BETHESDA, MD—A cancer of the white blood cells, multiple myeloma (MM) is the second most common hematologic malignancy in the US, with about 20,000 Americans affected by the disease each year. It is characterized by the level of monoclonal protein in the blood, the level of monoclonal plasma cells in bone marrow, and the presence or absence of organ damage.

However, MM is a clinical syndrome, and little is known about the pathophysiology of the illness. Researchers at NIH hope to change that, and believe that this year will see great progress in the field. Speaking on the topic at NIH, Ola Landgren, MD, PhD, an investigator at the Center for Cancer Research, declared, “I think 2010 is going to be the year that a lot of things are going to fall out clinically so we can open our studies.”

Currently, Landgren and his colleagues at NIH have three areas of focus. The first is to focus on the precursor diseases for MM; the second is to look specifically at the highest risk precursors; and the third is to focus on therapies for people who have already developed MM.

Going After the Precursors

Landgren hopes that, by studying the precursors for MM, researchers can better diagnose and prevent the full-blown version of the disease. Multiple myeloma has two precursor conditions—smoldering myeloma and monoclonal gammopathy of undetermined significance (MGUS). MGUS resembles multiple myeloma, but the level of antibodies in the blood are lower, as is the level of
protein. With smoldering myeloma, the protein builds up slowly over time. The risk of MGUS patients developing the full-blown disease increase by about 1% every year. The risk of smoldering myeloma transforming into multiple myeloma is much higher.

Researchers followed 77,000 healthy men and women for several years. Of those, 71 went on to develop multiple myeloma. Of those, all had MGUS before the full-blown disease. “This is an important finding,” Landgren said. “Now we can spend more time thinking about mechanisms of transformation and come up with strategies so we can target patients with higher risk.”

He is about to begin a study looking at tumor cells and bone marrow microenvironmental cells using immunohistochemistry. “We are planning to use more molecularly-focused technologies,” Landgren said.

Using samples taken from biobanks, Landgren will be looking for a variety of biomarkers, including microRNA. “There’s some evidence in the literature that microRNA plays a role in the pathogenesis of MM,” Landgren explained. “Hopefully, we will identify candidate markers that we will plug into our prospective NCI natural history study—the first natural history study of multiple myeloma in the country.”

Researchers will also enroll 100 smoldering patients in the same fashion. And they will be seen more often. Once the arm of the study using immunohistochemistry is complete, researchers will do full gene expression profiling. “I think this is going to be a very useful study to have a better understanding of those patients that progress from MGUS to MM versus those that do not.”

Better Imaging

Currently, the standard for detecting myeloma is a skeletal survey. But skeletal surveys remain an insensitive technology, Landgren noted. To catch the disease quicker and more accurately, physicians need a new method of detection.

Recently one patient with smoldering myeloma had lesions show up in a PET/CT scan. “We believe if we did PET or MRI on smoldering patients, it would maybe show a quarter of detectable lesions,” Landgren explained. “What we’re doing now is trying to develop new tracers.”

Currently, Landgren and his colleagues are working on a protocol using fluoride on PET/CT scans. “In the literature, there are small studies indicating this could be a very promising marker for early lesions,” Landgren said. “Also there is data that dynamic contact MRI could be used to visualize the androgenic effects in the bone marrow indicating differences between MGUS, smoldering myeloma, and multiple myeloma.”

Targeted Therapy

While researchers continue their work into the pathology of MM, a big question remains unanswered: Is there something medical science can do for myeloma and smoldering myeloma patients that does not include traditional myeloma therapy? “If we don’t do anything, we know what’s going to happen. They’re going to progress and they’re going to proliferate,” Landgren said of smoldering myeloma patients. “The first scenario is the dream scenario, and I don’t think we’re there yet. The dream scenario is if you have this wonderful drug, you treat the patient very early, the patient is now cured. The other scenario is when you treat and you get rid of a lot of disease, but not all and you have to repeat it. And so you convert myeloma into a chronic disease. Now myeloma is like hypertension.”

Currently researchers are looking at using natural killer (NK) cells—part of the innate immune system of the patient. “They go after cells that are infected by infections and tumor cells,” Landgren explained. “And in myeloma the tumor cells are being recognized, but then they inactivate the NK cells.”

However, using data taken from transplant recipients, researchers know that when there is a mismatch between donor and patient, this inactivation does not happen. “We are right now looking into opportunities to use a monoclonal antibody that mimics the mismatch situation [and] designing a trial for smoldering patients.”

As for multiple myeloma patients, Landgren explained that he and his fellows made a strategic decision to attack myeloma on the flanks. “We go early on. We go for precursor disease. We try to develop strategies for early treatment,” Landgren explained.

None of the novel drugs for MM have been designed to target particular pathways, he explained. Currently he and other researchers are looking for opportunities, particularly in the MEK/ERK pathway—a transduction pathway that promotes cell growth. “About 50% of myeloma patients should be susceptible to MEK inhibition,” Landgren surmised.

The Cancer Center is also working with the National Institute of Dental and Craniofacial Research to develop a myeloma mouse model with subcutaneous human bone to better track the progression of MM in animal models.

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