The phase II/III E3A06 randomized clinical trial found that lenalidomide (Revlimid) significantly reduces the risk of smoldering multiple myeloma (SMM) — a precancerous condition — from progressing to cancer in patients at moderate or high-risk. Organ damage is typically seen in myeloma, which is a way to differentiate it from SMM.

At three years, in 87% (phase II) and 91% (phase III) of people with SMM receiving lenalidomide, the condition did not progress to multiple myeloma compared with 66% of people who did not receive the therapy and were just observed for potential progression (phase III). Observation is the current standard of care. The study will be presented this week at 2019 ASCO Annual Meeting in Chicago according to the press release shared by ASCO.

“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,” said lead study author Sagar Lonial, MD, Chief Medical Officer at Winship Cancer Institute of Emory University, Atlanta, GA. “It’s gratifying to know that especially for the first group of patients there may now be a viable treatment option.”

Lenalidomide is an analog of thalidomide, a therapy developed decades ago as a sedative. Lenalidomide prevents the formation of blood vessels that can feed tumors, such as those found in multiple myeloma, and it also carries the risk of serious side effects.

A recent study looking at over 86,000 people with myeloma found that 13.7% were first diagnosed as having SMM, with a median age of 67 at diagnosis. When extrapolated to myeloma diagnosis data for the entire United States, this amounts to roughly 4,400 people in the United States being diagnosed with SMM each year. In only half of people diagnosed with SMM, however, the condition progresses to multiple myeloma in the first five years. Once diagnosed with multiple myeloma, the 5-year survival rate is over 50%. Survival rates have steadily increased over the last decade thanks to the availability of several new therapies.

Earlier this year, ASCO included “Identifying Strategies to Detect and Treat Premalignant Lesions” in its list of Research Priorities to Accelerate Progress Against Cancer. The findings of this trial support this critical need and help provide a new preventive therapy for patients with this precancerous condition.

About the Study

The E3A06 trial enrolled people with intermediate or high-risk SMM in two phases. In phase II, 44 people received lenalidomide to assess potential efficacy. In phase III, investigators randomly assigned 182 people to a 25 mg pill of lenalidomide daily for 21 of the first 28 days of a therapy cycle, or observation, and stratified them based on whether they were diagnosed with high-risk SMM within that past year or more than a year after enrollment.

In this trial, researchers used MRIs of the spine and pelvis to detect disease at enrollment, which is more sensitive than routine x-rays, which were used in previous studies exploring interventions for SMM. A 2015 trial in Spain demonstrated that the combination of lenalidomide and dexamethasone lengthened the time before people with SMM developed multiple myeloma and extended survival.

Key Findings

In both the phase II and phase III trials, lenalidomide led to improved outcomes for patents with moderate and high-risk SMM.

• Progression-free survival: In phase II, after 3 years on the trial, 87% of the enrollees were alive without SMM progressing to myeloma (progression-free survival, defined as the time before myeloma develops). In phase III, after 1, 2, and 3 years on the trial, respective progression-free survival rates were 98%, 93%, and 91% for those who received lenalidomide and 89%, 76%, and 66%, respectively, for those who did not receive the treatment and were just observed.

• Toxicity: The proportion of people who could not tolerate lenalidomide was concerning, with 80% of people in phase II and 51% of people in phase III discontinuing the medicine due to toxicity. The most common side effects, seen in 28% of patients, included fatigue and non-blood or bone related side-effects. High-grade neutropenia, which is a low count of neutrophils (a type of white blood cell), was seen in about 5% of people. There was no patient-reported difference in quality of life between those who took lenalidomide and those who did not.

According to the researchers, the combined positive results of this trial and the 2015 Spanish trial may support a change in clinical practice.

Next Steps

The investigators 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. Dr. Lonial noted that a major hallmark of this trial is that it shows that intervening early can prevent patients from developing organ damage, the current criteria by which patients are defined as having myeloma.