(RS)-lenalidomide

Overview

(RS)-Lenalidomide is an immunomodulatory drug (IMiD) belonging to the thalidomide analogue class, developed as a more potent and better-tolerated derivative of thalidomide. Its primary mechanism of action involves binding to cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase complex, which redirects the ligase to selectively ubiquitinate and degrade specific transcription factors, most notably Ikaros (IKZF1) and Aiolos (IKZF3). This targeted degradation disrupts lymphoma and myeloma cell survival signaling while simultaneously enhancing T-cell and natural killer cell activity, thereby combining direct cytotoxic and immunostimulatory effects. Lenalidomide also exhibits anti-angiogenic properties and modulates the tumor microenvironment through inhibition of pro-inflammatory cytokines such as TNF-α.

Clinically, lenalidomide is approved for the treatment of multiple myeloma, myelodysplastic syndromes with del(5q), and mantle cell lymphoma. It is typically administered orally and used in combination regimens with dexamethasone, proteasome inhibitors such as bortezomib, anti-CD38 monoclonal antibodies, and anti-CD20 agents such as rituximab. Its broad activity across B-cell malignancies and myeloid disorders, combined with its role as an E3 ligase recruiter in next-generation targeted protein degradation platforms, has made it one of the most widely studied agents in modern hematologic oncology.

Focus of Latest Publications

Recent literature underscores lenalidomide's sustained centrality across multiple hematologic malignancies, both as a backbone therapeutic agent and as a pharmacological tool in novel degrader technologies.

In multiple myeloma, several combination strategies have been evaluated. A retrospective pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS) database compared the real-world safety profiles of three first-line regimens: lenalidomide plus dexamethasone (Rd), bortezomib plus lenalidomide and dexamethasone (VRd), and daratumumab plus lenalidomide and dexamethasone (DRd), highlighting how the addition of agents such as bortezomib and TNF receptor superfamily member 17-targeting therapies modifies the toxicity landscape (PMID: 42171749). Separately, a phase 1/2 study investigated belantamab mafodotin in combination with carfilzomib, lenalidomide, and dexamethasone (KRd-b) in relapsed or refractory multiple myeloma (RRMM), evaluating belamaf administered every eight weeks within this quadruplet backbone (PMID: 41719502). In the transplant-ineligible setting, the BelaRd study combined belantamab mafodotin with lenalidomide and dexamethasone for intermediate-fit and frail patients with newly diagnosed multiple myeloma, demonstrating the feasibility of incorporating antibody-drug conjugates targeting TNF receptor superfamily member 17 into lenalidomide-based platforms (PMID: 41346230). A phase 2 investigator-initiated trial further evaluated selinexor combined with bortezomib, lenalidomide, and dexamethasone (SVRD) in newly diagnosed multiple myeloma patients with extramedullary disease (EMD), a high-risk subgroup with limited treatment options (PMID: 41564431).

In B-cell lymphomas, the five-year follow-up data from the phase III AUGMENT trial confirmed durable improved efficacy for the lenalidomide plus rituximab combination (R²) versus rituximab with placebo in patients with relapsed or refractory indolent non-Hodgkin lymphoma, including follicular lymphoma subgroups such as those with progression of disease within 24 months (POD24) (PMID: 41990300, 41587420). A phase 1 study explored the combination of zanubrutinib (BGB-3111) with lenalidomide in relapsed or refractory diffuse large B-cell lymphoma, motivated by preclinical evidence that lenalidomide and a Bruton agammaglobulinemia tyrosine kinase (BTK) inhibitor demonstrate synergistic antitumor effects (PMID: 41824782). In T-cell lymphoma, a phase 1 trial tested escalating doses of lenalidomide added to a backbone of romidepsin, azacitidine, and dexamethasone (RAdR) in relapsed or refractory T-cell lymphoma, including anaplastic large-cell lymphoma, exploring whether lenalidomide's immunomodulatory properties could augment epigenetic combination regimens (PMID: 41779512).

