Defying Definition
For some it was a lid of a Pandora’s Box never to be lifted again. For others it was the first glimmer of light at the end of a tunnel. Nothing about the history of thalidomide is clear-cut.
Born with disabilities caused by thalidomide his mother had taken during her pregnancy, Ralph Naumann intimately knew about the everlasting impact of one of the most tragic eras of medical history.
He recalled how some passionate thalidomide survivors reacted to his intent to lobby for the European Medicines Evaluation Agency (EMEA) to approve thalidomide (German brand name Contergan, Distavol in the United Kingdom and the Commonwealth nations, Kevadon in the United States) as a treatment for multiple myeloma, a rare cancer of the plasma cells, more than 20 years earlier.
“How could he?” they asked. After all, he was one of them. “No person should ever use it again” was how Naumann remembered it in 2023. But his views had changed. He had become a hematologist-oncologist who treated patients with multiple myeloma, a rare cancer of the plasma cells. And he had started to use thalidomide in some of his patients after a pioneer in myeloma therapy had success in using the drug in Little Rock, Arkansas in 1998. It was a—most experts would claim THE—paradigm-changing event in the history of an incurable cancer.
“Naturally it was a strange feeling that I, as a physician, would use it again,” Naumann admitted. “I appeared before the EMEA in London both as one affected and as a physician. I was the only one. Naturally they were both astonished and fascinated,” he continued. “I was authentic. But since then, we’ve all become older and wiser, no one holds it against me now. They value me as a physician and oncologist.”
Considering his personal history, “it didn’t tear me apart as it might have…I never denied my patients, even when I had resistance.” But this episode did demonstrate the value and worth of bearing witness to the consistent inconsistencies in the story of thalidomide. And as one chapter is coming to an inevitable closing, as aging naturally reduces the number of thalidomide survivors, its resurrection gave birth to an unprecedented era of proliferating treatment options for a once hopeless disease.
Naumann acknowledged their anxieties in a 2003 commentary published in the prominent Frankfurter Allgemeine Zeitung: “Forty years ago no one would have thought it possible that thalidomide would ever play a role in medicine ever again.” His perspective had changed. He knew clinical experience since 1998 had established thalidomide as a revolutionary treatment for many with myeloma, an incurable disease.
Thalidomide was approved to treat myeloma by the European Medicines Agency (EMA, formerly EMEA) in 2008, two years after the United States’ Food & Drug Administration (FDA).
Nauman recalled the origins of Contergan in the late 1950s: “Back then it was praised by (the pharmaceutical company) Chemie Grünenthal as a miracle cure for everything,” a “wonder drug” to help anyone with insomnia and expectant mothers to alleviate the symptoms of morning sickness. In an era of less-regulated drug approval, scientific and commercial exuberance outpaced methodical scrutiny. With catastrophic consequences. Thalidomide was a teratogen, “a substance that interferes with normal fetal development and causes congenital disabilities.”
From 1956 to 1963, at least 100,000 (some estimates were as high as 140,000) pregnancies in more than 40 nations worldwide—the vast majority in Germany—led to a minimum of 90,000 miscarriages, stillbirths, and almost immediate post-natal fatalities. Approximately 10,000 children survived—just ten percent of the estimated cases. Virtually all survivors experienced phocomelia, being born without arms and leg bones as well as missing elbow, wrist, ankle, and knee joints, and organ damage.
“In the first few years, it wasn’t clear where it was coming from, even Grünenthal prevented information from coming out. (Young attorney and father of a thalidomide child, Karl-Hermann Schulte-Hillen and) Prof. Widukind Lenz from the Hamburg-Eppendorf Medical University (credited with identifying the connection between Contergan and phocomelia) was pressured, even threatened. It was a great disgrace, what happened in Germany, not to report his evidence,” Naumann summed up bluntly.
