CHICAGO – That lenalidomide can improve overall and progression-free survival rates in multiple myeloma patients is evident, but whether the drug also increases their risk of second primary cancers is debatable.
Of three studies looking at the question, only one found an association between secondary primary malignancies and lenalidomide (Revlimid) in first-line therapy, investigators reported at the American Society of Clinical Oncology annual meeting.
And even then the risk was low – far less than the risk of death from multiple myeloma without a lenalidomide-containing regimen, said Dr. Antonio P. Palumbo of the University of Torino (Italy) and the Italian Multiple Myeloma Study Group.
Two other studies – one with 6-year follow-up data on continuous lenalidomide in first-line therapy and the other on lenalidomide in relapsed/refractory disease – failed to spot a signal for second cancer risk.
"I think it’s fair to say that currently we lack clear answers due to small numbers and study limitations," said Dr. C. Ola Landgren of the National Cancer Institute, the invited discussant for all three papers.
"I think we need to put both benefits and risks into the algorithms when we think about these things. ... I also think despite the fact that we don’t have clear data, we always have to discuss these things with our patients, and we as doctors have to stay updated as more information emerges," he said.
Three randomized clinical trials stirred the debate by reporting in separate presentations at the 2010 annual meeting of the American Society of Hematology that they saw more hematologic malignancies in lenalidomide treatment arms than in control groups (McCarthy, P.L. et al, abstract 37; Attal, M. et al, abstract 310; Palumbo, A. et al, abstract 622).
Despite these reports, 25 years after a multiple myeloma diagnosis, the cumulative incidence of all second cancers is about 8%, whereas the cumulative probability of death from competing causes is more than 90%, suggesting that any risk of a second malignancy is far outweighed by the risk of multiple myeloma and its sequelae, Dr. Landgren pointed out.
First-Line Therapy: Italian Experience
In the first of the three studies presented at ASCO 2011, Dr. Palumbo’s group looked at second-cancer rates among patients randomly assigned to first-line therapy with either melphalan and prednisone alone, or to melphalan, prednisone, and lenalidomide with or without lenalidomide maintenance in the international MM-015 trial.
They found that at a median follow-up of 30 months, 12 of 150 (8%) patients on melphalan-prednisone plus lenalidomide with maintenance (MPR-R) developed an invasive second primary malignancy, compared with 9 of 152 patients (5.9%) on the same combination without lenalidomide maintenance (MPR), and 4 of 153 (2.6%) patients on melphalan and prednisone only.
Hematologic malignancies accounted for 7 of the 12 new cancers among patients treated with MPR-R, 5 of 9 on MPR, and 1 of 4 on MP. Solid tumors accounted for the remaining invasive cancers in each group. In addition, one patient on MPR-R, four on MPR, and five on MP developed nonmelanoma skin cancers.
In an additional analysis of 9 pooled experimental studies, the investigators found that among 1,788 patients followed for more than 1 year, the risk of dying of myeloma was greater than 40% out to 7 years compared with about a 2% risk of developing a second hematologic malignancy, and a 3% risk of developing a solid tumor.
Among patients receiving lenalidomide and an alkylating agent, the risk of developing any malignancy was around 7%, and the risk of dying of myeloma was about 27%. The risk of a second malignancy was lower – about 2% out to 6 years– among those patients who did not receive lenalidomide, but their risk of dying of myeloma was about 45%, Dr. Palumbo said.
He also pointed out that in the general population, the risk of a second primary malignancy among 65- to 74-year-olds is around 2% per 100 patient-years, and that the risk doubles among people 85 and older.
First-Line Therapy: BiRD Regimen
In the second study, Dr. Adriana Rossi and her colleagues at Cornell University, New York, and New York–Presbyterian Hospital examined the incidence of second primary cancers in 68 transplant-eligible patients receiving lenalidomide in first-line therapy as part of the BiRD regimen (clarithromycin [Biaxin], lenalidomide, and dexamethasone).
There were five solid tumors (two colon, one metastatic melanoma, one pancreas, and one prostate), but no hematologic malignancies. The melanoma was diagnosed 8 months after the primary myeloma diagnosis; the other cases occurred 25-53 months after the initial myeloma diagnosis (median, 31.2 months). The authors found no association between second primary cancers and a specific multiple myeloma chromosomal abnormality, prior malignancy, transplant status, study status, or sex.