Lenalidomide
| Evidence Level: L2 | Predicted Indications: 6 |
Table of Contents
Lenalidomide: From Multiple Myeloma/Myelodysplastic Syndrome to Myeloid Leukemia
One-Sentence Summary
Lenalidomide is an immunomodulatory agent internationally established for multiple myeloma and transfusion-dependent anaemia in low-risk myelodysplastic syndrome (MDS) with del(5q). The TxGNN model predicts it may also be effective for Myeloid Leukemia (AML/MDS spectrum), with 62 registered clinical trials and 20 publications currently supporting this direction — though a key regulatory data gap limits immediate action in this market.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in this evidence pack; internationally, Lenalidomide (Revlimid) is established for multiple myeloma and transfusion-dependent anaemia in low-risk MDS with del(5q) |
| Predicted New Indication | Myeloid Leukemia (AML/MDS spectrum) |
| TxGNN Prediction Score | 99.49% |
| Evidence Level | L2 |
| UK Market Status | Not marketed (per this evidence pack) |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in this evidence pack. Based on known pharmacology, Lenalidomide is a thalidomide-derived immunomodulatory imide drug (IMiD) that binds cereblon (CRBN), promoting ubiquitination and degradation of IKZF1/IKZF3 transcription factors. This mechanism underlies its established efficacy in multiple myeloma and in del(5q) MDS, where it also has a direct cytotoxic effect on the deleted clone.
Myelodysplastic syndrome and acute myeloid leukemia (AML) are closely related clonal haematopoietic stem-cell disorders — MDS progresses to AML in roughly one-third of patients, and both share overlapping cytogenetic and molecular abnormalities. Since Lenalidomide’s proven efficacy already spans the MDS spectrum, mechanistic extension to AML is biologically plausible.
This is directly supported by the literature base: PMID 39881283 demonstrates that the histone demethylase KDM5C enhances AML cell sensitivity to Lenalidomide by stabilising cereblon, providing a direct mechanistic bridge between the drug’s known CRBN pathway and AML cell biology. PMID 23316859 (“Lenalidomide as a novel treatment of acute myeloid leukemia”) and a subsequent meta-analysis (PMID 30271212) further corroborate that the same immunomodulatory/anti-angiogenic mechanism translates into measurable clinical activity in AML, particularly in older or unfit patients.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT01029262 | Phase 3 | Completed | 239 | Randomised, double-blind, placebo-controlled trial of Lenalidomide vs placebo for transfusion-dependent anaemia in low/int-1-risk MDS without del(5q) |
| NCT00843882 | Phase 3 | Active, not recruiting | 247 | Lenalidomide alone vs combined with epoetin alfa for major erythroid response in low/int-1-risk MDS with symptomatic anaemia |
| NCT01358734 | Phase 2 | Completed | 88 | High-dose Lenalidomide vs sequential azacitidine+Lenalidomide vs azacitidine alone in older adults with newly diagnosed AML |
| NCT00065156 | Phase 2 | Completed | 148 | Pivotal single-arm study of Lenalidomide monotherapy in RBC transfusion-dependent MDS with del(5q) |
| NCT00546897 | Phase 2 | Completed | 48 | Lenalidomide in untreated AML (age ≥60) without chromosome 5q abnormalities |
| NCT00360672 | Phase 2 | Completed | 27 | Lenalidomide in relapsed/refractory AML or high-risk MDS with chromosome 5 abnormalities |
| NCT01772420 | Phase 2 | Completed | 52 | Lenalidomide + eltrombopag for symptomatic anaemia in low/int-1-risk MDS |
| NCT02126553 | Phase 2 | Completed | 29 | Lenalidomide maintenance therapy in high-risk AML patients in remission |
| NCT01743859 | Phase 2 | Completed | 37 | Sequential azacitidine and Lenalidomide for relapsed/refractory AML |
| NCT02472691 | Phase 2 | Completed | 50 | Lenalidomide + azacitidine + donor lymphocyte infusion for MDS/CMML/AML relapse after allogeneic stem cell transplant |
