Treating Patients with High-Risk Smoldering Myeloma

Name of the Trial

Phase III Randomized Study of Lenalidomide Versus Observation Alone in Patients with Asymptomatic High-Risk Smoldering Multiple Myeloma (ECOG-E3A06). See the protocol summary.

Principal Investigator

Dr. Sagar Lonial, Eastern Cooperative Oncology Group

Dr. Sagar Lonial

Dr. Sagar Lonial

Why This Trial Is Important

Multiple myeloma is a blood cancer characterized by the accumulation of plasma cells in the bone marrow (bone marrow plasmacytosis), monoclonal protein (M protein) in the blood and/or urine, and symptoms such as anemia, kidney damage, elevated calcium levels in the blood (hypercalcemia), and bone lesions. Although multiple myeloma can be treated, it cannot be cured with current therapies.

Occasionally people are found to have some level of bone marrow plasmacytosis and/or M protein, but they do not have the symptoms characteristic of multiple myeloma. Depending on the amount of M protein in the blood or the number of plasma cells in the bone marrow, these people are said to have either a benign condition known as MGUS or smoldering multiple myeloma. People with smoldering myeloma face a greater likelihood of progression to symptomatic myeloma.

Historically, multiple myeloma has been treated with very intense therapies, such as cytotoxic chemotherapy and stem cell transplantation, which carry a high risk of adverse side effects. Therefore, people with smoldering myeloma, many of whom may not need therapy for many years (if at all), are not treated until symptoms warrant it. Instead, they are managed with careful observation.

"Any time you have a patient who has no symptoms and give them a treatment, you run the risk of exposing them to side effects," Dr. Lonial explained. "It's hard to take a patient who feels well and make them better."

The development of newer, less toxic targeted therapy drugs for multiple myeloma, however, has generated considerable interest among doctors and patients, raising hopes that treating smoldering myeloma could delay, or even prevent, progression to symptomatic disease.

"Organ damage has historically been the benchmark that we look for before we initiate treatment for myeloma," Dr. Lonial said. But by the time organ damage occurs, he continued, the disease is already causing problems, and symptoms, particularly bone lesions, can be painful and debilitating. "What we want to do is take those patients with a very high risk of progressing in a short time and see if we can prevent the kind of bad events—such as bone fractures, kidney failure, serious infections—associated with the conversion from smoldering to symptomatic myeloma.

"The availability of newer agents that are not only more active than chemotherapy but that also produce fewer side effects has encouraged us to revisit this concept of intervening earlier in a cohort of smoldering myeloma patients," said Dr. Lonial. "Furthermore, we are better at identifying those patients most likely to transform in a short period of time, and thus can focus more on the most 'at risk' population. These two developments, better treatment and improved identification of those who may gain the most from early intervention, have provided the impetus for investigators to try again to treat smoldering myeloma patients in the context of a clinical trial."

In this phase III clinical trial, patients with smoldering myeloma classified as high risk for progression will be randomly assigned to undergo standard observation or six 4-week courses of treatment with the drug lenalidomide, which will be taken daily for the first 3 weeks of each course. Lenalidomide is a targeted drug that disrupts the formation of new blood vessels (angiogenesis) and modulates the immune response to cancer cells. It was approved in 2006 to treat multiple myeloma based on studies that showed it delayed disease progression in patients who had progressed on or not responded to previous treatment.

"Our primary endpoint in this study is progression-free survival, or the difference in the time it takes to convert to symptomatic myeloma; however, an important secondary endpoint is quality of life," Dr. Lonial said. "We need to find out if there are side effects that make treatment unrealistic. If patients go longer before converting to symptomatic multiple myeloma but they end up having a poor quality of life, is that a worthwhile balance?"

For More Information

See the lists of eligibility criteria and trial contact information or call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.