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A PUBLICATION OF

WINTHROP P. ROCKEFELLER

CANCER INSTITUTE

SUMMER 2020

NEW THERAPIES AND DRUGS EXTENDING AND IMPROVING LIVES


from the director

“Our researchers are on the frontlines of work that will advance care for our patients now and for years to come.�

It is my pleasure both to present the latest edition of Myeloma and introduce myself as the new director of the UAMS Winthrop P. Rockefeller Cancer Institute. Since its founding in 1989, the Myeloma Center has impacted thousands of lives through advanced research and clinical programs. As this tradition continues, I am proud to witness the amazing work accomplished by our Myeloma Center faculty and staff every day. I have seen many promising and innovative research advances during my career as a medical oncologist specializing in gynecological cancers. The same holds true for myeloma. Our researchers are on the frontlines of work that will advance care for our patients now and for years to come. You can read about the latest research and clinical care advancements in this issue of Myeloma. These include our participation in the national Prospective Multiple Myeloma Impact Study (PROMMIS) and the work of Sarah Johnson, Ph.D., focused on understanding minimal residual disease and how resistant cells can be targeted to prevent relapse. The cover story featuring Frits van Rhee, M.D., Ph.D., shares exciting news about Total Therapy 7 for high-risk patients and how new therapies and drugs are extending and improving lives. We also are proud to feature some of our dedicated staff members you are sure to recognize, along with stories of our resilient survivors. As we work together toward our goal of achieving National Cancer Institute Designation, our Myeloma Center and other cancer programs will only continue to grow and reap benefits for the people of Arkansas and beyond. I invite you to join us on this exciting journey! Michael Birrer, M.D., Ph.D. Vice Chancellor, UAMS Director, Winthrop P. Rockefeller Cancer Institute Director, Cancer Service Line

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from the Myeloma Center Clinical Director I am honored to present the 2020 Summer issue of the Myeloma magazine. Our patients have expressed concerns about their treatment and safety during the COVID-19 pandemic. I want to assure you our expert myeloma team is committed to providing world-class care during this difficult time. To achieve this, adjustments have been made to our regular operations, such as digital health, to keep our patients safe while maintaining a high standard of care. Patients will continue to have access to treatment including stem cell transplantation Novel therapies will build on the progress we have already achieved, and cure will become a reality for many more patients. Research is crucial to innovation of treatment. It is my privilege to welcome Dr. Fenghuang Zhan back to our Myeloma Center as director of research. Dr Zhan’s research focuses on myeloma stem cells and overcoming resistance to therapy. I am also excited about the appointment of our new Cancer Institute Director, Dr. Michael Birrer, who will lead the drive for National Cancer Institute (NCI) Designation. NCI Designation will increase access to research funding, clinical trials and collaborative efforts with other high-profile cancer centers. The Myeloma team is greatly indebted to our patients and families who entrust us with their care and those who support us through philanthropic efforts. I thank you all for your continued and unwavering support. I trust you will find encouragement and hope in the inspiring stories shared by our patients. Having made great strides forward in the 30 years since the inception of the Myeloma program at UAMS, I look forward to the future. We will be in an excellent position to deliver high-quality care, improve quality of life, make new discoveries and improve long-term outcomes. Welcome to the new decade and all the progress it will bring! Frits van Rhee, M.D., Ph.D. MRCP(UK) FRCPath Clinical Director of the Myeloma Center

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contents New Treatments, Drugs, Approaches Benefit Myeloma Patients . . . . . . . . . . . . . . . . . . . . . . . . . 5 Drag Racer, Specialty Mechanic Praises Swift Success of Treatment at Myeloma Center . . . . . . . . . . . . . . . . . . 8 Social Work, Customer Service Managers' Dedication to Patients Runs Deep . . . . . . . . . . . . . . . . . . . . . . . 10 Partners in Care . . . . . . . . . . . . . . . . . . . . . . . . . 12 Woman Resumes Humanitarian Trips to China after Myeloma Treatment . . . . . . . . . . . . . . . . . . . . . . . 14 UAMS Aims for National Cancer Institute Designation . . . 16 Patient's Unique Gene Expression Profiles Guide Treatment . . . . . . . . . . . . . . . . . . . . . . . . . 17 Former UAMS Physician, Renowned for Introducing Benchmark Chemotherapy, Returns to the Myeloma Center . . . . . . . . . . . . . . . . . . . . . . . . . 18 The Immeasurable Impact of a Gift . . . . . . . . . . . . . . 20 Publications . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Patient Bikes East Coast to Fight Myeloma . . . . . . . . . 22 Researcher Believes Changing Cell's Metabolism May Boost Immune System . . . . . . . . . . . . . . . . . . . . . 24 Minimal Residual Disease Testing: What Does it Mean? . . 26

SUMMER 2020 EDITOR Linda Haymes CREATIVE DIRECTOR Mindy Stout PHOTOGRAPHER Bryan Clifton DIRECTOR UAMS Winthrop P. Rockefeller Cancer Institute Michael Birrer, M.D., Ph.D. CLINICAL DIRECTOR Myeloma Center Frits van Rhee, M.D., Ph.D. DIRECTOR OF RESEARCH Myeloma Center Fenghuang "Frank" Zhan, M.D., Ph.D. CHANCELLOR University of Arkansas for Medical Sciences Cam Patterson, M.D., MBA Myeloma is published twice a year by the Myeloma Center, University of Arkansas for Medical Sciences 4301 W. Markham St. #816 Little Rock, AR 72205 Phone: 501-526-2873 myeloma.uams.edu

On the Cover: Myeloma Center 's Clinical Director, Frits van Rhee, M.D., Ph.D.