A further ~52 trials (Phase 1 dose-finding, combination, and post-transplant maintenance studies) are on file but not shown above; see evidence pack for the complete list.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31221030 | 2019 | Systematic review & meta-analysis | Hematology (Amsterdam) | Efficacy and adverse events of azacitidine + Lenalidomide in AML, MDS and CMML |
| 30271212 | 2018 | Systematic review & meta-analysis | Cancer Management and Research | Efficacy and safety of Lenalidomide for AML treatment |
| 37874917 | 2023 | Review | Blood | Clinical decision-making and treatment framework for MDS |
| 37288607 | 2023 | Review | American Journal of Hematology | 2023 update on MDS diagnosis, risk-stratification and management |
| 24656536 | 2014 | Review | Lancet | Overview of MDS pathophysiology and progression to AML |
| 23644421 | 2013 | Review | Leukemia | Rationale for azacitidine + Lenalidomide combination in MDS/AML |
| 23316859 | 2013 | Review | Expert Opinion on Investigational Drugs | Lenalidomide as a novel treatment for AML |
| 35512188 | 2022 | Original research | Blood | Lenalidomide associated with development of TP53-mutated therapy-related myeloid neoplasms (key safety signal) |
| 39881283 | 2025 | Mechanistic study | Cellular & Molecular Biology Letters | KDM5C stabilises cereblon, enhancing AML cell sensitivity to Lenalidomide — direct mechanistic link |
| 35320468 | 2022 | Review | Current Treatment Options in Oncology | New approaches to MDS treatment, including IMiD-based regimens |
UK Market Information
No marketing authorisations are recorded in this evidence pack for the UK (total_licenses: 0, market_status: Not marketed/Not marketed). This does not necessarily reflect Lenalidomide’s true global licensing status (it is marketed elsewhere as Revlimid® for multiple myeloma and del(5q) MDS) — it reflects a gap in this dataset that should be independently verified against the MHRA product database and BNF before any decision is finalised.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (Immunomodulatory imide drug, IMiD; not a conventional cytotoxic) |
| Myelosuppression Risk | High — neutropenia and thrombocytopenia are well-documented, often dose-limiting toxicities across the MDS/AML trial programme |
| Emetogenicity Classification | Low |
| Monitoring Items | Full blood count (weekly for initial cycles, then periodically), renal function (dose adjustment required in renal impairment), venous thromboembolism risk assessment |
| Handling Protection | Oral antineoplastic/immunomodulatory agent with significant teratogenic risk — requires controlled distribution and pregnancy prevention programme safeguards; standard cytotoxic handling precautions (rather than full cytotoxic reconstitution controls) apply |
Safety Considerations
Please refer to the SmPC and BNF for safety information. Report suspected adverse reactions via the Yellow Card Scheme.
(Note: literature evidence, notably PMID 35512188, indicates an association between Lenalidomide and TP53-mutated therapy-related myeloid neoplasms — this signal should be reviewed alongside formal SmPC warnings once available.)
Conclusion and Next Steps
Decision: Hold
Rationale: Clinical trial and mechanistic evidence for Lenalidomide in AML/MDS is substantial (L2, including one completed Phase 3 RCT and multiple completed Phase 2 studies), but a Blocking data gap exists — no UK/TFDA safety data (warnings, contraindications) is currently available, and this evidence pack records no UK marketing authorisation, preventing entry into the S1 safety review stage.
To proceed, the following is needed:
- Confirm actual UK/MHRA marketing authorisation status for Lenalidomide (Revlimid®) independent of this evidence pack
- Obtain SmPC warnings, contraindications and DDI data from MHRA/BNF
- Detailed mechanism of action documentation from DrugBank
- Formal off-label evidence review for the AML indication, including safety signal follow-up on TP53-mutated therapy-related myeloid neoplasms (PMID 35512188)
- Assessment of pregnancy prevention programme/REMS-equivalent requirements applicable in the UK
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.