By Deborah Borfitz

June 3, 2025 | A small not-for-profit organization has set itself up as a model for turning the nitty-gritty of scientific research into a metaphorical “black swan event” with major impact on the lives of patients living with an incurable disease. The overarching strategy of the International Myeloma Foundation (IMF) is to function as the convener of the broader myeloma community in ways that lead to improved outcomes for patients in terms of both their quality and quantity of life, according to Joseph Mikhael, M.D., chief medical officer of the IMF. 

The Black Swan Research Initiative, as it is known, seeks nothing less than a “true cure” for myeloma, he says. Since no one knows the best way to do that, the “creative, collaborative, and comprehensive” project is intelligently and systematically trying different methods. 

Simply defining what constitutes a cure is tricky because people define it in different ways, says Mikhael. The descriptions run the gamut from an affordable pill patients take for a time and then never again have to think about myeloma to a “functional cure” where after treatment there is still some measurable disease but few if any of the awful symptoms present at the time of diagnosis. 

The added complexity when looking at “normal relative survival” is that the average age of a myeloma diagnosis is approximately 69 years (65 for those of African descent and 64 for Latino Americans), he adds. Many patients get diagnosed in their mid-80s and have already exceeded their life expectancy, and may die from something else (e.g., heart disease) within a few years. 

The biology of myeloma is such that no two patients are exactly alike, and the “cure trials” the IMF funds reflect that reality, he adds. “Some forms of myeloma are more indolent and slow-growing, and with even small amounts of treatment over time can just be suppressed; people live close to their natural life expectancy. But then there are other forms of myeloma that are extremely aggressive, and people need very dramatic treatment and [yet], sadly, succumb to their disease very early.”  

Other forms of cancer, including some lymphomas and solid tumors, are considered curable for most patients given a certain treatment regimen, Mikhael says. Only a small fraction of multiple myeloma patients experiences a true cure, Mikhael says, “but it’s growing as we’re introducing new therapies.” 

The disease itself is a key differentiator for the Black Swan Research Initiative, he points out. “When I   went into multiple myeloma 25 years ago because I wanted to treat patients with the worse cancer... the majority of patients didn’t live after two years, and it was inordinately challenging to manage.” 

Patients not only had a short lifespan but were typically in debilitating pain due to the disease’s multi-prong attack on the bones, blood, and kidneys. “To go into the heart of the beast and say let’s try and get this disease under control is unique,” says Mikhael, and even caused a bit of benign envy among his nonprofit colleagues focused on other, bigger cancers.  

Multiple myeloma is a relatively rare condition, accounting for just 2% of all cancers, Mikhael says. But the pre-myeloma conditions known as smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) are quite common. 

The disease is also “the most disparate cancer in the African American community,” he continues, and not only because it strikes Blacks twice as often as Whites. “A Black man or a Black woman diagnosed with myeloma today is expected to live half as long as the same aged White man or White woman, and that is unacceptable.”  

Birthing a Think Tank

The “crown jewel” of the IMF’s approach to research is the International Myeloma Working Group (IMWG), a union of myeloma experts from around the world whose number now exceeds 300, Mikhael reports. “There are things we can only do together that we couldn’t have done individually.” 

The list includes defining the disease more carefully, he says, noting that the IMWG has agreed on criteria for determining partial and full response as well as minimal residual disease (MRD) negativity.  That has in turn facilitated quicker drug approvals by giving regulatory agencies like the U.S. Food and Drug Administration (FDA) an accepted means to gauge patient response. 

Importantly, the IMWG functions as a “common think tank” for deciding which are the most critical scientific questions to ask in the quest to cure myeloma when designing clinical trials and then working on those projects collaboratively, says Mikhael. The agenda of individual institutions and companies is, of necessity, a bit different.  

Out of the “nest of the IMWG” the Black Swan Research Initiative was born, he says. And because this happened under the umbrella of the IMF, patients are involved in the design of all studies. In addition to research, the IMF’s mission also centers around the pillars of education, support, and advocacy for patients and their families.  

