Lingua franca
The Intergroupe francophone du myélome (IFM)
If a man will begin with certainties, he shall end with doubts; but if he will be content to begin with doubts, he shall end in certainties.
Francis Bacon, The Advancement of Learning
A first-time visitor to Paris’s Louvre Museum should at least try to get a glimpse of the Mona Lisa. It’s just expected. Like going to Times Square if you’ve never been to New York City.
Myeloma specialists attending an annual American Society of Hematology (ASH) meeting also have a “must do”: attend at least one presentation of the Intergroupe francophone du myélome (IFM) cooperative group. It’s been that way for three decades.
IFM sessions are packed, often requiring overflow rooms to handle crowds of attendees that can add up to the thousands. While patients following ASH often focus on studies about the latest drugs – are the new ones better? – they might miss out on IFM studies. They have a different template.
“Our trials are strategic,” said former IFM president, Jean-Luc Harousseau. Moreover, they are prospective – monitored and updated over time – and randomized. “The IFM started very early to perform randomized trials,” said Harousseau, “because the only way to demonstrate a treatment is better than another is to have fairly assessed groups of patients. If you don’t randomize, if the patient or the doctor choose the treatment, then there are biases.”
Early IFM trials focused on fundamental questions, “chemotherapy vs. high-dose, TBI (total body irradiation) vs. no TBI,” Harousseau recalled, but their design was driven by another problem, “there were no new drugs.” It’s one thing to prove one treatment better than another, it’s quite another to figure out how to use them and in which order.
Fast forward to the December 2023 ASH meeting. Now the “problem” in myeloma was unprecedented progress in prolonged lifespans linked to the large number of drug approvals in the past two decades. Simply put, myeloma patients are, on average, living too long. A substantial majority of patients can expect to live at least ten years. The current system based on progression-free survival (PFS) or overall survival (OS) based standards is not designed for patients who live that long.
“We cannot wait for eight, ten years after frontline treatment,” Harousseau spelled out, “this means you have to design very long trials. Very long trials mean expensive trials, and in addition to that, the results are so good that you need a large number of patients to show a significant difference. Designing a trial for frontline patients based on progression-free survival is very difficult and will be very expensive.” The IFM became pragmatically creative in designing the MIDAS (MInimal residual Disease Adapted Strategy) study, which promises to have a number of wide-ranging implications for myeloma treatment in the coming decade.
One IFM presentation at the December 2023 ASH meeting, the audience gathered to listen to one, Nantes’ Cyrille Touzeau, report on phase II results – which generally determine proper dosage levels, a phase I trial does so for safety – of a four drug combination followed by tandem transplant for high-risk, newly diagnosed myeloma. Rather than the report the results of one part of the study, I think it’s more important to understand its strategic goals.
“How can we measure improvement?” Harousseau asked. In putting together the MIDAS protocol, the IFM “decided to change the primary objective.” Rather than years survived, the new standard would be a measure – called a surrogate marker in medical jargon – minimal residual disease (MRD),* more precisely, sustained MRD-negativity – a measure of no detectable myeloma cells in 10-5 million parts (and lower) per million of the bone marrow.
[MRD is also called measurable residual disease. Although “minimal” is most accepted in myeloma, I prefer “measurable” because it is objective. The concept of “minimal” is subjective, definitions change when standards do. What is minimal today may or may not be tomorrow.]
“We look at PFS, of course, but the hypothesis and number of patients to be recruited has been calculated based on MRD-negativity, which is much easier,” explained Harousseau. “We were, again, the first, and now trials are based mostly on MRD-negativity.” Achieving it after induction became the objective to move patients along in the trial. Another reality had to be accounted for in the MIDAS equation.
“They become two different questions for standard- and high-risk patients. Standard-risk is a question of autologous transplantation or not, high-risk is a question of double transplant or not,” he continued. “We called it a risk-adapted strategy. Unlike the Germans, the British or the Spanish, we based the design, not on the initial prognostic factor, but response to treatment.” In a sense, this was changing the way survival is measured. The “starting gun” was not the day of diagnosis, but the day of achieving (or not achieving) MRD-negativity after induction treatment.
