Lenalidomide Maintenance Beneficial in Multiple Myeloma

Roxanne Nelson

May 10, 2012

May 10, 2012 — Lenalidomide (Revlimid) combined with dexamethasone has proven to be an effective treatment for patients with newly diagnosed or relapsed/refractory multiple myeloma.

Three new studies, all published in the May 10 issue of the New England Journal of Medicine, support the use of lenalidomide as maintenance therapy.

In the first study, conducted in the United States, 100 days after hematopoietic stem-cell transplantation, lenalidomide maintenance therapy was associated with a significantly longer time to disease progression and significantly better overall survival. The median time to disease progression was 46 months in the lenalidomide group and 27 months in the placebo group (P < .001).

"Lenalidomide can be considered a new standard of care for maintenance therapy for responding patients after a single autologous hematopoietic cell transplant," said lead author Philip McCarthy Jr, MD, director of the Blood & Marrow Transplant Program at Roswell Park Cancer Institute in Buffalo, New York.

"These are all very interesting studies that demonstrate that lenalidomide maintenance therapy is an important component of long-term control of multiple myeloma," he told Medscape Medical News.

The second study, conducted in France, also compared lenalidomide maintenance therapy with placebo in the transplant setting. Lenalidomide maintenance therapy improved median progression-free survival, compared with placebo (41 vs 23 months; hazard ratio [HR], 0.50; P < .001); this benefit was observed in all patient subgroups. The rate of overall survival at 4 years, however, was similar in the lenalidomide and placebo groups (73% vs 75%).

The third study, conducted by Italian researchers, evaluated lenalidomide maintenance therapy in patients 65 years and older with newly diagnosed multiple myeloma who were ineligible for transplantation. The researchers found that progression-free survival was significantly longer in the group treated with melphalan/prednisone/lenalidomide followed by lenalidomide maintenance therapy than in the group treated with melphalan/prednisone/lenalidomide followed by placebo (31 vs 14 months; P < .001) and than in the group treated with melphalan/prednisone followed by placebo (31 vs 13 months; P < .001). This benefit, however, was not observed in patients older than 75 years.

"Of note, all 3 studies show a time-to-progression benefit for lenalidomide as maintenance therapy following either induction plus transplant therapy or induction therapy alone," Dr. McCarthy explained.

The lack of overall survival benefit in the French study might be due to the different induction regimens, he noted, or to the use of intensive consolidation therapy in half the patients in both groups and discontinuation of the maintenance therapy.

Standard of Care? Maybe Not Yet

Lenalidomide is a well-known validated therapy for multiple myeloma that has significantly contributed to the improved survival of patients with this incurable disease, said Joseph Mikhael, MD, a hematologist at the Mayo Clinic in Scottsdale, Arizona, in an interview.

These 3 studies provide evidence supporting the benefit of this drug in patients who are eligible or ineligible for autologous stem-cell transplantation, he said.

"It's too early to consider lenalidomide maintenance as standard of care in all patients after transplant," said Dr. Mikhael, who was not involved in any of the studies. "Although there was a survival advantage in the American study, there was no survival advantage in the French study," he noted. He added that the benefit of this treatment strategy should be considered individually for each patient.

Dr. Mikhael also pointed out that the risks associated with this therapy are real, and include short-term toxicity. "The long-term risk of second cancers must also be considered," he said. "We require more information in the long term about the risk of second cancers, but it must be placed in the context of the proven benefit of this agent to delay progression of the disease," he explained.

He added that overall, "this will likely result in the increased use of this agent as maintenance therapy after transplant, although other approaches, such as more consolidation therapy immediately after transplant — instead of indefinite maintenance — must also be investigated."

An accompanying editorial echoes some of these concerns. Ashraf Z. Badros, MB, ChB, from the University of Maryland School of Medicine in Baltimore, writes that it is debatable whether these data establish a new standard of care for myeloma.

