Chadley Uekman

2022

Editor
Linda Haymes

Creative Director
Mindy Stout

Photographer
Bryan Clifton
Evan Lewis

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 once a year by the Myeloma Center, University of Arkansas for Medical Sciences

Behind the Scenes

John D. Shaughnessy Jr., Ph.D.

John Shaughnessy Jr. is a principal staff scientist and professor of medicine. He earned his doctorate in molecular biology from the University of Maryland and served his postdoctoral fellowship at the Mammalian Genetics Laboratory of the National Cancer Institute’s Frederick Cancer Research and Development Center. In 1996, he joined UAMS specifically to create a tissue archive and accompanying genetic profiles on myeloma patients. He rejoined UAMS in 2021.

His research focuses on developing new targeted therapies for multiple myeloma. Using the Myeloma Center’s patient cases, he investigates the genetics of extremely long survivors, seeking to understand their longevity.

David Mery, Ph.D.

David Mery is a postdoctoral fellow with the UAMS College of Medicine. He earned his doctorate in pharmaceutical sciences from UAMS in the summer of 2021 and joined the Myeloma Center that fall.

His research focuses on the pharmacokinetics and pharmacodynamics of small molecules for the discovery of therapies that can efficiently target and eliminate resistant myeloma cells. Mery is also working to understand the inter-tumor heterogeneity between multiple myeloma subtypes.

Myeloma Center Clinical Director, Research Staff Play Pivotal Role in Most Recent Discoveries in Castleman Disease

In addition to serving as clinical director of the Myeloma Center at the University of Arkansas for Medical Sciences (UAMS), Frits van Rhee, M.D., Ph.D., is also regarded as an international expert on Castleman disease, a rare disorder of the lymph nodes and related tissues.

“Because Castleman disease is rare, most physicians don’t know how to treat it, and until recently there was not any systematic approach,” said van Rhee, who also holds the Charles and Clydene Scharlau Chair for Hematologic Malignancies Research at UAMS. Castleman disease affects approximately 5,000 patients across the United States.

Identified by Benjamin Castleman, M.D., in 1954, Castleman disease occurs when an abnormal overgrowth of cells occurs in the lymph system, which serves as the main part of the body’s immune system.

“The average oncologist may only see one patient with Castleman disease in his career,” said van Rhee, who has worked to advance the research and treatment of the rare disease.

Van Rhee previously served as the principal investigator on a worldwide trial with siltuximab (Sylvant), which led to the first FDA-approved treatment for multicentric Castleman disease and the approval of the drug by the European Medicine Agency.

Recent new discoveries were led by researchers at Penn Medicine and the Castleman Disease Collaborative Network, (CDCN) which van Rhee co-founded in 2012 with David Fajgenbaum, M.D., an iMCD patient of van Rhee’s and the study’s senior author. Fajgenbaum, who received his medical degree after being diagnosed with Castleman disease, is an assistant professor of Translational Medicine and Human Genetics, director of the Center for Cytokine Storm Treatment & Laboratory at the Perelman School of Medicine at the University of Pennsylvania and associate director of patient impact at the Penn Orphan Disease Center.

One of these studies revealed a precision medicine test using blood proteins to identify a novel patient subgroup of iMCD patients who are more likely to respond to siltuximab. The study, published by Blood Advances, also found that using Janus kinase (JAK) inhibitors, which are already approved for treating certain cancers and rheumatoid arthritis, are a promising alternative treatment option for patients who do not respond to siltuximab, a monoclonal antibody treatment.

Other studies published by Fajgenbaum and van Rhee in the journals Blood and the Journal of Clinical Investigation found another new target for therapy, m-TOR, for patients who do not respond to siltuximab. The University of Pennsylvania and the University of Arkansas for Medical Sciences are currently conducting a clinical trial with sirolimus, which inhibits m-TOR, for MCD adult patients who are unable to benefit from the anti-IL-6 therapies, which include siltuximab and tocilizumab (Actemra).

