Summary
Single-agent lenalidomide can reduce the risk of smoldering myeloma progressing to overt multiple myeloma in high-risk patients. A phase II/III randomized clinical trial found that lenalidomide may also reduce the risk of smoldering myeloma from progressing to cancer in intermediate-risk patients.
To explore additional resources offered by Oncology Times and to subscribe, visit https://journals.lww.com/oncology-times/pages/default.aspx
Original Article
Lenalidomide Limits Progression of Smoldering Myeloma
Oncology Times
By Mark L. Fuerst
Single-agent lenalidomide can reduce the risk of smoldering myeloma progressing to overt multiple myeloma in high-risk patients. A phase II/III randomized clinical trial found that lenalidomide may also reduce the risk of smoldering myeloma from progressing to cancer in intermediate-risk patients.
“Smoldering myeloma is a heterogeneous group. Every risk group benefits from intervention. Early intervention with a prevention strategy can prevent conversion of smoldering myeloma to multiple myeloma,” said lead author Sagar Lonial, MD, Chief Medical Officer at Winship Cancer Institute of Emory University, at a press briefing before the ASCO Annual Meeting (Abstract 8001). “The idea is to identify the precursor condition and prevent the development of symptomatic cancer through early intervention.”
Smoldering myeloma is asymptomatic. Symptomatic multiple myeloma is characterized by evidence of organ damage, bone lesions or fractures, kidney issues, anemia, and high blood calcium levels from bone involvement.
“There is no question myeloma patients need immediate treatment. In many cases, we see irreversible morbidity with conversion to the symptomatic state. The challenge is to identify which myeloma patients are at highest risk,” Lonial noted.
A recent study looked at over 86,000 people with multiple myeloma and found that 13.7 percent were first diagnosed as having smoldering myeloma, with a median age of 67 years at diagnosis. When extrapolated to multiple myeloma diagnosis data for the entire U.S., this amounts to roughly 4,400 people in the U.S. being diagnosed with smoldering myeloma each year. In half of those diagnosed with smoldering myeloma, the condition progresses to multiple myeloma in the first 5 years.
About the Study
The E3A06 trial enrolled 226 patients with intermediate-risk or high-risk smoldering myeloma in two phases. In the phase II portion, 44 patients received lenalidomide to assess potential efficacy. In the phase III trial, researchers randomly assigned 182 patients to a 25 mg of lenalidomide orally daily for 21 of the first 28 days of a therapy cycle, or observation. The patients were stratified based on whether they were diagnosed with high-risk smoldering myeloma within that past year or more than a year after enrollment.
In both the phase II and phase III trials, lenalidomide led to improved outcomes for patients with moderate and high-risk smoldering myeloma. In the phase II trial, after 3 years, 87 percent of the patients were alive without progressing to multiple myeloma. In the phase III trial, after 1, 2 and 3 years on the trial, respective progression-free survival rates were 98 percent, 93 percent, and 91 percent for those who received lenalidomide and 89 percent, 76 percent, and 66 percent, respectively, for those who did not receive the treatment.
The researchers did see a benefit for intermediate-risk patients as well in terms of conversion to symptomatic myeloma and prevention of organ damage. Overall survival follow-up is still relatively short, noted Lonial, and therefore it is too early to state that intermediate-risk patients should be treated. At the moment, high-risk smoldering patients can be targeted to prevent development of symptomatic disease.
Toxicity issues were prevalent in the treatment group. Some 80 percent of patients in the phase II trial and 51 percent of those in phase III trial discontinued lenalidomide due to toxicity. The most common side effects, seen in slightly more than one-quarter of patients, included fatigue and non-blood or bone-related side effects. High-grade neutropenia was seen in about 5 percent of patients. There were no patient-reported differences in quality of life between the treatment and observation groups.
The researchers are currently performing an analysis of people who stopped taking lenalidomide due to toxicity to see if even limited doses of the medicine may have delayed progression to multiple myeloma.
A 2015 Spanish trial, named PETHEMA, demonstrated that the combination of lenalidomide and dexamethasone lengthened the time before people with smoldering myeloma developed multiple myeloma and extended survival. Lonial and colleagues used MRIs of the spine and pelvis to detect disease at enrollment, which is more sensitive than routine X-rays used by the Spanish researchers, which were used in previous studies exploring interventions for smoldering myeloma. The combined positive results of the new trial and the PETHEMA trial may support a change in clinical practice.
Lonial noted that a major hallmark of this trial is that it shows that early intervention can prevent patients from developing organ damage. “We typically see two types of patients—those who are anxious and want to do something to prevent cancer from developing, and those who are more cautious and are willing to watch and wait,” he explained. “It’s gratifying to know that, especially for the first group of patients, there may now be a viable treatment option.”
Future trials will look at a treatment strategy that combines lenalidomide, dexamethasone, and daratumumab “to explore more intensive regimens,” said Lonial. “Early treatment with low-intensity therapy may prevent clonal expansion, but control disease separate from major responses.”
ASCO President Monica M. Bertagnolli, MD, Professor of Surgery at Harvard Medical School, commented: “Living with the uncertainty of whether cancer will develop is very difficult, so it’s exciting to be able to tell patients at high risk of multiple myeloma that they can take a pill to prevent or delay cancer. This approach is not for everyone, however, because it comes with potentially heavy side effects and costs. Watching and waiting still has clear advantages that every patient should discuss with his or her doctor.”
Mark L. Fuerst is a contributing writer.