“We now know that response to initial treatment, and MRD-negativity achievement or not, is a major prognostic factor, so we based our strategy on the results to the initial treatment,” Harousseau explained, “there are six courses of a very good induction treatment [any can be chosen] and the goal for everybody, whatever the initial prognosis, is to achieve MRD-negativity in standard-risk, and they are randomized to autologous or not, or consolidation, and those who are still MRD-positive, we randomize between double and consolidation, so that the risk is defined by resistance to treatment, not by the initial prognostic factors. This is what we call dynamic risk-assessment.”
On April 12, 2024, the Oncologic Drugs Advisory Committee (ODAC) of the United States Food & Drug Administration (FDA) voted unanimously to accept MRD as an endpoint for future clinical trials. They could not have made such a confident choice without the evidence gathered and interpreted by the IFM.
MIDAS has different tracks and objectives, collecting the same data, reflecting the complexity of accurately determining each patients’ disease and prognosis. One approach MIDAS chose, said Harousseau “was for younger patients, eligible for stem cell transplantation. In Europe – not in the U.S. – we considered high-dose therapy with autologous transplantation to be the standard of care for transplant-eligible patients; that is the strategy, the ‘package’ — induction, autologous transplantation, post-autologous transplantation therapy.”
That, according to Harousseau, leads to obvious questions, “Do we really need autologous transplantation? In the past, we needed it, but now, with such effective drugs, maybe we don’t anymore. So that is the reason why we address the question of autologous transplantation in the era of modern, non-intensive therapy with, let’s say with anti-CD 38 activities like daratumumab or isatuximab. We give the very best non-intensive treatment and again we compare with autologous transplantation, but it’s only one part of this strategic trial, it’s for good prognosis patients.”
MIDAS asks, according to Harousseau, “the question that was the most important concern for Bart Barlogietwenty years ago: high-risk disease.” Once MIDAS participants had induction therapy, dynamic risk assessment separated them into standard- and high-risk groups to determine next steps. The latter pointed to another problem: no standard clinical definition of high-risk disease exists.
“If we choose risk-adapted treatment based on high-risk,” Harousseau asked, “how do we define high-risk?” This will continue to be a problem if no clinical consensus is reached, using the International Staging System(ISS) to illustrate his point. It defines “three cytogenetic abnormalities – t4; 14, del17p, t14; 16 – that’s not enough. Since there is no consensus, we prefer to define risk by response to treatment.”
MIDAS has been attracting attention for the past few years and promises to affect clinical practice throughout the coming decade. But it has a connection going back decades, to its roots, after the IFM had compared chemotherapy vs. high-dose, TBI (total body irradiation) vs. no TBI to change myeloma treatment. And just as MIDAS addresses questions Barlogie posed decades ago in systematic, original ways, the third big IFM study from the 1990s, did much the same.
In the days before new drugs were being discovered, “results obtained by Barlogie with tandem transplant were so encouraging, probably better than a single,” Harousseau recalled, “but the only way to demonstrate it was to do what Bart didn’t do: a randomized trial.” The IFM study findings were “positive” in confirming Barlogie’s trials “showing that double transplantation yielded longer progression-free survival (PFS) and overall survival (OS) than single.”
In 1999, Barlogie’s team in Little Rock announced thalidomide was the first single drug to show effectiveness against myeloma since Daniel Bergsagel tested melphalan in 1962. “Michel Attal said, ‘We have to use thalidomide, but not only in relapse, in front-line,’” said Harousseau, “that was not easy because the French authorities were reluctant to use this drug which was, of course, responsible for so many birth defects,” but they did get approval.
After getting approval, the IFM’s trial “compared thalidomide maintenance versus no maintenance, again randomized,” Harousseau continued, “Bart Barlogie did the same, [in an observational trial] and our results were approximately the same, showing that, of course, thalidomide maintenance improved the progression-free survival.” This “was not surprising, when you give a treatment for a long time versus no treatment, of course you delay the relapse. No mystery.”
