Questioning Boundaries
Celebrating France's Myeloma History on Bastille Day
You have to live for the effort of living, to leave a stone that will one day go to shape some far-off and mysterious edifice; and the only peace possible, on this earth, lies in the joy of having made such an effort.
Émile Zola, Le Docteur Pascal (Doctor Pascal)
“He told me that you will kill me, but I accept,” recalled Prof. Jean-Luc Harousseau about what a myeloma patient told him the second time they met. “That was the beginning of my involvement with multiple myeloma.” It was 1983.
“I’m a cardiologist, I’ve just been diagnosed with myeloma,” the patient said the first time they met, “and I know the prognosis. So if you have something new, I’m ready to try.”
Harousseau told the patient about a new procedure he had just finished reading about in “a prestigious paper by Tim McElwain and Ray Powles using high-dose melphalan (HDM 140) without any support in myeloma treatment, showing the possibility of reaching CR [complete remission].”
“It’s dangerous,” warned Harousseau, who had recently moved back to his hometown, Nantes, France, to build a hematology department from scratch at the local university hospital. Giving advice to a myeloma patient was a bit out of bounds of the agreement he made when arriving at the university hospital the year before, that he would focus mostly on aggressive leukemias.
Myeloma patients – like most with hematological diseases – would still be treated by the internal medicine department. This time was different, the HDM 140 paper gave Harousseau a good reason for optimism.
The side effects of this approach, Harousseau warned, could be brutal, even deadly. “I asked him to think it over, take his time, and get any advice he wished.”
He was told the procedure would be too risky by an expert at France’s top hospital for hematology, Paris’s Hôpital Saint-Louis, Harousseau’s old fellowship and residency stomping grounds. They would not do it – questioning whether it could be survived at all. The patient returned to Nantes.
Now, back at Harousseau’s office, the suggestion was not as theoretical. If anyone in France was going to try this new strategy, it would have to be in Nantes.
Not long after beginning his medical career in Paris in 1980, Harousseau was named full professor. At thirty-two, he was the youngest ever in France, where the average age of promotion was closer to forty-five or fifty. A decade earlier, as a medical student, he set an audacious goal of establishing a hematology department in his hometown, Nantes. “Hematology didn’t exist in my university hospital, and I said, I would like to be the person to create one.”
Seen from a distance of decades, it all seemed so poetic, a foregone conclusion. The honor (and novelty) of having the youngest professor in the nation – a local boy, no less, plus the encouragement and blessing of Harousseau’s mentor, Jean Bernard, “the father of French hematology” added up. It was too enticing a prospect to pass up.
Harousseau faced a big problem early: how would he find patients to treat, or they find him? The hospital’s internal medicine department treated all hematological disease and malignancies, making it politically difficult to start a hematology department that might “compete” for patients. And he had a lot of things on his professional plate.
As a professor, he had medical school teaching duties, covering all areas of hematology. As a new department head, he had to be an entrepreneur in an established institution without stepping on institutional toes. As a doctor, he was about to embark on a path even he, with his innate goal-setting nature, couldn’t see, much less determine where it was leading. And as promising as he seemed, no one could envision one day soon he would be shaping ideas in myeloma, not just for his hospital, not just for his nation, but for the entire world.
“I was extraordinarily lucky,” said Harousseau as he looked back.
Harousseau’s post-graduate period in Paris coincided with a growing global desire of clinics to replicate and build on Don Thomas’s team’s experiences in Seattle. BMT facilities were starting to proliferate around the world. “Very rapidly I understood,” Harousseau continued, “that I had to clearly separate from the internal medicine department…I said, the only way is to create a bone marrow transplantation unit.”
One problem. “I had not been trained in bone marrow transplantation,” Harousseau confessed. “I had a young fellow interested in hematology. I told him, ‘if you are interested then you must train in bone marrow transplantation.’ So I sent him to ‘la Mecca,’ Seattle, to learn transplantation. He came back, and we started our transplantation program in 1983,” initially focusing on aggressive treatments of leukemias with high doses of chemo plus allogeneic or autologous BMT.
Not treating myeloma didn’t bother Harousseau. He remembered Bernard “always told us, ‘Never accept a patient with multiple myeloma in your beds. It’s a terrible disease with an awful prognosis. If you accept, the patient will stay three months, and either die in your bed, or go back worse than before.’”
“I was one of the first, after McElwain and Powles, to use high-dose melphalan,” Harousseau reminisced, “I wanted to present the results and attended a special session of the European School of Hematology in Venice. In this meeting, I met three important people. The first was Régis Bataille, who worked at that time in Montpellier University Hospital – I later offered him a position of professor of biological hematology in Nantes. The second was Brian Durie, the third, Bart Barlogie.”
Harousseau remembered they discussed high dose therapy, “I said I had the idea of treating myeloma like acute leukemia,” which was medical shorthand for “aggressively.” Barlogie found an ally, “Exactly the same! Like my mentor, Freireich, said, you want to hit it hard at the very first treatment.” Harousseau found an intellectual sanctuary.
“I wanted to do very intensive treatment,” Harousseau explained to them, “Treat patients with high dose melphalan alone, as the induction treatment, obtain remission, collect the marrow, and perform a second course of high-dose melphalan, plus total body irradiation (TBI), plus autologous transplantation. I called it double intensive therapy and it was later published in Blood.”
Barlogie’s procedure differed. “He started a program of tandem transplants, but doing autologous transplantation up-front, which was safer.” Their professional, intellectual bond became a lifelong friendship; where they diverged, their work ended complementing each other.
