How Anderson Transformed Multiple Myeloma Care

Kenneth C. Anderson, MD

When Kenneth C. Anderson, MD, began his studies at Johns Hopkins Medical School, he fully intended to abandon the basic biological research he loved and focus instead on the sort of general clinical practice that would provide “real benefits to real people.”

Then he met Richard L. Humphrey, MD, a legendary pathology professor, who convinced him that research could provide even greater benefits to real people, if Anderson always followed two simple rules: make science count for patients, and treat patients like family.

Humphrey could not have imagined at the time how right he was. The discoveries that Anderson has made over the past 34 years at the Dana-Farber Cancer Institute have helped spur a revolution in the treatment of multiple myeloma— nine new treatments in less than 15 years.

When Anderson began that work, multiple myeloma was not only incurable, it was basically untreatable. Now, for many, it’s a chronic disease. “I’ve always enjoyed the intellectual challenge of discovering how the disease works and what can disrupt its workings,” said Anderson, who is now the director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber in Boston.

Setting Practical Goals

“But the real joy has come from watching patients live long enough to enjoy birthdays and graduations and other milestones they would have missed,” he said.When Anderson came to Hopkins, Humphrey was culturing multiple myeloma cells in test tubes and bombarding them with potential treatments. The effort did little to change myeloma care, but it did change Anderson’s life. That one experiment illustrated that very basic research could have very practical goals. It also convinced Anderson that myeloma research might prove particularly fruitful.

By that time, bone marrow aspirations made it easy to gather myeloma cells from patients, and even the simplest cultivation techniques kept those cells growing. Myeloma thus ranked among the easier cancers to study in the laboratory, but when Anderson turned his attention to the disease, virtually no one was doing so. After completing his internal medicine residency at Hopkins, Anderson began a medical oncology fellowship at Dana-Farber in 1980, pitching in with ongoing efforts there to develop and test treatment protocols for the first generation of monoclonal antibodies.

Anderson first used antibodies to deplete tumor cells from bone marrow taken from patients with multiple myeloma, which was then returned to them to restore blood and immune function after high-dose therapy.

Fewer cancer cells in the transplanted marrow led, in turn, to fewer relapses for transplant patients.

Turning to Thalidomide

Such work illustrated the breakthrough potential of treatments that prevented tumor cells from interacting normally with their microenvironments and inspired Anderson to embark upon a multidecade quest to understand and model the workings of multiple myeloma. For example, Anderson and his colleagues slowly discovered how multiple myeloma cells used cytokines to develop resistance to many treatments, and they speculated that a cytokine- inhibiting substance could retard the development of drug resistance.The problem was finding a drug that could interfere with cytokines. Anderson gathered as much information as he could about existing and experimental compounds. He tested possible candidates. Nothing offered much promise—until 1997, when Anderson heard that Bart Barlogie, MD, PhD, had undertaken a trial of thalidomide on 84 patients with previously treated multiple myeloma.

The idea for using thalidomide as a cancer treatment came from one of Anderson’s most eminent colleagues at Harvard, the pioneering angiogenesis researcher Judah Folkman, MD, a recipient of the Scientific Advances award of the 2013 Giants of Cancer Care.®

Folkman believed the drug would slow disease progression by depriving cancer of blood. The results, however, far exceeded anyone’s dreams, and Anderson soon suspected that thalidomide acted not only as an angiogenesis inhibitor but also as an immunomodulator, one that prevented the cell-signaling mechanisms that lead to drug resistance.

Research at Anderson’s laboratory confirmed that thalidomide does interfere with cytokines and does delay drug resistance. Better still, all that Anderson had learned about multiple myeloma’s biology over the years enabled him to create models of myeloma in its bone marrow microenvironment that helped predict how to administer the drug for maximum effect, first in animals and then in human patients.

Understanding the Biology

Those models also helped Anderson’s team to demonstrate preclinical antimyeloma activity of lenalidomide (Revlimid), a more potent thalidomide analog.Anderson and his team led both the preclinical and clinical trials that preceded FDA approval of lenalidomide in 2006. Then, using advances in both their own models and other research, they repeated the process 7 years later by leading the trials of pomalidomide (Pomalyst), which can be more effective and is well tolerated.

