CHICAGO — Single-agent lenalidomide (Revlimid) in smoldering multiple myeloma cut the risk of progression to symptomatic disease or organ damage compared with observation alone, according to results of a phase III trial.
At 3 years, 91% of lenalidomide-treated patients were alive and without disease progression compared with 66% of those randomized to observation (HR 0.28, P=0.0005), reported Sagar Lonial, MD, of Winship Cancer Institute of Emory University in Atlanta.
In the treatment arm, progression-free survival rates were 98% at year 1 and 93% at year 2, and the benefit of treatment appeared consistent across risk groups. In the observation arm, these rates were 89% and 76%, respectively.
“In our analysis, we do see benefit for intermediate-risk patients as well, in terms of converting to symptomatic myeloma and prevention of organ damage, but the overall survival follow-up is still relatively short to conclusively say that intermediate-risk should all be treated,” Lonial said during a press briefing ahead of the American Society of Clinical Oncology meeting (ASCO), which begins here on May 31.
He added that while high-risk smoldering patients may be the group targeted now for preventing development of symptomatic disease, trials for the intermediate-risk group could be a “fertile area” of future investigation.
Development of symptomatic disease in patients with smoldering myeloma is characterized by evidence of organ damage, be it bone lesions or fractures, anemia, or kidney or other bone marrow-related issues.
“In many cases those patients have developed irreversible morbidity and oftentimes mortality associated with that conversion from an asymptomatic to a symptomatic state,” said Lonial, explaining that this is where prevention strategies could play a role.
Patients in the E3A06 trial had mostly intermediate- or high-risk smoldering myeloma, and organ damage indicative of symptomatic multiple myeloma was ruled out with MRIs. A previous Spanish trial — PETHEMA — in high-risk smoldering patients found a reduced rate of disease progression and improved overall survival with lenalidomide plus dexamethasone (Rd) versus observation, but Lonial pointed out that the trial was criticized for using x-rays to rule out symptomatic disease (rather than MRI or PET), so patients with multiple myeloma may have been over-enrolled.
“While this current study may lead some to adopt the practice of offering single-agent lenalidomide to patients with smoldering myeloma, I think more data are needed before this approach becomes the standard of care for all patients with intermediate/high-risk smoldering myeloma,” Sarah Holstein, MD, PhD, of the University of Nebraska Medical Center in Omaha, told MedPage Today via email.
“What is unclear from the results of this study is whether this intervention (full dose, single-agent lenalidomide) is changing the disease biology long-term, and whether it is doing so in a favorable way,” said Holstein, who was not involved in the research. “What will be the natural history of the disease once patients progress on single-agent lenalidomide and how does that compare to individuals who were monitored until early signs of active disease, and then provided with standard of care induction regimens (i.e., triplet or quadruplet induction regimens)?”
Smoldering myeloma is a very heterogeneous disease, Holstein explained, with “some patients clearly fated to progress in a short period of time and others whose disease behaves much more indolently.” In roughly 50% of patients, smoldering progresses to symptomatic multiple myeloma, and previous research has shown that 13% of multiple myeloma patients were first diagnosed with smoldering disease.
Holstein noted that the single-agent lenalidomide approach for smoldering myeloma used in the current study is on the opposite end of the spectrum from GEM-CESAR, a trial testing aggressive curative therapy — induction with carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) followed by autologous stem-cell transplant, KRd consolidation, and then maintenance Rd.
“Although cross-trial comparisons, particularly in the smoldering myeloma realm, are difficult, it will be important to evaluate the long-term outcomes of both approaches,” she said.
The phase III trial from Lonial’s group randomized 182 patients with smoldering myeloma to either observation (n=92) or daily 25 mg lenalidomide on days 1-21 of 28-day cycles plus 325 mg aspirin daily (n=92), with high-risk patients stratified by time of diagnosis (≤1 year or >1 year). Overall, about 50% achieved an objective response to therapy.
Previous research in lower-risk smoldering patients suggested that the immune systems of those who didn’t progress had control of the plasma cell clone, Lonial noted.
“So one thought behind this trial is if you use an immune-enhancing drug such as lenalidomide you may be able to enhance that control and delay or even prevent conversion from a smoldering state to a symptomatic state,” he said.
Lenalidomide/aspirin therapy was continued until disease progression or unacceptable toxicity. In the lenalidomide group, 52.3% of patients experienced any hematologic or non-hematologic adverse events (AE), and 35.2% were deemed treatment related. The most common grade 3 or higher AEs were infections (20.5%), decreased neutrophil count (13.6%), hypertension (9.1%), and fatigue (6.8%). In all, 51% of patients discontinued treatment because of toxicity. Two non-treatment related deaths occurred in the lenalidomide group.
A single-arm phase II run-in portion of the trial using the same lenalidomide regimen reported a rate of progression-free survival of 78% at a median 5 years follow-up. Lonial estimated that in a similar group of untreated patients, roughly 50% to 60% would be expected to convert to symptomatic disease. Adverse events were an issue in this earlier trial as well, with 81% of patients eventually discontinuing treatment because of toxicity.
The study was funded by the National Institutes of Health.
Lonial disclosed relationships with Celgene, Bristol-Myers Squibb, Janssen Oncology, Novartis, GlaxoSmithKline, Amgen, Abbvie, Takeda, Merck, Juno Therapeutics, and others. Co-authors reported various relationships with industry entities.
Holstein has served on advisory boards or as a consultant for Celgene, Takeda, GlaxoSmithKline, Sorrento, and Adaptive Biotechnologies.
last updated
Source: MedicalNewsToday.com
