Lenalidomide Slows Progression of Smoldering Multiple Myeloma

By Will Boggs MD

November 23, 2019

NEW YORK (Reuters Health) - Early treatment with lenalidomide significantly delays the progression of smoldering multiple myeloma to symptomatic disease, according to the results of a randomized trial.

"This trial is now the second randomized trial to show benefit for patients in the high-risk category," Dr. Sagar Lonial of Emory University School of Medicine, in Atlanta, told Reuters Health by email. "There is now sufficient evidence to prevent damage in these patients."

The risk of progression of smoldering multiple myeloma, an asymptomatic precursor stage of multiple myeloma, can be as high as 25% per year in high-risk patients. Observation until the emergence of end-organ dysfunction meeting the criteria for clinical multiple myeloma has been the standard of care.

Dr. Lonial and colleagues assessed the efficacy of single-agent lenalidomide, compared with observation, in 182 patients with intermediate- or high-risk smoldering multiple myeloma. The primary endpoint was progression-free survival based on disease progression to the development of end-organ damage attributable to multiple myeloma and biochemical progression.

The lenalidomide group received oral lenalidomide 25 mg on days 1 to 21 of every 28-day cycle, with therapy (or observation) continued until disease progression, toxicity, or withdrawal for other reasons.

At the second planned interim analysis (median follow-up, 35 months), the rate of partial or better response was 50% in the lenalidomide group, compared with no responses in the observation arm, the researchers report in the Journal of Clinical Oncology, online October 25.

Progression-free survival for lenalidomide versus observation was 98% versus 89% at one year, 93% versus 76% at two years, and 91% versus 66% at three years, with a cumulative incidence of progression at three years of 7.3% in the lenalidomide group and 31.6% in the observation group.

There were two deaths in the lenalidomide arm and four in the observation arm (hazard ratio, 0.46; 95% confidence interval, 0.08 to 2.53).

The benefit of lenalidomide was evident in all risk groups but was most pronounced in the high-risk category of patients.

Treatment-related adverse event rates were higher with lenalidomide than with observation for grade-3 hematologic and nonhematologic events combined (35.2% vs. 3.5% with observation), for grade-4 hematologic and nonhematologic events combined (5.7% vs. 1.2%, respectively), and for grade-3 nonhematologic events (28.4% vs. 3.5%, respectively).

"For the high-risk group using the new Mayo 2018 criteria (20% plasma cells, M protein of 2, free:light ratio >20), they should be offered a trial or lenalidomide or lenalidomide/dexamethasone as treatment," Dr. Lonial said. "Obviously enrolling on a trial is the best option, but for those who cannot, getting lenalidomide or lenalidomide/dexamethasone reduces their risk of progression significantly."

"Patients can make their own decisions, but at least be willing to provide them the evidence that supports early therapy and reduction in risk for organ damage," he said.

Dr. Ola Landgren, chief of Myeloma Service at Memorial Sloan Kettering Cancer Center, in New York City, told Reuters Health by email, "It is not obvious why a study had to be done with only lenalidomide, given that the drug is always given together with dexamethasone for the treatment of multiple myeloma (U.S. Food and Drug Administration (FDA) approved in 2003). Several newer studies have been published/presented the past few years showing that combination therapies with 3 drugs - always including lenalidomide - can result in deep and durable responses for the same patient category (high-risk smoldering myeloma)."

"In 2019, there is no FDA-approved therapy for smoldering myeloma," he said. "Lenalidomide is only FDA-approved for multiple myeloma."

"Important tasks for the future are: better understanding of the genomics of early myeloma disease allowing better identification of the optimal timing to treat a plasma cell clonal disorder at the very early stages, when the chances of eradication are higher," Dr. Landgren said. "Using modern combination therapy together with modern treatment-response monitoring (i.e., minimal residual disease (MRD) testing) will pave the way towards curative strategies for patients with plasma cell disorders."

"Importantly," he added, "in the JCO study, about 30% of the patients stopped the therapy. On randomized clinical trials, as a general rule, an imbalance of follow-up time due to dropout (between the two arms) introduces bias, which limits the validity of the results."

Dr. Maria Victoria Mateos Manteca of the University Hospital of Salamanca/IBSAL, in Spain, who has researched various aspects of multiple myeloma and its treatment, told Reuters Health by email, "Asymptomatic myeloma patients at high risk of progression to myeloma should be treated. The data we have today support the use of lenalidomide or lenalidomide-dexamethasone."

"There are some other trials going on trying to evaluate other options of therapy similar to those we prescribe to active myeloma patients," said Dr. Mateos, who was not involved in the study. "If the data are positive, in the future the concept of high-risk smoldering myeloma would disappear, and all these patients would qualify for myeloma and be treated as myeloma."

The study had no commercial funding. Several of the authors report ties to Celgene, the manufacturer of lenalidomide.

SOURCE: https://bit.ly/34av2ej

J Clin Oncol 2019.