Lenalidomide Reduces Risk for Smoldering Multiple Myeloma Progression

Sagar Lonial, MD

In patients with smoldering multiple myeloma, lenalidomide (Revlimid) induced a 72% reduction in the risk for progression to symptomatic disease at 3 years, according to findings from the ECOG E3A06 study to be presented at the 2019 ASCO Annual Meeting.

Moreover, the time to develop multiple myeloma was delayed with lenalidomide [2-year progression-free survival (PFS): HR, 0.93; 95% CI, 0.88-0.99) compared with observation (2-year PFS: HR, 0.76; 95% CI, 0.66-0.87).

“It is pretty clear that many of us would argue that early intervention with a prevention strategy — not a treatment strategy – can reduce the risk of conversion to symptomatic myeloma,” Sagar Lonial, MD, FACP, chief medical officer, Winship Cancer Institute of Emory University, said during a presscast held ahead of the meeting.

He added that — because many issues associated with multiple myeloma can result in irreversible morbidity and, at times, mortality – healthcare providers struggle to identify patients at high risk for progression and also how to intervene by risk stratification.

Therefore, in the randomized phase II/III trial, led by the ECOG-ACRIN Cancer Research Group and sponsored by the National Cancer Institute, the researchers evaluated the efficacy and safety of lenalidomide compared with observation in patients with asymptomatic high-risk smoldering multiple myeloma to determine the reduction in risk and 2-year PFS associated with development of symptomatic disease.

“This is the idea of trying to identify a precursor condition and potentially prevent the development of symptomatic cancer through early intervention, which I think was really a major goal we have had in this field for a long time,” said Lonial, also professor and chair, department of hematology and medical oncology, and Anne and Bernard Gray Family Chair in Cancer.

“Separating the patients at highest risk, and then demonstrating that that intervention can make a difference, is part of what we were trying to do with this trial,” he added.

In phase II of the trial — the run-in portion, according to Lonial – patients received 25 mg of oral lenalidomide once daily on days 1 through 21 for every 28-day cycle, as well as 325 mg of aspirin on days 1 through 28, until disease progression or unacceptable toxicity.

In phase III, 90 patients in the treatment arm received the same treatment regimen, while 92 patients in the control arm underwent observation until progression to symptomatic myeloma. Patients were stratified by their time from diagnosis of smoldering multiple myeloma.

Lonial explained that the reason intervening with an immune-modulatory agent is key in preventing symptomatic myeloma is because of the immune system’s control of the plasma cell clone. “One thought behind this trial is if you use an immune-enhancing drug, such as lenalidomide, you may be able to enhance that immune control and delay or even prevent conversion from a smoldering state to a symptomatic state,” he said.

While the researchers found a 72% reduction in the risk for progression of smoldering multiple myeloma to symptomatic disease with organ damage, they also discovered this benefit was consistent across low-, intermediate-, and high-risk groups — highlighting the potential for future study.

“What is really quite interesting is that each group appeared to benefit almost equally with early intervention with lenalidomide as a single agent, suggesting that while the high-risk group may be the group that we target now, this may be a fertile area for further investigation in the intermediate-risk group as well, which no trial has ever demonstrated benefit for the prevention of smoldering [disease] from developing into symptomatic myeloma,” Lonial said.

In addition, he noted that about 50% of patients had an objective response to lenalidomide in both the phase II and phase II trial. Moreover, in the phase II portion of the study, 78% of the 44 patients enrolled did not progress to myeloma, with a median follow-up of over 5 years.

“With a similar-risk group of patients, one would expect that 50% to 60% of those patients would have converted to myeloma in that same time frame, suggesting that we would have prevented the development of organ damage and symptomatic myeloma in a large fraction of patients — not just in the randomized trial, but also in the smaller portion – and that is occurring with just some adverse events [AEs],” he added.

With this, the researchers observed hematologic and non-hematologic AEs, including decreased neutrophil count, infections, dermatologic/skin effects, dyspnea, fatigue, hypertension, and hypokalemia. Grade 3 non-hematologic AEs occurred in 50% of patients and non-hematologic AEs in 52.3%, while 28.4% experienced non-hematologic treatment-related (TRAE)s and 35.3% with hematologic TRAEs.

While there were few Grade 4 AEs, Lonial noted the treatment was well-tolerated among patients.

“It is pretty clear that we need to differentiate treatment of myeloma versus prevention of smoldering to developing myeloma. That treatment or prevention strategy is likely to be less intensive and may actually try to focus on enhancing immune surveillance of the existing malignant clone and preventing that clone from progressing, as opposed to eradication of the disease when you treat symptomatic myeloma,” he concluded.

Lidia Schapira, MD, FASCO, a breast cancer expert, associate professor of medicine at Stanford University School of Medicine, and director of cancer survivorship at the Stanford Comprehensive Cancer Institute, applauded the researchers for their findings and for identifying an unmet need in this patient population.

“It really covers an area that is a very important ASCO research priority, which is identifying strategies to actually detect and treat pre-malignant lesions,” she said. “This area of prevention rather than treatment is one where we have far too few successes and we really need to see more.”

Lonial S, Jacobus S, Fonseca R, et al. E3A06: Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma. Presented at: 2019 ASCO Annual Meeting Presscast; May 15. Abstract 8001.

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