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Early treatment shows long-term benefit for high-risk smoldering myeloma
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Early treatment with lenalidomide plus dexamethasone prolonged time to progression and OS compared with observation for patients with high-risk smoldering multiple myeloma, according to long-term follow-up results of the phase 3 QuiRedex trial.
“The standard of care for most patients with smoldering multiple myeloma is observation until the development of myeloma-defining events,” Maria-Victoria Mateos, MD, PhD, associate professor of hematology at Instituto do Investigación Biomédica de Salamanca in Salamanca, Spain, and colleagues wrote. “However, this no-treatment approach, which was probably suitable in the era of restricted treatment options also associated with notable toxic effects, might not be the best options in a new era of myeloma treatment.”
Mateos and colleagues compared watchful waiting with early treatment composed of lenalidomide (Revlimid, Celgene) plus dexamethasone in 119 patients aged 18 years or older with high-risk smoldering myeloma.
Researchers randomly assigned patients to receive lenalidomide and dexamethasone (n = 57; median age, 61 years; 56% women) or undergo observation (n = 62; median age, 65 years; 55% women). Therapy consisted of nine 4-week cycles of lenalidomide (25 mg/day on days 1-21) and dexamethasone (20 mg/day on days 1-4 and 12-15). Following the initial cycles, the therapy group also received maintenance therapy with 4-week lenalidomide cycles (10 mg/day on days 1-21) for up to 2 years.
The primary endpoint was time from randomization to progression to symptomatic myeloma.
At an earlier median follow-up of 45 months, patients who received therapy experienced longer time to progression of symptomatic disease compared with the observation arm (median not reached vs. 21 months; HR = 0.18; 95% CI, 0.09-0.32).
In the current long-term analysis, Mateos and colleagues sought to address concerns regarding the potential selection of resistant clones and the possibility that patients in the control arm did not receive optimal treatment at time of progression.
Median follow-up for the long-term analysis was 75 months (interquartile range, 67-85).
The updated analysis showed the benefit in terms of time to progression persisted in the treatment arm (median not reached vs. 23 months; HR = 0.24; 95% CI, 0.14-0.41).
Further, fewer patients in the therapy arm progressed to multiple myeloma (39% vs. 86%) and had died at the time of data cutoff (18% vs. 36%).
Median OS was not reached for either arm (treatment, 95% CI, 65 months-not reached; observation, 95% CI, 53 months-not reached), but appeared better with treatment (HR = 0.43; 95% CI, 0.21-0.92).
Survival did not differ between the groups among patients who received subsequent treatments at the time of progression to active disease (HR = 1.34; 95% CI, 0.54-3.3).
Researchers evaluated safety based on the intent-to-treat population (n = 125).
The most common adverse events in the treatment group were grade 1 to grade 2 infections (18%). The most common grade 3 adverse events were infection (6%), asthenia (6%), neutropenia (5%) and skin rash (3%), all of which occurred during induction therapy.
No grade 4 adverse events occurred, but one patient died as a result of a respiratory infection during induction therapy.
More patients in the therapy group developed second primary malignancies compared with the observation group (10% vs. 2%), but the cumulative risk for second malignancies did not significantly differ between the groups.
“We can confirm that this preemptive strategy was effective, with five patients continuing to receive lenalidomide plus low-dose dexamethasone with the disease stabilized,” Mateos and colleagues wrote.
The ideal timing of treatment initiation among asymptomatic patients has been the central question in this setting, Heinz Ludwig, MD, professor and head of the department of medicine and medical oncology at Wilhelminen Cancer Research Institute of Wilhelminenspital in Vienna, Austria, wrote in an accompanying editorial.
“Several patient attempts to improve outcomes remained futile, for two main reasons,” he wrote. “First, the prognosis of patients with smoldering myeloma is very heterogeneous, with some patients progressing to multiple myeloma rapidly and others only after long-term follow-up or even not at all. Second, before the introduction of novel drugs, the efficacy of available treatment was suboptimum at best.
“Mateos and colleagues' trial of early treatment in patients with high-risk smoldering myeloma is likely to change the present strategy of no treatment,” Ludwig added.
However, prospective confirmatory trials are needed, he wrote. Further, patients should be assessed for early signals of progression with light chain assays, and new algorithms to define patients at high risk are needed, he wrote. – by Nick Andrews
Disclosure: Celgene provided funding for this research. Mateos reports advisory board roles with and honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen and Takeda. Other researchers report honoraria, research and grant support from, and employment and advisory board roles with Celgene and other pharmaceutical companies. Ludwig reports no relevant financial disclosures.
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