Lale Kostakoglu, MD, MPH, a professor of radiology and medical imaging at the University of Virginia School of Medicine (Charlottesville), talked with Vincent Rajkumar, MD, the Edward W. and Betty Knight Scripps Professor of Medicine at the Mayo Clinic (Rochester, MN) about his collaborative work in publishing findings that have established influential guidelines in the treatment of myeloma. Dr. Rajkumar is the cochair of the International Myeloma Working Group (IMWG) and chair of the Eastern Cooperative Oncology Group (ECOG) myeloma committee. He is the editor in chief of the Blood Cancer Journal and serves as an associate editor for Mayo Clinic Proceedings, Leukemia, and the European Journal of Haematology. Dr. Rajkumar has received several international awards, including the Robert A. Kyle Lifetime Achievement Award from the International Myeloma Foundation (2016), the Giants of Cancer Care Award (2019) from OncLive, and the Jan Waldenstrom Award (2021) from the International Myeloma Society. He was named as a Mayo Clinic Distinguished Investigator in 2018. He has led numerous phase I, II, and III clinical trials investigating new agents in myeloma, including pivotal trials that led to the approval of thalidomide for myeloma in the United States. He was named as a Mayo Clinic Distinguished Investigator in 2018. He has published more than 400 peer-reviewed articles and more than 200 reviews and book chapters, primarily on myeloma and related plasma cell disorders.
Dr. Kostakoglu: Vincent, thank you so much for setting aside time to talk to us today. Could you tell us a little about your amazing journey from Madras to Minnesota and the defining moments of your career choices?
Dr. Rajkumar: I was born in Madras, India, now called Chennai. Getting into medical school in India is very difficult. I was unable to secure a spot in any of the medical schools in my first 2 attempts, but in 1984 I finally achieved acceptance to Christian Medical College (Vellore), one of the leading medical schools in the country. The difficulty getting into medical school probably made me more mature, focused, and keen on excelling. During medical school, I became interested in hematology, because I had a very strong role model, Mammen G. Chandy, MD. However, India had no real formal training program for hematology at that time, so I wanted to move to the United States for training. It took me 2 years to get into a residency program after medical school. In those 2 years, I had an obligation to work in mission hospitals in India, which were mainly focused on delivering care for the underprivileged. I worked in a rural mission hospital that focused on the treatment of leprosy. It was really interesting, because as part of my work there I used the myeloma drug thalidomide.
Dr. Kostakoglu: This is one of the most impressive stories I have heard. Seeing medicine at all layers of society has probably made you a more critical thinker.
Dr. Rajkumar: I had a mentor from Australia, Alan Gijsbers, MBBS, who introduced me to clinical epidemiology and critical review of the literature. As a medical student I read all of the works of David Sackett, MD, MSc, and Robert Fletcher, MD, MPH, on evidence-based clinical epidemiology and became good at critical appraisal. This helped me differentiate opinion-driven from evidence-driven decisions.
S. Vincent Rajkumar, MD
Dr. Kostakoglu: Your background also made you one of the most impactful leaders in myeloma, transforming it from a highly fatal to a manageable chronic disease. How did you select myeloma as your primary area of interest?
Dr. Rajkumar: I went straight from 110° in Madras, India, to subzero temperatures in Fargo, ND, for residency. My program director there, Anthony Gustafson, MD, was a remarkable person who became aware of my interest in critical appraisal of clinical research as well as hematology. He propelled my career and helped me get into the Mayo Clinic for my fellowship. I was fortunate to train at Mayo with legends such as Robert Kyle, MD, Philip Greipp, MD, and Morie Gertz, MD, who were all very important in my choice of career path.
Dr. Kostakoglu: If you had to name the 3 most remarkable advances in the field supporting progress in myeloma, what would they be?