The benefit associated with lenalidomide seems to outweigh the risk of second cancers, he explains. "Nevertheless, the small increase in the risk of second cancers is significant."

Another concern involves the cost and duration of maintenance therapy. "Lenalidomide costs $447.62 per 10 mg tablet (or $163,381 per year for the average patient)," notes Dr. Badros. "This total does not account for the costs of laboratory monitoring, physician visits, and management of side effects. Is it cost effective?"

The data on progression-free survival support its use as maintenance therapy after careful assessment of the risks and benefits, he notes, adding that other drugs for maintenance therapy are now being tested.

"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. Badros concludes.

Risk for Second Primary Cancers

Lenalidomide is a derivative of thalidomide and has antiangiogenic and antineoplastic properties. In 2006, it was approved by the US Food and Drug Administration (FDA) for use in combination with dexamethasone in patients with multiple myeloma who have received 1 previous therapy. Since that time, it has become a standard treatment in initial disease and in relapsed disease, and a number of studies have looked at the use of lenalidomide in combination with other drugs and in a range of myeloma settings.

It also has an indication for the treatment of patients with transfusion-dependent anemia resulting from low- or intermediate-risk myelodysplastic syndromes associated with a 5q deletion abnormality with or without additional cytogenetic abnormalities.

However, clinical trials investigating the use of lenalidomide in patients with newly diagnosed multiple myeloma have shown that treatment carries a nearly 3-fold risk for second primary cancers. There seems to be a smaller increased risk for second primary cancer in patients who received lenalidomide for relapsed or refractory myeloma. This prompted the FDA to initiate a safety review last year, and new safety information has now been added to the warnings and precautions section of the lenalidomide label.

The FDA does not recommend delaying, modifying, or restricting the use of lenalidomide in the treatment of conditions for which it is indicated, but advises that the potential benefit of lenalidomide and the risk for a serious adverse event need to be weighed when considering treatment with this agent.

Lenalidomide and Stem-Cell Transplantation

In the American study, Dr. McCarthy and colleagues evaluated whether lenalidomide maintenance therapy can prolong the time to disease progression after autologous hematopoietic stem-cell transplantation.

Results of the fifth interim analysis of this study were presented last year at the International Myeloma Workshop, and were reported at that time by Medscape Medical News.

In the current analysis, the median follow-up was 34 months.

The authors randomized 460 patients younger than 71 years with either stable disease or a marginal, partial, or complete response 100 days after stem-cell transplantation to lenalidomide (n = 231) or placebo (n = 229).

At the most recent follow-up, 86 patients (37%) in the lenalidomide group and 132 (58%) in the placebo group had disease progression or had died (HR, 0.48). The 3-year rate of freedom from progression or death was higher in the lenalidomide group than in the placebo group (66% vs 39%).

A benefit in overall survival was also seen in this study, the authors note; more patients in the lenalidomide group than in the placebo group were alive at a median follow-up of 34 months (85% vs 77%).

As expected, the cumulative incidence of a second primary cancer was higher in the lenalidomide group (P = .008), and the cumulative incidence of progressive disease and the incidence of mortality were higher in the placebo group (P < .001 and P = .002, respectively).

Maintenance After Transplantation

In the French study, Michel Attal, PhD, professor of hematology at the Purpan Hospital in Toulouse, and colleagues looked at lenalidomide maintenance after transplantation. They randomized 614 patients younger than 65 years with nonprogressive disease after first-line transplantation to maintenance treatment with either lenalidomide (10 mg/day for the first 3 months, increased to 15 mg if tolerated) or placebo until relapse.

After transplantation, patients received either consolidation treatment with lenalidomide (25 mg/day on days 1 to 21 of each 28-day cycle for 2 cycles) followed by maintenance therapy with lenalidomide, or the same consolidation treatment with lenalidomide followed by maintenance therapy with placebo.

An interim analysis of this study was presented at the 2010 annual meeting of the American Society of Clinical Oncology, and reported at that time by Medscape Medical News.

