Introduction
The history of thalidomide
How thalidomide modulates the immune system and tumor microenvironment
Thalidomide in multiple myeloma care
The expanding role of thalidomide
Ensuring safe thalidomide use
Future directions
References
Further reading
Once synonymous with one of medicine's greatest tragedies, thalidomide has re-emerged through decades of scientific discovery as a cornerstone of modern immunomodulatory therapy, reshaping the treatment of multiple myeloma while providing enduring lessons in drug development and patient safety.
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Introduction
Few drugs have undergone a clinical trajectory as extreme as thalidomide, from widespread use to global withdrawal following catastrophic teratogenic effects. The subsequent reintroduction of thalidomide in carefully controlled settings has repositioned it as a clinically important treatment for multiple myeloma and erythema nodosum leprosum (ENL), while its use in many other inflammatory diseases remains investigational or limited to selected refractory cases.1,4,7
The history of thalidomide
Thalidomide was developed during the early 1950s and introduced by the German company Chemie Grünenthal as the nonbarbiturate sedative Contergan in the mid-1950s. Historical accounts differ on whether its earliest development began at CIBA or Grünenthal.2,4 However, independent observations in 1961, William McBride and Widukind Lenz linked prenatal thalidomide exposure to severe congenital anomalies like phocomelia and amelia, which culminated in its withdrawal from most major commercial markets beginning later that year; withdrawal and prohibition elsewhere continued through the remainder of the decade.2
Thalidomide teratogenicity involves binding to cereblon (CRBN), the substrate receptor of a CUL4–DDB1 E3 ubiquitin ligase complex. This interaction alters the complex's activity and substrate recognition; downstream disruption of developmental signaling, including reduced fibroblast growth factor 8 activity and impaired angiogenic outgrowth, has been proposed to contribute to limb malformations. The complete causal sequence is more complex than a single vasculogenic pathway.3,6
Preclinical testing at the time was inadequate and did not include reproductive-toxicity studies comparable to those required today; later work also demonstrated marked species differences in susceptibility and drug metabolism. This disaster, which affected an estimated 10,000 infants worldwide, in addition to uncounted miscarriages and stillbirths, led to sweeping legislative reform, strengthening the United States Food and Drug Administration (FDA) regulatory process, informed-consent requirements, drug-manufacturer transparency, and expectations for reproductive-toxicity testing.2,7
In 1964, Dr. Jacob Sheskin reported the rapid improvement of erythema nodosum leprosum (ENL) during thalidomide treatment. By 1998, thalidomide gained FDA approval for ENL, under stringent controls intended to prevent fetal exposure. For example, a response rate of 32% was subsequently observed in refractory multiple myeloma, which has historically been associated with poor patient prognoses.1,2,4,6
By 2006, the U.S. FDA approved thalidomide in combination with dexamethasone for newly diagnosed multiple myeloma patients, with subsequent approvals for thalidomide derivatives lenalidomide and pomalidomide in 2006 and 2013, respectively.5
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How thalidomide modulates the immune system and tumor microenvironment
Thalidomide selectively inhibits tumor necrosis factor-α (TNF-α) production in monocytes, primarily through enhanced degradation of TNF-α messenger ribonucleic acid (mRNA). Thalidomide also modulates nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) signaling and the production of several inflammatory cytokines.2,4
Thalidomide also co-stimulates T cells, increases interleukin-2 production, and can enhance natural killer cell-mediated cytotoxicity. In multiple myeloma, these immune effects complement direct antiproliferative and pro-apoptotic actions against malignant plasma cells.2,6
Multiple myeloma is associated with increased bone marrow microvascular density and elevated serum vascular endothelial growth factor (VEGF) concentrations. Targeting these angiogenic and microenvironmental pathways, thalidomide inhibits angiogenic responses induced by VEGF and basic FGF, in addition to disrupting adhesion molecule-mediated communication between malignant plasma cells and the bone marrow stroma.2