Beyond direct therapeutic use, lenalidomide has emerged as a critical pharmacological handle in targeted protein degradation research. Structural studies characterized the thalidomide binding domain (TBD) of cereblon, confirming via NMR that purified TBD retains functional interaction with lenalidomide, providing a validated platform for structure-guided PROTAC design (PMID: 42101529). In a separate medicinal chemistry study, lenalidomide was incorporated as a cereblon-recruiting E3 ligase warhead alongside VH032-Me in heterobifunctional degraders targeting peroxisomal D-aspartate oxidase (hDASPO), guided by saturation transfer difference NMR (STD-NMR), as a potential strategy for schizophrenia treatment (PMID: 41785830).

Key Publications

• NEWJun Tafasitamab plus lenalidomide and R-CHOP versus R-CHOP for first-line treatment of patients with high-risk diffuse large B-cell lymphoma (frontMIND): a global, phase 3, randomised, double-blind, placebo-controlled trial. (Lancet (London, England), 2026, PMID 42217458): "We aimed to investigate the addition of tafasitamab (an Fc-enhanced anti-CD19 monoclonal antibody) and lenalidomide to R-CHOP (tafa-len-R-CHOP) in patients with high-risk aggressive B-cell lymphomas."
• Jun Lenalidomide plus rituximab for previously untreated advanced follicular lymphoma: the 10-year RELEVANCE trial analysis. (Blood, 2026, PMID 41915772): "...to receive rituximab + lenalidomide (R2; n = 513) or rituximab-based immunochemotherapy (R-Chemo; n = 517)."
• Jun Phase 1 study of zanubrutinib plus lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma. (Blood advances, 2026, PMID 41824782): "In preclinical studies, lenalidomide and a Bruton tyrosine kinase (BTK) inhibitor demonstrated synergistic antitumor effects."
• Jun Lenalidomide Plus Rituximab for Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: 5-Year Follow-Up and Subgroup Analyses From the Phase III AUGMENT Trial. (Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2026, PMID 41990300): "The phase III AUGMENT trial (ClinicalTrials.gov identifier: NCT01938001) demonstrated improved efficacy for lenalidomide plus rituximab (R2) versus rituximab with placebo (R-placebo) in patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL)."
• May A phase 1 trial of romidepsin, azacitidine, dexamethasone, and lenalidomide in relapsed or refractory T-cell lymphoma. (Blood advances, 2026, PMID 41779512): "In a phase 1 trial, we tested escalating doses of lenalidomide added to romidepsin, azacitidine, and dexamethasone (RAdR) for patients with R/R TCL."
• May The safety profile of lenalidomide, dexamethasone, daratumumab, and bortezomib combinations in multiple myeloma: a retrospective analysis of the FAERS database. (Naunyn-Schmiedeberg's archives of pharmacology, 2026, PMID 42171749): "The current study aimed to compare the real-world safety profiles of first-line multiple myeloma regimens-lenalidomide plus dexamethasone (Rd), bortezomib plus lenalidomide and dexamethasone (VRd), and daratumumab plus lenalidomide and dexamethasone (DRd)-using the FDA Adverse Event Reporting System (FAERS) database."
• May Belantamab mafodotin, carfilzomib, lenalidomide, and dexamethasone for relapsed or refractory multiple myeloma. (Blood advances, 2026, PMID 41719502): "This phase 1/2 study evaluated the safety and preliminary efficacy of belamaf administered every 8 weeks in combination with carfilzomib, lenalidomide, and dexamethasone (KRd-b) in patients with RRMM."
• May PROTAC-mediated degradation of peroxisomal d-aspartate oxidase: A novel strategy to modulate d-aspartate homeostasis for schizophrenia treatment. (European journal of medicinal chemistry, 2026, PMID 41785830): "Guided by STD-NMR, we designed a series of heterobifunctional degraders integrating a hDASPO-binding ligand (olanzapine) with established E3 ligase recruiters (lenalidomide or VH032-Me) and aliphatic linkers of varying lengths."
• May Backbone resonance assignment of the Thalidomide Binding Domain (TBD) of cereblon. (Biomolecular NMR assignments, 2026, PMID 42101529): "The purified TBD was shown to interact with the cereblon ligand lenalidomide, confirming its functional integrity."
• Apr Treatment and survival outcomes for patients with follicular lymphoma and POD24: a systematic review and meta-analysis. (Blood advances, 2026, PMID 41587420): "Additionally, bispecific antibodies, anti-CD19 ADCs/mAbs, and the combination of lenalidomide with obinutuzumab or rituximab also exhibited excellent efficacy."