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Benefit Myeloma Patients New Treatments, Drugs, Approaches

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hree decades after the establishment of the UAMS Myeloma Center, its focus remains on the future by striving to cure more patients. “Our treatment approach, which comprises an induction, transplant, consolidation and maintenance phase has now been widely adopted in myeloma care,” said Frits van Rhee, M.D., Ph.D., clinical director of the Myeloma Center. “Using this approach and incorporating novel drugs into treatment has yielded a significant improvement in outcomes over the years.” “We estimate that 40% of patients with standard-risk myeloma can enjoy long-term, disease-free survival. Many of these patients will not relapse and we consider them functionally cured,” he said. “The challenge remains in patients with high-risk myeloma and those with low risk who have an early relapse.” He said other treatment centers face the same challenge. Total Therapy 7, a clinical trial open to highrisk patients, focuses on doing just that. TT-7 launched in August 2017 has 45 patients enrolled. Early results suggest that it leads to higher complete remission rates than in previous clinical trials for high-risk patients. “We believe it is critically important to improve our maintenance strategy because historically, the high-risk patients tend to relapse in their maintenance phase,” van Rhee said. The Total Therapy 7 protocol calls for a different approach in maintenance, giving the monoclonal antibody daratumumab (DARZALEX) together with carfilzomib (KRYPROLIS), a second-generation proteasome inhibitor, in a three-month block, then switching to a combination of lenalidomide (REVLIMID), daratumumab and dexamethasone for the next three months, alternating between the two combinations every three months for a period of three years. Daratumumab uses the patient’s immune system to kill myeloma cells. “The hope is that, used in this way, daratumumab synergizes and enhances the effects of carfilzomib and lenalidomide,” van Rhee said. “In essence we are trying to incorporate an

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immunological approach by using daratumumab rather than adding yet another chemotherapy drug. The hope is that maintenance will be more tolerable, and the patient will be more compliant with it.” He said that overall, the development of immunological approaches such as monoclonal antibodies, bi-specific antibodies and CAR-T cells will likely improve the outcome of patient groups that are presently difficult to treat. “Furthermore, the emergence of new drugs such as venetoclax allows for the development of more effective and more targeted therapy for certain patient groups. This increasing therapeutic arsenal will allow us to both use the immune system to combat myeloma as well as develop more effective strategies using a precision medicine type of approach. I think this is a very exciting time for myeloma patients with so many new treatment methods becoming available,” van Rhee said. “We have already established, through our longterm follow-up care data that myeloma patients can be cured,” he said. “And we anticipate that our percentages of patients with excellent long-term outcomes will increase in the future. We’ve made a lot of progress in the treatment of myeloma in the past 30 years, but I think the future looks bright. The next 30 years holds great promise for myeloma patients.”

The Challenge - High-Risk Patients 100% Events / N TT2 - Thal 19 / 20 TT2 + Thal 23 / 26 TT3a 33 / 40

80% 60%

Logrank P-value = .10

5-Year Estimate 10% (0,20) 19% (5,33) 25% (12, 38)

40% 20% 0%

0

5

10 15 Years After Enrollment

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Total Therapy (TT) Concept Clinical Trials at UAMS The name for the Total Therapy protocols came from the work that was being done at St. Jude Children’s Research Hospital with newly diagnosed ALL patients, called the “Total” protocols.

TT7 TT6 TT5A/B

TT4 TT3 TT2

Bortezomib

Thalidomide

TT1

Low Risk

Induction, Tandem transplant, consolidation, maintenance

• • • • • •

High Risk, Daratumumab

Previously Treated

High Risk, Bortezomib (A), Carfilzomib (B)

Incorporate novel drugs upfront Address complicated mutational spectrum Overcome drug resistance Optimize the response Prevent clonal evolution and disease escape Eradicate the disease

Total Therapy 7 for High-Risk Myeloma Dia

Transplant #1

gno

Melphalan

sis

Transplant #2 Melphalan

“The challenge remains in patients with high-risk myeloma and those with low risk who have an early relapse.”

Maintenance

Immunotherapy + Chemo: Dara (monthly) + carfilzomib, dexamethasone alternating Dara (monthly) + Revlimid, dexamethasone

Induction then Stem Cell Collection Immunotherapy + Chemo: Carfilzomib Thalidomide Dexamethasone Daratumumab Platinum Adriamycin Cytoxan Etoposide Stem cell collection

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Consolidation #1

Immunotherapy: Daratumumab starts 28 days after stem cell infusion, given for 4 weeks Immunotherapy + Chemo: Daratumumab + carfilzomib for 8 weeks

Consolidation #2

Immunotherapy: Daratumumab starts 28 days after second stem cell infusion, given for 8 weeks

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Brian Macy runs diagnostics on his race car.

Drag Racer, Specialty Mechanic PRAISES SWIFT SUCCESS of Treatment at Myeloma Center

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rag racer and specialty mechanic Brian Macy, 49, was diagnosed with myeloma in June 2016. Just a little more than a year later, he was back on track, literally.

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Macy, of Lake Havasu City, Arizona, owns Horsepower Connection, an automotive customization shop that specializes in electronic fuel injection programming and conversions of older

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domestic cars and boats for motor racing. He also tunes EFI motors and large horsepower drag race cars and street cars. Upon seeking treatment at the UAMS Myeloma Center, Macy greeted his doctor by saying, “I’ve researched you and know all about you and what you do. But do you know what I do?” Macy asked, pointing to a photo of the car he races in the Pro Modified division. “I told him, ‘That’s what I do and I’m going to drive that again,’” he recounted. “I also told him that he was cutting into my racing season,” he added, chuckling. Unlike other patients with the rare blood-related cancer, Macy has not experienced any broken bones but did have a cracked pelvis and a large tumor in the lowest portion of his spine. Before his myeloma diagnosis, “I really thought it was my sciatic nerve,” he said. “I kept going to this doctor in Arizona, complaining that my back hurt. It got so bad I wasn’t drag racing anymore and I could hardly work at that point.” He was in so much pain when he and his wife, Heather, first arrived at UAMS he could barely walk. “I was determined to find the best place I could go to for treatment.” A friend in Memphis, whose father had myeloma and was being treated at the Myeloma Center, suggested he come to UAMS. Macy’s treatment included chemotherapy and a tandem stem-cell transplant, completed in early 2017. By August, he was back behind the wheel and racing.