Thalidomide binds cereblon, a substrate receptor within an E3 ubiquitin ligase complex, alters its substrate specificity, and redirects it toward the degradation of transcription factors critical for myeloma cell survival.2,3,6 For thalidomide-related immunomodulatory drugs, degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) reduces expression of IRF4 and MYC in myeloma cells while relieving repression of IL-2 in T cells.6 Lenalidomide and pomalidomide were developed as more potent analogs with distinct toxicity profiles, but differences among these agents cannot be explained solely by cereblon-binding affinity.1,2,6
Thalidomide in multiple myeloma care
In the treatment landscape described by the reviewed studies, the thalidomide-dexamethasone combination treatment was associated with overall response rates of more than 60% in newly diagnosed patients.2,6
The subsequent addition of bortezomib to this treatment protocol yielded complete or near-complete response rates of 31% in a phase III study of 474 patients. Among transplant-ineligible patients, the combination of melphalan, prednisone, and thalidomide has been associated with overall survival of 40 to 52 months and median progression-free survival of 15 to 28 months.2 These figures reflect the clinical evidence available in the predominantly 2000s-era studies reviewed here and should not be interpreted as defining all current preferred regimens.2,5
Thalidomide has been shown to improve progression-free survival in post-transplant maintenance trials. Nevertheless, one study reported that neurological toxicities caused drug discontinuation in 60% of patients, which complicates the interpretation of its net clinical benefit.2 Moreover, one population-based cohort study of 1,264 myeloma patients found no significant difference in mortality risk between thalidomide and lenalidomide users; however, lenalidomide was associated with a lower risk of developing peripheral neuropathy as compared to thalidomide.5 In that study, neuropathy occurred in 35% of new thalidomide users and 29% of new lenalidomide users; after adjustment, lenalidomide was associated with a 29% lower hazard of neuropathy, while the hazard of death was equivalent.5
The Return of Thalidomide
The expanding role of thalidomide
ENL is characterized by a reactive inflammatory state that causes painful skin nodules and systemic inflammation in patients with multibacillary leprosy. Thus, the selective TNF-α suppression by thalidomide provides a mechanistic basis for its efficacy in this condition.4
The anti-inflammatory properties of thalidomide are largely mediated through cytokine modulation, NF-κB inhibition, and suppression of monocyte activation, highlighting its broader immunomodulatory activity.4 To this end, thalidomide has been investigated for its potential therapeutic efficacy in treating a wide range of immune-mediated conditions, including Crohn's disease, Behçet's syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis. Evidence for these uses is substantially less established than for ENL and multiple myeloma.2,3,7
Thalidomide has also been studied for human immunodeficiency virus (HIV)-associated aphthous ulcers, Kaposi's sarcoma, and refractory gastrointestinal bleeding from angiodysplasia. Importantly, these clinical indications remain largely investigational or are reserved for patients who have failed standard therapies.2
Thalidomide has been investigated as a treatment for solid tumors where angiogenesis contributes to disease pathogenesis, including renal cell, hepatocellular, and prostate cancers.2 Although some early studies reported biological or clinical activity, the supplied literature does not establish thalidomide as standard therapy for these solid tumors.1,2,7 Variable preliminary activity has also been reported separately in myelodysplastic syndromes, myelofibrosis, and Waldenström macroglobulinemia, but these uses were investigational in the reviewed literature.2,7
Ensuring safe thalidomide use
The teratogenicity of thalidomide remains a significant limitation, with limb malformations typically manifesting when the drug is ingested by pregnant women 34-49 days after the last menstrual period.2 Exposure during this critical interval may cause severe defects after even a single dose, and pregnancy is contraindicated throughout treatment.2,7
In the U.S., access to thalidomide was historically regulated through the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program, which required participation by prescribers, dispensing pharmacies, and patients, along with mandatory pregnancy testing and documentation of contraception for women of childbearing potential.2,7 This restricted distribution model informed later risk-management systems for lenalidomide and pomalidomide.2
