Smoldering multiple myeloma is a precursor to myeloma. The current standard of care is observation until the patient becomes symptomatic. However, new findings suggest that early treatment can delay progression to full-blown disease.
For patients who received early treatment with lenalidomide (Revlimid, Celgene Corp), 3-year progression-free survival (PFS) was 91%, compared with 66% for those who were followed with observation.
These results come from E3A06, a randomized phase 3 intergroup trial. The study was discussed at a press briefing held in advance of the 2019 annual meeting of the American Society of Clinical Oncology, where it will be presented (abstract 8001).
"It's pretty clear that smoldering myeloma is a heterogeneous group of patients," commented lead author Sagar Lonial, MD, professor and chair, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia. "What's really interesting is that every risk group appeared to benefit from early intervention."
Experts who were approached for comment welcomed the new findings. One suggested that the results are "somewhat practice changing," but another disagreed, saying more data are needed.
"For what it's worth, I believe further study is needed to evaluate, at a granular level, who is certain to progress to symptomatic disease," commented Joshua Richter, MD, assistant professor of medicine, the Tisch Cancer Institute at Mount Sinai, New York City.
"Otherwise, single-agent therapy may be undertreating those with functionally symptomatic disease for which triplet therapy has emerged as a standard approach and overtreating those that may have extremely long times to progression — if they progress at all," he said.
Has Been a Major Goal for a Long Time
Lonial explained that a major goal has been to identify a precursor condition and potentially prevent the development of symptomatic cancer through early intervention. "That's a major goal that we've had in this field for a long time," he commented.
"But one challenge that we've struggled with in myeloma is to identify which patients are at highest risk of progression and trying to intervene, as well as identifying those at lower risk and leaving them alone, as their time to developing myeloma may be much longer," he said.
The results of a randomized Spanish trial conducted in 2013 showed that a combination of lenalidomide and dexamethasone (multiple brands) increased the time to development of myeloma and improved overall survival in patients with high-risk, smoldering multiple myeloma. However, these patients weren't screened with advanced imaging techniques, and the use of combination therapy limited the ability to isolate the effect of lenalidomide alone.
Lonial noted that this Spanish trial was small (n = 119) and that modern imaging was not used. "The reason that is so important is that patients with a negative x-ray may have bone involvement, which can be seen on MRI or PET [positron-emission tomography] scanning," he explained.
Lenalinomide Delayed Progression
The E3A06 trial assessed the effect of lenalidomide monotherapy in comparison with observation for patients with intermediate- or high-risk smoldering multiple myeloma.
In the initial phase 2 portion of the study, all 44 patients were administered lenalidomide to demonstrate safety. In the phase 3 portion of the study, 182 patients were randomly assigned to receive lenalidomide (n = 90) or to undergo observation (n = 92). The primary endpoint for both phases was PFS.
In the phase 2 study, the overall response rate (ORR) was 47.7%. In the phase 3 study, the ORR was 48.9% for the lenalidomide arm and 0% for the observation arm. At a median follow-up of 71 months for the phase 2 portion, the 3-year PFS was 87%.
For the phase 3 cohort, the median follow-up was 28 months. One-year PFS was 98% for the lenalidomide arm vs 89% for the observation arm; 2-year PFS was 93% vs 76%; and 3-year PFS was 91 % vs 66% (hazard ratio, 0.28; P = .0005).
"There was a pretty significant reduction in the risk of progression of almost 72% in the group that received lenalidomide," said Lonial. "This was seen for both the intermediate- and the high-risk group. When broken down by risk group, it is quite interesting that each group seemed to benefit almost equally.
"This suggests that while the high-risk group is the one that we target now, this may be a fertile area for further investigation for the intermediate-risk group also," he said.
"No trial has ever demonstrated a benefit for prevention from smoldering to myeloma," he commented.