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Macy is now in remission. He has not experienced any relapses and has not taken any medications for myeloma for more than two years. “I’m clean with no residual trace of myeloma,” said Macy, who sees Sharmilan Thanendrarajan, M.D., at the Myeloma Center, part of the Winthrop P. Rockefeller Cancer Institute, for six-month checkups. His last checkup was in October. “The care at the Myeloma Center has been great,” he said. “The system they have in place is wonderful. You get your information and results back so quickly. At other places, it can take two weeks to get your results back, but here you know what they are almost overnight.” “Everyone, from the doctors and nurses down to those who drew blood, contributed in different ways. They are all great here at UAMS,” Macy said. Visiting with other patients was also therapeutic for him. “Everybody has a story and everybody is at different stages in their treatments,” Macy said. “It’s like you’re in this huge patient support group and you don’t even realize it.” He appreciates that UAMS is as aggressive about eradicating myeloma as he is about driving and tuning souped-up race cars. “They’re serious at the Myeloma Center,” Macy said.“The attitude is ‘We’re going to kill this disease and make it go away.’”

“Everyone, from the doctors and nurses down to those who drew blood, contributed in different ways. They are all great here at UAMS.”

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Social Work, Customer Service Managers'

Dedication to patients runs deep

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t the Myeloma Center, patients have more than just their physicians and nurses looking out for them. Harold Dean, clinical social work program manager, and Sonja Thornes, customer service manager, are integral parts of the patient care team. “My goal is to try to make our patients’ time at UAMS easier,” Dean said. He joined UAMS in 1988 and what is now the Winthrop P. Rockefeller Cancer Institute in 1993. “A cancer diagnosis can be so overwhelming on so many levels,” Dean said. “I hope my work provides patients with resources from emotional support to practical assistance that helps them feel empowered and better able to cope with their diagnosis and treatment.” Dean, who also serves as president of the Board of the Directors of the Association of Social Work Boards, credits his commitment to patient care to his early home life. 10

“My family placed value on trying to help others,” he said. “Serving others gives meaning to my life and enriches me personally.” In addition to being responsible for the daily operations of the Myeloma Center’s social work department, Dean meets with patients for their initial social work assessments. “Meeting new patients is one of the most enjoyable parts of my job,” he said. “I learn so much from our patients and they inspire me with their courage and resiliency.” He also coordinates his department’s presentation of the numerous special projects and events his department offers, ranging from holiday-themed gatherings for outpatients and those admitted to the hospital to educational programs focusing on both medical care and coping skills.

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A team effort

“There is absolutely no way I could do my job without the other members of my staff,” Dean said. “I am one of the luckiest people at UAMS to be able to have Jael Hastings, LCSW, Margaret Srygley and Carol Wallace on my social work team. I would not be nearly as effective in my current role were it not for the support and skill of such fine, smart, dedicated professionals.” Dean oversees the training activities of the University of Arkansas at Little Rock graduate students pursuing a master’s degree in social work who intern with the Myeloma Center. He is also involved in support groups, serving as co-facilitator of the Leukemia and Lymphoma Society’s monthly Little Rock Blood Cancer Support Group and oversees a twicemonthly cancer support group for the UAMS Cancer Institute.

Lovin’ from the oven

Dean is renowned among colleagues and patients for baking well into the morning hours (his shortbread cookies are a favorite) for the fall and spring bake sales his staff and other Myeloma Center employees have held to benefit the patient support fund.

The ties that bind

Thornes, like Dean, goes the extra mile for the center’s patients. She joined UAMS in 1990 in the admissions office and previously worked in the Myeloma Center’s insurance department. In 2008, she became customer service manager where she works closely with the center’s new patients, volunteers and social work department. myeloma.uams

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“I try to develop close relationships with our patients, especially during active treatment,” Thornes said. “During those times, we become family. “Harold and I have similar ideals for our patients, which is why we work so well together,” she said. “We want to treat the whole person, not just the cancer.” One of her favorite duties is leading the new patient orientation each Wednesday afternoon at 3 p.m. “I get to meet all of our new patients, introduce them to our facility and answer questions regarding their initial visit here,” Thornes said. “I have befriended many of them and their families as we all have,” she said. “I feel blessed to say that many of the patients ask to visit with me when they return for checkups.” Thornes, a U.S. Army veteran, said working at the Myeloma Center shares some similarities with being in the military. “I continue to get to meet people from all over the nation and the world and it is my privilege to represent UAMS.”

“I learn so much from our patients and they inspire me with their courage and resiliency.”

Compassion and care are key “I think it’s the personal touch, and the caring nature of the professional relationships that develop between our patients and all the members of our treatment team that sets us apart from other oncology centers,” Dean said . “Our people make the difference,” Thornes added. “Our amazing physicians, nurses, our extremely hardworking staff and their attention to detail.” .

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Partners in Care

Patient, Now Physician, Joins his Doctor in Conquering his Rare Disease

"UAMS and the Myeloma Center are extremely focused on the patient experience,” said David Fajgenbaum, M.D., who was a medical student when he met his physician Frits van Rhee, M.D., Ph.D., but today collaborates with him on several projects related to Castleman disease.