Peripheral neuropathy is a clinically significant and dose-limiting adverse effect of thalidomide treatment. This symptom typically manifests as a sensory, axonal neuropathy with painful paresthesia or numbness.2,5,7 Its frequency and severity increase with cumulative exposure and treatment duration, and symptoms may be irreversible if not recognized promptly.2,7
Genetic susceptibility, through specific single-nucleotide polymorphisms, may contribute to individual risk of neuropathy.2 Additional toxicities of clinical relevance include somnolence, fatigue, constipation, rash, neutropenia, bradycardia, hypothyroidism, and venous thromboembolism. Thrombotic risk is particularly increased when thalidomide is combined with dexamethasone or chemotherapy.2,7
Structured monitoring and neurological assessment should be conducted at baseline and at regular intervals to detect emerging neuropathy, with dose reductions or treatment interruption determined by the development of early sensory changes.7 Prophylactic anticoagulation with aspirin, low-molecular-weight heparin, or warfarin may be indicated according to patient-specific thrombotic and bleeding risk, particularly when thalidomide is combined with dexamethasone or chemotherapy.2 Compliance with applicable pregnancy-prevention and restricted-distribution requirements, including pregnancy testing, effective contraception, and repeated counseling, further constitutes an essential component of safe prescribing.7
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Future directions
Lenalidomide and pomalidomide were originally developed as structural analogs of thalidomide, intended to preserve antitumor activity while improving tolerability and potency.2 Lenalidomide exhibits greater T-cell co-stimulatory and antiproliferative activity, along with significantly lower neuropathy risk. Pomalidomide is a later-generation immunomodulatory analog with potent anti-myeloma and immunomodulatory activity.1,2
The discovery of cereblon as the molecular target of thalidomide has established a rational basis for mechanism-guided drug development. Cereblon-modifying agents, or immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide, are shifting drug development from empirical to mechanistic frameworks. Cereblon abundance and function have been investigated as determinants of IMiD sensitivity, although the supplied papers do not establish cereblon expression alone as a validated clinical biomarker.3,6
Although progressive refinement in IMiDs has incrementally improved the therapeutic index, the teratogenicity of this class of drugs remains a serious concern. The potential availability of lower-cost thalidomide generics in resource-limited settings similarly warrants further research.1,5 Any expanded use must therefore balance affordability against neuropathy, thrombosis, sedation, and the continuing need for rigorous pregnancy prevention.5,7
References
- Zhou, S., Wang, F., Hsieh, T.C., et al. (2013). Thalidomide – a notorious sedative, to a wonder anticancer drug. Current Medicinal Chemistry 20(33); 4102-4108. DOI: 10.2174/09298673113209990198. https://www.eurekaselect.com/article/56227.
- Rehman, W., Arfons, L. M., & Lazarus, H. M. (2011). The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development. Therapeutic Advances in Hematology 2(5); 291-308. DOI: 10.1177/2040620711413165. https://journals.sagepub.com/doi/10.1177/2040620711413165.
- Ito, T., Ando, H., & Handa, H. (2011). Teratogenic effects of thalidomide: molecular mechanisms. Cellular and Molecular Life Sciences 68(9); 1569-1579. DOI: 10.1007/s00018-010-0619-9. https://link.springer.com/article/10.1007/s00018-010-0619-9.
- Teo, S., Resztak, K. E., Scheffler, M. A., et al. (2002). Thalidomide in the treatment of leprosy. Microbes and Infection 4(11); 1193-1202. DOI: 10.1016/s1286-4579(02)01645-3. https://linkinghub.elsevier.com/retrieve/pii/S1286457902016453.
- Luo, J., Gagne, J. J., Landon, J., et al. (2017). Comparative effectiveness and safety of thalidomide and lenalidomide in patients with multiple myeloma in the United States of America: a population-based cohort study. European Journal of Cancer 70; 22-33. DOI: 10.1016/j.ejca.2016.10.018. https://www.ejcancer.com/article/S0959-8049(16)32502-3/abstract.
- Licht, J. D., Shortt, J., & Johnstone, R. (2014). From anecdote to targeted therapy: the curious case of thalidomide in multiple myeloma. Cancer Cell 25(1); 9-11. DOI: 10.1016/j.ccr.2013.12.019. https://www.cell.com/cancer-cell/fulltext/S1535-6108(13)00545-X
- Ghobrial, I. M., & Rajkumar, S. V. (2003). Management of thalidomide toxicity. Journal of Supportive Oncology 1(3); 194-205. https://pmc.ncbi.nlm.nih.gov/articles/PMC3134146/
Further Reading
Last Updated: Aug 4, 2026