The IFM study, however, “showed a benefit in overall survival.” Over the next few years, six national cooperative groups conducted similar trials, “and not all showed a survival advantage, all showed a PFS benefit, but not all on overall survival.” Nonetheless, “because of this and Bart’s trial, the concept of maintenance treatment was adopted and still persists.”
Government spending throughout the world supports medical research, treatment, and infrastructure, but not clinical trials. Although regulated by government agencies, most of the tab is picked up by pharmaceutical companies, which pay fees to regulatory agencies as well as pick up the costs of the trials themselves. The IFM’s success drew more attention from pharmaceutical companies as new drug candidates were being developed. Additionally, it inspired creation of cooperative groups in other European nations.
“When we started, randomized trials were only being performed by the United Kingdom’s Medical Research Council (MRC),” said Harousseau about the group that confirmed the IFM 90 study seven years after its release. “They were so long in publishing the results, but it’s not the case now. After our initial success, our example was followed in many countries; Italians, Spanish, Germans, the Dutch, created their own cooperative groups, and there was a ‘competition’ regarding the new drugs.”
Because of the IFM’s demonstrated success, “the pharmaceutical companies wanted to work with us. [Although not yet approved, in clinical trials] we could use bortezomib for frontline induction treatment prior to autologous transplantation and we could use lenalidomide for maintenance after autologous transplantation,” Harousseau noted, “two major randomized trials for the IFM.”
Success didn’t just expand the number of national cooperative groups, documentation and record-keeping requirements grew exponentially. Harousseau remembered the difference, “I wouldn’t say it was easy, but it was easier than now to design a clinical trial. It was easier and feasible with a small budget, so we could design and initiate clinical trials. Starting in the 90s and improving progressively, we had to create an official association with a budget, with employees, and that became like a small company. Now we are a big institution, we have a budget coming mostly from the pharmaceutical companies, but also from the French government, especially from taxes to help research, which allows us to pay for employees at the central office in Paris, research assistants, shipping samples, and so on.” This increasing reach led to the creation of another IFM asset, one that pays dividends through France to the entire myeloma community worldwide.
Herve Avet-Loiseau, joined Nantes to work with Regis Bataille in the mid-1990s to do lab work for the department in biological hematology. He was soon becoming a world-recognized expert in cytogenetics and integral to the work of the IFM. Thankfully, just as its budget was growing.
“That gave Herve Avet-Loiseau the possibility to create his database,” said Harousseau about a project initiated in 2004 that became a crown jewel for the IFM, “he succeeded in convincing all investigators to send him samples – blood samples, marrow samples – and their clinical data.” After 20 years, he “has information on more than 32,000 patients. It’s an extraordinary source of information and the reason why we were so successful in doing studies in translational research, mostly based on cytogenetics.”
The data, and more importantly, how to gather, interpret, and apply it, made the IFM and Avet-Loiseau “the leaders in the world for genetic risk assessment.” His other interest was to develop next-generation sequencing (NGS) techniques to assess MRD. He moved to the university in Toulouse, building on work the Spanish cooperative group had done in developing flow cytometry-based MRD assessments (far more sophisticated than the flow cytometry equipment Barlogie brought with him from Germany to Houston).
“He was the first to demonstrate the impact of NGS-assessed MRD and to show that the level of MRD was important,” Harousseau summarized, the lower the better. Initially tests could be developed to determine if no myeloma cells could be found to 10-5 parts per million in healthy cells, a level that now can go down to 10-6and lower. Celgene made use of the database to design a trial that led to the approval of lenalidomide maintenance after autologous transplantation.
“We were happy they could take advantage of the IFM structure,” and especially, Harousseau said, “the power of the IFM to rapidly recruit many patients. The next IFM study, initiated by Thierry Facon, compared lenalidomide (Revlimid)/low dose dexamethasone to the standard of care at that time, melphalan/prednisone and thalidomide.” It further confirmed Michael Katz’s suggestion years earlier and led to Revlimid with low dose dexamethasone becoming a so-called backbone therapy for myeloma.
