Charting the Course in Myeloma: Durie Keeps Standards, New Goals in Sight

Photo courtesy of the International Myeloma Foundation

Dr Durie is chairman of the International Myeloma Foundation while his wife, Susie Novis, left, serves as president.

As one of the world’s top multiple myeloma physicians and researchers, Brian G.M. Durie, MD, can boil his mission down to one simple goal: saving lives. But it was two people the doctor couldn’t save who have most affected his path.

His father died, after a long illness, when Durie was 11.

“In the years leading up to that, the doctor was constantly visiting our house,” recalled Durie, who grew up in a fishing village in Scotland and is now in his 60s. “I became very much familiar with doctors and looked up to the ones who were helping the family. So my desire to become a doctor stemmed from that experience.”

Years after he’d become a driving force in the multiple myeloma community, Durie treated a patient, Brian Novis, who also eventually succumbed to aggressive disease.

During the time they knew each other, Durie and Novis launched the nonprofit International Myeloma Foundation (IMF), meant both to inform patients and to push forward research into new and better treatments.

When Novis died, Durie left a senior post at a London hospital to take over as medical director of the foundation and chairman of its board, working side by side with Novis’s wife, Susie, who moved into the position of president.

Three years later, Durie and Susie Novis were married. Circumstances put the two together, Durie said, and “we connected.”

Today, the couple continues to run the IMF, whose role in changing outcomes for patients with multiple myeloma has grown exponentially.

Durie heads up the foundation’s International Myeloma Working Group, the research arm of the organization. In that role, he has forgone running his own lab for an alternative method of conducting research—collaboratively, with scientists around the world.

“I started my career with a biology lab in myeloma, but as the IMF evolved, I began to contract out sequencing and molecular genetics projects to larger labs with sophisticated equipment that we couldn’t afford to buy,” he said. “Now, one of my functions is to coordinate collaborative projects where research of a certain type is done in one lab—for instance, DNA sequencing in Rotterdam—and then cell biology is done in another lab with expertise in that area. This type of networking in science is a new way forward.”

Since the Working Group has grown to include 160 of the world’s top experts in multiple myeloma, it is able to assess outcomes for very large numbers of patients, and to issue guidelines that “are sensible and based on facts”—including recommendations on risk stratification and maintenance therapy for patients with the disease, Durie said. “It has allowed us to focus on which treatment will work for a patient and which will allow the best quality of life.”

Another recent project, also made possible by the size and reach of the Working Group, identified the key features of the 20% of patients with multiple myeloma likely to attain meaningful longevity by undergoing stem cell transplant.¹

Managing a Full Roster

“It’s very satisfying to know who should get a recommendation for stem cell transplant,” Durie said. “Although not trivial, the procedure can allow these patients to go off treatment or onto maintenance, function well, and return to their families and their work for many, many years.”Durie is also very involved in conducting clinical multiple myeloma research outside of the foundation.

As chairman of the Myeloma Committee within the cooperative SWOG (formerly the Southwest Oncology Group), he is principal investigator for SO777, a phase III, 600-patient trial comparing lenalidomide plus dexamethasone against the two drugs in combination with bortezomib (NCT00644228).

“This is a key question in myeloma right now—whether patients need to be treated with three or more drugs versus maybe just two, while saving the third for later,” Durie said. “This is an important trial, and a lot of people are waiting to see the results.”

Durie is also the founder of the Academic Myeloma Consortium, or AMyC, a group of a dozen investigators across the United States working together to develop trials and enroll patients.

“Our goal is to pick up drugs at phase I and II, assess their effectiveness and toxicity, and try to move them forward into other trials,” Durie said.

The group is particularly proud of a trial that combined two drugs that were then experimental—carfilzomib and pomalidomide— administered along with dexamethasone. ² Both drugs have since been approved by the FDA for the treatment of multiple myeloma under the trade names Kyprolis (Onyx) and Pomalyst (Celgene), respectively.

“The combination turned out to have a very high response rate in patients who’d failed everything,” Durie said. “Our lead patient in that trial was in remission at 16 months, although the expectation of survival for such a patient is three to six months. In addition, because the results were so promising, we just got permission from Celgene and Onyx to move this study to patients with earlier stages of disease.”

