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Lenalidomide delays progression of smoldering myeloma
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Early treatment with lenalidomide significantly reduced the risk for progression of high-risk smoldering multiple myeloma to symptomatic multiple myeloma, according to results of a randomized trial scheduled for presentation at ASCO Annual Meeting.
Results showed that 91% of patients with intermediate- or high-risk smoldering multiple myeloma who received lenalidomide (Revlimid, Celgene) did not experience progression to overt multiple myeloma, compared with 66% of patients who underwent observation for progression without therapy.
The results provide more evidence that treatment with lenalidomide can prevent progression to multiple myeloma, according to Sagar Lonial, MD, chief medical officer at Winship Cancer Institute of Emory University, and a HemOnc Today Editorial Board Member. He referred to an earlier study by Mateos and colleagues that showed treatment with lenalidomide plus dexamethasone delayed development of multiple myeloma and improved OS compared with observation in patients with high-risk smoldering multiple myeloma.
“For high-risk patients, early therapy with lenalidomide alone or lenalidomide plus dexamethasone is supported by the data,” Lonial told HemOnc Today. “For intermediate-risk patients we may know more soon, but [the data are] not quite ready yet. Both groups are well-served to enroll in trials.”
In the phase 2/phase 3 trial, Lonial and colleagues compared preventive lenalidomide with observation and its effect on progression to multiple myeloma. The researchers enrolled 226 patients with intermediate- or high-risk smoldering multiple myeloma, including 44 patients in phase 2 and 182 patients in phase 3.
In phase 2, all patients received lenalidomide to assess its safety.
In phase 3, researchers randomly assigned patients to 25 mg daily lenalidomide for 21 of the first 28 days of the therapy cycle (n = 90) or observation (n = 92). They stratified patients based on the time since the diagnosis of smoldering multiple myeloma ( 1 year vs. > 1 year).
PFS served as the primary endpoint.
Median follow-up was 71 months for the phase 2 study and 28 months for the phase 3 study.
Results of the phase 2 study showed PFS rates of 98% at 1 year, 87% at 3 years and 78% at 5 years. In the phase 3 study, the lenalidomide group demonstrated higher PFS rates at 1 year (98% vs. 89%), 2 years (93% vs. 76%) and 3 years (91% vs. 66%) than the observation group (HR = 0.28; P = .0005).
Researchers observed overall response rates of 47.7% in the phase 2 study and 48.9% for the lenalidomide group in the phase 3 study.
There was no reported difference in quality-of-life scores between the two study groups.
Eighty percent of patients in the phase 2 study and 51% in phase 3 stopped receiving lenalidomide because of adverse events or patient withdrawal.
Grade 3 or grade 4 nonhematologic adverse events occurred in 28% of patients in the phase 3 study, with fatigue (n = 5) being most common. The rate of grade 4 hematologic adverse events rate among patients in the phase 3 study was 5.7%, with neutropenia (n = 4) being the most common.
Lonial said the results point to a 72% risk reduction for delay to symptomatic multiple myeloma for high- and intermediate-risk patients who received preventive lenalidomide. This early treatment strategy prevented progression for a large percentage of patients despite the occurrence of some adverse events.
“This speaks to the power of immune modulation in a condition that is regulated by the immune system,” he told HemOnc Today. “The 5-year data from the phase 2 study were quite striking, and I think sets a good bar for what we hope will be the result from the phase 3 study with longer follow-up.” – by Drew Amorosi
References:
Lonial S, et al. Abstract 8001. Scheduled for presentation at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Mateos MV, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1300439.
Disclosures: Lonial reports consultant/advisory roles with AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Juno Therapeutics, Merck, Novartis and Takeda and research funding from Bristol-Myers Squibb, Celgene and Takeda. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Joshua Richter, MD
Multiple myeloma continues to represent a diverse group of disorders with unique biological features leading to different phenotypes of progression and response.
Smoldering myeloma is no different. This was reflected in a paper by Rajkumar and colleagues in which the so-called “SLiM CRAB” criteria were laid out to better define those who may have “myeloma-defining events” and could warrant therapy.
Despite positive findings of an earlier study by Mateos and colleagues, most patients with smoldering disease in the United States are followed with observation alone. The current gestalt is to only treat in the context of clinical trials.
The findings of Lonial and colleagues support an improvement in PFS with lenalidomide, with an acceptable toxicity profile. There was a slightly higher rate of secondary primary malignancy, which has been described in several previous studies with lenalidomide.
What is not reported is the results of the OS analysis. Without a clear OS benefit, in conjunction with a somewhat higher secondary primary malignancy rate, I do not think that this is likely to become the standard approach for most patients.
That said, the study provides data to support clinicians wishing to provide low-dose therapy for high-risk patients for whom they have concern. Every clinical scenario is unique, and the key benefit is evidence-based support for those cases that we feel warrant intervention without fitting the strict criteria of symptomatic disease.
There are ongoing single-agent studies with daratumumab (Darzalex; Janssen Biotech), isatuximab (SAR-650984; ImmunoGen, Sanofi-Aventis) and ibrutinib (Imbruvica; Pharmacyclics/AbbVie, Janssen Biotech) seeking to delay progression of smoldering multiple myeloma. There is also a subset of studies, such as the ASCENT trial (NCT03289299), seeking to potentially cure smoldering multiple myeloma with aggressive therapy using multiagent chemotherapy in an induction, consolidation and maintenance regimen.
Although patients with high-risk smoldering multiple myeloma are more likely to progress as a group, there are subsets of patients that never progress. Further study is needed to evaluate, at a granular level, who is “certain” to progress to symptomatic disease. In turn, we need to ensure that we are neither overtreating nor undertreating patients. Single-agent therapy may be undertreating those with functionally symptomatic disease (for which triplet therapy has emerged as a standard approach) and overtreating those who may have extremely long times to progression, if they progress at all.
References:
Rajkumar SV, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70442-5.
Mateos MV, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1300439.
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