When Janssen Pharmaceuticals needed to prove their new drug, daratumumab, might change myeloma treatment paradigms, the IFM fit the bill. They could quickly recruit patients and had a national structure to implement a trial comparing the then standard of Revlimid/dexamethasone with the addition of daratumumab. The MAIA trial, also proposed by Facon, ultimately led to the new triple combination, or triplet, replacing the doublet standard. Based on the clinical experience, the myeloma treatment landscape would be unthinkable without daratumumab today.
Rafael Fonseca of the Mayo Clinic in Scottsdale, Arizona, recently wrote two articles, one posted on the Substack of the Multiple Myeloma Fighters, the other on his Substack. Both are examples of the type of patient education that are sorely needed. They are concise, with simply understood points patients can discuss with their doctors, and they demonstrate the wide-ranging impact of IFM ideas.
In the first paper, Fonseca unequivocally concludes, “My typical recommendation to patients is to use the best available therapies early, and in combination, if possible.” When Barlogie had this philosophy as early as his MD Anderson days in the 1970s through his first decade in Little Rock, he was an outlier in myeloma. The combination of his reported results and the IFM subjecting them to randomized trials has been borne out; this view is no longer controversial.
The latter is a short article commenting on an IFM-led global study authored by Facon called IMROZ, which compared the triplet Velcade, Revlimid, dexamethasone (VRd) alone or with addition of the anti-CD38 monoclonal antibody isatuximab. He also cites a study of a smaller French cooperative group that compared adding isatuximab to VRd and comparing it with isatuximab plus Rd. “These results finalize the notion that anti-CD38 monoclonal antibodies should be part of the standard of care for all patients with newly diagnosed myeloma,” concludes Fonseca.
Both are examples of what medical research is: the systematic search for answers, one idea building on another, discarding those disproven. IFM studies have an exceptional history of building solid foundations upon which myeloma treatment strategies are built. I believe they embody more than science or medicine; they are reflections of Jean-Luc Harrousseau, who combined brilliance in science with diplomatic political skills to realize goals. But he did so not by dominating, but by facilitating diverse, talented people into a common goal to understand and overcome myeloma.
Harousseau’s successor in Nantes and the IFM, Philippe Moreau, stepped down from the latter post to assume the presidency of the International Myeloma Society (IMS), the global association of myeloma professionals. Avet-Loiseau is now president of the IFM. Harousseau stays involved. He is a familiar presence and speaker at annual IMS meetings and serves on the IFM board, he half-jokingly says is “to save the spirit of the IFM’s first years, which was to design strategic trials.”
To transplant or not? TBI or no TBI? Is double transplant better than a single? Is adding thalidomide, whether the patient had a transplant or not, helpful? Do better combinations exist than melphalan/prednisone, which was a standard treatment for myeloma for more than three decades? Is a quadruple therapy with daratumumab essential? Is transplant still relevant? Is MRD-negativity the path to control myeloma, maybe even cure it? What are the differences between standard- and high-risk in myeloma?
These are among the BIG questions in myeloma. The IFM has been answering them, or at the very least, identifying what can’t yet be answered, by leading national and international studies for more than three decades.
It should now be obvious whey IFM ASH presentations are essential. Even if attendees don’t know about the specific topic beforehand, they know they will leave with information that will likely affect patient therapies in the foreseeable future. Physicians attending will likely apply IFM ideas in their clinics, perhaps as soon as they get back home.
That’s because, despite being French, the IFM speaks a lingua franca, a language clearly understood and cherished by the myeloma community.
In my next article, I will explain further how my thinking about patient education has changed. Much of it has to do with the French experience. How is it that a nation with about twenty percent of the population as compared to that of the United States can produce such vital information relatively quickly?
I have come to conclude assumptions guiding patient education and advocacy, the concept and categories that accompany and are defined by them, are not what we may think they are. We many have been viewing success and failure the wrong way for a long time.
Photo: Detail, Leonardo Da Vinci, Mona Lisa (c. 1503-1506), The Louvre Museum, Paris, France