Working on the Frontlines of a Revolution in Multiple Myeloma Care

Rafael Fonseca, MD

Born and raised in Mexico City, Mexico, Rafael Fonseca, MD, always had an eye toward the US, but he knew his home nation had the US outclassed in 1 key area: his favorite sport. “Growing up in Mexico, I always thought, ‘Americans have everything so much better; they have NASA, they can put a man on the moon, [and] they have computers, but they will never catch up with us [in soccer],’” Fonseca said with laughter.

Although he had an early fondness for the US, medicine was not on his radar until the latter chapter of his formative years. Growing up with his 2 brothers and his sister, math was Fonseca’s first love. “I never thought I would end up doing medicine. Math is great, if you like it, because you can just solve a problem and then walk out of the exam before other people, and you don’t have to study a lot. I thought math would be [my] path to success,” he said.

During his childhood, he was an avid painter, spending time in front of the canvas at least once a week, and competitive swimming was his sport of choice growing up—although he has always maintained his lifelong love for soccer. When he was a teenager, Fonseca also enjoyed training hawks, teaching them to fetch things and fly back to him.

At age 17, a severe accident landed Fonseca in the hospital, which ended up changing his life and setting him on a course that would eventually make him one of the most impactful oncologists in the field of multiple myeloma. During his recovery, he felt a special connection with the clinical staff who were caring for him and guiding his treatment. He became enamored with the process of care and the empathy that the staff showed him and decided that medicine was what he wanted to pursue as a career.

Building the Tools to Facilitate Improved Care

After completing medical school at Universidad Anáhuac in Mexico City in 1991, Fonseca was weighing his options for his next steps when a conversation with friends ultimately convinced him to move to the US to complete his training.

“I ended up coming to do my training at the University of Miami, mostly because of peer pressure,” he said. “Some friends asked me, ‘Have you ever taken the exams to go to the US?’ I said, ‘No, but I’ll take them.’ So, I took the exams and landed a residency spot at the University of Miami in internal medicine. My plan was to do gastroenterology, [then] go back to Mexico and start a private practice. Then I started reading journals, and even the general medical journals had so much science [centered] in oncology and hematology. I loved my rotations because I was the primary doctor for the patient. I thought, ‘This brings the best of [both] worlds together.’ [It was then] that I decided to do hematology/ oncology and applied for my fellowship.”

After finishing his internal medicine residency in Miami, Fonseca began his career at Mayo Clinic—the only institution he has ever been a member of since— in 1998. He began as a hematology/oncology resident at the Mayo Clinic College of Medicine and Science in Rochester, Minnesota, and completed his fellowship in clinical hematology and medical oncology at the institution’s graduate school of medicine before relocating to its Arizona campus, where he still resides today.

During his time in Rochester, Fonseca credits several instructors with fostering his development, but Philip Robert Greipp, MD, who, among many other achievements, led the development of the International Staging System for multiple myeloma, was his most significant mentor. Fonseca notes that it was Greipp’s mentorship that steered him into the myeloma field, even though the prognosis for patients with the disease was poor at the time, with only 1 available agent.

Throughout his research career, one of Fonseca’s primary interests has been elucidating the genomic properties of multiple myeloma and other hematologic malignancies. Collaborating with Greipp, Fonseca was the lead author of a paper published in Blood in 2002, in which he and his coauthors used interphase fluorescent in situ hybridization to describe the clinical and biological significance of translocation t(11;14) (q13;q32) in multiple myeloma.

“[By] 2003, we [had] published a paper that brought together the presence of translocations, deletions, and other [factors] to define what we would call high-risk myeloma. In many ways, it’s a classification that has stood the test of time. It’s been augmented and refined but is a backbone of how we [classify] high-risk myeloma [to this day],” Fonseca said.

“In my first year of fellowship, I encountered a patient from Mexico, whose family I remain close with to this day, who presented in the clinic with an unknown diagnosis,” he said. “But shortly after his arrival, we figured out that the patient had...plasma cell leukemia. When we did the genetic analysis, he had t(11;14), like [what is seen] in mantle cell [lymphoma]. I connected with that patient and identified with a lot of the elements in his past. I felt awful because he was such a young individual. At the same time, I was exposed to the whole science behind this; this is what is driving his disease. That piqued my interest in the genetics of myeloma.”

Throughout the course of his career at Mayo Clinic, Fonseca has participated in several studies that have influenced the treatment landscape of hematologic malignancies. He has been a key figure in the ongoing development of venetoclax (Venclexta), specifically for patients with relapsed/refractory light chain amyloidosis. Building on his experience with t(11;14), he has coauthored multiple journal articles since 2020 outlining the potential role of venetoclax in these patients.^2,3

“When we published the [paper in Blood] in 2002, we noted that, one day, there would be [an agent] that targets this specific translocation. [Fast-forward] several years, and this molecule venetoclax was under development for [several] conditions, including chronic lymphocytic leukemia and myeloid leukemia. It was noted that it could be effective for a subset of patients with multiple myeloma, and it turned out to be patients with t(11;14). This line of work hasn’t been completed—we don’t have an approved drug—but it’s clear that targeting this [alteration] is one of the best ways to treat these patients,” Fonseca said.

