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Previously Treated Multiple Myeloma

///Previously Treated Multiple Myeloma

From the Director

Gareth Morgan, M.D., Ph.DDear Readers,

I am pleased to share with you my excitement about discoveries in myeloma biology that are unfolding at a rapid rate and raising the bar for effective, precision treatment.

As you will learn in this issue of Myeloma, a collaborative international study has revealed gene variants that increase the risk of developing myeloma. These findings have given us new insights into the biological mechanisms of myeloma development and are helping us craft strategies for myeloma prevention.

Additionally, our talented research team is mining and integrating large data sets in order to zero in on the subtleties involved in molecular relationships and processes that support myeloma growth.

While our laboratories are busy with novel scientific investigation and our bioinformatics experts are analyzing “big data,” our clinicians are focused on delivering comprehensive patient care with compassion, expertise and overall excellence. It is the partnership between our sophisticated research and clinical components that gives us an edge in making a cure a reality.

We look to our supporters to help us maintain the momentum of our cutting-edge research and clinical care. The generosity of so many donors who believe in our program makes it possible for us to advance curative treatments and bring promise to patients worldwide.

In the spirit of the holiday season, I hope you will respond to our annual appeal in this issue of Myeloma and help us make the future brighter for patients and their families. My thanks and gratitude in advance.

Cheers and kind regards,

Gareth Morgan, M.D., Ph.D
Director, UAMS Myeloma Institute

From the Editor

Janet AronsonThe development of personalized medicine approaches to treating myeloma and related diseases takes center stage in this issue of Myeloma. With a wealth of patient sample-derived data, sophisticated systems for analyzing the data, and talented experts who can interpret the analyzed data, the Myeloma Institute is making significant progress in the understanding of myeloma biology at the molecular level. This enables our translational research team to get better answers to questions related to diagnosis and treatment and maximize the potential for improved health.

Making a difference in the lives of patients and their loved ones is what makes the Myeloma Institute tick. It is the basis of our focus and drive, and it is exemplified by our patients’ stories. We hope all patients have access to care that is informed by advances in personalized medicine approaches and that offers a new lease on life. We welcome your comments. Feel free to contact us via email.

Sincerely,

Janet Aronson
Editor
AronsonJanetL@uams.edu

Big Data Analysis Fuels Personalized Medicine

A truly unique feature of the Myeloma Institute is its wealth of patient-derived clinical and research data. With more than 11,750 patients over a period of 27 years, the Myeloma Institute has amassed a treasure trove of data elements, many at the molecular level, that have the potential to yield new understandings of disease biology and response to treatment. Data from current patients is continually added to the collection. Additionally, the Myeloma Institute’s large tissue specimen archive presents the opportunity to mine even more data, utilizing today’s sophisticated analytics tools.

A single patient can generate a lot of meaningful pieces of data — up to 100,000 — based on information gleaned from the 20,000 to 30,000 genes in the human genome. Data are derived from patient samples that are subjected to DNA sequencing, gene expression profiling, and proteomics expression studies and are annotated with various patient information such as age, sex and disease state.

Multiplying so much data by thousands of patients results in “Big Data.” Big Data implies large volume and complexity, such that advanced mathematics and large, high-performance computers are needed. Big Data requires very big computers, massive amounts of storage, and sophisticated mathematics.

Computational biology, also known as bioinformatics, is the field of using computer-based analysis and statistics to understand biology. It covers both basic research (in the laboratory) and translational research (developing clinical applications from basic research), and spans the full spectrum from molecules to human population studies. Computational biology/bioinformatics is a subset of Biomedical Informatics (BMI).

BMI is focused on the management of large data sets in health care. It is a means of organizing and understanding data and turning it into knowledge, with the overarching goal of improving human health, and is an integral part of the search for disease-associated genes. An interdisciplinary field, BMI involves the development, study and application of theories, methods and processes for the generation, storage, retrieval, use and sharing of biomedical data. It encompasses the utilization of existing computational and statistical methods and algorithms, as well as the development of new methods to extract knowledge from the underlying data and advanced decision support systems to improve clinical practice. BMI is integral across the whole spectrum from molecules to populations, bridging basic and clinical research and practice.