“When I started out in my career, very few teams did everything from basic research to late-stage trials, and I think my experience has demonstrated some real value in that. Understanding the biology improves your ability to predict what experimental compounds to test and how to optimize their usage. Performing drug trials on real patients gives you ideas about the underlying workings of the disease, which, in turn, gives you better ideas about fighting it. It’s a positive cycle,” Anderson said.

Roots of Inspiration

“The other thing my career demonstrates is the value of focusing on the same subject for long periods of time. You will run into brick walls, but if you keep old ideas on the back burner, you will be ready to capitalize when technology improves or new discoveries take place or you simply get an inspiration,” Anderson explained.Anderson grew up in Auburn, Massachusetts, a small town in the center of the state. He developed his interest in medicine by talking to his mother, who was a nurse, and the town doctor, who befriended Anderson during grade school and encouraged his aspirations.

Anderson studied biology at Boston University and, in 1973, became the first member of his family to earn a college degree. He then set off for Johns Hopkins, intent on becoming the sort of small-town doctor who might inspire other precocious kids.

While Anderson ended up as a world-famous researcher at Harvard, he has still proved an inspiration to precocious youth. A good percentage of all the world’s top myeloma researchers started their medical careers in Anderson’s laboratory, learning the keys to effective medical research: make science count for patients, and treat patients like family. Anderson, in turn, credits his gifted students and colleagues with much of “his” success. His colleagues disagree.

“He always gives credit to others and talks about ‘we’ rather than ‘I’ because he is a modest man and because he genuinely regards his team as a family that succeeds together,” said Nikhil C. Munshi, MD, director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center.

Targeting the Proteasome

“His generosity and obvious sincerity inspire people to give their all and to work together for the common good, and that produces results,” Munshi stated.Still, like all great researchers, Anderson has benefited from serendipity. In the mid-1990s, for example, Anderson discovered that the protein complex nuclear factor κB (NF-κB) performed several vital functions that enabled myeloma cells to survive and grow. That discovery might have had little practical impact, but for the fact that another team at Harvard happened to develop the first chemical that inhibits NF-κB at almost the same time.

Anderson quickly tested the compound against myeloma and saw dramatic results. Human trials proved equally encouraging, and the FDA approved the proteasome inhibitor bortezomib (Velcade) just three years after it was first tested in humans.

The speed of bortezomib’s approval and the powerful effects it had on patient outcomes dramatically illustrated the power of Anderson’s seminal idea: basic biological research can reveal the weaknesses in even the most powerful of diseases.

No other approach had yielded a single truly novel myeloma treatment in decades. Anderson had not only found a novel treatment but also gotten it through trials in record time because he understood its mechanisms well enough to use it properly from the start.

Managing Relationships

It was, to be sure, a triumph that had taken many years of work to attain, but that work provided the basis for a series of breakthroughs that followed soon after. It uncovered the mechanisms whereby novel agents work and thus informed their optimal use both alone and in combination. That, in turn, helped bring about FDA approval for the second-generation proteasome inhibitor, carfilzomib (Kyprolis), and the immunomodulatory drug pomalidomide.The sheer speed of change says much about Anderson’s scientific skills, but it may say even more about his ability to manage relationships. “Bringing a compound from the lab to the clinic requires cooperation among a lot of organizations: the National Cancer Institute (NCI), the FDA, pharmaceutical companies, biotech companies, academia, and, most importantly, patients,” Anderson said. “Patients are the inspiration for all that we do.”

“We’ve had success at moving things quickly because we’ve reached out to all the team members over the years and figured out how to best work together. For example, we’ve spent years talking to folks at the FDA about myeloma and what are the correct trials to evaluate novel agents to rapidly provide the data needed for their approval. They have been wonderful and worked tirelessly to help patients get access to novel life-prolonging treatments,” Anderson explained.

Anderson has already been given a number of lifetime achievement awards, but he thinks that his most valuable work may still lie ahead of him. New discoveries in genomics and other areas have combined with improving technology to allow for in-depth understanding of myeloma biology, which in turn identifies new targets for next-generation treatments.