The volume and minutiae of information Barlogie’s labs and clinic produced fed his obsession to decipher and interpret it clinically in an all-consuming quest to cure myeloma. Harousseau, on the other hand, looked out. He intuitively understood researching myeloma – all cancers, for that matter – was about more than pure science. In medicine, progress has to follow certain rules to ensure safety and efficacy before transforming ideas into actionable clinical practice.
“I understood we couldn’t do anything in France, especially in Nantes, if we didn’t work together, because the disease is not that rare, but it’s not so frequent,” Harousseau, reasoned. “My objective became to create a cooperative group. At that time, I already created a cooperative group for acute leukemia in western France. We started to do the same with myeloma.” He invited the two top myeloma specialists in France, Michel Attal to the south in Toulouse, and Thierry Facon in Lille to the north, near the Belgian border “to start discussions about merging our groups.”
They agreed “to address randomized questions;” the gold standard to determine a therapy’s safety and effectiveness was – and still is – a “prospective randomized trial.” In plain English, that means monitoring and comparing participating patients over time to determine the efficacy of a standard therapy versus the one being investigated. What arm the participants are put in is up to the luck of the draw, not even the doctors and nurses supervising the trial know.
For all of his reverence of his mentor, Barlogie rejected Emil Freireich’s first big idea, from the 1950s: cooperative groups of institutions to study questions in diseases, especially those with small numbers. His confidence in knowing what he felt, what he knew, what was best for each patient, didn’t agree with his fear that a random distribution would put some at risk of not getting the therapy he knew to be superior. Colleagues disagreed, but as I wrote earlier, they couldn’t deny his results.
Harousseau, on the other hand, agreed with Freireich: patients needed to be recruited to address questions in clinical trials, not an easy task for a disease like myeloma. So did Attal and Facon. Together they decided each would take the lead on one of three trials in which all would participate to study different aspects of myeloma, formally becoming the Intergroupe Francophone du Myélome (IFM), which in coming years would be referred to by myeloma specialists throughout the world as “the French group.”
Facon focused on “the very young, where we proposed a very aggressive treatment, based on my double intensive therapy.” Nantes would study “elderly patients. The question was about alpha-interferon, which was about the only new drug at the time.” The third, led by Attal, considered by Harousseau to be the “most important one, was a randomized trial comparing conventional chemotherapy to intensive treatment plus autologous bone marrow transplantation.”
The latter study “was a great success, it was the first trial that was published by our group,” the IFM 90 trial, one legendary in myeloma lore. “It was the first trial showing the superiority of intensive therapy compared to conventionally dosed chemotherapy,” said Harousseau, “and it was a huge success, all over the world.”
Although it would take seven years before another study replicated and confirmed the results, “everyone adopted high dose therapy plus autologous transplantation as the upfront treatment of what we now call the transplant-eligible patient, which means a patient not too early, not too old, and without severe comorbidities.”
Success begot more success. “All centers in France wanted to work with the IFM [author’s note: except for a small Hôpital Saint-Louis-led group in Paris, which joined the IFM in 2010.],” Harousseau looked back with pride. “We had the idea to compare TBI plus melphalan-140 to a higher dose of melphalan-200 without TBI. And the result was that both were equally active, but high-dose melphalan alone was less toxic and survival was better.”
His colleague and protégé Philippe Moreau – current president of the International Myeloma Society (IMS) – became the first author, it was published, and, to Harousseau’s great joy, “everybody accepted it, everybody abandoned TBI – including Bart! – and used high-dose melphalan-200, which is still, thirty years later, the standard of care.”
But not everyone was convinced. Harousseau knew it would take a while if they ever would be. He recalled attending the 1991 International Myeloma Workshop (now the annual meeting of the IMS) in Turin, Italy to present preliminary data on double intensive therapy. “There were the giants of myeloma, Daniel Bergsagel, Robert Kyle, and Sidney Salmon.” Salmon, from the University of Arizona, was one of the early pioneers in myeloma and later worked with Durie to create the Durie-Salmon scale, the first systemic classification of myeloma patients.
Salmon’s response remains vivid to Harousseau to this day, “That’s completely crazy! Never do that! He was really against the idea of high dose therapy for chronic disease.” Even after the IFM 90 results were made public five years later, it did little to change the minds of those who still felt high-dose therapy was too risky for eligible patients.
Robert Kyle published an overview of the state of high-dose therapy and transplant in myeloma treatment in 2000. He dispassionately, thoroughly, described what best practices in the clinic and lab were informing treating physicians, noting in the conclusion that a “major question is whether double (tandem) transplants are superior to a single autologous stem-cell transplant.”
Harousseau’s life’s work in myeloma received something of a seal of approval from Kyle’s in the next sentence: “A current French Myeloma Group Study randomized study should answer this question.” Their findings were considered legitimate even before being published. Robert Kyle said so. Few things, if any at all, carried more weight when it came to myeloma.
Looking back, more than forty years after a trip to Venice opened his eyes to possibilities in myeloma, it is indisputable that Harousseau’s influence on myeloma has ramifications for virtually every myeloma patient in the world.
In the next post, we’ll learn more about Harousseau’s life adjacent to myeloma. On Sunday we’ll conclude with a look into the global influence of the IFM.
Remembering the fall of the Bastille gets a day in France. I’ll give a week to celebrate just a little of the vast French influence on myeloma’s history.
Top Photo: Colonne de Juillet (left) on the Place de la Bastille, Opéra Bastille (right, background), Paris, France.
Photos of Jean-Luc Harousseau and family courtesy of Florence Harousseau.