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avid Fajgenbaum, M.D., was a 25-year-old medical student and a patient with Castleman disease when he met Frits van Rhee, M.D., Ph.D. a decade ago. Now he is a fellow physician collaborating with the UAMS Myeloma Center clinical director on several projects related to the disease. “David is an incredible advocate for those with Castleman disease,” van Rhee said. “He has made great strides regarding this rare lymph node disorder, from raising awareness of it to advancing research and treatment.” 12

Fajgenbaum was a student at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia when he became ill in 2010, and was hospitalized for six months. He was eventually diagnosed with idiopathic multicentric (iMCD), a subtype of Castleman disease. The disorder affects 5,000 patients in the U.S. each year. “I did some research and found that Dr. van Rhee was the world’s leading expert for the study and treatment of Castleman, specifically iMCD, so I went to see him,” Fajgenbaum, 34, said. “But while there, I relapsed and spent two months in the hospital,” said Fajgenbaum. “I was on dialysis, needed transfusions, and gained 30 to 40 pounds of fluid all over my body.” “Dr. van Rhee did a multi-agent chemotherapy, treating me with an experimental drug, siltuximab, of which he was the principal investigator, and he saved my life. He got me through a really tough time.” “It was incredible,” Fajgenbaum said of his care in Little Rock, Arkansas. “UAMS and the Myeloma Center are extremely focused on the patient experience,” he said. “Sometimes at major academic centers they are so focused on treatment and research, the staff can lose sight of the patient, but that never happened once at UAMS.” myeloma.uams

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Back in medical school, Fajgenbaum relapsed a second time and learned the experimental drug, siltuximab, was the only one in development. “But I survived, thanks to chemotherapy,” he said. “That’s when I decided to dedicate my life to trying to advance the treatment of Castleman disease.” “A few weeks later, I asked Dr. van Rhee if he would partner with me to help co-found the Castleman Disease Collaborative Network, and he graciously agreed.” “We are trying to accelerate treatment of the disease with an innovative approach of including patients, researchers and physicians who all contribute ideas toward research and then fundraise and drive forward the science.” Fajgenbaum remains in remission and is an assistant professor of medicine in Translational Medicine & Human Genetics at the University of Pennsylvania. There he runs a research lab dedicated to studying Castleman disease and is the associate director of patient impact with the Orphan Disease Center focusing on supporting advances for rare diseases. He and van Rhee have also established and published the first international diagnostic criteria in 2017, the first Castleman disease treatment guidelines in 2018, and launched ACCELERATE, a global patient registry of Castleman disease patients who share their medical records to help advance treatments.

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“We learned a lot about Castleman disease from the medical records of the patients enrolled in this study,” Fajgenbaum said. About two years ago, he and van Rhee received an RO1 grant from the National Institutes of Health. “It was the first-ever federal grant to study iMCD,” Fajgenbaum said. Part of that grant includes launching a clinical trial of sirolimus, a drug developed to prevent kidney transplant rejection that Fajgenbaum identified about 5 ½ years ago in his lab and began using himself. “I have been in extended remission ever since I started on it,” he said. Fajgenbaum is holding a clinical trial with the drug at the University of Pennsylvania in Philadelphia, while van Rhee has the same trial open at UAMS in Little Rock. In 2019 Fajgenbaum released a book on his experience, “Chasing My Cure: a Doctor’s Race to Turn Hope into Action.” Since his diagnosis, he has wed and he and wife, Caitlin, recently had a daughter, Amelia. It has been six years since his last relapse but he remains vigilant. “I know I can relapse at any time,” Fajgenbaum said. “So I fight with everything I’ve got to make sure I’m making progress as quickly as possible for my disease.”

“Sometimes at major academic centers they are so focused on treatment and research, the staff can lose sight of the patient, but that never happened once at UAMS.”

For more information on the Castleman Disease Collaborative Network, visit: https://cdcn.org/.

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Woman Resumes

HUMANITARIAN TRIPS TO CHINA

after Myeloma Treatment

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indy Sites loves sharing her gift of music with others. Whenever she visits the Myeloma Center, she plays the Steinway piano in the lobby. “I usually play for an hour or so in between my tests or while waiting for my appointments,” Sites, 57, said. “I enjoy visiting with the people who come along.” The excellent treatment Sites received from the Myeloma Center over the last decade allows her to bring care and comfort to others in an even more profound way. Sites and her husband, Doug, live in Springfield, Missouri, but their humanitarian work through a foundation recognized by the Chinese government, keeps them on the go. They often visit remote, rural areas of China to help others, specifically children with special needs. They provide goats and other 14

agricultural items, winter clothing, school supplies and offer family training and music seminars. “Before my medical issues, we took up to three major trips annually, some lasting as long as six weeks,” said Sites, who has two adult children. “But for more than four years, I couldn’t go overseas because I was receiving weekly chemotherapy shots.” After Sites’ diagnosis of high-risk myeloma in 2009, the couple lived in Little Rock for seven months while she went through five heavy rounds of chemotherapy and two stem cell transplants at UAMS. Bart Barlogie, M.D., Ph.D., and his team treated her. “His mind was so sharp to catch a few numbers in my reports that indicated I was high-risk,” said Sites.

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In 2010, she returned home in remission and with a three-year maintenance plan. About a year later, she convinced Doug to return to China without her to continue their work. “It was a very challenging time, but it was what we needed to do. I needed to get well because I fully believed I would be working alongside him again someday.” She remained in Missouri, traveling to a nearby treatment center for weekly chemotherapy shots while Doug traveled overseas for three weeks at a time. “It was quite a struggle, but I pushed through,” Sites said. “I followed the doctor’s orders, took all my medications and came to UAMS for my checkups every three to four months,” Sites said. After three years of maintenance, she was in remission. “It was quite a moment of rejoicing!” Sites returned to China a little less than two months after completing chemotherapy in late 2013. For the next two years, she continued traveling overseas and in the United States. During a checkup in 2015, a small lesion on her leg indicated the myeloma had returned. By then a patient of UAMS’ Frits van Rhee, M.D., Ph.D., she underwent additional chemotherapy and by May 2016, the cancer was gone. She credits van Rhee with providing the care that returned her to her life’s mission. “He listened to my story, heard my desires and worked on a treatment plan that would allow me to get back to China as soon as possible,” Sites said. “He believed that a third

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transplant was necessary to extend my life because he saw my passion for the work we felt we needed to do.” “The third transplant was more difficult and I was sicker, but about three weeks later I was back home and recovering for a few months.” Sites was put on a one-year maintenance plan and in early 2019 learned she was in complete remission with no sign of minimal residual disease. “As Dr. van Rhee said, ‘You can’t get any better than that!’” She remains in remission, has had no chemotherapy for more than a year and continues to travel regularly. “I am extremely grateful to Dr. Barlogie and Dr van Rhee and all the staff who went beyond the call of duty to restore me to complete health,” Sites said. “I am thankful every day for this great gift of life.” “I am convinced that if we had not come to the top doctors at UAMS I would not be here today,” said Sites, whose first grandchild arrived in late 2018. “I prayed that God would allow me to see my children’s children. I have seen one and hope for many more.”

