Revolutionizing Multiple Myeloma Treatment

Author(s): Scott Douglas Jacobsen

Publication (Outlet/Website): The Good Men Project

Publication Date (yyyy/mm/dd): 2025/07/23

Carl Ola Landgren, M.D., Ph.D., is Director of the Sylvester Myeloma Institute and Chief of the Division of Myeloma at the Sylvester Comprehensive Cancer Center, University of Miami. An internationally recognized leader in multiple myeloma research, he pioneered the use of minimal residual disease (MRD) as a surrogate endpoint for the accelerated approval of drugs. His work integrates cutting-edge diagnostics, personalized therapies, and innovative clinical trial models to improve outcomes and quality of life. Dr. Landgren’s long-term vision focuses on redefining disease classifications, eliminating toxic treatments, and advancing MRD-based strategies to move the field closer to functional cures.

Scott Douglas Jacobsen: So, what motivated the original push to recognize minimal residual disease as an endpoint for accelerated drug approval?

Dr. Carl Ola Landgren: I led the early work on using minimal residual disease, or MRD, as an endpoint for accelerated approval in multiple myeloma over fifteen years ago. At the time, I was working at the National Cancer Institute (NCI), apart of the National Institutes of Health (NIH) in Bethesda, Maryland. We had access to highly effective drugs and treated patients directly at the NIH Clinical Center. We observed that a significant proportion of patients achieved complete responses or remissions.

Given the level of success, I began to consider a critical question: if nearly every patient achieves remission, how do we determine whether any disease remains—and whether that matters for long-term outcomes? It became clear that we needed more sensitive tools to distinguish between truly disease-free patients and those who had undetectable but persistent residual disease.

We began developing and refining more sensitive assays to detect minimal residual disease (MRD). As these technologies advanced, we observed that patients who were MRD-negative—meaning no residual disease was detectable even with the most sensitive methods—had significantly better long-term outcomes. This was a crucial insight.

MRD status could function as a predictive biomarker. If MRD-negative patients consistently showed improved progression-free survival (PFS), then MRD could serve as a surrogate endpoint. That, in turn, would allow us to evaluate new treatments much earlier—potentially within a year—rather than waiting ten to fifteen years for traditional endpoints, such as PFS or overall survival, to mature.

Without a validated early endpoint, I feared that the pace of innovation would stall. Drug developers might be reluctant to invest in new therapies if proving their efficacy requires prohibitively long trials. The field needed a way to measure meaningful benefits much sooner.

In 2009, I helped launch an interagency initiative between the NIH and the FDA to formally evaluate MRD as a potential surrogate endpoint. This effort eventually culminated in the Evidence Meta-Analysis, which we submitted to the FDA last year. That work formed the basis for regulatory consideration of MRD as an endpoint in clinical trials.

Jacobsen: Regarding MRD as an endpoint in clinical trials, specifically for multiple myeloma, how does its inclusion affect the speed and structure of drug development?

Landgren: Incorporating MRD as an early endpoint is a transformative development. Under the traditional model, you need a large, randomized, controlled trial comparing an experimental therapy to a standard-of-care control arm. You then have to wait—often ten to fifteen years—for enough progression or death events to occur in both arms to conduct a mature statistical analysis based on PFS or overall survival.

That timeline delays patient access to promising new therapies, making clinical development slower and more expensive. However, if we can rely on MRD as a validated surrogate endpoint—one that strongly predicts long-term benefit—we can potentially assess efficacy within a year after randomization.

This allows for much earlier readouts and faster regulatory decisions. It also provides a more dynamic and adaptive framework for evaluating treatment regimens. Importantly, it gives patients faster access to therapies that show strong early indications of benefit.

Jacobsen: You are saying you have a biomarker, and that biomarker can be tested one year after randomization to predict what will happen ten to fifteen years later?

Landgren: That means you can open the study, enroll patients, and one year after randomization, check the biomarker in both study arms. If you see a higher rate of MRD negativity—MRD being the biomarker—that means you can predict that progression-free survival ten or fifteen years later will be more prolonged.

So, you submit your MRD results to the FDA, and they can review that data and potentially grant accelerated approval. Once that happens, the drug becomes immediately available to patients, giving them access to treatment more than ten years earlier than they would under traditional timelines.

Of course, the study must continue in order to capture the clinical endpoint—progression-free survival. If that data, once mature, confirms the superiority of the drug, then the FDA may grant full approval. While the drug company can use the early MRD endpoint to obtain accelerated approval, it still must complete the study, collect all required data, and pursue full approval.