Van Rhee has also written a book, Castleman Disease, as part of the Hematology/Oncology Clinics of North America series of clinics review articles published bimonthly by Elsevier Inc. The book, published in early 2018, marked the first time since the disease was identified more than 50 years ago that anyone had written a book exclusively about it. In late 2018, van Rhee was the lead author on a paper that established international guidelines for treating idiopathic MCD. The guidelines were designed to give treating physicians a framework for the diagnosis and treatment of this type of Castleman disease. Most of the recommendations were reached by consensus of an expert panel, which met through coordinated meetings of the CDCN. In late 2016, an international registry for patients with Castleman disease was created to collect patient outcomes to increase the evidence base for selection of future therapies.

Van Rhee also was lead author on a paper published in 2020 that established consensus diagnosis and treatment guidelines for another form of the disease, unicentric Castleman disease (UCD), which affects a single lymph node area. It is the most common type of Castleman disease and can usually be treated with surgery, said van Rhee.

State-of-the-Art Infusion Center Opens at UAMS Winthrop P. Rockefeller Cancer Institute

A new infusion center for patients undergoing chemotherapy for myeloma and related blood cancers was unveiled in late 2020 at the University of Arkansas for Medical Sciences (UAMS) Winthrop P. Rockefeller Cancer Institute.

Located on the institute’s sixth floor, Infusion Center B replaces the former Infusion Center on the fourth floor and primarily serves patients with blood cancers, such as myeloma, leukemia and lymphoma, as well as those participating in clinical trials.

“This new state-of-the-art infusion center greatly expands our ability to provide essential cancer therapies for our patients, as well as provide them with the warm, comfortable environment they deserve,” said UAMS Chancellor Cam Patterson, M.D., MBA.

The center can accommodate a total of 50 patients, with 20 in private rooms, 10 in infection control rooms and 20 in open pods. Patient areas enjoy access to natural light.

Arkansas’ recently launched first Phase 1 Cancer Clinical Trial Unit is embedded within the center, allowing patients access to new and innovative therapies unavailable elsewhere in the state.

“Phase 1 clinical trials involve new drugs that are being tested in a small number of patients to evaluate their safety, determine the correct dosage and identify side effects. Patients will come to the Cancer Institute from across the country to gain access to these therapies. This is the cutting edge, and it’s what our patients need,” said Michael Birrer, M.D., Ph.D., vice chancellor and Cancer Institute director.

Two additional areas that opened at the Cancer Institute in 2021 included a new, greatly expanded Breast Center on the third floor and additional clinic space on the seventh floor.

“The sixth floor is one of three that were left unfinished after the Cancer Institute’s new tower opened in 2010. Now, we are proud to say that we now have the fully functional building promised to Arkansans,” Birrer said.

Patient Travels Nearly 4,000 Miles for his Care; Recently Diagnosed Sister Joins Him

When he was first diagnosed with myeloma, Alan Martins traveled 3,938 miles to Little Rock from his home in Hawaii every three months for his care. The 73-year old has been a patient at the UAMS Myeloma Center since 2013, when he came to the Winthrop P. Rockefeller Cancer Institute for a second opinion.

“I did a lot of research, and the University of Arkansas for Medical Sciences (UAMS) just stood out from all the other programs and seemed to have the best outcomes,” said Martins, a lifelong resident of Hilo, Hawaii. “And I want the best for the rest of my life how ever long it is.”

He first visited UAMS after an oncologist at Queens Medical Center in Honolulu noted that his markers showed high protein and recommended that he come to Little Rock for a second opinion.

He originally needed no treatment but visited the Myeloma Center every three months so his physician could watch his markers.

“I told him I’ll meet you halfway, I’ll come here to see you, and you do what you do best,” Martins said recently.

Martins was diagnosed with low-risk myeloma in 2018 and takes an infusion treatment once a month back home in Hilo, where his physician, Anthony DeSalvo, M.D., of the North Hawaii Community Hospital, works closely with Sharmilan Thanendrarajan, M.D., at the Myeloma Center.

Martins is now close to remission and sees Thanendrarajan every six months.

“With the time difference, I really appreciate all the other employees here like the infusion center and phone nurses.”

Throughout his journey with myeloma, Martins has taken an active role in his care and the decision-making process.

