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.

Despite this crossover, lenalidomide maintenance continued to demonstrate a significant advantage at a median follow-up as of Oct. 31, 2011. By then, investigators reported, only 37% of the lenalidomide group had disease progression or death, compared with 58% of the placebo group (HR, 0.48). Median time to progression reached 46 months in the lenalidomide group vs. 27 months in the placebo arm (P less than .001), according to the new report.

The 3-year rate of freedom from progression or death was higher with lenalidomide maintenance (66% vs. 39%), as was the overall survival rate (88% vs. 80%, HR 0.62) (N. Engl. J. Med. 2012;366:1770-81).

Younger Group in IFM Trial

Dr. Michel Attal of Hôpital Purpan in Toulouse, France, and his colleagues from the Intergroupe Francophone du Myélome (IFM) conducted a similar trial in a population of 614 patients under age 65 whose disease had not progressed after stem cell transplantation. All patients received two 28-day cycles of consolidation treatment with lenalidomide (25 mg daily on days 121) followed by maintenance with placebo or lenalidomide (10 mg daily for 3 months, after which the dose could be increased to 15 mg if tolerated) until disease progression.

At the time the study was unblinded at a median follow-up of 30 months in July 2010, median progression-free survival was nearly twice as long with lenalidomide maintenance – 41 months, compared with 23 months with a placebo (HR, 0.50; P less than .001). Overall survival was similar between the groups, and neither group had reached median overall survival.

By October 2011, median follow-up from time of randomization had reached 45 months, and the probability of surviving without progression 4 years after randomization was still about double with lenalidomide: 43% vs. 22% (HR, 0.50; P less than .001).

The overall survival rate was still similar, however, at 73% with lenalidomide and 75% with placebo. These survival rates are high, the authors noted, and longer follow-up may show an advantage for lenalidomide maintenance.

"Together with the findings reported by McCarthy et al., our data support the use of lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stem-cell transplantation in patients with myeloma, but the impressive benefits must be weighed against the increased risks," said Dr. Attal and his coauthors (N. Engl. J. Med. 2012;366:1782-91).