“He listened to my story, heard my desires and worked on a treatment plan that would allow me to get back to China as soon as possible.”

Editor’s note: When news of the coronavirus erupting in China broke in February, Cindy and Doug were in Hong Kong. From there, they traveled to Thailand and changed their tickets to return home early. “I am here, but my heart is there, in China, with our friends at the orphanage and villages we have had our hands in helping for many years,” she reported after returning home.

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National Cancer Institute Designation

UAMS Aims for LEARN

RECRUIT

Cancer Institute Director

BUILD

infrastructure that aligns with NCI Designation guidelines which are modified every 3 years

are he

re

We

about NCI Designation • read guidelines • attend meetings

SUBMIT p30 grant

RECRUIT

and retain leading cancer researchers who collectively bring in $10M + in NIH cancer research funding annually

Timeline 4 - 6 months

O B TA I N

approval from EAB and NCI to apply for NCI Designation and determine application date

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he UAMS Winthrop P. Rockefeller Cancer Institute has provided research-driven cancer care for thousands of patients from every corner of Arkansas and around the world. Now, the institute’s research focus pushes it closer to achieving the country’s most distinguished status for cancer centers: National Cancer Institute (NCI) Designation. There are 71 NCI-Designated Cancer Centers in the United States, with some of the closest to Arkansas being in Memphis (which only provides pediatric care), Dallas and Oklahoma City. “Achieving NCI Designation will benefit all Arkansans and place the Cancer Institute among the top 2% of cancer centers nationally,” said Myeloma Center Clinical Director Frits van Rhee, M.D., Ph.D. To achieve designation, cancer centers undergo a highly competitive assessment process that demonstrates an outstanding depth and breadth of basic laboratory, patient/clinical

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NCI Designation

or

FA I L Timeline 2 - 5 years

ASSEMBLE

a new External Advisory Board (EAB) and meet with NCI Leadership

RECEIVE

HOST

NCI site visit

to meet NCI Designation standards

R E A P P LY

in 5 years

and population-based research. Centers also are expected to transform their research into measurable clinical outcomes for patients. Achieving NCI Designation would provide both UAMS and Arkansas with multiple benefits: • Significantly increased ability to receive federal and other research funding • Improved access to clinical trials and therapies unavailable elsewhere in the state • Creation of new, high-paying health care jobs • Increased research collaboration opportunities with leading cancer treatment teams In addition, it is projected that NCI Designation would have an economic impact of $72 million to the state annually. “The Cancer Institute provides the highest quality cancer treatment for all patients. NCI Designation will only increase this capability by significantly expanding our clinical trials and research abilities across the board,” van Rhee said.

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Patient's Unique Gene Expression Profiles Guide Treatment

The PRospective Multiple Myeloma Impact Study (PROMMIS) at the UAMS Myeloma Center studies the impact of gene expression profiling on treatment intention decision in myeloma care This gene expression profiling study, which is at UAMS under the direction of Myeloma Center Clinical Director Frits van Rhee, M.D., Ph.D., is only taking place at eight academic centers across the U.S. and aims to enroll 250 patients. Gene expression profiling measures the activity of thousands of genes at once, giving physicians an overall picture of a patient’s myeloma. “The Myeloma Center began conducting gene expression profiling (GEP) nearly twenty 20 years ago,” van Rhee said. “It helps determine whether a patient is classified as high risk or low risk. Patients with low risk myeloma have in general an excellent

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outcome, whilst those with high risk disease are at risk of early relapse.” The Myeloma Center has a Total Therapy protocol specifically designed to treat high-risk disease. Van Rhee said gene expression profiling has not been widely adopted by most physicians treating myeloma because they are not familiar with the test and unsure how to adjust the treatment, depending upon the results. “Through the study, we hope to demonstrate to other physicians that knowledge of the gene expression profile results plays a role in our decision making and can influences treatment choices,” van Rhee said. The expectation is that the study sponsored by SkyDiagnostics will lead to a FDA-approved gene expression profiling test, which can be made widely available to patients.

“Through the study, we hope to demonstrate to other physicians that knowledge of the gene expression profile results plays a role in our decision making and can influence treatment choices.”

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Former UAMS Physician, Renowned for Introducing Benchmark Chemotherapy, Returns to the

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uido J.K. Tricot, M.D., Ph.D., recently rejoined the University of Arkansas for Medical Sciences (UAMS) Myeloma Center. While at UAMS

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Myeloma Center

previously, Tricot developed one of the most effective first-line therapies for multiple myeloma, now used around the world.