In addition to his research roles, Durie continues to see patients. At the Cedars- Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute in Los Angeles, the doctor sees about a dozen patients with multiple myeloma a month for high-level referrals, either telling them whether they have the disease or what approved or experimental treatment might be best for them.

In between, Durie finds time to teach myeloma courses for physicians, such as a recent two-week master class for doctors from China. He also lectures around the world, from Moscow to Sydney to Beijing.

Brian G.M. Durie, MD . . .

• Has two children, a 31-year-old son, Ben, who is a lawyer, and a 29-year-old daughter, Annabel, an event planner.
• Married the wife of a late patient, years after collaborating with the couple to create the International Myeloma Foundation (IMF). Today, Durie and Susie Novis continue to run the foundation together.
• Cites the book by Nobel Prize-winning physicist Erwin Schrödinger What Is Life? as a favorite. “It explains why our bodies retain their physical integrity and function in a sophisticated way, rather than collapsing into a pool of water at the end of the day,” Durie said.
• Loves the movie Hair, directed by Miloš Forman. In the movie, two men, one a hippie and the other about to enter the Army to fight in the Vietnam War, switch places. “I was interested in the idea of what one friend would do for another, and the consequences,” Durie said.
• Lives by the saying “Try, try again.” It’s an attitude he said was inspired by the old Scottish story of warrior Robert the Bruce, who found motivation to follow through on his battle plans by watching a spider laboriously, but successfully, spinning its web.
• Had some bad experiences while spending a summer working on a kibbutz in Israel. “Picking cotton was really tough, but the worst part was that I ended up getting bitten by a snake, a pit viper, and had to go to the hospital for antivenom,” Durie recalled. “I was fine, but it was not my favorite thing.”

• Has always enjoyed participating in sports. Durie has worked as a tennis coach, and played tennis and squash for Edinburgh University while in medical school. He still plays racquet sports and golf, and also likes traveling and meeting new people.
• Has presented and served as the organizing chairman of numerous teaching sessions hosted by the American Society of Hematology. Durie has also taught sessions at the George Washington University Medical Center, and at meetings of SWOG, the American Society of Clinical Oncology, and other organizations and institutions.
• Has won numerous awards, including $100,000 a year for five years from the Leukemia and Lymphoma Society in 1976; the organization gives the “scholar” award to help develop the careers of promising young researchers. In 2002, Durie won the Society of Nuclear Medicine and Molecular Imaging’s annual first-prize award for Best Clinical Medicine Study, for his paper on whole-body FDG/PET scanning in myeloma (J Nucl Med. 2002;43[11]:1457-1463). He also has received the IMF’s Robert A. Kyle Lifetime Achievement Award and the Waldenstrom’s Award for lifetime achievement in myeloma research.

Making an Impact

From the beginning of his career, Durie’s research has led to practice-changing developments in the treatment of multiple myeloma.

One such development emerged after he had finished his education and was starting his first job at the University of Arizona College of Medicine in the early 1970s.

As a researcher in the lab of Sydney E. Salmon, MD, Durie’s first task was to help develop a staging system for multiple myeloma. Salmon had been conducting studies to calculate the number of myeloma cells in patients’ bodies, and Durie used that type of query as the basis for his system. It was the first time such a method had been devised for use in a blood cancer, and the first paper Durie ever published about myeloma.³

“This became the foundation of all the new trials we developed, to stage the disease and then develop therapies or approaches for each of the different stages,” said Durie. “This strategy has become a mainstay in terms of everyone’s approach to cancer treatment.”

Durie generated another medical “first” nearly a decade later, when he collaborated with Salmon to develop a stem cell assay that involved growing myeloma cells, and then trying to wipe them out with different drugs.⁴ Such a test had never been used in cancer before.

“This technique was subsequently picked up by the NCI and used as a national screening technique for all cancers to test drugs,” said Durie, referring to the National Cancer Institute. “We ended up having an annual, international stem cell conference in Tucson, and people would come from all over the world to learn about this.”

In 2006, Durie and colleagues contributed yet another technique for measuring the success of myeloma treatment when they published an updated version of the uniform response criteria authored by the European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry. Durie’s system included new categories—stringent complete response and very good partial response—that made it easier to quantitate patients’ responses to therapy, and thus to compare the effectiveness of drugs. His team also made other changes, including a new emphasis on time to event and duration of response as critical endpoints.⁵

“The FDA now uses this system across all kinds of cancers to assess whether they’re going to approve a new drug,” Durie said.