Beyond his immense clinical impact, Fonseca has also contributed greatly to the study of the relationship of disease progression and patient quality of life (QOL) and has sought to bring visibility to the cost of care for patients with multiple myeloma. He coauthored a publication exploring the variation in health-related QOL by insurance coverage in multiple myeloma and was the lead author of a review that examined the effect of disease progression, line of therapy, and response on patient QOL. Fonseca has also written about the relationship between cancer drug pricing and innovation in the US, advocating for continued investment into novel therapies to ultimately improve care for patients.

A 1-Institution Wonder

Among his many career achievements, Fonseca is a clinical investigator of the Damon Runyon Cancer Research Foundation, having earned the Damon Runyon Clinical Investigator Award for his research on genomic instability in plasma cell dyscrasias in 2000. In 2010, he earned the International Waldenström’s Macroglobulinemia Foundation research grant for his study on IL-6 dysregulation in Waldenström macroglobulinemia, which showed that an increase in serum IL-6 levels could be associated with a significant increase in anemia in these patients.4 He is also a Mayo Clinic distinguished investigator, which is the highest academic distinction that the institution bestows upon investigators. However, he says the highest honor he can receive is receiving a phone call from a patient who specifically wants to see him.

“I’ve been a lifer at Mayo Clinic; they have a rotating system of leadership, and I’ve played various roles of leadership here,” he said. “Previously, I was the

interim director for the [Mayo Clinic Comprehensive Cancer Center] and the chair of the Department of Internal Medicine....[In my current role], I am in charge of fostering our relationship with Arizona State University, which is a wonderful university. That brings me a lot of joy to work with them. I am also currently a member of the board of governors and the board of trustees at Mayo Clinic.”

As he moves toward the latter phase of his career, Fonseca has great hope for the future of multiple myeloma treatment and anticipates that the dramatic gains made in the field will only continue to accelerate. He is particularly excited about the prospects of the continued development of immunotherapeutic agents, as well as the potential growth of genetic testing, minimal residual disease evaluation, and identification of biomarkers to better develop novel therapies and individualize treatment for patients.

“One of the things that happens with professional development—some would say with age—is that you can have a perspective of how to integrate information,” he said. “I feel privileged to have acquired that background of knowledge and to work with incredibly smart colleagues. I believe we’re on the cusp of being able to cure a significant fraction of patients with myeloma. For the rest of my career, I want to be a part of teams and publications in the era where we will be able to look back and say ‘that’s when we started curing a large fraction of patients.’”

Making the Most of Life in Arizona

Beyond his current appointments as the director of innovation and transformational relationships and the Getz Family Cancer Professor, Fonseca enjoys his personal life in Arizona by spending time with his family. He has 2 children, Bernardo and Matias, who are adults; Bernardo is an attorney who is planning to be married in 2025, and Matias is attending college in Arizona. Fonseca also has 2 younger children—Rafael and Lulu, ages 7 and 3, respectively—who he is raising with his wife, Brie.

Fonseca greatly enjoys living in Arizona, calling it “the best state in the nation,” and spends his free time there playing golf and grilling by the pool with his family. But after the COVID-19 pandemic subsided, Fonseca picked right back up where he left off and continued his life as an avid traveler.

He loves to see his colleagues at meetings and other professional activities, but he more so enjoys the freedom and exposure to different cultures world-wide. As a member of the exclusive group of fliers who hold an American Airlines Concierge Key—the unpublished top-tier status of the airline—Fonseca takes advantage of the perks to travel across the globe. He counts Spain, Portugal, and Japan as his favorite destinations of late.

Despite several more years before retirement, Fonseca looks back on the work he has done in the multiple myeloma space with great pride, never forgetting to enjoy the ride. “I have been in the front row of a revolution that has occurred for the treatment of [patients with] multiple myeloma. Over the past 20 years, we have seen a very large number of drugs approved. When I started, the median overall survival for patients was approximately 2 years; nowadays, it’s estimated that it can easily be up to 15 years. I firmly believe there [is] a subset of patients... being cured,” he said.

References

1. Fonseca R, Blood EA, Oken MM, et al. Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients. Blood. 2002;99(10):3735-3741. doi:10.1182/blood.v99.10.3735
2. Premkumar VJ, Lentzsch S, Pan S, et al. Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. Blood Cancer J. 2021;11(1):10. doi:10.1038/s41408-020-00397-w
3. Sidiqi MH, Al Saleh AS, Leung N, et al. Venetoclax for the treatment of translocation (11;14) AL amyloidosis. Blood Cancer J. 2020;10(5):55. doi:10.1038/s41408-020-0321-6
4. Kundranda MN, Henry TJ, Dispenzieri A, Gertz M, Ansell SM, Fonseca R. Role of hepcidin in anemia of Waldenström macroglobulinemia. Blood. 2010;21(19):4984. doi:10.1182/blood.V116.21.4984.4984