If the follow-up study fails to confirm the benefit, the drug will be removed from the market. However, we have shown that MRD is a powerful predictor of progression-free survival. If everything follows the expected trajectory, it provides much faster access to effective treatments.

Jacobsen: What types of cancer are most likely to follow multiple myeloma in adopting MRD as a regulatory endpoint?

Landgren: I first saw the potential for this approach when I was working at the National Cancer Institute, part of the NIH, more than twenty years ago. I began pursuing this work then, though it took a long time to convince others. Many people told me it was just a theory—that it would be impossible to persuade the FDA. However, I knew it was the only viable path forward, so we persisted.

Other groups eventually became interested in this area as well. One group formed during our work—the so-called I² team or I-team group. They began similar work in myeloma after seeing what we were doing.

Our efforts also inspired others to begin thinking about MRD in additional disease areas. I have many friends around the world working on related research. Long ago, I was also interested in diseases such as chronic lymphocytic leukemia, lymphomas, and other hematologic malignancies, and I maintained close contact with colleagues in those fields.

Just this week, I spoke with colleagues working in the field of lymphoma. A few weeks ago, I spoke with researchers in the chronic lymphocytic leukemia space. These conversations happen frequently. Many of them are trying to replicate, in their respective fields, the kind of work we did in myeloma. They often reach out to me for advice.

At some point, they may succeed. However, it is not as simple as copying what we did and submitting it. They must generate all the data themselves. It is a substantial undertaking. You need to conduct numerous studies, including randomized controlled trials. You need to analyze different drugs in parallel. You must also conduct a detailed statistical analysis.

That analysis must follow a predefined statistical analysis plan, and the FDA must endorse that plan. Once you have sufficient data and an FDA-endorsed plan, you can perform the analysis and submit your results for FDA review. With enough rigour and compelling data, you may receive approval.

For us, that entire process took about fifteen years. So, I worked on it for fifteen years. However, given that we have now created a precedent—that it is possible to do so—other diseases may be able to adopt this approach in just a few years. Hopefully, the timeline can be much, much faster. That could apply to other diseases, potentially including some solid tumours.

The critical part is that you need several key components in place: you must have good drugs, a standardized tool to measure the biomarker—MRD—and studies conducted in a harmonized way. This ensures you can pool data and conduct a large-scale analysis involving multiple drugs studied in parallel. Yes, it requires multiple components.

Jacobsen: What about the limitations of MRD as a biomarker, particularly in solid tumours or other blood cancers?

Landgren: That is an important question. In general, biomarkers have inherent limitations simply because they are proxies—they are not the final clinical outcome. If progression-free survival is the ultimate goal, nothing can be more definitive than measuring progression-free survival itself. You could think of it like this: if you are navigating through the wilderness, a map can be very accurate, but the real landscape is always more precise. However, with an excellent map, you can get very far.

That analogy holds for biomarkers. They serve as intermediate indicators of reality. What we demonstrated—across many drugs, many studies, and various patient populations—is that MRD is a robust and predictive measure. However, as a general caveat, reality always wins. That is why, under current regulatory frameworks, you must still submit final clinical outcomes, such as progression-free survival, to gain full approval.

That said, I do believe that with the accumulation of data in myeloma—if more and more studies continue to replicate our findings—MRD could eventually become accepted as a standalone endpoint for full approval. For now, though, MRD remains an endpoint for early or accelerated approval. You still need to submit the clinical data showing progression-free survival.

So, that is one type of limitation—one that applies to any biomarker, not just to MRD or to myeloma. It is a general limitation of surrogate endpoints.

When we think about MRD in solid tumours or other hematologic malignancies, additional limitations may arise. Some diseases may not shed detectable disease into the bloodstream or not in a way that lends itself easily to tracking via blood-based assays. So, depending on the biology of the disease, the effectiveness of MRD monitoring may vary.

Still, I believe that with increasingly sensitive assays, most—if not all—diseases could eventually be tracked through blood. This becomes a technological issue more than a biological one. I have not conducted this ranking exercise myself. However, I am confident that if you were to rank diseases by their suitability for MRD monitoring, some would be easier to adapt to this approach, while others would be more challenging.

Another limitation arises in disease areas where effective therapies are not available. In such cases, it is challenging to achieve MRD negativity simply because the treatments are not potent enough. However, my counterargument is that in those disease areas, there is also less immediate need for MRD as a regulatory endpoint. MRD becomes useful when effective therapies are already available, allowing many patients to achieve responses. However, you do not yet have a cure—and when further progress depends on being able to distinguish levels of residual disease.