The rate of a complete or very good response was higher in those receiving lenalidomide maintenance than in those receiving placebo (84% vs 76%).

The median follow-up period was 45 months from the time of randomization (55 months from diagnosis). The probability of surviving free of disease progression for 4 years after randomization was higher in the lenalidomide group than in the placebo group (43% vs 22%; HR, 0.50; P < .001), Dr. Attal and colleagues report.

Grade 3 or 4 peripheral neuropathy was similar in the 2 groups. However, thromboembolic events were more frequent in the lenalidomide group (6% vs 2%; P = .01), as were grade 3 or 4 hematologic events (58% vs 23%; P < .001).

There were 32 second primary cancers in 26 patients in the lenalidomide group and 12 second primary cancers in 11 patients in the placebo group. The incidence in the lenalidomide group was 3.1 per 100 patient-years and in the placebo group was 1.2 per 100 patient-years (P = .002)

On multivariate analysis, the incidence of second primary cancers was significantly related to study-group assignment, age, sex, and International Staging System stage. Four-year event-free survival was higher in the lenalidomide group than in the placebo group (39% vs 20%; P < .001).

Maintenance Therapy in Newly Diagnosed Patients

The Italian researchers compared the efficacy and safety of melphalan/prednisone/lenalidomide (MPR) induction therapy followed by lenalidomide maintenance therapy with MPR or melphalan/prednisone (MP) without maintenance therapy. The study, led by Antonio Palumbo, MD, from Turin University, and conducted at 82 centers in Europe, Australia, and Israel, randomized 459 patients to MPR plus lenalidomide maintenance (n = 152), MPR (n = 153), or MP (n = 154).

The patients were 65 years or older with newly diagnosed disease and were not candidates for transplantation.

Partial results of this study were presented in 2009 at the American Society of Hematology annual meeting. At that time, Dr. Palumbo noted that this regimen "can be considered a new standard" for patients older than 65 years newly diagnosed with multiple myeloma.

Dr. Mikhael questions that premise. "This study establishes the feasibility of using this drug in the longer term, but more study is required before it becomes the standard of care, especially as it did not compare this strategy to the current standard of care," he said.

"The lack of overall survival benefit is concerning and requires more follow-up," Dr. Mikhael added. "The lack of improvement in progression-free survival in those older than 75 years also bears consideration."

Median follow-up was 30 months. Median progression-free survival was significantly longer with MPR plus lenalidomide than with MPR or MP. The response rates were better with MPR plus lenalidomide than with MP (77% vs 50%; P < .001) and with MPR than with MP (68% vs 50%; P = .002).

However, the progression-free survival benefit of MPR plus lenalidomide was only seen in patients 65 to 75 years of age, not in those older than 75 (P = .001 for treatment-by-age interaction). In the older age group, the median progression-free survival was 19 months with MPR plus lenalidomide, 12 months with MPR, and 15 months with MP.

One third of the patients in the MPR plus lenalidomide group and the MPR group experienced a very good partial response or better, compared with only 12% in the MP group.

During induction therapy, the most frequent adverse events were hematologic; these occurred more frequently in the lenalidomide groups. Grade 4 neutropenia was reported in 35%, 32%, and 8% of the MPR plus lenalidomide, MPR, and MP groups, respectively. The incidence of second primary tumors was higher with MPR plus lenalidomide; the 3-year rate of second primary tumors was 7% with MPR plus lenalidomide, 7% with MPR, and 3% with MP.

The American study was funded by the National Cancer Institute. The French study was supported by the Programme Hospitalier de Recherche Clinique, the Swiss Group for Clinical Cancer Research, and a grant from Celgene, the manufacturer of lenalidomide. The Italian study was supported by Celgene. Detailed disclosures are noted in the 3 papers.

N Engl J Med. Published online May 10, 2012. American Abstract, French Abstract, Italian Abstract, Editorial


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