5 Questions... with Rafael Fonseca, MD

Rafael Fonseca, MD, is a professor of medicine at Mayo Clinic and a consultant in the Division of Hematology/Oncology. He also serves as deputy director for the Mayo Clinic Cancer Center. In addition, Dr. Fonseca has an adjunct appointment at the Translational Genomics Research Institute, where he works in collaboration with Drs. John Carpten and Jeffrey Trent. Dr. Fonseca concentrates on the genomic nature of late B-cell neoplasms, particularly focused on multiple myeloma. He is interested in the clinical implications for prognosis and treatment selection of specifi c molecular markers in the myeloma cells. Dr. Fonseca worked for 10 years at the Mayo Clinic in Rochester and transferred his research program to the Mayo Clinic in Scottsdale in January 2004.

1 What is your primary focus at the Translational Genomics Research Institute?

I have a joint appointment at TGen with a goal of participating in joint projects relating to the genetics and genomics of multiple myeloma. In partnership with Dr. John Carpten, we have been successful in establishing a large number of genomic studies that have already resulted in joint grant applications as well as high-profile publications. Mayo brings research expertise at the laboratory level, as well as the clinical expertise for understanding the implications of new findings. Working with scientists such as Dr. Carpten, we were able to leverage some of the great power of TGen genomic tools, such as the array-based comparative genomic hybridization (aCGH). Together, we have tried to tackle one of the challenges in genomics research—how to integrate all of the information related to the sample quality, clinical features associated with the samples, data associated from the DNA copy number, gene expression profiling, etc. In one example, our team found that NF-kappa B was constitutively activated in up to 50% of myeloma patients.

2 What have been some of your successes over the last four years since joining the team?

Since I came to Mayo in 2004, I was fortunate to have worked with two great friends and colleagues, Drs. Leif Bergsagel and Keith Stewart. We had long talked about the possibility of joining forces and working together toward applying genetics and early drug development for the treatment of myeloma. We were successful in recruiting Dr. Bergsagel nine months after my arrival in Arizona and Dr. Stewart the year following that. I consider the formation of this team one of my biggest successes. We now have a laboratory meeting that encompasses up to 20 individuals, including postdoctoral fellows, research technologists, and principal investigators. These individuals come from all over the world, including Singapore, New Zealand, Argentina, Brazil, Canada, and Mexico. This is a highly collegial team, but nevertheless competitive, and in a short period, we have been able to produce a large stream of publications. However, our greatest success is our ability to translate some of these findings and research to the clinic. Since coming to Arizona, we have had a very significant growth in the number of myeloma patients that we can care for in the clinic and with whom we can work in clinical trials and on basic research projects. We are clearly honored to have this partnership with those individuals who entrust us with their healthcare.

3 What clinical trials are you and your colleagues currently involved with?

We have an ample portfolio of phase I and phase II clinical trials. We have been involved in the development of a third generation of immunomodulatory drug, related to thalidomide and lenalidomide, CC 4047. Currently at Mayo, we are running a clinical trial with CC 4047, which we are hoping to ultimately bring to the clinic. We have also been engaged, primarily through the leadership of Dr. Stewart, in the development of novel proteasome inhibitors, such as carfilzomib. We have participated in the early development of this drug and are currently involved in phase II and phase III clinical trial design. Our team, in conjunction with the Multiple Myeloma Research Consortium, was also the first to lead a clinical trial targeting a specific genetic marker in myeloma. We had a small molecule inhibitor of the oncogene FGFR3 in myeloma patients.

This clinical trial was the first ever attempt to target such genetic lesions in multiple myeloma. Our hearts were really close to the development of that trial because of our close participation in the concept development. Dr. Bergsagel, and his wife Dr. Marta

Chesi, discovered the translocation almost 10 years ago. My laboratory uncovered the clinical implications for this genetic abnormality, and ultimately, the preclinical development of the compound was lead by Dr. Stewart.

4 How has patients’ expanded access to medical information affected clinical care and research?

We clearly live in the age of information. In an era with patients who are much better informed than in the past, access to healthcare information becomes of paramount importance to the treating physician. It is a huge challenge to practice general oncology today (because of the amount of information generated daily), and I can see a future in which there will be multiple subspecialties within oncology. We use electronic tools for accessing the latest research and most up-to-date publications about the multiple clinical trials for myeloma. Our patients likewise present to our clinical offices with copies of the most recent papers, wanting to understand the relevance to their particular situation and whether treatments proposed there are appropriate. Patients often come with some basic or translational research papers, and they question us about the implications of several genetic markers or other findings in the analysis of the bone marrow! Oncologists can no longer provide superficial answers to very complex questions, and patients can quickly discern who is not up-to-date on the latest information.

Patients also find information regarding ongoing clinical trials on the Internet. We value participation in clinical research as one of the basic tenants of our clinical practice. It is often through these clinical trials that we can provide patients access to cutting-edge drugs, or those that are not available otherwise but have already shown activity against disease. There needs to

be a seamless integration between our clinical research activities and our clinical practice. Needless to say, participation in clinical trials is always voluntary, but we value such opportunities as ways that can improve our patients’ well-being.

5 What are your thoughts on patients who use the Internet to find information and connect with support groups andorganizations?

I frequently hear about people who complain about patients accessing the Internet and how it may create confusion at the time of the appointment. I could not be in greater disagreement. I think my patients are much better informed now as a consequence of the information available on the Internet. People in general have become more savvy consumers, capable of discerning the

more important fi ndings from the “fluff .” I think the well-educated patient and caregiver provide a much better context for the overall care and management of a patient with multiple myeloma. Not only that, but patients and families with this information frequently ask additional questions that undoubtedly help improve the quality of the care provided.

I am a great advocate for patients working with grass roots organizations and other Internet-based information sources. Many of our patients work with the Multiple Myeloma Research Foundation, the International Myeloma Foundation, and the Leukemia and Lymphoma Society to find information about the diagnostic implications for their condition, as well as the many treatment options and available clinical trials. It would be nearly impossible for a physician’s office or practice to try to provide all of this information that is available to patients. It is true that this amount of information poses an extra burden to patients, and that sometimes it can be confusing as they try to make decisions, but in the end, their decisions are more informed, and patients and their families are empowered by working jointly with their healthcare providers.