However, it is too early to conclude that intermediate-risk patients should receive early treatment, he said. "In our analysis, we do see benefit for intermediate-risk patients, but the overall survival analysis is still relatively short to conclusively say that intermediate-risk patents should all be treated," Lonial said.
Among the patients who received lenalidomide, nonhematologic adverse events of grade 3 or 4 occurred in 28% of patients in the phase 3 cohort, with fatigue being most common (n = 5). Grade 4 hematologic toxicities, primarily neutropenia, occurred in 5.7% of treated patients (n = 4). The 3-year cumulative incidence of invasive secondary primary malignancies was 5.2% in the lenalidomide group and 3.5% among observation patients. There was no difference in quality-of-life scores among the two groups.
"When you put our trial in aggregate with the Spanish trial, it's pretty clear — and I don't think many of us would argue — that early intervention with a prevention strategy and not a treatment strategy can reduce the risk of progressing to symptomatic myeloma," Lonial concluded. "And at least in the Spanish study with longer follow-up, there was an improved overall survival."
In the abstract, Lonial and colleagues conclude that, in conjunction with the Spanish data, this trial may support a change in clinical practice.
Not Quite Practice Changing
Approached for comment, Henry C. Fung, MD, FACP, FRCPE, vice-chair, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, explained that although observation has been the standard of care for patients with smoldering multiple myeloma, the current study has demonstrated a PFS benefit for treating patient with single-agent lenalidomide. However, no overall survival benefit has as yet been observed.
"Despite the positive results, it is very unlikely that this will be long lasting, and it makes me wonder how we should treat these patients at the time of disease progression," said Fung, who was not involved in the study. "Of course, they cannot be treated with RVD [lenalidomide, bortezomib, and dexamethasone] anymore, and I am not sure if we can collect any stem cells for transplant after prolonged treatment with lenalidomide."
One question, said Fung, is whether patients for whom treatment with lenalidomide failed would still respond to treatment and/or transplant. Another question concerns whether high-risk smoldering myeloma should not be treated in the same way as active myeloma.
"Based on this prospective study, I will discuss the risks and benefits of early treatment with my patients, but I will not routinely recommend single-agent lenalidomide for every patient with newly diagnosed intermediate-/high-risk smoldering multiple myeloma," he added.
"This study is somewhat practice changing, but longer follow-up will be required to determine the true impact of earlier treatment," Fung commented.
Another expert said that he did not think it was likely that this would become the standard of care for most patients.
Mount Sinai's Riochter commented that, as the "definitions and delineations of smoldering myeloma and high-risk smoldering myeloma continue to evolve, we must continue to evaluate the role of early intervention on patients that we would otherwise not treat."
He pointed out that despite positive findings for the earlier Spanish study, in the United States, most patients with smoldering disease are followed with observation alone, with a small percentage being enrolled into interventional clinical trials.
"The findings of this study support an improvement in progression-free survival with an acceptable toxicity profile, but what is not reported at this time is the results of the overall survival analysis," said Richter. "Without a clear overall survival benefit, in conjunction with a somewhat higher rate of secondary primary malignancies, I do not think that this is likely to become the standard approach for most patients."
He added that the study's data serve to support clinicians who wish to provide low-dose therapy for high-risk patients for whom they have concern.
The was study was supported by the National Cancer Institute of the National Institutes of Health. Lonial has had a consulting or advisory role with Celgene, Bristol-Myers Squibb, Janssen Oncology, Novartis, GlaxoSmithKline, Amgen, AbbVie, Takeda, Merck, and Juno Therapeutics and has received research funding from Celgene, Bristol-Myers Squibb, and Takeda. Fung has received honorarium from Celgene. Richter had relationships with Celgene, Janssen, Karyopharm, Oncopeptides, Adaptive Biotechnologies, and Takeda.
American Society of Clinical Oncology (ASCO) 2019: Abstract 8001. To be presented June 2, 2019.
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Cite this: Lenalidomide Delays Onset of Multiple Myeloma - Medscape - May 20, 2019.