Myeloma journal will become one of your trusted sources for news and authoritative commentary on breakthroughs and treatment trends.
We welcome your comments. Feel free to contact us via email.
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.