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Previously Treated Multiple Myeloma

///Previously Treated Multiple Myeloma

From the Director

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

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

From the Editor

Janet AronsonWelcome to the inaugural issue of Myeloma, the journal of the Myeloma Institute at the University of Arkansas for Medical Sciences.

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.

Sincerely,

Janet Aronson
Editor
AronsonJanetL@uams.edu

The Myeloma’s Institute Approach for Advances and a Cure

Dr. Frits van Rhee visits with a patient prior to his infusion.

Dr. Frits van Rhee visits with a patient prior to his infusion.

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.High Risk Myeloma

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.

Distilling Excellence

America’s largest family-owned and operated distilled spirits producer, Heaven Hill Brands, based in Louisville, Kentucky, has grown beyond its traditional roots as a Bourbon distiller to become the country’s seventh largest overall distilled spirits producer with a portfolio of innovative and relative products. Commitment to excellence… focus on customers… ongoing improvement… ingenuity and resourcefulness… treating others with dignity and respect… nimbly adapting to new developments.

These are values that help an organization perform at its best and endure. They have guided Heaven Hill Distilleries throughout its 80-year history and have ensured its success.

America’s largest family-owned and operated distilled spirits producer, Heaven Hill Brands, based in Louisville, Kentucky, has grown beyond its traditional roots as a Bourbon distiller to become the country’s seventh largest overall distilled spirits producer with a portfolio of innovative and relative products.

Since Heaven Hill was founded in 1935, the Shapira family has been at the helm. Heaven Hill has always taken great pride in being family run. With its third generation of family management in place, the company’s unique position in the industry is assured well into the future.

Andy Shapira, member of that third generation, is committed to upholding Heaven Hill’s lauded excellence in the industry. He is also committed to ensuring that Heaven Hill does its part to enhance quality and enjoyment of life through philanthropic support.

Shapira and his family have exercised their profound belief in “giving back” by supporting the Myeloma Institute and its cutting-edge research.  Here’s why…    γ

distill (us) verb
or chiefly British distil /di’ stil/
to take the most important parts of something and put them in a different and usually improved form; to extract the essence of.

-Merriam-Webster Dictionary

In 2013, Shapira visited his local emergency department with a bout of food poisoning. A CT scan of his gut revealed abnormal spots on his bones, and blood work indicated myeloma – certainly not what he expected from a hospital encounter triggered by eating bad food. With the mindset of a thorough businessman, Shapira researched his options and was intrigued by the depth of research and clinical excellence of the myeloma program at UAMS. His Louisville oncologist confirmed the wisdom of his choice.

After his first visit with Frits van Rhee, M.D., Ph.D., at the Myeloma Institute, Shapira knew he was at a center that shared the values so fundamental to Heaven Hill. Surrounded by compassionate experts, he was confident he was at the right place. Based on the nuances of his disease, he underwent two stem cell transplants as part of his personalized care plan.

“The outcome was great, although I have to admit the treatment was difficult. But, that’s why I came to UAMS. I was young and wanted aggressive treatment,” he said.

Shapira had three young daughters at the time – the twins are now 11 and the youngest is 7 – and he was determined to fight hard to knock out the myeloma. His wife did solo parent duty at home with the girls while his mother, Ellen, took on the caregiver role in Little Rock.
Shapira and his mother found a lot of silver linings while in Little Rock. It was an easy place to set up a home away from home and work remotely. In fact, they had numerous Heaven Hill business connections here, all of whom were eager to help if needed. They readily bonded with other patients and caregivers, including some from the Middle East, Asia, and Mexico.

“There is a real connection here, even with the people who clean the infusion unit floor. Everyone knows what you are going through,” he said. 

The best silver lining of all: Andy continues to be in sustained, complete remission. “I was so fortunate that I had the resources to go to Little Rock for treatment. It’s important to go where you can get the best treatment, if possible.”

In the spirit of giving back and with the goal of doing their part to ensure continued excellence for other patients, Shapira and his mother chose to make a meaningful donation to the Myeloma Institute. “UAMS is leading the charge with new treatment options, and we want to help,” he said.

“We are making steady progress in our research on harnessing the immune system to fight off myeloma,” said van Rhee. “This exciting research has tremendous potential for improving patient outcomes. Support from the Shapira family helps make this possible.”

The family’s commitment to ongoing improvement and ingenuity guides their investment in programs of excellence that are making a difference. The Myeloma Institute is exceedingly grateful to the Shapira Family for its strong vote of confidence.

New Clinical Trials

new clinical trialsA Phase II Trial of a Novel Proteasome/IMiD Combination, Ixazomib, Pomalidomide, and Dexamethasone, in Relapsed Multiple Myeloma Patients

UARK 2015-03
Principal Investigator: Faith Davies, M.D.
ClinicalTrials.gov Identifier: NCT02578121

The primary objective is to determine the efficacy of ixazomib when combined with pomalidomide and dexamethasone, in terms of overall response rate in patients with relapsed myeloma. Previous studies have shown that the combination of ixazomib, lenalidomide and dexamethasone had a VGPR (very good partial response rate) of over 60 percent in newly diagnosed myeloma patients, suggesting that the combination of an oral proteasome inhibitor with an IMiD is an effective treatment modality. This single arm Phase II study is designed to build on that data in order to develop an effective oral regimen which is well-tolerated for patients with relapsed disease. The long-term aim is to develop a backbone regimen to which future novel targeted treatments can be added as part of a personalized medicine approach.