Lenz and other researchers linked thalidomide to peripheral neuropathy, a persistent, irreversible, and often debilitating numbness in hands and feet. His findings were integral for Frances Oldham Kelsey, one of the first staff members of the FDA’s pharmacology center, to resist political and administrative pressures to approve thalidomide in the United States. Additional research later determined thalidomide was severely inhibiting the development of circulatory systems needed to nourish developing arms and legs in the womb.
Prolonged by the politics of unaccountability, governmental policies and foundations were begrudgingly established in many affected nations to provide life-long support for thalidomide survivors, including the Conterganstiftung für behinderte Menschen (Contergan Foundation) in Germany and The Thalidomide Trust in the United Kingdom. Grünenthal is now focused on pain management medications, but no longer works with thalidomide, only to create and manage the Grünenthal Foundation for the support of thalidomide-affected persons in recent years, decades after the crisis. The United States government is alone in not setting up compensation programs for thalidomide survivors.
Between 3,000-3500 are estimated to be alive now, about 2,000 of whom live in Germany. For most, the pain and obstacles in daily living are never-ending. As recently as November 29, 2023, the Australian government announced a “national apology to all Australians impacted by the thalidomide tragedy.”
Thousands of thalidomide births survived into adulthood by the time EMA started considering authorizing its use in myeloma. Most of them survived years of severe disability, but support from foundations and governments could only go so far. Without living it, one could not fully understand the significant challenges thalidomide-affected persons had in activities of daily living, healthcare, education, opportunity, employment, or having and maintaining social and personal relationships.
Despite its calamitous history, thalidomide was never completely discarded or forgotten by medical researchers. A few scientists around the world still thought it had untapped medical applications. In the late 1990s, it was approved for the treatment of leprosy.
In 1998, research by an attorney whose husband was a myeloma patient led to her prodding myeloma pioneer Bart Barlogie to try thalidomide on a few myeloma patients in his Little Rock, Arkansas clinic. Thirty-four percent of a small group of treated patients had dramatic responses, confirming a novel theory in cancer treatment: a process called anti-angiogenesis, attacking the feeding lines of tumors. A new opportunity in cancer treatment was born out of the historical evidence of constricting growth of limbs in the womb.
Unexpectantly and more importantly, it was the first new agent known to kill myeloma cells in almost four decades. Soon it would be recognized as a transformational event that changed myeloma treatment from desperate hope to cautious confidence that it might be turned into a chronic, manageable disease with possibilities of cures for a growing number of patients.
In the United States, thalidomide’s approval for leprosy opened the door for investigational use in myeloma as an off-label indication, meaning a drug approved for one disease could be used for others. This new application of thalidomide gave birth to a new category of drugs, immune-mediated inflammatory disease—also known as immunomodulatory drugs (IMIDS).
A year later, Naumann tried using thalidomide, with limited success, to treat graft-versus-host disease (GVHD), an often-vicious side effect of leukemia and myeloma stem cell transplants designed to rebuild immune systems. Instead, transplanted stem cells would not only attack malignant cells, but healthy tissues as well. Results were often catastrophic and deadly. Naumann postulated thalidomide might inhibit and stop this destructive activity.
As study after study on both sides of the Atlantic confirmed thalidomide’s efficacy in myeloma, two side effects became common complaints. Peripheral neuropathy could become severe and irreversible. Another, when combined with steroids—which boost effectiveness of some drugs—could lead to alternating feelings of high energy and severe fatigue, which doctors called “flash-crash.”
The greatest fear, however, was that thalidomide’s reuse might once again lead to birth defects. After all, some female patients were still potentially capable of getting pregnant. Another concern was transmission by males through sexual activity. Drug regulators were skeptical and cautious; approval for myeloma would require unprecedented scrutiny as well as implementation of safety controls.
Celgene, the pharmaceutical company owning thalidomide’s licensing rights hadn’t considered it for myeloma until Barlogie requested it in 1998. Pressure to create a stringent protocol—which turned out the be the most significant part of their business model—made thalidomide and its IMID successors, lenalidomide and pomalidomide, the most cumbersome prescriptions in medicine. Celgene licensed European rights to another company, Pharmion. “I advised Pharmion about safety measures,” remembered Naumann as he insisted, “naturally only with the highest safety levels.”