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“We were thrilled to have Dr. Tricot rejoin our team,” said Frits van Rhee, M.D., Ph.D., clinical director of the Myeloma Center. “His vast clinical expertise and experience with cuttingedge research is invaluable to us,” he said. “He is absolutely helping us in furthering the innovative treatment we have offered here for the past three decades.” Tricot, who originally saw patients upon his return to the center now focuses exclusively on research. Tricot’s longtime researcher, Fenghuang “Frank” Zhan, M.D., Ph.D., also recently returned to UAMS. Zhan, previously at UAMS from 2002 to 2008, was an assistant professor in the College of Medicine. He worked with Tricot at the Myeloma Center and later in Utah and Iowa. In his projects, Zhan focuses on genes and drug resistance, molecular genetics and the biology of myeloma, genomic classification of the disease, and identifying and targeting myeloma stem cells. Zhan, who holds the Morrison Family Endowed Chair in Myeloma Research, has received two grants from the U.S. Department of Defense and the National Institutes of Health, totaling almost $3.14 million to study the molecular genetics and drug resistance of myeloma. When Tricot, a hematologist originally from Belgium, was first at UAMS, he was intimately involved in developing and pioneering the Total Therapy approach to myeloma involving induction chemotherapy, stem cell transplantation consolidation, and maintenance. This treatment method has been adopted worldwide and has been responsible, together with the introduction of novel drugs, for the greatly improved median survival rate for myeloma, which exceeds 10 years, with some patients achieving cure.

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“When I left UAMS in 2007, the program here was the largest myeloma program in the world,” Tricot said. “Many of us worked hard to build the myeloma program here into something unique.” Tricot received his medical and doctoral degrees at the University of Leuven in Belgium and served on the faculties of the Division of Hematology/Department of Medicine at University of Leuven, and the Department of Medicine and Pathology at Indiana University in Indianapolis, Indiana. He practiced at UAMS from 19931997, then returned in 2000 to serve as director of clinical research for myeloma. In 2007, Tricot left UAMS to launch the Utah Blood and Marrow Transplant and Myeloma Program at the University of Utah’s Huntsman Cancer Institute. In 2012, he joined the Holden Comprehensive Cancer Center at the University of Iowa Health Care in Iowa City, Iowa, where he most recently worked as an emeritus professor of internal medicine with hematology, oncology, and blood and marrow transplantation. Through the past 20 years, Tricot researched multiple myeloma and treated thousands of myeloma patients. After retiring from the University of Iowa, Tricot continued collaborating with his research team, working to defeat drug resistance, prevent relapse, and lengthen life expectancy. “Even with the most intensive therapies for myeloma, many patients still relapse, indicating that there is a small fraction of myeloma cells very resistance to chemotherapy,” said Tricot.

“When I left UAMS in 2007, the program here was the largest myeloma program in the world, many of us worked hard to build the myeloma program here into something unique.”

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Eddie and Mona Morgan with UAMS Chancellor Cam Patterson (middle).

THE

IMMEASURABLE IMPACT OF A GIFT

A

multiple myeloma diagnosis put the brakes on Mona and Eddie Morgan’s dream European vacation. Mona had been given six months to live and was in intensive care for a month. Doctors did not think she’d make it and the family was asked to come say their goodbyes. That was nine years ago after the Shreveport, Louisiana, couple found their home away from home in Little Rock for treatment at the UAMS Myeloma Center. Though there’s no mistaking central Arkansas for the majestic backdrop of Spain and Portugal, Mona says the unexpected detour turned out to be a pleasant surprise. “We were no different than the thousands of other patients from around the world who were surprised to learn that UAMS was the place to be if you were diagnosed with multiple myeloma,” Mona said. 20

“We are grateful for the expertise and caring that we have received from UAMS,” Eddie said. “The doctors, nurses and staff are all wonderful and we really feel that they care about us.” Mona continues to travel to Little Rock with Eddie for treatment and her smile is as big as ever. Recently they were recognized as the newest members of the UAMS Society of the Double Helix, honoring the institution’s most generous philanthropists. Like so many others who have received world-class care at the Myeloma Center, they are looking to the future. “Mona and I are proud to be able to give to the research of multiple myeloma,” Eddie said. “We feel that if it weren’t for UAMS, Mona may not be with us this day. We would love to see the day where multiple myeloma can be cured.” myeloma.uams

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publications An acquired high-risk chromosome instability phenotype in multiple myeloma: Jumping 1q Syndrome A new publication in Blood Cancer Journal August 2019 Primary author: Jeffrey R. Sawyer, Ph.D. Some multiple myeloma patients develop adverse chromosome abnormalities such as increases of the long arm of chromosome arm 1. The longer arm of the two sections of chromosome 1 is referred to as chromosome 1q. Sawyer describes a new syndrome in myeloma called “Jumping 1q Syndrome.” These patients

have instability of the genetic material in their myeloma cells and can develop multiple copies of 1 q, which ‘jump’ to other chromosomes with which they fuse. This way patients can have as many as five or more copies of 1q in their myeloma cells. The development of the chromosome 1q abnormalities can confer resistance to therapy. It is important to recognize these patients since they may require new approaches to treatment.

Daratumumab in high risk relapsed/refractory multiple myeloma patients: Adverse effect of 1q21 gain/amplification and GEP70 status on outcome A new publication in British Journal of Haematology Daratumumab in high-risk relapsed/refractory multiple myeloma patients: adverse effect of chromosome 1q21 gain/amplification and GEP70 status on outcome. Mohan M, Weinhold N, Schinke C, Thanedrarajan S, Rasche L, Sawyer JR, Tian E, van Rhee F, Zangari M. Br J Haematol. 2019 Dec 9. doi: 10.1111/bjh.16292. [Epub ahead of print] Daratumumab is a monoclonal antibody used for the treatment of relapsed and newly diagnosed multiple myeloma. Daratumumab

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recognizes a molecule called CD38 on myeloma cells and activates the immune system to kill myeloma. Human cells have 23 pairs of chromosomes containing the genetic material. The Myeloma Center was one of the first to report that the presence of multiple copies of the long arm of chromosome 1 in the myeloma cells is associated with worse outcome. Zangari and colleagues found that patients with relapsed myeloma who have multiple copies of chromosome 1 also respond less well to treatment with daratumumab. The results of this study will allow for targeting daratumumab treatment to those patients who are most likely to derive benefit.

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Patient Bikes

East Coast

to Fight Myeloma

Alan Wolfson’s eight-day 260-mile bicycle ride through the state of Virginia last year was just one of the many he has made over nearly 20 years in support of the UAMS Myeloma Center.