He further helped to set FDA standards by determining that patients with multiple myeloma who have failed every available therapy will typically live another three to six months.⁶

Looking Beyond His Village

“This establishes something called an unmet need criterion,” Durie said. “If the FDA is going to approve a new drug for myeloma, the drug has to fill an unmet need, meaning it will generate an improvement over that three-to-six month lifespan by a significant percentage. It turns out this is key if you want to make progress toward developing a new drug.”Durie grew up in North Berwick, a Scottish fishing town that was home to about 2000 people but no traffic lights. His father worked at the railway station and his mother as a nanny to the local doctor’s children.

While Durie knew the doctor and his partner fairly well, he didn’t consider following in their footsteps until he sat down with his mother to discuss his future. Since Durie was excellent at math and science, his mother asked him to consider what he could do with those skills.

“I started to think that, although I would need to continue my education, becoming a doctor could mean I’d always have a job doing something I was interested in, and actually helping people,” he said. “The other aspect was that, coming from this none-too-prosperous family, the possibility of having a job and being able to survive financially on a regular basis was attractive.”

But not everyone had faith that Durie would make good on his plans. “There was a lot of question among different family members as to whether I would get through medical school,” he said. “I had the grades, but they said ‘Could he be a doctor?’ There was a lot of speculation about that.”

As it turned out, the speculation was unnecessary.

Durie had no problem graduating from the University of Edinburgh Medical School in 1966, and then training for a year at the Royal Infirmary there.

Still, when he considered his prospects for practicing medicine in the United Kingdom, the outlook seemed grim.

“You need to wait for someone to die to get their job in the UK system,” he said. “I saw everyone waiting for jobs and decided that maybe the answer was to try something different. Not too many had done this at the time, but I decided I just would leave.”

Durie secured a fellowship at the Mayo Clinic in Rochester, Minnesota, first attending Wayne State University for part of a year to get the necessary US clinical training.

“I loved it because it represented a freedom of expression,” he said of Mayo. “The idea that I could work and get promotions and be able to do well if I did things properly was very, very exciting.”

It was his experience at Mayo, where he worked in cellular immunology, that inspired Durie’s interest in myeloma. He was influenced by his mentor there, Robert A. Kyle, MD, a prominent myeloma researcher.

“The other part was that I loved looking down a microscope, so, as a researcher, blood diseases were fantastic,” Durie recalled. “Studying cells under the microscope was a whole world for me.”

As his fellowship drew to an end, Durie learned that Salmon would be taking a position at the University of Arizona, and that junior research jobs were open. He applied and Salmon chose him, launching his two-decade association with the university. In 1981, Durie was named a full professor, and he stayed on through 1992.

Forming the Foundation

During his last three years in Arizona, Durie kept his position as professor while also serving in a high-profile role somewhere else. He’d been hired as head of the department of blood diseases at the University of London, and was flying back and forth to do both jobs.It was during that same time period that Durie began treating Brian Novis, who was in his early 30s when his multiple myeloma was discovered during a routine life-insurance blood test.

Eventually, Novis had his stem cells harvested at the University of London, and he and Durie took some time to talk. In a tea shop in the center of London, the two hatched the idea to start the IMF.

“Brian felt that this whole bone marrow stem cell therapy was pretty barbaric, and that there should be some more modern type of therapy that was not so drastic but would work,” Durie recalled. “Brian came back to the United States and created the foundation as a nonprofit in California. We faxed a lot of documents and did a lot of work day and night setting up all the things needed to get the foundation going.”

Two or three years later, when Novis died, Susie called Durie with a frantic question: What would become of the IMF?

“Everyone felt the foundation was important, because it had started to do some good things, so ultimately I decided I would come back to the States and continue as its medical director and the chairman of its board,” Durie said. Susie, meanwhile, left a corporate job to manage the business side of the organization.

To facilitate his move, Durie called a good friend, H. Phillip Koeffler, MD, currently the Mark Goodson Chair in Oncology Research at Cedars-Sinai, and asked if there were any positions available there. Koeffler was happy to have Durie’s help and hired him immediately.

