Multiple Myeloma Treatments Are Moving Rapidly from Bench to Bedside

TON - October 2011 Vol 4 No 7 — October 19, 2011

CHICAGO—Treatments for multiple myeloma have advanced rapidly over the past 15 years as research has fostered an improved understanding of the mechanisms of the disease. These discoveries have been translated into effective drugs, most notably bortezomib, thalidomide, and lenalidomide.

“Bench-to-Bedside Translation of Targeted Therapies in Multiple My eloma,” was the title of the Karnofsky Lecture delivered by Kenneth C. Anderson, MD, Kraft Family Pro fessor of Medicine, Harvard Medical School, and Director, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma, Dana-Farber Cancer In stitute, Boston. Anderson was awarded the David A. Karnofsky Memorial Award to recognize his outstanding achievements over 3 decades in multiple myeloma research at the annual meeting of the American Society of Clinical Oncology.

Kenneth C. Anderson, MDCombination therapy with melphalan and prednisone was long the standard of care for the treatment of multiple myeloma, with stem-cell transplant reserved for select patients.

Advances beyond these therapies have emerged rapidly as the research by Anderson broadened be yond the myeloma cell surface to the bone marrow microenvironment as a driver of disease pathogenesis.

“Multiple myeloma represents a new paradigm in drug development, due to the remarkable therapeutic efficacy of targeting tumor cells in their microenvironment,” he said. Newly discovered agents interfere with the mechanisms by which myeloma cells grow, survive, develop resistance, and migrate within the bone marrow.

Rapid Drug Development and Approval for Myeloma

The proteasome inhibitor bortez omib is an example of a new therapy for multiple myeloma that progressed from bench to bedside rapidly (<3 years). The drug, which has an action that targets multiple myeloma cells in the bone marrow macroenvironment, was approved as initial therapy for multiple myeloma after demonstrating an improvement in median survival from 3 to 7 years.

The immunomodulatory drug len alidomide, which directly induces apoptosis but also targets cells in the tumor micro en vironment, was another result of Anderson’s work.

Lenalidomide also progressed rapidly from bench to bedside and was approved in 2006 for use with dexa methasone for the treatment of relapsed multiple myeloma.

Along with thalidomide and bort ez omib, lenalidomide is used routinely in conventional cytotoxic and transplant regimens for multiple myeloma.

Novel Classes in the Pipeline

Nevertheless, the need for more effective and tolerable drugs remains, said Anderson. Second-generation proteasome inhibitors include carfilzomib, which is associated with less neuropathy than bortezomib, and oral chymotryptic inhibitors, which appear more potent at inhibiting myeloma cell growth.

Pomalidomide, another immuno modulatory agent currently under development, has shown good activity in patients resistant to lenalidomide and bortezomib.

Other novel classes of drugs are histone deacetylase inhibitors (eg, panobinostat), heat shock protein 90 inhibitors, and the alkylphospholipid AKT inhibitor perifosine. Some of these are being explored as a part of rational combinations of therapies.

For example, the combination of bortezomib and panobinostat is synergistic, as panobinostat blocks ubiquitinated protein via the aggresomal pathway and bor tezomib blocks these same proteins via the proteasomal pathway.

The use of genomics to personalize approaches to the treatment of multiple myeloma is another research interest of Anderson’s. Genetic profiling is identifying genes that are upregulated or downregulated in the progression to multiple myeloma.

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