Eliminating the Enemy

The Black Swan Research Initiative launched after a scientific brainstorming meeting at the 2012 IMGW Summit in Amsterdam. It brings together experts from academic institutions, governmental agencies like the FDA, as well as industry, “to allow everybody to function at the top of their game, almost like the Olympics where world records are broken,” says Mikhael. 

“[Initially] we couldn’t dream about eliminating all of the disease,” he says. “But we are now introducing new treatments and therapies that are getting patients down to almost immeasurable amounts of disease either in their blood or their bone marrow.” 

The Black Swan Research Initiative is today heavily connected to the concept of MRD because myeloma remains a challenging disease that tends to reappear after periods of remission. One central task has been detecting cancer cells that are missed by routine testing and standard medical imaging but can signal a higher risk of relapse, says Mikhael. 

“If you are going to cure a disease, you have to eliminate all of it,” he adds, making the goal MRD negativity. With standardized methods now in place to measure it, the technology can and is being incorporated into clinical trials.  

Currently, most multiple myeloma patients remain on therapy for their entire life, says Mikhael, much like people with diabetes or high blood pressure. “We just control it with treatment indefinitely.” The problem is that the treatments typically used for maintenance therapy are hard to take for long periods of time.  

Collaborative of Experts

The backbone of the Black Swan Research Initiative is a coordinated network of the “best of the best” experts connected via the IMF Global Technology Platform, says Mikhael, bringing many approaches to the singular goal of a cure. These include colleagues doing immune and blood monitoring and single cell resistance analyses (Spain), blood DNA mutational analyses and clinical trial assessment (Australia), and early disease and full sequencing (Iceland). MRD testing is also being done in the U.S., while Singapore has a virtual tissue bank facilitating the accessing and sharing of research data and Germany has family and retrospective studies underway.  

The Spanish group has exceptional expertise in flow cytometry, a technology enabling the detection of a single myeloma cell in a pool of 10 million or perhaps even 100 million other noncancerous cells, he says. “Sometimes a little smutch of disease that is left can be very aggressive; as I often say, Rambo was the last soldier to be killed.” 

Partner institutions in Australia are also scouting for “tiny bits of evidence” of myeloma cells in circulating blood, to spare patients a bone marrow testing involving a significant needle being placed into their hip, says Mikhael. Meanwhile, researchers in California are working on modern CAR T-cell therapy whereby patients’ own immune cells are trained to attack their cancer, and the learnings could potentially be applied to some of the cure trials.   

This collaborative of experts conducts IMF-funded projects together, and representatives from the various groups meet regularly, virtually or in person. This provides an opportunity for information sharing, although they publish individually—69 publications and 30 abstracts in all to date, Mikhael reports. 

The Cure Trials

The earliest and most significant study coming out of the Black Swan Research Initiative was the ASCENT (Aggressive Smoldering Cure Evaluating Novel Rx Transplant) Trial, led by the Mayo Clinic, Mikhael says. The trial launched in 2017 and is ongoing at nine sites around the U.S. 

Its goal is to evaluate the effectiveness of early treatment of SMM with a four-drug regimen, in lieu of a stem cell transplant, in terms of improving outcomes and potentially leading to MRD negativity and possibly a cure. The idea is to “catch people right before the disease takes off” instead of watching and waiting for myeloma’s potential development—what Mikhael compares to preventing a runner from unknowingly jumping off a cliff. “We used to define myeloma as falling off the cliff [organ damage].” 

Over three-quarters of study participants have achieved MRD negativity to date and many of them have maintained that status, he says, suggesting a functional or potential cure for a subset of patients. The next ASCENT trial is now in the design phase that will likely take a different approach, perhaps treating high-risk SMM less aggressively while still steering them clear of the cliff, so to speak.  

Like the ASCENT Trial, the CESAR Trial ongoing in Spain since 2015 uses a four-drug combination in the same setting, only patients are being treated less aggressively. The study is now in phase 3 and, “a significant fraction of patients who got into a deep response have remained in that [state],” he says. The addition of one of the agents used here (daratumumab) to the ASCENT Trial could help further enhance treatment response.  