Dr. Rajkumar: I think the first major advance was a better understanding of the disease biology and recognition of the different cytogenetic subtypes of myeloma. The second would be the discovery of multiple new effective drugs. I have been a small part of these discoveries, starting with thalidomide and continuing with bortezomib, lenalidomide, pomalidomide, and carfilzomib. More recently, immunotherapy has dramatically improved the life-span of myeloma patients. The third advance would be discoveries that have led to a better understanding of how the disease evolves from the premalignant stage of monoclonal gammopathy of undetermined significance (MGUS) to the smoldering myeloma entity and then to full-blown myeloma.
Dr. Kostakoglu: That’s a great summary. Let’s expand on the initial diagnosis of myeloma a bit. If we start with biomarkers, what are the most important current prognostic and predictive biomarkers of myeloma?
Dr. Rajkumar: When I started in the field, myeloma was unique among cancers in that it was defined using clinical endpoints such as hypercalcemia and bone lesions. Waiting for the development of end-organ damage delayed therapy in so many patents. I was fortunate to lead the effort to redefine myeloma in 2014. As the IMWG, we published that work in Lancet Oncology (2014;15:e538–e548); this article has now become the most-cited myeloma paper ever. These IMWG revised diagnostic criteria incorporated biomarkers to further define the disease. The biomarkers included more than 60% clonal plasma cells in the marrow, a very high free-light-chain ratio, and 2 or more focal lesions on whole-body MRI. After diagnosis, the main prognostic determinants are certain high-risk cytogenetic abnormalities: translocations t(4;14), t(14;16), t(14;20), deletion 17p, p53 mutation, and chromosome 1 abnormalities.
Dr. Kostakoglu: In the context of predictive biomarkers, there has been a lot of pressure, especially from drug companies, to approve cancer drugs based merely on surrogate endpoints. Is it really a good concept in myeloma to use surrogate endpoints?
Dr. Rajkumar: I am very much in favor of traditional surrogate endpoints for many settings in myeloma, because many of the ones that we use are quite reliable and well validated. If we had waited for the hard endpoint of overall survival for new drug approval, the availability of many life-saving drugs we currently have in myeloma would have been delayed by 2–3 years. Thalidomide, bortezomib, carfilzomib, and pomalidomide were all initially approved using surrogate endpoints. With the exception of a few rare occasions, drugs that prolonged progression-free survival (PFS) in myeloma have eventually shown survival improvement. I strongly feel that the initial call that was made early on to use response rate and PFS as surrogate endpoints for refractory myeloma drug approvals was the right call.
Dr. Kostakoglu: A surrogate endpoint for PFS is one thing, but using a molecular or even an imaging biomarker as a surrogate endpoint is another. Will these latter approaches be established one day?
Dr. Rajkumar: What we really need are new biomarkers that show that the drug is clinically active and has a high likelihood of providing clinical benefit to patients who are confronting a serious, life-threatening cancer. Drugs granted accelerated approval using surrogate endpoints or single-arm trials must show clear proof of clinical benefit in subsequent well-designed randomized trials. Thankfully, this is the process we have followed in the myeloma field so far.
Dr. Kostakoglu: The other big topic in myeloma is racial disparities. You were involved in an important metaanalysis of genome-wide association (Cancer Epidemiol Biomarkers Prev. 2016;25:1609–1618). Could you briefly tell us about the results of that study?
Dr. Rajkumar: The incidence of MGUS and myeloma is 2–3 times more common in Black than White people. We have done genomic studies and found that a lot of the disparity in MGUS is driven by an excess of t(11;14) translocation in people with African ancestry genes. I think we should screen for monoclonal gammopathy in African Americans who have one affected relative with myeloma. We need to enroll a diverse patient population in our clinical trials. Finally, we need to determine whether responses to current myeloma drugs vary by race or ethnicity. Our studies suggest that the reason for lower survival seen in African Americans may be more related to access and affordability than to biologic reasons such as a more aggressive form of myeloma.