At the Myeloma Institute, we are striving to better understand the intricate network of molecular processes involved in myeloma. The vast amounts of molecular and clinical data that we have amassed via genome sequencing and other high-throughput techniques (large-scale methods to purify, identify and characterize DNA, RNA, proteins and other molecules) contain crucial information with the potential of leading to development of more effective, targeted therapies. We are mining and integrating these data, and resolving the subtleties involved in the pathways and molecular relationships that support myeloma growth. By identifying molecular patterns that characterize each individual genome and discerning which of these individual variations is related to a disease subset or response to treatment, we can further the development of tools for diagnosis, prognosis and personalized treatment.

We do this, in part, through the identification of disease-related SNPs (single nucleotide polymorphisms) derived from large-scale techniques. Mutations in the genomic code often produce changes in the protein sequence, leading to diseases. The key to approaches that identify disease mutations lies in distinguishing between SNPs that are functionally relevant from those that are not.

Christopher Wardell, Ph.D., an experienced bioinformatician with particular expertise in next-generation sequencing, joined the Myeloma Institute in July. Educated and trained in the UK, Wardell was a lead bioinformatician at The Institute of Cancer Research in the UK and a research scientist with the Laboratory for Genome Sequencing Analysis at the RIKEN Center for Integrative Medical Sciences in Japan.

“We are aiming to spot the differences — to see what makes a normal cell become cancerous,” Wardell said. “By comparing the normal genome of a patient to the genome of their tumor, we can identify the DNA changes that predispose and cause someone to develop cancer.”

The ultimate goal is personalized medicine. “We can sequence a person and their cancer and then target treatment to the mutation or signaling pathway that is out of kilter,” Wardell said. “We can get better answers to questions of diagnosis and treatment.”

The more complicated the question, the more samples that are needed. Similarly, to determine how frequently a certain gene is mutated, high- resolution technology is essential.

In terms of sample quantity, the Myeloma Institute is unsurpassed. “We have one of the largest repositories of myeloma specimen samples in the world. Using today’s modern tools, we can take current data, compare it with data in the repository, and use this information to direct future research and treatment strategies. This puts us in a distinctive position,” Wardell said.

Having so much data enables drill-down to a very detailed level of information. Given the volume of data, the process is time consuming.

“But, processes that have been slow in the past are speeding up. Computational speed and capacity doubles every 18 months,” Wardell said.

Recognizing the importance of bioinformatics for developing curative therapies, the Myeloma Institute has a dedicated team of five specialists, including Wardell, who is the team leader. They are part of the first generation of full-time bioinformaticians, and they are poised to help the Myeloma Institute reach new heights in the development of curative therapies.

“What makes us tick is reaching the clinic, feeling like you are making a difference,” Wardell said.

While Wardell and two of his faculty colleagues are focused on the Myeloma Institute, their academic appointments are in the Department of Biomedical Informatics, established at UAMS one year ago. The department, directed by Fred Prior, Ph.D., develops computational tools to assess and manage medical and public health information and leverages data and maximizes its potential for improving health and health care.

Prior is the principal investigator for The Cancer Imaging Archive (TCIA). Supported by the National Cancer Institute, the TCIA provides researchers, educators and the general public with a vast, freely accessible, open archive of cancer-specific medical images and metadata (http://www.cancerimagingarchive.net/). TCIA is a service that de-identifies and hosts a large archive of medical images of cancer accessible for public download. The data are organized as “Collections,” typically patients related by a common disease (e.g. lung cancer), image modality (MRI, CT, etc.) or research focus. Prior’s group is in the process of hosting radiology images, including PET and CT scans, and gene expression data from the Myeloma Institute on TCIA.

Both the Department of Biomedical Informatics and TCIA are valuable resources to the Myeloma Institute that help ensure that Wardell and his team have access to sophisticated, state-of-the art technology, information and processes. This, in turn, translates into expanded understanding of cancer biology that will speed the development of precision medicine approaches to curing myeloma and related diseases.

Sources:

American Medical Informatics Association,
www.amia.org

Kann, Maricel G: Advances in translational bioinformatics: computational approaches for the hunting of disease genes. Brief Bioinform. 2010 Jan; 11(1): 96-110. PMID: 20007728

Twenty Years and Going Strong

Patricia Harrison-Yates has been a myeloma survivor for a very long time. Twenty years, to be exact. She came to the Myeloma Institute in 1996, underwent two transplants and has been doing well ever since.

Originally from California, Harrison-Yates moved to Joplin, Missouri, when she and her then-husband were ready to start a family. During a visit with relatives, they fell in love with the lush, green landscape and decided it was an ideal, rural area to raise children. So, they packed up and moved. Harrison-Yates’ in-laws, who had just retired, made the move with them.

