Updated data from three major randomized controlled trials in multiple myeloma confirmed higher rates of secondary malignancies along with significantly better outcomes for patients treated long-term with lenalidomide.

Two of the studies, CALGB 100104 and IFM-0502, presented at the annual International Myeloma Workshop on May 5 in Paris, examined patients following stem cell transplant. The third, MM-015, was done in patients who had not undergone transplant.

Lenalidomide (Revlimid) is currently approved for second-line treatment of multiple myeloma, but it is being positioned for first-line and maintenance settings and is already widely used in newly diagnosed patients in the United States. Manufacturer Celgene filed an application for newly diagnosed patients in Europe in December 2010, and plans to file in the U.S. in this segment in the second half of this year.

On April 8, the U.S. Food and Drug Administration announced that it was watching for reports of second malignancies in patients being treated with lenalidomide for multiple myeloma or myelodysplastic syndromes. The agency said it was not recommending any changes in the drug’s use as it believed "the benefits of Revlimid continue to outweigh the potential risks."

Questions about secondary cancers in lenalidomide patients surfaced in late 2010 at the American Society of Hematology meeting. The ASH data confirmed a more than doubling of progression-free survival with extended use of Revlimid, but all three studies showed a higher rate of secondary malignancies, ranging from 3% to 6.5%, compared with 1% to 2.6% for placebo.

All of the patients in the studies had received the alkylating agent melphalan at some point, and one theory has held the melphalan responsible for the higher rates.

New Standard of Care?

At a press conference held by the International Myeloma Foundation, leading clinicians said they supported maintenance treatment with lenalidomide based on the latest data. Trial investigators predicted a paradigm change founded on evidence of significant benefits for longer-term treatment with lenalidomide

In the posttransplant CALGB (Cancer and Leukemia Group B) study of patients who received a variety of induction therapies, those in the treatment arm received continuous daily treatment with lenalidomide until relapse. At a median follow-up of 28 months, there was a 90% overall survival rate for those on lenalidomide, compared with 83% on placebo, according to the study, which was backed by the National Cancer Institute.

Median time to progression was significantly higher at 48 months vs. 30.9 months for placebo, equivalent to a 56% reduction in risk of disease progression for patients on lenalidomide. Time to progression was longest in patients who had received lenalidomide as an induction therapy and as a maintenance treatment.

All patients benefited from treatment regardless of the degree of completeness of their response to treatment, said CALGB investigator Dr. Kenneth C. Anderson at the meeting. Dr. Anderson, the program director and chief of the division of hematologic neoplasias at the Dana-Farber Cancer Institute, Boston, described the results as a "tremendous advance."

"This is an extraordinary benefit. We want patients to live longer without cancer, but we obviously also want them to live longer in general. ... This is a historic moment for the treatment of this disease," he said. As a well-tolerated oral agent that can be used for maintenance for many years, the drug will change the paradigm for treatment of patients, Dr. Anderson predicted.

Secondary Cancer Rates

In the updated CALGB study, there were reports of 29 new cancers, including 7 that occurred prior to randomization. Of the rest, 8 of 231 on lenalidomide developed blood cancers vs. none of the 229 patients on placebo. And 10 of 231 on lenalidomide developed secondary solid cancers vs. only 4 of 229 for placebo.

However, Dr. Anderson concluded the benefits far outweigh the risks.

Speaking on behalf of the IFM (Intergroupe Francophone du Myélome) study group, Dr. Mario Boccadoro of the University of Torino, Italy, said that updated data from this study show a doubling of progression-free survival. An overall survival benefit has not been shown yet but is expected, he said.

Updated data were also released from the Celgene-sponsored MM-015 study, which compared combinations of treatments: melphalan/prednisone; melphalan/prednisone/Revlimid; and melphalan/prednisone/Revlimid plus Revlimid maintenance in patients aged 65 years or older. Secondary cancer rates respectively were 2.6% (4 cases); 5.9% (9 cases); and 8% (12 cases) for those on the MPR-R.

International Myeloma Foundation chairman Dr. Brian G.M. Durie, an attending physician at the Cedars-Sinai Medical Center in Los Angeles, suggested that the secondary malignancies seen in the Revlimid treatment arms were probably due to patients living longer.

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

Secondary Cancers Resurface in Lenalidomide Maintenance Trial Data