Lenalidomide and the Risk for Second Cancers in Myeloma

Roxanne Nelson

February 20, 2014

New treatments for multiple myeloma have greatly increased survival, and this longer life expectancy has led to renewed concern about the risk for secondary malignancies.

According to a study looking specifically at lenalidomide (Revlimid, Celgene), published online February 11 in the Lancet Oncology, it increases the risk for hematologic second primary malignancies. However, the risk appears to be primarily driven by coexposure to melphalan.

There was no difference in risk for lenalidomide plus cyclophosphamide, lenalidomide plus dexamethasone, and melphalan alone.

"These data suggest that the future role of oral melphalan in combination with lenalidomide should be readdressed using alternatives, such as cyclophosphamide or alkylating-free combinations," write Antonio Palumbo, MD, from the University of Torino in Italy, and colleagues.

The researchers note that the risk for death from multiple myeloma or from treatment-related adverse effects was higher than the risk for death from secondary primary malignancies.

"The overwhelming message from this meta-analysis is that the risk of developing second primary malignancies after treatment with lenalidomide is low, and far outweighed by the risk of death from myeloma," writes Guy Pratt, MD, from the University of Birmingham, United Kingdom, in an accompanying comment. "Nevertheless, the combination of oral melphalan and lenalidomide might be best avoided."

Longer-term Study Needed

In the 502 patients who received lenalidomide for more than 2 years, there was no effect on risk of second primary malignancies. However, follow-up of a larger cohort of patients receiving lenalidomide for more than 2 years "might be needed for reassurance regarding this point, particularly since lenalidomide is still given until disease progression," he notes.

As survival for patients with myeloma increases beyond 7 to 10 years, it is unclear whether the risk for second primary malignancies will become clinically relevant, Dr. Pratt adds. "In future studies, second primary malignancies should be carefully recorded and assessed for any possible links with lenalidomide dose and duration, particular combination regimens, and possible host biological factors."

Study Details

In their meta-analysis, Dr. Palumbo and colleagues compared the incidence of second primary malignancies in patients with and without lenalidomide exposure.

They looked at randomized controlled phase 3 trials in which at least 1 group received lenalidomide. All patients in the study cohort had newly diagnosed multiple myeloma and were recruited from January 1, 2000 to December 15, 2012.

Of the 3218 patients from 7 trials with data available, 2620 had been treated with lenalidomide and 598 had not.

Dr. Pratt notes that one of the limitations of this study is that it excluded several studies, either because they were ongoing and unpublished or because the data were unavailable.

Most Deaths Due to Myeloma

The 5-year cumulative incidence of hematologic second primary malignancies was higher in patients treated with lenalidomide than in those who were not (3.1% vs 1.4%; hazard ratio [HR], 3.8; P = .029).

In addition, the risk was significantly higher in patients treated with lenalidomide plus oral melphalan than in those treated with melphalan alone (HR, 4.86; P < .0001).

However, there was no increase in risk, compared with melphalan alone, for lenalidomide plus cyclophosphamide (HR, 1.26; P = .75) or for lenalidomide plus dexamethasone (HR, 0.86; P = .76).

Both solid and hematologic second primary malignancies were documented in 105 patients (3% of the entire cohort) — 87 who had received lenalidomide and 18 who had not. The researchers note that incidence of all second primary malignancies was significantly higher in patients who received lenalidomide than in those that did not (HR, 1.55; P = .037).

Solid second primary malignancies were documented in 70 patients (2% of the entire cohort) — 55 who had received lenalidomide and 15 who had not. The median time to developing another malignancy was longer in patients treated with lenalidomide than in those who were not (25 vs 20 months).

In addition, hematologic malignancies were documented in 35 patients (1% of the entire cohort) — 32 who had received lenalidomide and 3 who had not. The median time to occurrence was longer in the lenalidomide group (29 vs 20 months).

At a median follow-up of 26 months, 688 patients (21% of the entire cohort) had died — 545 who had received lenalidomide and 143 who had not.

At 5 years, the cumulative incidence of death related to the secondary cancers was higher with lenalidomide, but did not reach significance (HR, 2.93; P = .30). In both groups, mortality related to myeloma and adverse events (most frequently infection and cardiovascular events) was higher than that related to second primary malignancies, the researchers note.

The study was funded by Celgene, the manufacturer of lenalidomide. A number of the authors report financial ties to industry, including Celgene. Dr. Pratt reports receiving travel grants and speaking honoraria from Celgene.

Lancet Oncol. Published online February 11, 2014. Abstract, Comment


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