Leaving his post in London wasn’t a difficult decision for Durie, who was disillusioned with the work he was doing.

“It seemed attractive at the time to have the responsibility and the prestige, but it turned out to not be the ideal job in terms of my focus on myeloma,” he said. “I was in charge of too much, including the medical school teaching program and running the administration for the department. That did focus my attention about what I really wanted to be doing. The answer was not ‘sitting in meetings about administration until 8 or 9 o’clock at night.’”

What Durie did want was to use the foundation to address the concerns he’d developed about myeloma treatment during his years in Arizona.

Photo courtesy of the International Myeloma Foundation

Dr Durie works with Juan Du, MD, PhD, of Changzheng Hospital in Shanghai, China, whom the International Myeloma Foundation awarded a special research grant to develop a novel prognostic model.

After developing his stem cell assay there, he remembers realizing that the circumstances of the moment were imposing limitations on what the test could accomplish.

“One issue was that patients had to travel to the center to get the test, because it was hard to mail the sample in, and the other was that we simply didn’t have enough drugs to test yet,” Durie said.

Equally unsettling, he said, was watching the university’s myeloma center become “somewhat elitist. Patients with money, or who were able, would travel sometimes very, very long distances to get specialty assessment and care; yet, I wanted to provide education and help for every patient with myeloma. I also thought that there must have been a better way to get information and feedback to doctors without having them all travel to Arizona. These were the seeds of the idea for the foundation.”

Through the organization, Durie has also had a chance to rectify some of the personal challenges that affected him in his younger years.

Previously divorced and the father of two grown children, Durie looks back with regret on the family time he missed when he traveled the world to lecture. But these days, the doctor is enjoying a better balance between his personal and working lives.

Emphasizing Prevention

“Susie and I both work for the foundation,” he said, “so when we go to meetings, we travel together and don’t have to be apart.”Through his years in the myeloma field, Durie has seen the outlook for patients get better and better.

Early on, treatments with chemotherapy “did work, but remission lasted only a year or two, at best,” Durie said. “Later, we moved into the stem cell transplant procedure, which got a much deeper remission, but, unfortunately, was still not curing the myeloma. Now we have the novel agents, and these are the ones which have made such a dramatic difference.”

While the survival prognosis for those with multiple myeloma was two to three years when Durie joined the field, that outlook has improved to seven or eight years, or as many as 15 years for those with less-aggressive disease, the doctor said.

“It’s amazing for me that myeloma is not a death sentence anymore,” he said. “There is over a 90% chance that I can offer patients a treatment that will work and generate survival for five to 10 years. In fact, I have a patient who has had myeloma for 33 years. We’re not curing patients, but they can have one remission after another that can last for several years each.”

Looking ahead, the ultimate goal will be to find a cure for multiple myeloma, Durie said.

In the meantime, he is very interested in finding ways to prevent the disease. That seems increasingly possible, Durie said, as evidence emerges that multiple myeloma can arise from exposure to chemicals, such as the contaminants released into the New York City air as a result of the terrorist attack on September 11, 2001.

“If chemicals cause myeloma, then this can be the basis for a huge preventive effort over the next 10 to 20 years,” Durie said. “By then, maybe we will have cured some patients, but preventing a lot of people from getting the disease would be even better.”

References

1. Avet-Loiseau H, Durie BG, Cavo M, et al. Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project [published online ahead of print October 3, 2012]. Leukemia. 2013;27(3):711-717. doi: 10.1038/leu.2012.282.
2. Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (car-pom-d) in patients with relapsed/refractory multiple myeloma. Blood [ASH Annual Meeting Abstracts]. 2012;120(21): abstr 74.
3. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36(3):842-854.
4. Durie BG, Young LA, Salmon SE. Human myeloma in vitro colony growth: interrelationships between drug sensitivity, cell kinetics, and patient survival duration. Blood. 1983;61(5):929-934.
5. Durie BG, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma [published online ahead of print July 20, 2006]. Leukemia. 2006;20(9):1467-1473. doi:10.1038/sj.leu.2404284.
6. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter International Myeloma Working Group study [published online ahead of print July 29, 2011]. Leukemia. 2012;26(1):149-157. doi: 10.1038/leu.2011.196.