We are concerned about the conclusions reached in the July 30th communication by Mahony et al. entitled, “Pomalidomide…in vitro” published in PNAS (1). Under the conditions in which the authors conducted their experiments, teratogenicity or neurotoxicity was not observed. However, neither the zebrafish nor the chicken embryo assays are definitive for predicting these drug-related adverse effects. The lack of a finding does not mean that this finding will not occur in a different animal or even in the same species if the experiment is conducted differently. For example, lenalidomide, a marketed drug in the same class as thalidomide and pomalidomide, produced thalidomide-like fetal malformations in monkeys (2), but not in rabbits (3). Both thalidomide and pomalidomide are teratogenic in rabbits.
The detection of a teratogenic or neuropathic effect in any animal from a licensed and marketed drug overrides any negative observations made in other models except perhaps in humans. As stated in the FDA approved Package Insert (4), “pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis”. Fetal abnormalities observed in rabbits included cardiac malformations, and anomalies in limbs and digits (similar to those observed with thalidomide). In rats, pomalidomide produced fetal visceral defects and abnormalities in the vertebral elements. In clinical studies of pomalidomide in multiple myeloma, 7–10% of treated patients did develop new or worsening peripheral neuropathy.
Our concern is that a casual review of this article might lead clinicians to conclude that they do not need to follow the stringent Risk Evaluation and Management System (REMS), Pomalyst REMS, which is a mandatory aspect for prescribing this drug to patients. The approved product labeling including Pomalyst REMS must be followed to prevent a fetal exposure. Clinicians should monitor their patients for emerging or worsening neuropathy.
Footnotes
Conflict of interest statement: The authors declare a conflict of interest (such as defined by PNAS policy). The authors work for Celgene Corporation that is currently marketing pomalidomide - the subject of the article in question.
References
- 1.Mahony C, et al. Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro. Proc Natl Acad Sci USA. 2013;110(31):12703–12708. doi: 10.1073/pnas.1307684110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Revlimid (Lenalidomide; Package Insert). Summit, NJ: Celgene Corporation; 2005, revised 2013.
- 3.Christian MS, et al. Evaluation of the developmental toxicity of lenalidomide in rabbits. Birth Defects Res B Dev Reprod Toxicol. 2007;80(3):188–207. doi: 10.1002/bdrb.20115. [DOI] [PubMed] [Google Scholar]
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