“I’ve always done whatever it takes to keep a close eye on my condition so that I can watch my family grow,” he said.

That family includes his wife Alecia and his daughter Crystal Momilani, both of whom traveled with him to UAMS. When they couldn’t get a connecting flight out of Las Vegas, his daughter had a solution.

“My daughter said, ‘We’re driving!’ so we rented a car and she drove us, arriving the night before the appointment. We were tired but we got here,” he said.

Martins has three other children, 12 grandchildren and five great-grandchildren.

In an unexpected turn of events, his sister Peggy Martins, 68, who also lives in Hilo, was diagnosed with myeloma in June 2021.

“When Alan had his follow-up visit with Dr. Thanendrarajan last spring, he brought my markers to show him and the doctor said, ‘Your sister is very, very sick and needs to be treated right away,’ said Peggy Martins, a retired restaurant hostess.

This past October, she traveled to Little Rock with her brother, where she was admitted to the hospital. By early November, she was harvesting stem cells for a transplant.

“I think anyone diagnosed with multiple myeloma should come to the UAMS Myeloma Center if they want the very best treatment and cutting-edge therapies available,” Alan Martins said.

For him, the quality of care he gets in Arkansas is worth every second of the 12-hour flight from Hawaii.

“The folks at the Myeloma Center know what they are doing,” Alan Martins said. “Everyone here is so good at what they do.”

Publications

Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma

Blood Advances, American Society of Hematology

November 2021

Primary author: Mauricio Zangari, M.D.

The minimal residual disease (MRD) test can identify myeloma in the bone marrow of patients in remission by standard criteria. This research describes 568 patients who achieved MRD negativity after autologous stem cell transplant. With a follow-up of nearly 10 years, 61% of patients remained MRD negative after stem cell transplant, while 39% became MRD positive at six years, with the highest risk of MRD conversion five years after treatment. MRD conversion was linked to increased risk of relapse. Importantly, not all MRD positive patients experienced a relapse, and 27% of positive patients had not relapsed at 10 years. MRD conversion from negative to positive correctly predicted relapse in 70% of patients. This study demonstrates the benefits of continued MRD assessment.

TRIP13 modulates protein de-ubiquitination and accelerates tumor development and progression of B cell malignancies

The Journal of Clinical Investigation

June 1, 2021

Primary author: Can Li, Ph.D.

The carefully orchestrated abundance of proteins within a cell controls cell proliferation. Proteasome inhibitors act as anti-myeloma agents by disabling the machine that degrades cellular proteins tagged with a molecule called ubiquitin. The increased ubiquinated protein levels within the tumor cell causes stress-induced cell death. The removal of the ubiquitin “tag” from cellular proteins, a process termed “deubiquitination,” can also increase protein stability. Research at UAMS identified TRIP13 as a gene abnormally overexpressed in high-risk myeloma. The research also noted that TRIP13 causes resistance to proteasome inhibitors, and that the tumor promoting activity of TRIP13 can be overcome by inhibiting deubiquitinase, called USP7. The data point to the central importance of protein stability in cancer biology and that targeting ubiquitination of proteins may complement the already established anti-myeloma effects of proteasome inhibition therapy.

Grateful Husband Donates in Honor of Late Wife

Nine years ago, Jane Ketcher was unusually tired for several months. She visited her family doctor, and subsequent blood work revealed she had myeloma.

“It’s just a shock to learn that you or someone you love has cancer,” said her husband Henry Ketcher. “Back then, fewer doctors knew much about myeloma or how to treat it.”

His wife was referred to the University of Arkansas for Medical Sciences (UAMS) Myeloma Center at the Winthrop P. Rockefeller Cancer Institute, where she was treated for seven years before passing away in 2019 at 77.

“It was a comfort to go somewhere where nearly everyone had the same type of cancer and all the employees were so caring,” Ketcher said.

Ketcher Family

During an early visit to UAMS, a patient from Austria underscored how special the Myeloma Center was.

“She told us, ‘You don’t understand what you have here; this is the best place in the world for this type of treatment. If the queen of England had myeloma, she’d come here for her care,’” Ketcher recalled.

He considers it a blessing that the Myeloma Center was so close to their North Little Rock home and his roofing business.

