ArticlesSecond primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data
Introduction
In patients with multiple myeloma, substantial improvements in survival have been obtained since the introduction of high-dose melphalan and autologous stem-cell transplantation (ASCT), as well as with bortezomib and the immunomodulatory agents thalidomide and lenalidomide (Celgene Corporation, Summit, NJ, USA).1, 2, 3 Increased survival, and therefore increased life expectancy, has led to renewed concern about the risk of second primary malignancies.4, 5
Many factors contribute to the risk of second primary malignancies in myeloma, such as age. In the general population, the incidence of cancer per year of life is 0·3% in individuals aged 45–49 years, 1·7% in those aged 65–69 years, and 2·3% in those aged 85 years or older.6 Myeloma also increases the risk of developing second primary malignancies. Registry data show that patients with myeloma are 1·26 times more at risk of having any second primary malignancies, and about twice as likely to develop haematological second primary malignancies than the general population, mainly as a result of myelodysplastic syndrome and acute myeloid leukaemia.7
A well known treatment-related risk factor for second primary malignancies is extended exposure to the cytotoxic agent melphalan. In the pretransplant era, 5-year cumulative incidence of myelodysplastic syndrome and acute myeloid leukaemia in patients who received alkylating agents was 3%.8 The same analysis showed that melphalan was more oncogenic than cyclophosphamide, and reported a relation between length of treatment with melphalan and myelodysplastic syndrome and incidence of acute myeloid leukaemia.8 In a recent report, 5-year cumulative incidence of myelodysplastic syndrome and acute myeloid leukaemia after ASCT was 1·0%.9 Regarding immunomodulatory agents, there is a suggestion of an increased risk of developing second primary malignancies with exposure to thalidomide.9 Furthermore, three phase 3 trials reported an increased incidence of second primary malignancies in patients with newly diagnosed myeloma given lenalidomide maintenance after melphalan-based induction, compared with patients who did not receive lenalidomide.10, 11, 12 In one trial, after 3 years, invasive second primary malignancies were noted in 7% of patients who received lenalidomide and 3% of those who did not.10 No significantly increased risk of developing invasive second primary malignancies was reported in relapsed patients who received lenalidomide and dexamethasone.13
We did a meta-analysis of individual patient data from phase 3 trials in which at least one group received lenalidomide as part of first-line myeloma treatment. The primary purpose of this study was to compare the incidence of second primary malignancies in patients with and without lenalidomide exposure. Secondary aims were to assess the effects of treatment regimen (eg, coadministration with melphalan, cyclophosphamide, and dexamethasone) on risk of developing second primary malignancies, and compare the risk of death due to second primary malignancy versus the risks of death due to myeloma progression, or adverse events related to myeloma treatment. We broadly divided our analysis by patients who received lenalidomide versus those who did not—and subsequently, into those who received lenalidomide in combination with melphalan, cyclophosphamide, or dexamethasone—based on clinical evidence that these agents have different oncogenic effects.
Section snippets
Search strategy and selection criteria
We searched PubMed, and abstracts from the annual meetings of the American Society of Clinical Oncology, the American Society of Hematology, and from the International Myeloma Workshop, which occurs every 2 years, with the search terms “lenalidomide” and “phase 3 trial/study” (or “randomised trial/study”), and “myeloma” and “up-front therapy” (or “diagnosis”). Searches were limited to reports published in English. The date of the last search was Dec 30, 2012. Randomised, controlled, phase 3
Results
Our initial search identified nine eligible trials: eight investigator-sponsored trials11, 12, 16, 17, 18, 19, 20, 21 and one manufacturer-sponsored trial.10 At the time of analysis, after contacting the principal investigators of these studies, we excluded two studies because patient-level data were unobtainable;11, 21 four of the seven remaining trials were not published in peer-reviewed journals.16, 17, 18, 19 Descriptions of the seven trials included in the meta-analysis, including key
Discussion
This meta-analysis of pooled individual participant data from 3254 patients with newly diagnosed multiple myeloma shows that lenalidomide is associated with an increased rate of haematological second primary malignancies. We noted no difference in the incidence of solid tumours. The increased risk of developing haematological second primary malignancies was mainly driven by coexposure to lenalidomide and melphalan; we found no difference in the risk of developing haematological second primary
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