Dr. Kostakoglu: That is an ongoing and fascinating research field; hopefully it will lead to easier access to effective treatments. Let’s move on to another important topic: big data. Are there any ongoing landmark studies that will provide unprecedented big data on myeloma genomics to further personalize treatments?
Dr. Rajkumar: I think a lot of groups are undertaking efforts in this direction. There’s really a lot of opportunity to pull these resources in and get impactful data out. We need to open these resources to all interested parties who want to use them for scientific advancement.
Dr. Kostakoglu: What are the barriers to accessing these data?
Dr. Rajkumar: I’ve been disappointed at how difficult it has been to obtain data on cooperative group studies that we have conducted. I think bureaucratic barriers should be reduced so that we can help advance the field. We have a complicated system with many strict rules and procedures to access samples and data. We can keep talking about big data, but by the time we produce any information it may be outdated because of existing barriers.
Dr. Kostakoglu: It certainly sounds frustrating. We will probably rely on you as the leader to push this forward. We should touch more on the kaleidoscopic landscape of myeloma treatment. In the past decade, the U.S. Food and Drug Administration (FDA) approved numerous new agents that have significantly transformed the myeloma treatment paradigm. Could you tell us why myeloma is so challenging to treat?
“We need to be clear about whether a treatment is curative or primarily for disease control.…True cure means you do not need continuous suppressive treatment. That’s the goal.”
Dr. Rajkumar: In the last 20 years, we have probably had more than 16 drugs approved for myeloma treatment. The overall survival rates for patients of all ages have more than doubled. It is true that it has become a little more complicated, because we have so many drugs and regimens from which to choose. But by and large it is easier to control myeloma now than before. At Mayo we publish our guidelines on mSMART.org, where we outline precisely our recommendations on the regimen we use at each stage of the disease.
Dr. Kostakoglu: You have led and participated in many pivotal trials in myeloma. In fact, you led the ECOG trial using thalidomide and then a second-generation lenalidomide study. Could you describe the major breakthroughs in the treatment of myeloma?
Dr. Rajkumar: I think the most important breakthrough would be the discovery that thalidomide works in multiple myeloma in relapsed refractory disease. The credit goes to Bart Barlogie, MD. I was fortunate to lead the first confirmatory study at the Mayo Clinic (Mayo Clin Proc. 2000;75:897–901) and the subsequent ECOG randomized trial of thalidomide plus dexamethasone versus dexamethasone for newly diagnosed myeloma (J Clin Oncol. 2008;26:2171–2177).
The second big breakthrough would be the discovery of the effectiveness of proteasome inhibitors in myeloma treatment. Many people worked on this, including Robert Orlowski, MD, PhD, and Kenneth Anderson, MD, and associated researchers. Dr. Orlowski’s father, Marian Orlowski, MD, was a pioneering scientist in proteasome inhibition decades earlier.
The third breakthrough would be the finding that lenalidomide plus low-dose dexamethasone (Rd regimen) is a great backbone for myeloma therapy. The credit there goes to Michael Katz, MBA, patient advocate at ECOG, who challenged us to find a tolerable myeloma regimen. The Rd regimen was developed through the ECOG E4A03 trial, which I was fortunate again to lead. We found that low-dose dexamethasone was not only more tolerable with fewer side effects but also associated with better overall survival. That led to the Rd backbone, which subsequently became the frontline regimen in the Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide (FIRST) trial and then became the backbone of almost all major myeloma regimens we use right now.
The fourth advance would be the concept of maintenance therapy after transplantation as something that prolongs overall survival, which allows us to do a transplantation and then get a prolonged duration of remission.
And then, finally, the immunotherapy revolution: first with the introduction of monoclonal antibodies (daratumumab, isatuximab, and elotuzumab) and then subsequently now with CAR T cells and bispecific antibodies.
Dr. Kostakoglu: If I hear correctly, the most recent revolution in myeloma treatment is in immune-based therapies. In that sense, how do CAR T cells work in myeloma?