But what could be the most influential study of the decade is iStopMM (Iceland Screens, Treats, or Prevents Multiple Myeloma), which was featured on CNN back in 2017. “This study did something that no other study has done or potentially ever could do because of the uniqueness of Iceland,” says Mikhael. 

Investigators at the University of Iceland were responsible for the conceptual design of iStopMM, which is looking at whether screening asymptomatic people for the precursor conditions (SMM and MGUS) saves lives as do mammograms for breast cancer and colonoscopies for colorectal cancer, he continues, with the answer to that question expected within the next two years. Iceland was the perfect location for the study because “more patients than in any country in the world have had their whole genome sequenced through the huge deCODE Genetics laboratory there.” 

The healthcare system in Iceland is also ideally suited to the project, since it is so united that when people consent to being tested, they just get their blood drawn the next time they see their doctor, he marvels. “We’ve already processed over 75,000 samples from these patients and I know they are filling out their surveys.” Icelanders—over 80,00 of whom consented to have their blood taken—“trust the system.” 

Among the large volume of information expected out of iStopMM study is “the real incidence” of MGUS and SMM, whether the conditions have been defined correctly, the variables predicting who really needs a bone marrow biopsy, and the psychological effect of screening, says Mikhael. 

The Big Win

In addition to the output of the iStopMM study, one of the other great accomplishments of the Black Swan Research Initiative emerged from the data and expertise it provided to the FDA’s Oncology Drug Advisory Committee (ODAC) last year regarding MRD testing. The verdict of the ODAC, on a 12-0 vote, was that such testing should be a clinical trial endpoint which predicts progression-free and overall survival for drug approval, says Mikhael. 

Up to now, oncology drugs have been approved only after very long-term trials revealing how many patients they put and keep in remission. But MRD testing can predict who will stay in remission early on in their treatment, which could potentially mean savings of billions of dollars on clinical trials as well as faster drug approvals for patients, Mikhael says. Trials that incorporate MRD testing are already being designed and implemented.  

Only two years ago, two new myeloma drugs (Elrexfio and Talvey) were approved by the FDA. The Black Swan Research Initiative was involved in the studies leading up to those approvals and now, post hoc, are going after some of the “still-huge questions that remain,” Mikhael says. It is unknown, for example, if the immunotherapy drugs can be used in the one-third of myeloma patients whose kidneys have been compromised by the disease, since they were excluded from clinical trials. 

To that end, the Black Swan Research Initiative has created an Immune Therapy Registry to collect deidentified information on thousands of myeloma patients from institutions around the world, he reports. That large, aggregated data pool will enable researchers to start asking questions and looking for patterns that wouldn’t be visible on a smaller scale.  

“Maybe we don’t need to give the drugs as frequently,” Mikhael says. Or perhaps, he further muses, a more aggressive infection prophylaxis should be more routinely given since patients are at significantly increased risk of infections.  

Tackling Health Disparities

As lead of the IMF’s M-Power Project, Mikhael is all too aware of the health disparities in multiple myeloma that are “scientific and without question.” The awareness initiative seeks to enhance the care that gets delivered to African Americans with the disease.  

Studies have shown that when given equal access to the diagnostic and therapeutic strategies for myeloma, “Black patients do just as well if not better than White patients,” he points out, “so the disparity is not biological.” 

The hope here is that M-Power will improve the short- and long-term outcomes of individuals who have historically had inferior outcomes, Mikhael says. While efforts were initially focused on the African American community, the work is now extending to the Latino American community, especially in terms of the diagnostic overlap between diabetes and myeloma. 

The strategy includes engaging the community to build trust and raise awareness of disease signs and symptoms, as well as reminding primary care practitioners of the disproportionate incidence rates in these communities—or the fact that mild kidney dysfunction might be attributable to myeloma rather than high blood pressure. Physicians and nurses providing direct care to myeloma are also taught, and encouraged to provide, the most culturally competent care possible.   

Given that about 20% of all myeloma patients in the United States are of African descent, they also need to be adequately represented in clinical trials to know if approved drugs are safe and effective for them. By that yardstick, they are woefully underrepresented at present with an approximately six percent enrollment rate in myeloma studies, which Mikhael (himself of African descent) is adamant about changing.