“In Germany, only registered physicians were allowed to prescribe using a special prescription form for IMIDs,” explained Naumann. “In this case, Germany was extremely cautious because the Contergan catastrophe naturally caused fear about once again having cases should it be reintroduced. Thank God, that has never happened.”
Although thalidomide is now rarely used for myeloma treatment in the United States—having been mostly replaced by the newer IMIDs, lenalidomide and pomalidomide—it still is a first-choice drug in most of the world, mostly due to cost. Used in combination with other medications for induction therapy, the first round of treatment for newly diagnosed myeloma patients before transplant or other treatments, Nauman explained, “currently thalidomide is in-label (EMA approved) for myeloma first-line induction, in the DVTd scheme (a combination of daratumumab [D], bortezomib [V], thalidomide [T], and dexamethasone [d]), VRD (more commonly used in the United States, bortezomib, lenalidomide [R], daratumumab, and dexamethasone) is still formally off-label.”
Even today, prescriptions are anything but routine, requiring authorization codes for every prescription. They are not refilled automatically. Patients are required to fill out lengthy surveys to ensure they do not engage in unprotected sexual activity, donate blood, or share the medication. Physicians must also verify that they’ve gone over the same information with patients with each prescription. This occurs worldwide, with the same procedures for lenalidomide and pomalidomide since they share many chemical structures with thalidomide.
Today, Naumann said, it “belongs to my daily bread, more as a physician than as one affected by it, but it accompanies me always…I don’t tell my patients that I am thalidomide-affected. But they have an inkling, although they usually don’t dare to ask me about it. But the older ones sometimes ask, ‘What kind of disability do you have?’ Contergan. Ah, of course, the generation that’s around 60 now.’”
More than twenty years after he first made his case to EMA authorities, the criticism he received from others in the thalidomide-affected community has waned and been put into perspective. “It was more of a misunderstanding, not confrontational…but I still feel a certain distance from some,” Naumann admitted. Now more value his insight: “Recently I was elected to the Scientific/Medical Advisory Board of the Contergan Foundation.”
When the connection between thalidomide and birth defects was confirmed, the term “thalidomide victims” became commonplace in English. In German, they were known as Contargon Betroffene, which translates to something closer to “thalidomide affected.” Naumann never considered himself a victim but being called “affected” is also imprecise.
“I was one of the last ones,” he noted. His mother, Ilse, had just one pill administered in a Karlsruhe, Germany hospital late in her pregnancy in 1962. Its effects led to Naumann being born with a smaller than average frame and without thumbs. As compared to most thalidomide babies, as they commonly came to be known, the effects on Naumann were not nearly as “severe.”
Naumann’s childhood took him from Karlsruhe to Ulm, eventually settling in the picturesque northern Black Forest town of Calw (pronounced Kahl-v). There he graduated from the Hermann-Hesse-Gymnasium, named after the Nobel Prize laureate and Calw’s native son. Nevertheless, he “was teased throughout his school years, the way children can be brutal.” Many of his teachers also had low expectations for him, saying his disability would never allow him to become a doctor. “But all that didn’t interest me.”
Naumann’s dismissal of self-imposed limitations could be traced back to surgeries he had in his fifth and sixth years, “I had a super hand surgeon in Hamburg who performed the so-called pollicization surgery,” a complex procedure in which his index fingers were “repurposed” to become thumbs, allowing him to grasp things. “It was such a positive medical experience that ever since I became interested in medicine. I knew by the eighth grade I wanted to go into medical studies.”
After graduation, he was accepted for the University of Tübingen’s medical education track. He recognized his disability would impact his choices. “It was clear to me that I could not become a surgeon, because it wouldn’t have worked because of my hands. From then on, I would do something more conservative. Neurology or internal medicine came into consideration.”