Life was good, with three children, involved grandparents and expansive acreage of beautiful land. Harrison-Yates had a busy career and also pursued her passion for gardening by becoming a Master Gardener.

A diagnosis of myeloma hit Harrison-Yates when her kids were in college. Fortunately, the UAMS Myeloma Institute was just a four-hour drive away. Not one to waste time, Harrison-Yates was determined to face the myeloma head-on and get started with treatment. Her “can do” attitude was in high gear.

In addition to being enrolled in a clinical trial for treatment, Harrison-Yates also participated in a research bone marrow and blood donation protocol for myeloma and related disorders; she has always had an interest in helping move the science forward. She has had more than 30 bone marrow biopsies done, all without any sedation. Her mindset is to “put on your big boy pants” and do what has to be done.

At home between cycles of treatment, Harrison-Yates found solace and confirmation in the land.

“Pulling out a weed — even just one weed ­— was my validation that everything was OK,” she said.

Although her children were not physically close by when she was undergoing treatment, they were able to follow her progress and provide support from a distance. Harrison-Yates thinks that probably inspired them to gravitate to health-related professions.

Reminiscing recently with Sonja Thornes, the Myeloma Institute’s customer services manager and a 25- year employee, Harrison-Yates said, “When I had problems, Sonja took care of me.”

She was referring to insurance issues. Harrison-Yates met Thornes on her first visit to the Myeloma Institute, when Thornes led the new patient intake and insurance division. They have been in touch on a regular basis since then, including the years when Harrison-Yates was back in California and was followed by a physician there.

Harrison-Yates has made special trips to Little Rock to attend two long-term survivor celebrations at the Myeloma Institute – one in 2007 and one in 2012. There was no way she was going to miss the opportunity to gather with fellow patients and Myeloma Institute doctors and nurses in the spirit of thanks, gratitude and hope for a cure in the future.

Harrison-Yates feels confident that she is cured. She enjoys each day, cherishes her time with her children and grandchildren, all of whom are in the Joplin area, and travels extensively (a trip to Puget Sound is coming up next). By continuing to participate in the research bone marrow and blood donation protocol, she is helping ensure progress in developing treatments that will bring a cure to many patients today and in the future. In her words, “Life
is good.”

We Dig Crystals4Cancer!

Last summer (2015) we shared with our readers a heartwarming story about Bailey McNeill, 17 years old at the time, from Raleigh, North Carolina. McNeill had created a web-based business, Crystals4Cancer.com, to sell her hand-crafted jewelry featuring crystals from the North Carolina mountains. Fueled by a desire to help cure myeloma, McNeill has been donating half of the proceeds from her sales to support research at the Myeloma Institute. “Though my contribution is small, I hope that my business is helping the program that has done so much to help my family and me; it’s the least I can do,” she said.

Before McNeill left home this fall for the University of North Carolina, Chapel Hill, Christer Berg, a local photographer doing a series on people making a difference in the area, captured this image of her at the entrance to Randall Glen, the gem mine where she finds crystals. We know that McNeill is indeed making a difference and that she has tremendous strength of spirit and generosity. Berg definitely found a gem in McNeill.

publication

Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

A new publication in Blood (2016 Sep 29;128(13):1735-44,
PMID: 27516441)

Primary Author: Niels Weinhold, M.D., Assistant Professor

Despite the introduction of novel agents, relapse remains a challenge in the treatment of multiple myeloma. Understanding the underlying molecular mechanisms of myeloma growth and relapse following dose-intense chemotherapy could lead to new avenues of therapy aimed at overcoming these mechanisms. Dr. Gareth Morgan, Myeloma Institute director, and his research team performed the first longitudinal study that addressed the impact of a specific treatment. (A longitudinal study is an observational research method in which data is gathered for the same subjects repeatedly over a period of time; in this study at enrollment into a total therapy clinical trial and at relapse.) Investigating gene expression, chromosomal and mutation profiles, Morgan’s team identified activation of oncogenes and complete inactivation of tumor suppressor genes, as well as Darwinian-style evolutionary processes, as important contributors to myeloma cell death resistance. The study emphasizes the benefit of using alternate therapies with different action mechanisms to induce myeloma cell death and prevent relapse, especially in high risk patients with an inactivated TP53 gene.