S

ince 2002, Alan Wolfson of Lakewood Ranch, Florida, has taken an annual bike ride most years along the east coast to raise money for the UAMS Myeloma Center. Averaging about $20,000 in contributions from his friends and supporters for each ride with the donations divided between the Myeloma Center and two other

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programs, he has already pedaled his way to nearly $250,000 for the center. In 2019, Wolfson, 70, took an eightday, 260-mile ride from Virginia Beach, Virginia, to Front Royal, Virginia, and raised $9,443.40 for the Myeloma Center. “My goal is to raise money to help people overcome damage to their lives caused by myeloma. It’s easy for me.

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The donors do the heavy lifting. All I need to do is pedal my bike.” Wolfson, recently retired from a Florida-based real estate development firm, was diagnosed with smoldering myeloma at 47 in 1996. When he arrived for an appointment with clinic founder Bart Barlogie, M.D., Ph.D., the myeloma program was just being established. “There was construction everywhere and patients sitting in the hallways,” he said. “Dr. Barlogie told me, ‘I can tell you honestly that your blood chemistry is not good. You are in no immediate danger but without more testing over time, I can’t tell how quickly, if at all, it’s progressing.” Subsequently, he had numerous visits to the UAMS Myeloma Center and many tests. Eventually his diagnosis was changed to MGUS. Fortunately, he has never undergone a day of treatment. However, at the start he had no idea what was going to happen with him. He was afraid for his future, and was profoundly affected by the courage and stoicism of the other patients he met and observed. “When I was coming every three months, I got to see a lot of the other patients and we began recognizing one another,” Wolfson said. “I was affected by the seriousness of this illness and how ordinary people are so brave in the face of it.” After coming to Little Rock for regular visits over a dozen years, he shifted to a local oncologist in his home of Sarasota, Florida, for regular monitoring and began to wonder if there was something he could do to help myeloma patients.

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“One day the idea just came to me that I was going take a bike ride and ask people for money. It was very spontaneous,” said Wolfson, who was then living in Buffalo, New York. That Friday morning, he put his bike on the back of his car on the way to work and at 4 p.m., called his wife and told her he was going for a bike ride that weekend. “I just changed clothes and went,” he recalled. “All I had with me was my wallet. I didn’t have any pack or bike tools. “ “I did no pre-planning and everything I did was wrong,” he recalled of his first ride. Despite a flat tire, heat, rain, strong opposing winds, and steep hills, he rode 240 miles in three days from Buffalo to Pittsburgh. When he returned home, he sent an email to 20 people, told them what he’d done and asked them to make a donation. The first ride raised $9,000. Each year thereafter he continued north, traveling eventually to Cochrane, Ontario, and, hitching a ride on a train, made it as far as the Hudson Bay shore at Moose Factory, Ontario. His rides after moving to Florida have included a trek to Mobile, Alabama, followed by a series of northerly trips. “I figured if I kept riding north, I could continue on and eventually make it back to Pittsburgh, where I concluded that first ride,” said Wolfson. In 2019, he intended to go from Virginia Beach to Pittsburgh, where he ended his inaugural ride, but, for the first time, had to cut his ride short after realizing he had underestimated the steepness of the hills in West Virginia. He plans to complete the final leg of his trip this year and arrive in Pittsburgh then.

“I was affected by the seriousness of this illness and how ordinary people are so brave in the face of it.”

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Researcher Believes

Changing Cell’s Metabolism May Boost Immune System

“The hope is that we can alter the cell’s metabolism so that in addition to targeting the tumor cells, we can also improve the response of the immune system,” said Sarah K. Johnson, Ph.D., a researcher with the Myeloma Center

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arah K. Johnson, Ph.D., a research assistant professor with the UAMS College of Medicine, in the Myeloma Center, has been researching residual disease in myeloma patients for about seven years.

24

She and her colleagues study several things including the observable characteristics of a cell and surface markers that can be gleaned from a basic minimal residual disease test but also dig deeper, using those markers

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to isolate those cells and test them more extensively. “Once a patient has relapsed, they can then receive novel therapies such as daratumumab (DARZALEX) and immunotherapies,” said Johnson, who joined the Myeloma Center in 2002. In addition to targeting myeloma, daratumumab also affects the metabolism of all the cells that have CD38, a molecule that is present on several cell types but is especially prominent on myeloma cells.

A Common Thread

Through the course of the disease, there’s a distinct difference in the metabolism of residual myeloma cells, Johnson said. It has also been shown that targeting the CD38 molecule on T cells, a type of white blood cell that is essential to the immune system, actually enhances their activity. “The hope is that we can alter the cell’s metabolism so that in addition to targeting the tumor cells, we can also improve the response of the immune system,” Johnson said. She said the key rests in finding the best time to treat with daratumumab followed by targeting the tumor cells with immunotherapy to increase treatment’s effectiveness. “We know myeloma affects the immune system, suppressing it so it can’t naturally target the tumor cell like it should and we want to change that,” Johnson said. “With mass cytometry, we’re able to look at both the tumor cell and the immune system at the same time.” In her work, Johnson uses a mass cytometer or a CyTOF to identify certain cell types by studying the proteins on a cell using antibodies. The CyTOF instrument is similar

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to a traditional flow cytometer, used to label up to 8 to 10 surface markers on a cell’s surface using fluorescent chemical compounds known as fluorochromes coupled with antibodies. In contrast, a CyTOF machine offers identification of up to 40 markers by using heavy metal ion tags instead of fluorochromes. “Mass cytometry is basically the same as flow cytometry which uses antibodies to look at the surface and markers on the inside of the cell,” Johnson said. “And by looking at up to 40 markers at a time, we can now not only detect the tumor cells but also multiple immune populations within the bone marrow or the blood,” Johnson said.