While in medical school in the mid-1980s, a revolutionary procedure, bone marrow transplantation (BMT) was fundamentally changing treatment leukemias and other blood cancers throughout the world. “By chance, I came under the tutelage of Dr. Gerhard Ehninger, who was building up a BMT department at the University of Tübingen,” remembered Nauman, “he became my mentor for my under- and postgraduate medical studies.”
In 1986, Prof. Ehninger “sent me to The Hutch (Fred Hutchinson Comprehensive Cancer Center in Seattle, Washington) to study with Dr. Rainer Storb. It’s important to pause here to consider why before proceeding with Naumann’s story.
E. Donnal Thomas, the head of The Hutch, was a singular figure in the history of cancer. Born in 1920, the only child of a rural Texas physician who made house calls in a horse-drawn buggy, he was self-described as “not an outstanding student.” He went from a one-room schoolhouse to the University of Texas at Austin to the Harvard Medical School, where he earned his MD in 1946.
In Boston, he worked with Sidney Farber, whose controversial, trailblazing work on chemotherapies in childhood leukemia created the foundation for modern cancer research and treatment. This relationship “intensified” Thomas’s focus on bone marrow and leukemia, but a philosophical difference in cancer treatment philosophy led Thomas to Cooperstown, New York in 1955, where he “began to work on marrow transplantation in human patients and in the dog.”
The concept of transplanting marrow from one person to another, known as allogeneic transplant, proved to be “very difficult.” The donated marrow became an aggressive, incompatible “invader” of sorts, causing GVHD. But his research found promise in patients who were identical twins.
Serendipitous events and a growing reputation took Thomas to Seattle’s Public Health Service Hospital in the early 1960s. In 1965, he brought in Rainer Storb a native German Fulbright scholar who completed his medical studies at the University of Munich around the same time the linkages between thalidomide and birth defects became known. “We were in this old hospital that was part of the university teaching hospital,” Storb remembered, “there was Don, Bob Epstein, a good friend and colleague who was an instructor, and I was the senior fellow. We had one technician, one secretary, and two assistants. And that was the group. That was it.”
After Storb decided against returning to Germany, Thomas figured out how to keep him in Seattle: “Well, I’ve got a salary for another year, and then we’ll see from there.” Being on a visitor visa, Storb could not apply for National Institutes of Health (NIH) grants, “so we applied for a Green Card, and they allowed me to put in a grant a little earlier.” Both the card and the grant approval came on the same day, July 1, 1971.
Thomas’s team moved to The Hutch in 1975 after the federal government decided to close the nation’s public health hospitals. It was one of eight comprehensive cancer centers first created by President Nixon’s War on Cancer initiative, the only one focused almost exclusively on BMT research and treatment. Around the same time, progress being made worldwide in identifying and learning how to separate stem cells—the blood-generating elements in plasma cells in bone marrow—known as autologous stem cell transplant. In this procedure, a patient’s own cells were extracted and manipulated before being reintroduced to fight malignancies.
Taken together with Thomas’s preeminence in allogeneic transplant, the new procedures spurred medical institutions throughout the United States and Europe to invest billions in education, facilities, and staff to successfully treat leukemias and other blood malignancies and diseases.
The Hutch became a Mecca for patients seeking transplants, and more significantly, for physicians. “We had people coming from other countries trying to learn how this actually worked, hundreds of them. Visiting physicians came for a minimum of three months, a maximum of, sometimes, two years.” As beds proliferated in their clinic, “they helped us greatly.”
Storb was a sought-after speaker at medical meetings throughout the world, getting to know Ehninger when he spoke in Germany. Ehninger, who was establishing his own BMT clinic in Tübingen as well as one of the world’s first bone marrow registries in the world to match healthy donors with candidates for allogeneic transplant, arranged to have Naumann sent to Seattle. It was an opportunity few had; for Naumann it was both an honor and validation.