Dr. Rajkumar: CAR T cells have been found to be effective in diffuse large B-cell lymphoma and acute lymphoblastic leukemia. In myeloma, we have 2 CAR T-cell products approved, and both target B-cell maturation antigen (BCMA), with a high response rate of 80%–100%. Unlike in leukemia and lymphoma, they don’t appear to be curative, but they do give a PFS of about 1–2 years.
Dr. Kostakoglu: What about the newly approved bispecific antibody teclistamab? Are you excited about that? Bispecific antibodies and CAR T cells are both immune therapies, but which one would you favor?
Dr. Rajkumar: Teclistamab is a bispecific that targets T cells through CD3 and plasma cells by binding to the BCMA. It has a single-agent response rate of about 60% in relapsed refractory disease, which is amazing considering that prior myeloma drugs, such as thalidomide, lenalidomide, and even carfilzomib, had a single-agent response rates of only 30%. Several other BCMA-targeted bispecifics are in the pipeline in addition to teclistamab. CAR-T availability is very limited, so a lot of patients are going to get bispecific antibodies because these are more easily available. We also have new bispecific antibodies that target other antigens besides BCMA.
Dr. Kostakoglu: Can we briefly talk about response assessment in imaging? The latest IMWG response criteria have been amended to include molecular minimal residual disease (MRD) as well as PET imaging. What is MRD negativity, and does it really translate to longer survival?
Dr. Rajkumar: MRD negativity is defined as complete response by immunofixation plus a bone marrow assessment that shows no evidence of residual plasma cells by either a highly sensitive flow cytometry approach or a next-generation sequencing approach. Determining MRD negativity requires PET negativity in addition to paraprotein and bone marrow MRD criteria. We know that MRD status is a major prognostic factor. What we are struggling with now is whether we can use MRD status to adjust treatment. Here we need data from randomized controlled trials, and these are ongoing.
Dr. Kostakoglu: The PET-based response criteria were proposed by the Italian and French groups in a 2020 JCR article (Zamagni E, Nanni C, Dozza L, et al. Standardization of 18F-FDG-PET/CT According to Deauville Criteria for Metabolic Complete Response Definition in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2021;39(2):116-125.). So what are your thoughts about the use of these criteria?
Dr. Rajkumar: We use PET scan and imaging responses very much in the clinic. When we publish the response criteria, however, these are not formally included in the definition of partial or complete response, because when we change the established response criteria or the definition of progression, we change metrics by which the FDA has been adjudicating drugs for approval. Having said that, PET response assessment in day-to-day clinical practice is invaluable. The response criteria as written in articles are mostly for drug approval and for clinical trials. We use additional measures of response assessment in practice, including imaging.
Dr. Kostakoglu: You were recognized as an outstanding researcher and leader in the field of myeloma and have been the recipient of many prestigious awards, including the Giants of Cancer Care recognition in 2019 and Waldenström Award in 2021 from the International Myeloma Society. What do you believe to be the most important achievement that contributed to your recognition?
Dr. Rajkumar: I think in terms of sheer clinical impact and lives saved, the ECOG trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone has saved a significant number of lives, as well as spared people an enormous amount of toxicity. The initial reviews suggested that it was a boring trial, because we just wanted to compare high- and low-dose dexamethasone. But I really thought it was a very important question and saw it through.
Dr. Kostakoglu: You have a leadership role in the IMWG producing consensus guidelines. In that capacity, you work closely with European colleagues. Have you observed differences between European and U.S. physician scientists in their approach to clinical trials?
Dr. Rajkumar: That’s a great question. Our myeloma community is very close-knit and works well together. The unifying factor is that all of us are very much interested in how to improve outcomes for myeloma patients. But in terms of approach to clinical trial design and implementation, the main difference is that the United States has a lot more bureaucracy, making it difficult for myeloma experts to do the trials we want to do. European colleagues are able to put together proposals that are quickly approved, because the process recognizes that these are the best minds designing these trials for the best outcomes. The second difference is that in the United States we are more reluctant to put patients on clinical trials and more willing to put people on experimental therapy outside of trials. In Europe, they put more patients on clinical trials and treat them on study with much faster recruitment rates. They are better at working across countries than we are at working across institutions.