Sights Set on the Future

While myeloma has a very diverse genetic background with seven different molecular subgroups, Johnson hopes to find a target that is more general by studying metabolism, something that all cells have in common as a group. “By incorporating the immune system we can also use that in defined chemotherapies or immunotherapies to alter the metabolism of the immune cells and hopefully kill the tumor cells,” Johnson said, adding that she hopes to build a mass cytometry platform to examine various profiles to determine which treatment courses will work best. “The next step is to generate a metabolism-specific panel that will allow us to identify both the tumor cells and the immune cells to determine their current status and then identify which drugs are needed to target them,” she said.

“We know myeloma affects the immune system, suppressing it so it can't naturally target the tumor cell like it should and we want to change that. With mass cytometry, we're able to look at both the tumor cell and the immune system at the same time.”

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Minimal Residual Disease Testing:

What Does it Mean?

T

he goal in treating myeloma is to cure the patient or achieve longterm remission. But there is always the chance that some myeloma cells remain, despite the patient being in complete remission. One test that may indicate that myeloma is not completely eradicated is to check for what doctors call minimum residual disease (MRD). “MRD testing detects myeloma cells on a much more sensitive level inside the bone marrow,” Carolina Schinke, M.D., said. “MRD is a hot topic right now in the scientific myeloma community.” During treatment, all myeloma patients at UAMS undergo testing for

26

minimal residual disease with results being either positive for the disease or negative. The Myeloma Center uses two types of MRD testing — flow cytometry and next generation sequencing. With flow cytometry, a laser light beam measures physical and chemical characteristics of cells. The test studies the difference in the proteins on the surface of a cell to distinguish regular plasma cells from myelomatous plasma cells. The Myeloma Center began MRD testing in early 2014. It is conducting a study with the flow cytometry tests and is still gathering data. “The flow cytometry can detect one myeloma cell in 100,000 cells which

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is pretty sensitive,” Schinke said. “The pathologist would never be able to see that.” With next generation sequencing, a baseline sample is taken when the patient has active myeloma to identify unique DNA markers in the myeloma cells. These DNA sequences can then be searched for in the marrow when the patient is in remission by standard criteria. The test, conducted off site by Adaptive Biotechnologies, can detect one myeloma amidst a million normal cells. The criteria of complete remission are no detectable myeloma protein in the blood and less than 5% plasma cells in the bone marrow. The presence of a negative MRD test either by flow or sequencing means that the patient has achieved a so-called stringently defined complete remission. In addition, the Myeloma Center looks for active disease by imaging studies such as MRI and PET-scan. “Achieving complete remission may mean just the tip of the iceberg has been treated and there may be a lot more tumor burden that wasn’t able to be identified,” Schinke said. “There is the potential for relapse if there are remaining cancer cells as detected by MRD testing.”

New MRD offer greater insight

“The goal is to try to get each patient to an MRD negative state because over time we see those patients don’t relapse or have overall better outcomes with less relapses,” Schinke said. However, the interpretation of MRD testing is complex and depends on whether the patient’s disease is characterized as low risk or high risk. Some patients have more indolent,

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non-aggressive myeloma and these patients can remain MRD positive without ever relapsing. On the other end of the spectrum there are patients with high-risk disease, 15% to 20% of the myeloma population, where MRD positivity after transplantation indicates a high risk of relapse. These patients remain a challenge and the question is how to best alter therapy. Patients with standard or low risk may take longer to achieve MRD negativity after transplant. “We have found that those low risk patients who are MRD positive more than two years after transplant have an increased risk of relapse.” Schinke said there is a lot of information available on MDR testing but few, if any, other treatment centers have systematically examined the difference between wlow-risk and high-risk disease. “I believe we were the first ones to publish on that, but there are important questions we are trying to answer,” she said. “How do you guide your treatment around being MRD negative? If a patient achieves MRD negativity does that mean you can stop the three-year maintenance treatment early? How long does the patient need to be MRD negative to be safe? Can one use the flow test or does one need to use the more sensitive sequencing test?” The other side of the coin is the positive MRD test. “We will now actually change a treatment regimen based on positive MRD testing, especially in high-risk patients, even if everything else looks good,” Schinke said. “We have definitely become more proactive in preventing relapses when we see the MRD tests trending up.”

“The goal is to try to get each patient to an MRD negative state because over time we see those patients don't relapse or have overall better outcomes with less relapses.”

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behind

the scenes

Fenghuang “Frank” Zhan, M.D., Ph.D. Frank Zhan is a professor of medicine with the UAMS College of Medicine. He earned his doctorate in cancer molecular genetics from Hunan Medical University in Changsha, China. He began his postdoctoral fellowship in neuroscience at the University of Louisville in Louisville, Kentucky. In 2000, he joined UAMS where he completed his postdoctoral fellowship and later was promoted as assistant professor. Zhan’s research focuses on translational research in multiple myeloma and aims to identify treatment approaches to overcome drug resistance in myeloma. His projects include molecular genetics and biology of tumor cells and microenvironment, genes and drug resistance, genomic classification, and identifying and targeting myeloma stem cells.

Sarah K. Johnson, Ph.D. Sarah K. Johnson is a research assistant professor with the UAMS College of Medicine. She earned her doctorate in biochemistry from UAMS. She completed her postdoctoral fellowship in pharmaceutical sciences from the Medical University of South Carolina in Charleston, South Carolina. In 2002, she joined UAMS as a research assistant professor in the Myeloma Center. Johnson’s research focuses on the characterization of residual disease gene expression, epigenetic and metabolic profiles to identify resistant myeloma cells at any stage of the disease and to identify novel targets for the eradication of resistant tumor cells. Johnson studies myeloma cells and their interaction with the immune environment in the bone marrow. The goal is to learn how this interaction affects resistance to treatments to improve existing therapies as well design novel, especially immune-based therapies.

Profile for University of Arkansas for Medical Sciences

Myeloma Magazine Summer 2020  

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