Translation Translation

works against multiple myeloma did not come to light until after the drug’s approval, says Boise, professor of hematology and medical oncology and Georgia Cancer Coalition Distinguished Scholar.

It turns out that multiple myeloma cells’ vulnerability to bortezomib may have a link to the healthy cells the cancerous cells arise from: plasma cells. Plasma cells are part of the immune system and live in the bone marrow. Their job is to produce antibodies, proteins that fight invaders like bacteria or viruses.

“If you look at both plasma cells and multiple myeloma cells, they are chock full of the machinery cells use to pump out proteins,” Boise says.

A drug with a second life

Lenalidomide is a chemical relative of thalidomide, which has its own peculiar history.

Itwas first marketed as a sedative in the 1950s, often to pregnant women with morning sickness. The revelation of thalidomide’s awful effects on limb development in unborn children eventually helped drive expansion of the regulatory powers of the FDA in the 1960s.

As a helpful drug, thalidomide was reborn a decade ago, when it was first tested on leprosy. How thalidomide works in the context of multiple myeloma is complex – it appears to both block blood vessel growth and encourage the immune system to fight the cancer. Lenalidomide was designed to soften the side effects, which can include neuropathy and blood clots.

Rudolph Byrd, diagnosed with multiple myeloma 11 years ago, embarked on his eighth clinical trial in the summer of 2011.

for example, had the potential to be qualitatively different than conventional treatments and was instrumental in the clinical trials leading to its approval.”

Byrd, a professor of African American studies and founding director of the James Weldon Johnson Institute at Emory, underwent what would be the first of three stem cell transplants the following spring. Under Lonial’s care, Byrd was one of the first people in Georgia with multiple myeloma to receive bortezomib (Velcade), then an experimental drug. In the summer of 2011, he was embarking on his eighth clinical trial.

Participating in clinical trials made sense to Byrd as a historian and researcher. His core beliefs instructed him: “If you can choose to be helpful to others, you make that choice.”

In turn, Lonial has helped him, he says. “Each time there is a relapse, it’s a new disease with its own personality: aggressive, intent on its own survival,” Byrd says. “All this means he [Lonial] has had to be extremely creative. I wouldn’t have survived all these years without his efforts.”

“Every successful drug in myeloma, he’s gotten them before they were approved,” Lonial says. “It also really shows the importance of clinical trials in providing a foundation for scientific advances.”

Although Byrd received bortezomib and lenalidomide as well as other drugs after his stem cell transplant, they are now standard as initial treatment for most patients.

This transformation of the field means that patients like Kate Groover, embarking on a course of treatment for multiple myeloma in the summer of 2011, will receive a panel of effective therapies without having a stem cell transplant scheduled, perhaps for years.

During the time Lonial was conducting clinical trials in Atlanta and studying the effects of bortezomib, another young researcher in Miami was investigating how cells make decisions to live and die in response to stress and had begun to focus on multiple myeloma.

Lawrence Boise, PhD, joined Winship in 2009 so he could work side by side with clinicians like Lonial to better understand multiple myeloma with the hope of developing more effective therapeutic strategies.

“Larry’s arrival has been a turbo boost for our program,” Lonial says. “He’s a phenomenal scientist who’s tuned in to the problems we face in multiple myeloma.”

Much of researchers’ understanding of how bortezomib

He and his co-workers have shown that multiple myeloma cells are more sensitive to drugs that perturb their ability to clean up the waste byproducts of all that protein production. This may explain the effectiveness of bortezomib, which inhibits proteasomes, cellular machines that act as garbage disposals.

Part of Boise’s lab’s research is oriented toward exploiting this vulnerability, by finding ways to heighten the stress on myeloma cells. If proteasomes, one way for cancer cells to clean up, are shut down, they might escape by directing waste down a second path. Drugs have been identified that could specifically interfere with this second path, called aggresomes.

Based on these insights, Lonial and another colleague, Jonathan Kaufman, MD, assistant professor of hematology and oncology, have designed a clinical study, in which an add-on drug to the standard regimen, vorinostat, might further interfere with cancer cells’ trash cleanup. Lonial and R. Donald Harvey, PharmD and director of Winship’s phase I clinical trials program, are testing a new drug against multiple myeloma, ACY-1215, with the same rationale.

“Our objective isn’t to improve response rates, because response rates to the standard treatment panel are already quite high,” Lonial says. Rather, his aim is to purge myeloma cells so effectively from the body that sensitive laboratory assays can’t detect them for months or years – what he gingerly calls “closer to a cure.”

Sagar Lonial is leading a nationwide clinical trial, coordinated by the Eastern Cooperative Oncology Group, on the use of lenalidomide with “smoldering” multiple myeloma. Multiple myeloma that is asymptomatic at diagnosis is called smoldering. For example, Rudolph Byrd’s cancer was initially discovered as a result of a blood test, and remained asymptomatic for some time.

The study compares treatment with lenalidomide versus a “watch and wait” approach. Lonial says the study is designed to address the questions: is giving patients lenalidomide early using up valuable ammunition; and can it prevent long-term damage and improve quality of life?