Dr. Kostakoglu: We all know that oncologists mostly focus on treatment choices to increase survival. With increasing survival times, quality-of-life issues are as important to patients as longer survival. Could we allow incorporation of quality-of-life endpoints in clinical trial designs?
Dr. Rajkumar: Certainly. I think for certain stages of the disease, such as maintenance, it’s better to show that PFS is prolonged and quality of life is also improved rather than simply showing that PFS is prolonged. We have tried to include quality of life as at least a secondary endpoint in all our ECOG trials.
Dr. Kostakoglu: Is it easy to use patient-reported outcomes in myeloma trials?
Dr. Rajkumar: It is a little bit harder in myeloma to evaluate patient-reported outcomes that truly reflect improvement in disease status. On the other hand, if a treatment prolongs PFS and we can show that it also improves quality of life, that’s definitely better than just showing improvement in PFS. A finding that quality of life was also improved is a very strong indication of clinical benefit.
Dr. Kostakoglu: The last topic is health economics—a big ugly bag. You’re well known for your advocacy of disease control versus cure. But controlling disease with maintenance therapies increases cumulative treatment costs. What’s the solution for cost containment?
Dr. Rajkumar: Great question. We need to be clear about whether a treatment is curative or primarily for disease control. I am all for a cure, because a cure is by far the most economical, most desirable endpoint for myeloma as well as other cancers. Achieving a cure means that treatment is given for a finite period of time and that in a certain number of people the disease will not recur, as we’ve seen with acute leukemia or Hodgkin disease. True cure means you do not need continuous suppressive treatment. That’s the goal.
On the health economic side, cure is clearly associated with a better approach than trying to control a disease with very expensive drugs for a protracted period of time. I’ve been very vocal on drug costs. The U.S. prescription drug system is broken. It allows new drugs to be highly priced regardless of the value they provide. We need to make major changes to drug prescription and pricing policies so that our public has access to affordable drugs. This includes Medicare’s being able to negotiate from the launch of the drug and strict policies that prevent drug companies from increasing prices when they feel like it. It includes reforming the patent system, easier entry of generics and biosimilars, and pharmacy benefit manager reforms. Physicians should also be aware of and advocate for access and affordability.
Dr. Kostakoglu: I don’t see a quick cure for this problem, which is unsustainable, with new targeted treatments costing $300,000–$400,000 per year.
Dr. Rajkumar: If insulin can cost 10 times more in the United States than in other countries, it is no wonder that cancer drugs are so expensive. I want to make a plug for a film that recently premiered called Pay or Die, which highlights the insulin price crisis.
Dr. Kostakoglu: I will certainly watch that film. Let’s conclude with an aside about your personal unknowns. What is your most unexpected or unusual hobby?
Dr. Rajkumar: I have a strong passion for music. I sing, play the guitar a little, learned a little bit of the piano, and can record and edit music.
Dr. Kostakoglu: So diversified! A final question: which 3 famous people would you invite to a dinner party?
Dr. Rajkumar: One would be Michael Jordan, who has been an incredible role model. He strived for perfection every day on the court. It would be amazing to talk to him. The second would be President Obama. He is another great role model. The third person I would love to have dinner with is a composer from India, Ilaiyaraaja. He is among the most prolific composers in the world and can compose a song in 30 min using only pencil and paper. He composed 2 songs a day for decades. So he’s someone I would love to talk to about how he does it.
Dr. Kostakoglu: Thank you, Vincent. It has been a great pleasure talking to you on many interesting topics. Thanks for your generosity of time and willingness to share your valuable perspectives.
Dr. Rajkumar: It is an honor to be interviewed. Thank you so much.
- © 2023 by the Society of Nuclear Medicine and Molecular Imaging.
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