Ketcher recently expressed his gratitude with a $10,000 gift to the new Infusion B center in the Cancer Institute.

“They did so much for her, and we just wanted to give back,” he said.

Last summer, he and his adult children — Karen Keathley and Hank Ketcher — were given a tour of the new center. “My wife Jane had such a strong faith in God that she was an inspiration to everyone,” Ketcher said.

“If you ever have this type of cancer this is the place to be,” he said.

Car T-Cell Therapy Underscores a New Era in Myeloma Treatment

Dave Puente of Elk Grove, California, the first patient to receive CAR T-cell therapy at the UAMS Myeloma Center, awaits treatment from his physician, Frits van Rhee, M.D., Ph.D.

By Frits van Rhee, M.D., Ph.D.

Novel immune therapies are making a dramatic entry into the options for myeloma therapy and bringing with them a renewed hope to patients. These new treatments include chimeric antigen receptor (CAR) T-cells, antibody drug conjugates and bispecific antibodies. Approvals and clinical trials for these new treatments presently focus on patients with relapsed myeloma.

CAR T-cells, made from the patient’s own T-lymphocytes immune cells, are collected in a process very similar to stem cell collection. However, no prior chemotherapy or administration of growth factor is required. During a four- to five-week manufacturing process, the immune cells are genetically altered in a laboratory to recognize a protein on the surface of myeloma cells known as B-cell maturation antigen (BCMA).

Prior to the infusion of the CAR T-cells, the patient must undergo three days of chemotherapy treatments to empty their immune system and make room for the genetically altered immune cells. When the infused CAR T-cells encounter the myeloma cells, they become highly activated, rapidly multiply and kill the myeloma cells.

Ide-cell (short for idecabtagene vicleucel) (® ABECMA) is the first CAR T-cell product for myeloma, approved by the Federal Drug Administration (FDA) in March 2021. In clinical trial, complete responses were seen in up to 40% of patients at the highest dose of CAR T-cells infused. Equally encouraging or even better results were seen with a second CAR T-cell product called cilta-cel. The FDA is expected to approve it this year.

Side effects of CAR T-cell therapy include cytokine release syndrome with symptoms such as fever, low blood pressure and neurological toxicities such as confusion. In general, most of these side effects are not severe and can be easily managed.

Belantamab mafodotin (® BLENREP) was approved for relapsed myeloma in August 2020. It is an antibody drug conjugate, a type of immune therapy in which an antibody carries a chemotherapy drug directly to the myeloma in a “silver bullet” type of approach.

Like the CAR T-cells, belantamab targets the BCMA protein on the myeloma cells. Overall, approximately one-third of patients respond to therapy with some achieving complete remissions. The principal side effect of belantamab is blurry vision, a result of irritation of the corneas of the eyes. Because of this, patients need to have their eyes evaluated by an ophthalmologist or optometrist before receiving each dose.

Bispecific antibodies, not yet approved by the FDA, recognize both myeloma cells and immune cells, causing the immune cells to become activated and attack the myeloma cells, similar to the CAR T-cell approach. They also have the similar side effects of cytokine release syndrome and neurotoxicity.

Several antibodies are currently in clinical trial, most of which target the BCMA protein, while bispecific antibodies that attack other targets are also being developed. The FDA’s approval of one or more of these antibodies is eagerly awaited and may occur later this year.

These approaches all have their pros and cons. CAR T-cells can induce rapid and deep responses; however, creating them is complex and time-consuming, and the capacity to manufacture them is limited, reducing the number of patients who can receive the treatment. Hopefully, the arrival of cilta-cel will help.

An advantage of antibody therapy is that it is immediately available for infusion and no chemotherapy is needed. The sight-related side effects of the antibody, belantamab, are reversible and can be managed by adjusting the dosing interval and amount.

Bispecific antibodies require hospitalization for the first doses due to the risk of cytokine release syndrome and the treatment’s effectiveness depends on how healthy the patient’s own immune cells are. While bispecific antibodies have not been directly compared to belantamab, initial clinical trial results suggest that bispecific antibodies may be more effective.

