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Lenalidomide Maintenance Stalls Myeloma in Trio of Clinical Trials

Lenalidomide maintenance therapy delayed recurrences significantly when given to patients newly diagnosed with multiple myeloma in a trio of clinical trials that reported much-anticipated outcomes May 9 in the New England Journal of Medicine.

Only one trial showed a gain in overall survival, however, and the prospect of lenalidomide (Revlimid) maintenance becoming a standard of care remains uncertain despite the substantial benefit clearly demonstrated in these multicenter, double-blind, placebo-controlled phase III studies.

Notably, investigators reported that prolonged administration of lenalidomide was associated with an increased incidence of second cancers in patients who had undergone stem cell transplantation. This led the Food and Drug Administration to add a warning to the drug’s label on May 7 after a yearlong analysis of early data from the trials.

In addition, a bevy of new drugs, both approved and in the pipeline, has changed the course of multiple myeloma from one with a short life expectancy to that of a chronic disease, with most patients embarking on second-line therapies after experiencing recurrences within 3 years of initial treatment.

"It remains to be determined whether the incorporation of other new agents with lenalidomide will further increase the time to disease progression and overall survival," Dr. Philip L. McCarthy and his coauthors wrote at the conclusion of their report on the one trial that showed a benefit in overall survival.

Two trials compared maintenance lenalidomide with placebo in patients who achieved stable disease or better after stem cell transplantation. The third trial focused on an older group of patients that was not eligible for transplantation. All were stopped early after achieving their goals.

Crossover Did Not Erase Benefit

The Cancer and Leukemia Group B (CALGB) trial reported by Dr. McCarthy, of the Roswell Park Cancer Institute in Buffalo, N.Y., and his associates randomized 460 patients up to 70 years of age after stem cell transplantation. Patients in the lenalidomide arm started at 10 mg daily, and doses ranged from 5 to 15 mg until disease progression.

When the study was unblinded in December 2009, disease progression or death had occurred in 44% of the placebo group, but only 20% of patients on lenalidomide maintenance (hazard ratio, 0.37; P less than .001). Investigators reported that median time to progression was nearly twice as long with lenalidomide – 39 months vs. 21 months (P less than .001). At that point the study’s primary end point – time to progression – had been met, and 86 of 128 eligible patients in the placebo group began to receive lenalidomide maintenance.

Continued...

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Compelling Evidence, Critical Questions

Though the studies provide compelling evidence that lenalidomide maintenance can improve progression-free survival, they also raise critical questions for Dr. Ashraf Z. Badros. In an accompanying editorial, he listed the following issues:

• "First, is progression-free survival the appropriate primary end point in maintenance trials?"

That all patients with myeloma will receive lenalidomide is "a given," he noted. The studies do not address how early use of lenalidomide maintenance compares with its use at relapse in improving overall survival. Nor do they determine whether prolonged exposure could "select a refractory clone" that would result in shortened overall survival after relapse. "Is delayed progression beneficial to patients in and of itself?" he asked (N. Engl. J. Med. 2012;366:1836-38).

• "Second, is lenalidomide maintenance therapy safe?"

Though secondary cancers are a known risk in myeloma, the incidence seen in the trials was surprising. "Unfortunately the way in which lenalidomide increases this risk could not be explained solely by longer survival, and is currently under investigation," said Dr. Badros.

• "A third concern involves the duration and cost of maintenance therapy."

Optimal duration is not established, according to Dr. Badros. "Lenalidomide costs $447.62 per 10-mg tablet (or $163,381 per year for the average patient), as listed on the manufacturer’s website. This total does not account for the costs of laboratory monitoring, physician visits, and management of side effects. Is it cost-effective?" he wrote.

"Whether these data establish a new standard of care for myeloma may be debatable," Dr. Badros concluded, citing newer investigational therapies currently in clinical trials. "As myeloma evolves from an ‘incurable’ cancer to a chronic disease, physicians are faced with the task of maximizing available treatments not only to improve survival but also to maintain their patients’ quality of life."

Dr. Ashraf Z. Badros is a professor of medicine at the University of Maryland in Baltimore. He disclosed receiving grants from seven drug companies as the principal investigator in clinical trials in myeloma. He also disclosed payment for writing a review of maintenance therapy in myeloma for a symposium sponsored by Millennium Pharmaceuticals.

05/09/12  

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

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