A Randomized Phase II Trial to Evaluate Three Daratumumab Dose Schedules in Smoldering Myeloma

UARK 2015-13
Principal Investigator: Gareth Morgan, M.D., Ph.D.
ClinicalTrials.gov Identifier: NCT02316106

The purpose of this study is to evaluate three daratumumab dose schedules in participants with smoldering myeloma.

It is a randomized, open-label (identity of assigned treatment will be known to participants and study staff), 3-arm (3 treatment groups), multicenter study of daratumumab in patients with intermediate or high-risk smoldering myeloma.

Primary outcome measures include:

Percentage of participants who achieve a complete response.

Percentage of participants who have an
adverse event per patient-year.*

Secondary outcome measures include:

Percentage of participants who are minimal residual disease negative.

Percentage of participants who achieve a complete response or partial response.

Median time of progression free survival.

Percentage of participants with symptomatic myeloma.

Overall survival rate.

*The concept of patient-years is used in many clinical studies and statistical assessments of risk. It enables researchers to look at a population more generally, rather than trying to separate out and process data from each individual member of a group. To obtain the number, researchers add together all of the years that patients in a study were followed, and then divide those years by the event of interest.

Advancing Cure with CyTOF Technology

Based on our years of experience in the research and treatment of myeloma and related diseases, we are confident that personalized approaches to treatment hold the best promise for a cure. The ability to customize treatment demands comprehensive knowledge about the nuances of each individual’s disease. With CyTOF technology, we will be able to explore cell populations and biological systems with unprecedented depth and take our outstanding treatment modalities to new levels of excellence in the pursuit of superior outcomes for every patient.

Background

Over the past decades, our understanding of myeloma stem cell biology and immunology has been greatly enhanced by improvements in single cell analysis technologies that have made it possible to quantify the expression of multiple genes on the surface of individual cells and determine the cellular subtypes of the immune system. We have been able to determine what makes cancerous myeloma cells different from normal cells and use this information to design optimal treatments and stimulate the immune system to fight cancer.

Fluorescence-activated cell sorting, or flow cytometry, has been the standard technique for recognizing the cellular subtypes of the immune system for many years. However, this technique is limited by the number of fluorescent tags that can be used to identify cells, and therefore not all of the integral components of the immune system can be identified simultaneously. Typically, up to eight markers can be used in this type of cell sorting.

To combat this limitation, a new technology has been developed that can detect up to 35 markers at the same time, allowing a more detailed examination of the many cell types present in the bone marrow and their interactions. The technology couples flow cytometry with time-of-flight mass spectrometry, and is known as CyTOF (Cytometry by Time of Flight). With CyTOF, many more of the immune cell subtypes can be identified simultaneously. This will allow us to be more precise with our treatments.

How can CyTOF translate to improved patient care?

  • Our researchers will be able to study how different immune populations in the bone marrow interact with myeloma cells and influence tumor growth and survival.   
  • CyTOF can study the function of the immune system at a single cell level, enabling us to further develop immune therapy treatment options.
  • We will gain a better understanding of the features of the cells that cause myeloma and related diseases by identifying signaling pathways that we can then target with specific therapies for improved outcomes with minimal toxicities. 
  • CyTOF and its analytic tools will help us evaluate and interpret disease evolution in serial patient samples and response to specific therapies.
  • We will be able to expand serial patient samples into larger groups of disease-resistant cell populations and cell signaling pathways that predict the risk of relapse.

Your Support

Your support of CyTOF technology will help ensure that every patient receives optimized treatment for his/her disease. Please contact Jennifer Gurley, Senior Director of Development, at JMGurley@uams.edu for more information.

Bone marrow is the spongy tissue inside our bones that produces blood cells — red blood cells, platelets, and white blood cells.

White blood cells help the body fight against infection. There are many different types of white blood cells, including lymphocytes, neutrophils, and monocytes. They fight against invading bacteria, viruses or fungi to help destroy infection. 

Three major types of lymphocytes play an important role in the immune system.

B-lymphocytes (B-cells) originate in the bone marrow. They make proteins called antibodies, which attach onto the surface of infection-causing microbes. Generally, these are Y or T shaped. Each type of antibody reacts to different microbes by sticking to molecules, called antigens, which sit on the surface of the microbe. It is this antibody-antigen binding that triggers B-cells to grow and produce more antibodies, which fight infection.

T-lymphocytes (T-cells) mature in the thymus, which is a small organ in the upper chest, just behind the sternum (breastbone). T-cells help B-cells make antibodies against invading bacteria, viruses or other microbes. Unlike B-cells, T-cells can produce chemicals that kill infected cells after binding to the antigen on the surface of the infected cell.

T regulatory cells suppress immune responses of other cells. This is an important “self-check” built into the immune system to prevent excessive reactions.

Natural killer (NK) cells are a type of lymphocyte that directly attacks cells which have been infected by
a virus.