Lenalidomide
| Evidence Level: L2 | Predicted Indications: 6 |
Table of Contents
- Lenalidomide
- Lenalidomide: From Multiple Myeloma and del(5q) Myelodysplastic Syndrome to Myeloid Leukemia
Lenalidomide: From Multiple Myeloma and del(5q) Myelodysplastic Syndrome to Myeloid Leukemia
One-Sentence Summary
Lenalidomide is an oral immunomodulatory drug. The literature in the Evidence Pack describes its FDA approval for transfusion-dependent anemia in low-risk del(5q) myelodysplastic syndrome (MDS) and for multiple myeloma. The TxGNN model predicts it may be effective for myeloid leukemia, with 50 registered clinical trials and 20 publications linked to this direction. Most of that evidence is small Phase 1/2 studies, and several trials ended early.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Multiple myeloma and del(5q) MDS (from published literature; the US license records contain no indication text) |
| Predicted New Indication | Myeloid leukemia |
| TxGNN Prediction Score | 99.49% |
| Evidence Level | L2 |
| US Market Status | ✓ Marketed |
| Number of NDAs | 20 licenses on record (the five listed are all ANDAs, i.e. generics) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data from DrugBank is not available in the Evidence Pack. The mechanistic rationale below comes from the pack’s analysis notes.
Lenalidomide binds cereblon (CRBN) and redirects the CRL4-CRBN E3 ubiquitin ligase to degrade specific target proteins. One of them is CK1alpha (CSNK1A1, encoded on chromosome 5q32). It also modulates immune function. This gives a plausible basis for activity in myeloid malignancies, especially those with a chromosome 5q deletion.
Its established uses in myeloma and del(5q) MDS are closely related to myeloid leukemia. MDS often progresses to acute myeloid leukemia (AML), and many trials enroll MDS and AML patients together. Most of the supporting work combines lenalidomide with azacitidine or chemotherapy in older or previously treated patients.
The evidence is not consistent. Several trials were terminated early, and the meta-analysis and retrospective studies do not show a uniform benefit.
Clinical Trial Evidence
Ten of the 50 linked trials are shown, chosen for relevance and design.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01358734 | Phase 2 | Completed | 88 | Randomized comparison of high-dose lenalidomide, sequential azacitidine + lenalidomide, and azacitidine alone in newly diagnosed AML, age ≥65 |
| NCT01442714 | Phase 2 | Terminated | 33 | Azacitidine + lenalidomide in previously treated elderly AML and high-risk MDS (VIREL2) |
| NCT00867308 | Phase 2 | Terminated | 32 | High-dose lenalidomide in MDS and AML with trilineage dysplasia |
| NCT00352001 | Phase 1/2 | Completed | 37 | Lenalidomide + azacitidine in advanced MDS |
| NCT00831766 | Phase 1/2 | Completed | 51 | Idarubicin + cytarabine followed by lenalidomide in RAEB-2 MDS or untreated AML |
| NCT01578954 | Phase 1 | Completed | 20 | Dose-finding of lenalidomide as reinduction/consolidation and maintenance in AML patients ≥60 |
| NCT04490707 | Phase 3 | Unknown | 60 | Azacitidine + lenalidomide maintenance guided by MRD monitoring in elderly or unfit AML |
| NCT01556477 | Phase 2 | Unknown | 72 | Randomized azacitidine ± lenalidomide in high-risk MDS/AML with del(5q) |
| NCT02472691 | Phase 2 | Completed | 50 | Lenalidomide added to azacitidine and donor lymphocyte infusion for relapse after allogeneic transplant |
| NCT01301820 | Phase 2 | Completed | 120 | Alternating lenalidomide and azacitidine maintenance after LIA induction in elderly poor-prognosis AML |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 35277655 | 2022 | Randomized Phase II | Leukemia | Azacitidine ± lenalidomide in higher-risk MDS and AML with del(5q) (no abstract available) |
| 31221030 | 2019 | Meta-analysis | Hematology | Efficacy and adverse events of azacitidine + lenalidomide in AML, high-risk MDS and CMML |
| 37259567 | 2023 | Prospective trial (Azalena) | Haematologica | Azacitidine + lenalidomide + donor lymphocyte infusion as first salvage for post-transplant relapse of MDS, AML or CMML |
| 30653424 | 2019 | Clinical study | J Clin Oncol | Lenalidomide + azacitidine as salvage therapy after allogeneic transplant relapse in AML |
| 37435080 | 2023 | Prospective cohort | Front Immunol | Azacitidine + low-dose lenalidomide as relapse prophylaxis after allo-HSCT in AML |
| 34955443 | 2022 | Phase Ib | J Geriatr Oncol | Safety of lenalidomide as post-remission therapy in older AML patients, with geriatric functional assessment |
| 34471239 | 2021 | Phase I | Bone Marrow Transplant | Safety and tolerability of lenalidomide maintenance (5–15 mg) in 16 post-transplant AML/high-risk MDS patients |
| 40250191 | 2025 | Phase I | Leukemia Research | Lenalidomide + bortezomib for AML/MDS relapsing after allogeneic transplant |
| 31009835 | 2019 | Clinical study | Leukemia Research | Sequential azacitidine + high-dose lenalidomide in relapsed/refractory AML, with predictive modeling |
| 23316859 | 2013 | Review | Expert Opin Investig Drugs | Review of lenalidomide trials in higher-risk MDS and AML |
US Market Information
The five main authorizations are listed below (20 licenses on record). All are generic ANDAs for oral capsules. The records contain no approved-indication text.
| Authorization Number | Product Name | Dosage Form | Manufacturer |
|---|---|---|---|
| ANDA210435 | lenalidomide | Capsule | Exelan Pharmaceuticals Inc. |
| ANDA210154 | LENALIDOMIDE | Capsule | Zydus Lifesciences Limited |
| ANDA217281 | Lenalidomide | Capsule | Novugen Pharma (USA) LLC |
| ANDA210154 | LENALIDOMIDE | Capsule | Zydus Pharmaceuticals USA Inc. |
| ANDA201452 | Lenalidomide | Capsule | Teva Pharmaceuticals, Inc. |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Immunomodulatory / targeted protein-degradation agent (CRBN E3 ligase modulator), not a conventional cytotoxic |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Please refer to the package insert warnings and precautions |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
Please refer to the package insert for safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The mechanism is plausible and there is a completed randomized Phase 2 study (NCT01358734, n=88). However, the rest of the evidence is mostly small Phase 1/2 combination trials, and several were terminated early. The meta-analysis and retrospective data do not show consistent benefit. Package-insert safety data, a blocking gap for safety screening, is also missing.
To proceed, the following is needed:
- FDA package insert warnings and contraindications (blocking data gap)
- DrugBank mechanism-of-action data
- Published results of NCT01358734 and the randomized azacitidine ± lenalidomide studies (NCT01556477, PMID 35277655), to test whether lenalidomide adds benefit over azacitidine alone
- Subgroup analysis by del(5q) or monosomy 5 status, where the CK1alpha mechanism is strongest
- Separate from this indication, the pack ranks “partial deletion of the long arm of chromosome 5” as the strongest candidate (L1, Proceed with Guardrails), based on the randomized Phase 3 NCT00843882. Its results should be verified before that candidate advances.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.