These new treatments offer exciting options for patients with relapsed myeloma. It seems likely that in future, these treatments alone or in combination with other treatments, will be used much earlier and eventually may partially or completely replace chemotherapies, such as stem cell transplants. There is the real prospect of treatment approaches with no or only limited chemotherapy, and ultimately a cure for myeloma.

Physician, Pioneering Researcher Join UAMS Myeloma Center/Researcher Returns

Samer Al Hadidi, M.D., recently joined the UAMS Myeloma Center in the Winthrop P. Rockefeller Cancer Institute and is treating patients with myeloma and other plasma cell disorders.

“I’m very happy to welcome Dr. Al Hadidi,” said Frits van Rhee, M.D., Ph.D., clinical director of the Myeloma Center upon Al Hadidi’s arrival. “I believe he is a strong addition to our team.”

Al Hadidi also serves as an assistant professor in the UAMS College of Medicine Department of Hematology and Oncology.

He completed his fellowship in hematology/oncology from Baylor College of Medicine in Houston, where he focused on cell and gene therapy. He completed his residency in internal medicine at Michigan State University in Flint, Michigan, and received a master’s degree in clinical research and statistical analysis from the University of Michigan in Ann Arbor.

Al Hadidi received his medical degree from School of Medicine, University of Jordan, in Amman, Jordan.

Researcher Returns

Pioneering researcher John D. Shaughnessy, Jr., Ph.D., has returned to the Myeloma Center as a principal staff scientist and professor of medicine.

Shaughnessy’s research is focused on developing new targeted therapies for multiple myeloma.

“Dr. Shaughnessy’s return to UAMS expands and strengthens our research and subsequent treatment here,” said Fenghuang (Frank) Zhan, M.D., Ph.D., director of research at the Myeloma Center. “He came to UAMS in 1996 specifically to create a tissue archive and accompanying genetic profiles on myeloma patients.”

The archive and profiles require long-term follow-up on uniformly treated patients to learn more about the genetics of short and long survival, Zhan added.

Shaughnessy received his doctorate degree in molecular biology from the University of Maryland and served his postdoctoral fellowship in the Mammalian Genetics Laboratory of the National Cancer institute’s Frederick Cancer Research and Development Center.

UAMS Raises $15 Million in Quest for National Cancer Institute Designation

The University of Arkansas for Medical Sciences (UAMS) recently announced that it has raised more than $15 million towards National Cancer Institute (NCI) Designation, the halfway point toward its $30 million goal.

NCI Designation is the country’s most distinguished status for cancer centers.

“Raising $15 million for a single cause in such a short time is remarkable, and I want to thank every single donor who has helped make this possible,” said Cam Patterson, M.D., MBA, UAMS chancellor and UAMS Health CEO.

A recent $1 million gift from Kim and Chris Fowler of Jonesboro put UAMS over the halfway mark.

“We are humbled and extremely grateful to the Fowlers for their generosity and love for their fellow Arkansans,” said Patterson.

“Cancer did not take a break during the pandemic, and neither did we,” said UAMS Winthrop P. Rockefeller Cancer Institute Director Michael J. Birrer, M.D., Ph.D., during a ceremony announcing the fundraising achievement. “NCI Designation is an ambitious challenge that demands the hearts and minds of everyone you see here, and hundreds more across UAMS and the state of Arkansas.”

The Cancer Institute’s research focus pushes it closer to achieving NCI Designation.

There are 71 NCI-Designated Cancer Centers in 36 states across the country, with the closest to Arkansas being in Memphis (pediatrics only), 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.

Approximately 68 percent of the funds awarded by the National Cancer Institute for research and clinical trials goes to NCI-Designated centers. The centers without such designation are left to compete for the other 32 percent, and many NCI community outreach and program grants are only offered to NCI-Designated cancer centers.

To achieve designation, cancer centers undergo a highly competitive assessment process that demonstrates an outstanding depth and breadth of basic laboratory, patient/clinical and population-based research. Centers also are expected to transform their research into measurable clinical outcomes for patients. It is also 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,” said van Rhee. “NCI Designation will only increase this capability by significantly expanding our clinical trials and research abilities across the board.”