ASCO 2011—At the opening session of ASCO 2011, Dr. Kenneth C. Anderson, the Kraft Family Professor of Medicine at Harvard Medical School and director of the LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute, was awarded ASCO’s highest award—the David A. Karnofsky Memorial Award, which recognizes outstanding achievement in cancer research. Dr. Anderson was honored for his accomplishments in three decades of research in the field of multiple myeloma.
The title of the Karnofsky Lecture, which Dr. Anderson delivered following his award, was “Bench-to-Bedside Translation of Targeted Therapies in Multiple Myeloma.” In it, he reviewed the impressive list of achievements in the area of multiple myeloma therapeutics that he has been intimately involved in. In particular, he stressed the rapidity with which he and his colleagues have been able to translate their laboratory discoveries into approved drugs that can directly benefit patients, and the collaboration—between industry, academia, regulatory agencies, and patient advocates—that has been largely responsible for this speedy progression.
He is especially proud of what his work—and the speed with which he has brought new treatments to approval—has meant to patients. He noted that the first patient with multiple myeloma whom he was able to cure decades ago—a fellow physician named Francesca Thompson—had a memorable response when someone asked her how a patient would know when he or she was cured: “’Cure means growing old and dying from something else,” he quoted Dr. Thompson as having said. He went on to add that “multiple myeloma patients today are doing that.”
One of the chief thrusts of Dr. Anderson’s research has been to widen his focus to include not just the myeloma cell surface but also the bone marrow microenvironment. In doing so, he has been able to move beyond the identification of cell surface diagnostic and therapeutic targets—to the discovery of a number of novel molecules directed at targets within the cell and within the microenvironment. These agents interfere with the mechanisms by which myeloma cells grow, survive, resist drugs, and migrate within the bone marrow milieu.
One of the most important of these agents whose action encompasses the tumor cell microenvironment has been the proteasome inhibitor bortezomib(Drug information on bortezomib), which extended the median survival of patients with multiple myeloma from 3 to 7 years. Dr. Anderson pointed out that bortezomib, which was approved by the FDA as initial therapy in 2008, progressed from bench to bedside in less than 3 years. Currently, Dr. Anderson’s lab is working on next-generation proteasome inhibitors, including carfilzomib, which produces markedly less neuropathy than bortexomib, the oral chymotryptic inhibitor ONX0912, and the oral chymotryptic inhibitor MLN2238/9708, which is proving more effective than bortezomib at inhibiting myeloma cell growth.
Another of Dr. Anderson’s most notable achievements in multiple myeloma therapeutics has been the development of the immunomodulatory agent lenalidomide. Lenalidomide directly induces apoptosis – but it also has action in the tumor microenvironment. And like bortezomib, it went rapidly from bench to beside, achieving FDA approval for use with dexamethasone(Drug information on dexamethasone) for the treatment of relapsed multiple myeloma in 2006. At present, Dr. Anderson is working with a new agent in the same class—pomalidomide—whose demonstrated action in patients resistant to lenalidomide and bortezomib is meeting a heretofore unmet medical need.
In addition to his work on agents that target the tumor microenvironment and the interaction between tumor cell and microenvironment, another important thrust of Dr. Anderson’s research has been the development of rationally based combination therapies. One of the most exciting of these combination regimens is that of bortezomib and panobinostat. When the histone deacetylase (HDAC) 6 inhibitor panobinostat is used to block ubiquitinated protein via the aggresomal pathway—and given together with bortezomib, which blocks these proteins via the proteasomal pathway—the effect is “incredibly synergistic,” Dr. Anderson said. Currently, the panobinostat/bortezomib combination is in phase 1 and 2 trials in relapsed and refractory multiple myeloma – and is resulting in response rates of 60% to 70%.
Finallly, Dr. Anderson is working on utilizing genomics to personalize therapy for multiple myeloma patients. He noted that genetic profiling is helping delineate the pathogenesis of the disease by providing a close look at genes that up- and down-regulate during the progression from normal to MGUS (monoclonal gammopathy of undetermined significance) to frank multiple myeloma; in the process, it is helping identify new gene targets.