Research Advances Hold Promise for Multiple Myeloma Treatment

Multiple myeloma is one of the most compelling examples of a cancer in which research has markedly improved the length and quality of patients’ lives in the last decade. A malignancy of certain white blood cells in the bone marrow known as plasma cells, myeloma is still considered incurable, but treatment advances have significantly improved survival. Not long ago, patients with myeloma lived a median time of two to three years after diagnosis. Today, median survival is seven to 10 years, although this can be unpredictable, with some patients living longer and others surviving for significantly shorter time periods.

(From L-R) Ken Anderson, MD, Paul Richardson, MD, and Nikhil Munshi, MD

(From L-R) Ken Anderson, MD, Paul Richardson, MD, and Nikhil Munshi, MD, of Dana-Farber’s Multiple Myeloma Program

Scientists have gained a better understanding of the basic biology of the disease, particularly of the way myeloma cells interact with their “microenvironment,” the web of cells and tissues that surround them. This has enabled investigators to devise new ways of interfering with the cancer process – of cutting off myeloma cells’ access to nutrients and of jamming the chemical signals that spur the cells’ growth.

Here are some recent advances:

Researchers are testing drugs that block various growth factors produced by bone marrow support cells that stimulate the growth of myeloma cells, as well as blocking the pathways that trigger these interactions, which include both novel agents (so-called small molecules) and monoclonal antibodies.

One very important recent advance is the development of a new drug — currently awaiting regulatory approval — known as panobinostat, which inhibits several enzymes that myeloma cells need to survive. It has shown very promising results when used in combination with the drugs bortezomib and dexamethasone, which are mainstays of current myeloma therapy. Panobinostat is given orally and appears to be very active in high risk and resistant myeloma. Side effects can be challenging, however, and Dana-Farber scientists and others are working to develop more potent and better tolerated agents..

The pipeline of new agents is very promising. Laboratory researchers at the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics recently found that even though myeloma cells often have extensive DNA damage – which would normally trigger their death – low levels of a protein called YAP1 can prevent them from dying. They also found that production of YAP1 is controlled by an enzyme known as STK4. This suggests that drugs targeting STK4 offer a new strategy for treating patients with myeloma and other hematologic cancers whose tumor cells have DNA damage and low levels of YAP1.

Similarly, scientists at Dana-Farber and Brigham and Women’s Hospital have developed a drug-delivery system that uses tiny nanoparticles to precisely attack cancer cells in the bone. In a recent study, mice were pre-treated with nanoparticles loaded with the cancer drug bortezomib, then injected with myeloma cells. The treatment resulted in slower myeloma growth and prolonged survival. The pre-treatment technique also enhanced bone strength and volume.

Researchers have used a technique called gene expression profiling to determine which genes are overactive in patients’ myeloma cells, which may indicate which patients are likely to benefit most from drugs that specifically target those genes.

Studies by Dana-Farber scientists over the last decade have shown that bortezomib, as well as the immune system-modulating drug lenalidomide, when combined with dexamethasone, target myeloma cells in the bone marrow, helping overcome resistance to other agents and dramatically improving depth and duration of response in relapsed myeloma patients. Remarkably, this in turn has led to a paradigm shift in therapy across the whole field. Dana-Farber investigators are now leading large national and international clinical trials of this combination treatment for patients newly diagnosed with advanced myeloma.

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