Suppose a field is still in an early stage, where few treatments exist and survival rates are unfortunately very low. In that case, traditional endpoints such as overall survival or basic response rates may still be more appropriate. MRD becomes vital only when you have reached a sort of plateau—when new progress depends on differentiating deep responses from superficial ones and speeding up drug development by using reliable surrogate markers.

I have attempted to shed light on the overall limitations of biomarkers—technical limitations, disease-specific limitations, and the broader context of where a field stands in terms of therapy development. Those are my perspectives.

Jacobsen: Now, with the shift toward blood-based MRD testing versus bone marrow aspirates, how do you see this affecting clinical research in the medium-term future—say, over the next ten years—and how will it impact both research and clinical practice?

Landgren: My answer is this: life, in general, is about change. Everything evolves. And when it comes to medicine, we will continue to see innovation and the emergence of new technologies.

There is a strong push for blood-based technologies in minimal residual disease (MRD) testing. These methods offer significant advantages from a patient perspective. Drawing blood is much more appealing to patients than undergoing a bone marrow biopsy.

That said, there are technical challenges. In multiple myeloma, for example, which resides in the bone marrow, a biopsy may detect disease that a blood test cannot. This is because myeloma cells may not circulate into the bloodstream at the same rate or in sufficient quantities to be detectable by the bloodstream. So, we need to demonstrate a strong correlation between blood-based MRD and bone marrow–based MRD. That correlation work is still ongoing.

Furthermore, as I mentioned earlier, some diseases may or may not release tumour material into the blood as readily. Therefore, there are biological and technical limitations, and we must show statistically that blood-based testing is reliable.

Now, I have worked extensively with DNA, RNA, protein, circulating tumour cells, and free circulating DNA. I’ve been involved in many of these studies for over ten to fifteen years. I am aware of the research being conducted globally. I also chair an annual meeting focused exclusively on MRD in myeloma and all related technologies. Based on everything I have seen, blood-based testing is on the horizon.

I believe that within the next year, we will begin to see the first blood-based MRD tests enter clinical practice. Within five to ten years—the timeframe you mentioned—I think blood-based MRD testing will become far more prominent and even dominant in the field.

This shift will not only enhance drug development, which is the main context I’ve discussed so far, but it will also expand the use of MRD in routine clinical practice. In drug development, as I explained earlier, we test MRD one year after randomization to predict outcomes ten to fifteen years later.

But if you have a reliable blood-based MRD test, you can do something different altogether: you can use it for real-time, daily decision-making in the clinic. This extends beyond research—it directly informs the standard of care for patients. Say you treat one hundred patients and monitor them using these new sensitive blood-based tests. If all of them are MRD-negative, then over time—perhaps after a year or more—you may begin to see disease activity re-emerge in one or two patients. In the future, that could prompt an earlier change in therapy.

Currently, these blood-based tests are not yet available for routine use. So, patients are monitored without fully knowing what may be happening beneath the surface. The disease can progress “under the radar,” and by the time clinical symptoms appear, it may be too late to intervene early. At that point, therapy is changed, but the patient may already be significantly sicker.

The availability of these tests will likely lead to earlier detection of changes in disease trajectory. Physicians will be able to tailor therapy more precisely—this is the essence of personalized or individualized treatment. I also believe that MRD testing will work both ways: it can help you escalate therapy when the disease reappears, but it can also help you de-escalate therapy when the disease becomes undetectable.

For example, if a patient receives combination therapy and achieves MRD negativity, you may be able to scale back the treatment—reducing the number of drugs or dosing intensity. This minimizes unnecessary toxicity.

Multiple myeloma has long been treated with combination regimens. In the past, high-dose chemotherapy followed by autologous stem cell transplant—often just called “transplant” in the U.S. or “high-dose chemotherapy” in Europe—was the standard. With modern, effective therapies, if patients become MRD-negative, they might avoid these older, more toxic treatments altogether.

That could have a huge impact—not only on clinical decision-making but also on patient quality of life. This is how MRD testing contributes to personalized care, where treatment is tailored to the individual’s needs and disease response.

Jacobsen: So, what role will the Kenneth C. Griffin Breakthrough Cancer Research Building play in scaling MRD research and, as you were discussing, personalized cancer treatment strategies? That is always the big challenge—scaling promising treatments so that they are accessible and affordable for a broader population.