According to Storb, Naumann’s experience was typical of every visiting physician who came to The Hutch, “this was in the era before physician assistants. They came and the next day they were on clinical service, just thrown right into the midst of it.” Storb was Naumann’s attending physician. Naumann was “attending as a physician-scientist, with time devoted to lab work, research, and grant-writing, which financed our group because the center didn’t really provide much money, you had to bring it in. A typical day included early morning rounds at 8 o’clock that ended about 9:30, we had grand rounds on Thursdays and Fridays, radiology rounds, and then they had to deal with the patients they were assigned to on the service,” while working with other specialty physicians.
Recalling thalidomide from his time as a medical resident in Munich in 1961, Storb could “remember very vividly when this news came out and exploded. Because it was advertised as a very safe agent and—all of a sudden—bang! These birth defects hit, and the news was shocking.” Although he doesn’t remember speaking with Naumann in detail, he knew, based on Naumann’s age and disability, that he was thalidomide-affected. He recalled Naumann was “not bitter about his physical handicap. I was impressed, actually. He was accepted like any other physician here.”
Naumann was learning from the best, the people who had created a medical discipline that was fundamentally transforming hematology, oncology, and immunology. Moreover, he was on his way to becoming a respected specialist. Upon returning to Germany and finishing his residency in Tübingen, Naumann’s first clinical position was in the Sindelfingen, a suburb of Stuttgart.
In 1994, just five years after the fall of the Berlin Wall, Ehninger was offered a position in the former East German University of Dresden, recruiting Naumann to join his faculty. “They weren’t doing transplantation and relatively early—back then one could pick specialties to work on—I decided to concentrate mostly on Hodgkin’s lymphoma and myeloma,” Naumann said. “It was by chance, there were a few diseases that hadn’t been taken. So multiple myeloma it was. And then I met Hartmut Goldschmidt [from the University of Heidelberg] and we joined” the German-Speaking Myeloma Multicenter Group (GMMG) to participate in clinical trials and studies.
Naumann was “working quite early with thalidomide” after the news of Barlogie’s study became known. He spent fourteen years on Dresden’s faculty—it was during this time he was engaged with the EMEA—before moving to become the Director and Chief Physician in the Division of Gastroenterology, Hematology/Oncology at the Stiftungsklinikum Mittelrhein in Koblenz. He inaugurated patient education activities and hosted events featuring Robert Kyle from the Mayo Clinic, Goldschmidt, and Hermann Einsele from the University of Würzburg and leader of the German Study Group for Multiple Myeloma (DSMM).
In 2017, Naumann moved to become a chief physician at the St. Marien-Krankenhaus in Siegen and since May 2023 he has been chief physician at Siegen’s Diakonie Klinikum Jung-Stilling, where he cofounded and co-leads a new Department of Hematology, Oncology and Palliative Medicine. He and Martin Klump have been responsible for bringing new emphasis on myeloma, autologous transplantation, and accessing the most novel therapies available.
Naumann’s parents gave him “maximum support, my memories of my childhood are very positive.” With one exception. One underscoring how language is often inadequate and futile.
His mother Ilse never found the words to talk about her feelings about the experience in the fifty-three years she lived with the self-imposed guilt, “because she was ashamed” about the consequences of having taken that one pill in 1962. From the time Naumann could understand his first words until her death in 2015, Contergan “was never a topic of discussion.”
Shortly before his father Rolf died in 2011, he confided that Naumann had an older brother who only lived for just one day. “It was never proven that my brother died of Contargon, but was very close [to that time], it was extremely close.” It was only after going through their personal papers after his parents passed away that he found the birth and death certificates of his brother. Naumann speculates his parents were likely too filled with remorse and shock to have more children after him.
Although Ilse and Rolf Naumann never found the words to communicate their deepest pain with Ralph, they spoke clearly through deeds as parents. They lived to see him become a respected physician-scientist, Naumann remembered, and were “extremely proud once they understood I was on my way to becoming a chief physician and full professor.”
Naumann’s unique embodiment of thalidomide’s divergent repercussions, his acceptance of and response to each, make it difficult to pigeonhole his legacy. It defies definition.
What a remarkable man and story.