Multidrug Combinations

Dozens of new compounds are under development for the treatment of multiple myeloma, and Anderson hopes to shepherd the best ones to the clinic and, more importantly, to discover how they should be used in combination with other treatments. Recent studies in his group have shown that myeloma is very heterogeneous at diagnosis and that genetic mutations and evolution are associated with disease progression. These findings suggest that, as with infectious diseases such as tuberculosis or HIV, combination therapies will be needed early to make the most impact.Anderson currently recommends a three-drug combination—bortezomib, lenalidomide, and dexamethasone—along with stem cell transplantation and lenalidomide maintenance therapy for all eligible patients. Looking further ahead, however, Anderson believes that four-drug or five-drug combinations will become the new standards of care, standards with curative potential.

The challenge, of course, will lie in determining which four or five drugs should be given, at what dosages, on what schedule, and to which patients. The sheer number of possible combinations will prohibit researchers from simply trying every combination, so the work of deciding which combinations to test will most likely rely on those laboratory models that Anderson has spent the last three decades building.

Anderson hopes those models will soon be able to move beyond predicting which combinations will be best overall and begin to use information about patient and tumor DNA to predict which will be best for individual patients. Targeted therapy has obviously proved very successful against other tumor types, and Anderson believes it will prove equally valuable in fighting multiple myeloma.

“Combinations of targeted therapies against those abnormalities present in a given patient are the greatest hope for the future,” he said.

Medical profiles necessarily focus more on breakthrough discoveries than on clinical practice, but it is clinical work that motivates Anderson to do all the rest.

He spends as much time asking patients about their work, hobbies, and family life as he spends discussing symptoms and treatments. He celebrates their victories. He sympathizes with their troubles. He works for them.

“My patients have placed their lives in my hands, and that is a sacred trust. I do everything I can to give every single patient every possible day,” he said.

“I still mourn every patient I lose, but I feel incredible joy whenever I consider how much things have improved. I used to know patients for months. Now I know most of them for many years, and I celebrate milestone after milestone with them. “They are my heroes and inspiration. It has been a privilege and a blessing for me to help change the natural history and treatment paradigm of myeloma.

“Providing the gift of life and hope to our patients, working with teams of selfless researchers, watching them become world leaders in myeloma, keeping them as lifelong collaborators and friends—it doesn’t get any better than this,” Anderson said.

“He’s Certainly One of a Kind”

Constantine S. Mitsiades, MD, PhDAssistant Professor, MedicineHarvard Medical SchoolDana-Farber Cancer InstituteBoston, MA

“Most of the major progress that has happened in the myeloma field over the last 10 to 15 years has been directly or indirectly associated with Ken Anderson. There are very few people who are at such a high level in their expertise, especially when discussing a particular disease and research. For many years now, when the term ‘myeloid research’ is used, the first name that comes to mind is Ken Anderson’s. I think he’s certainly one of a kind.”

A Research Sampler

• Mateos MV, Richardson PG, Dimopoulos MA, et al. Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib-melphalan-prednisone in the phase III VISTA study. Am J Hematol. 2015;90(4):314-319.
• Bianchi G, Richardson PG, Anderson, KC. Promising therapeutics in multiple myeloma [published online June 1, 2015]. Blood. 2015;126(3):300-310.
• Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621-631.
• Cottini F, Hideshima T, Suzuki R, et al. Synthetic lethal approaches exploiting DNA damage in aggressive myeloma. Cancer Discov. 2015;5(9):972-987.
• Mimura N, Hideshima T, Anderson KC. Novel therapeutic strategies for multiple myeloma. Exp Hematol. 2015;43(8):732-741.
• Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-2869.
• Richardson PG, Laubach JP, Munschi NC, Anderson KC. Early or delayed transplantation for multiple myeloma in the era of novel therapy: does one size fit all? Hematology Am Soc Hematol Educ Program [published online November 8, 2014]. 2014;(1):255-262.
• Bianchi G, Richardson PG, Anderson KC. Best treatment strategies in high-risk multiple myeloma: navigating a gray area. J Clin Oncol. 2014;32(20):2125-2132.
• Bae J, Munshi NC, Anderson KC. Immunotherapy strategies in multiple myeloma. Hematol Oncol Clin North Am. 2014;28(5):927-943.
• Görgün G, Calabrese E, Soydan E, et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood. 2010;116(17):3227-3237.
• Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10(11):2034-2042.
• Anderson KC. Oncogenomics to target myeloma in the bone marrow microenvironment. Clin Cancer Res. 2011;17(6):1225-1233.