Landgren: Yes—the Kenneth C. Griffin Building plays a vital role for the Sylvester Comprehensive Cancer Center and the University of Miami. It provides a dedicated facility specifically for the cancer center. This focus is critical because Sylvester is not only advancing cutting-edge innovation but also delivering world-class care to patients with many different malignancies.

The University of Miami is a large, evolving institution. But within that broader context, having a dedicated cancer center—housed in a focused, specialized facility like the Griffin Building—makes a significant difference.

Why? Because it enables us to concentrate our resources, build specialized infrastructure, set strategic priorities more effectively, and assemble the best people in the field. It helps us recruit top-tier researchers and clinicians who want to work in an environment focused exclusively on oncology innovation.

So, the Griffin Building is not just a physical space. It will become a hub for those of us—myself included—who are driving research and innovation in cancer. It allows us to work outside the constraints of a more general medical system and be part of a highly focused, mission-driven cancer center.

We are all part of the University of Miami, but having a more focused structure within the university is a considerable advantage. Organizationally, there is still much we can do to further align reporting structures to support cancer-focused work for those of us in oncology. That way, there is no dilution of effort with broader, more general approaches. Instead, the focus becomes the defining theme—allowing us to be more competitive and more successful.

In life, in general, when you focus, focus, and focus again—you go further, faster. That is exactly what this building represents. The Kenneth C. Griffin Breakthrough Cancer Research Building is a vehicle to help us achieve that.

Jacobsen: My final question, which I should be asking all scientists: in your area of research, what would you consider—within your lifetime of work—looking back and looking forward, to be the “holy grail” of your research in terms of disease prevention and treatment? So, you’ve studied certain cancers, and MRD is part of that puzzle in terms of developing better treatments. 

Landgren: Yes, that makes sense. I believe minimal residual disease (MRD) is a central part of that vision—a key component in the success formula going forward. The ability to test for and confirm that no disease is left behind is critical to truly curing a disease. You can have the best drugs in the world, but if you cannot confirm whether they worked, you’re flying blind. MRD gives you that resolution—it tells you whether the disease is gone or not.

So, in that regard, MRD is essential. Looking ahead, MRD tools will continue to improve. They will become blood-based, more sensitive, and undergo iterative refinement. But that is only part of the picture.

We are also witnessing the ongoing development of new therapies. The field is steadily moving away from traditional, toxic chemotherapies and toward chemotherapy-free regimens. We’re seeing the rise of immunotherapies, novel monoclonal antibodies, and innovative combinations with small molecules. These can eradicate disease in a high proportion of patients. This shift will also help eliminate outdated treatment modalities.

In addition, the development of biomarkers that can help us understand both mechanisms of response and mechanisms of resistance will be crucial. We now know that, in response to therapy, cancer cells can evolve and acquire mutations that allow them to evade treatment—often by losing or modifying the very targets the drugs aim for. Therefore, having tools that track such changes and guide treatment adjustments will be essential in the pursuit of a cure.

Another important aspect will be optimizing the timing of treatment initiation. Starting therapy at the right time—based on predictive and dynamic biomarkers—will help ensure better outcomes and avoid overtreatment or delayed care.

In summary, the holy grail is a future where we can detect diseases early, eradicate them with tailored, less toxic regimens, and verify that they are truly gone—all guided by precise, adaptive biomarkers. That is the direction I believe we are heading, and MRD is at the heart of that evolution.

The disease I work on—multiple myeloma—is still diagnosed clinically. To illustrate, if someone has a broken leg, youcan take an X-ray and see the fracture. You immediately identify the problem and treat it accordingly.

However, myeloma exists in a more gray area. You can be visibly sick from it and receive a diagnosis of myeloma. However, you can also have all the biomarkers associated with active disease—yet still not show outward symptoms.

That condition is often referred to as smouldering myeloma, and for a long time, it has been managed quite differently from active disease. But with today’s newer technologies, we now understand that many patients in that smouldering group have the full biological signature of active disease. They are, in a sense, silently progressing.

Therefore, redefining the clinical definition of multiple myeloma will be a crucial step moving forward. If we can detect the disease earlier—before symptoms manifest—and if we apply our best available therapies in that early phase, alongside MRD tools to confirm disease eradication, then we can dramatically shift the treatment paradigm. The short-term goal is to cure many more patients.

Jacobsen: Excellent. Well, Dr. Landgren, thank you very much for your time. I truly appreciate it—and thank you for sharing your expertise.

Landgren: Thank you so much for having me. I hope you enjoy your trip.

Jacobsen: Thank you.

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