lenalidomide

Overview

Lenalidomide is an immunomodulatory antineoplastic agent used primarily in hematologic malignancies. It is a thalidomide analog and is best known for its ability to modulate the tumor microenvironment, enhance immune effector function, and exert direct anti-myeloma and anti-lymphoma activity. A key molecular feature of lenalidomide is its interaction with cereblon, the substrate receptor component of the CRL4 E3 ubiquitin ligase complex, which underlies many of its downstream biological effects and has also made lenalidomide a widely used chemical tool in targeted protein degradation research.

Clinically, lenalidomide is an established backbone therapy in multiple myeloma and several B-cell lymphomas, often combined with dexamethasone, rituximab, bortezomib, daratumumab, carfilzomib, tafasitamab, or other agents. Its use in combination regimens reflects both its immunostimulatory properties and its synergy with monoclonal antibodies and other anti-cancer drugs. In recent research, lenalidomide has also been explored in T-cell lymphoma and in mechanistic studies involving cereblon-binding and PROTAC design.

Focus of Latest Publications

Recent publications have continued to examine lenalidomide primarily as part of combination regimens in hematologic malignancies, especially multiple myeloma and B-cell lymphomas. In newly diagnosed multiple myeloma, a longitudinal observational study of bortezomib-lenalidomide-dexamethasone (VRd) found that treatment was associated with a transient expansion of circulating monocytic myeloid-derived suppressor cells, which normalized after autologous stem cell transplantation. The increase in M-MDSCs during VRd induction correlated with shallower response depth, although it did not remain an independent predictor after adjustment. A separate phase 2 study of selinexor combined with bortezomib, lenalidomide, and dexamethasone in extramedullary disease-positive newly diagnosed multiple myeloma reported high response rates, frequent extramedullary disease regression, and manageable toxicity, with many patients able to proceed to autologous stem cell transplantation.

Lenalidomide has also been studied in relapsed or refractory multiple myeloma in newer triplet and quadruplet combinations. In a phase 1/2 trial, belantamab mafodotin plus carfilzomib, lenalidomide, and dexamethasone produced deep responses, including very good partial responses or better in most patients, with a recommended belantamab dose of 1.9 mg/kg every 8 weeks and manageable toxicity dominated by keratopathy. Real-world pharmacovigilance analysis of lenalidomide-containing first-line regimens in the FAERS database compared lenalidomide plus dexamethasone, VRd, and daratumumab plus lenalidomide and dexamethasone, identifying regimen-specific safety signals, including infections with daratumumab-based therapy and neurological disorders with VRd.

In lymphoma, lenalidomide remains a key component of immunotherapy combinations. Long-term follow-up from the phase III AUGMENT trial showed that lenalidomide plus rituximab improved progression-free survival and overall survival versus rituximab plus placebo in relapsed or refractory indolent non-Hodgkin lymphoma, with manageable safety over more than 5 years of follow-up. The 10-year RELEVANCE analysis in previously untreated advanced follicular lymphoma found comparable long-term progression-free survival, overall survival, and time-to-next lymphoma treatment between rituximab plus lenalidomide and rituximab-based immunochemotherapy, supporting lenalidomide plus rituximab as a chemotherapy-free alternative. Additional studies extended lenalidomide into investigational combinations for relapsed or refractory diffuse large B-cell lymphoma and T-cell lymphoma, including zanubrutinib plus lenalidomide and romidepsin, azacitidine, dexamethasone, and lenalidomide, both of which showed antitumor activity but were limited by hematologic toxicity and, in the T-cell lymphoma study, lack of durable responses.

Mechanistic work also continued to reinforce lenalidomide’s interaction with cereblon. Backbone resonance assignment studies of the thalidomide-binding domain of cereblon confirmed interaction with lenalidomide and provided a structural foundation for characterizing ligand binding in targeted protein degradation research.

Key Publications

• NEWJul Circulating M-MDSC Expansion During Therapy Associates With Treatment Response in Multiple Myeloma: A Longitudinal Observational Study. (Clinical and translational science, 2026, PMID 42374568): "VRd, but not daratumumab-based regimens, significantly expanded M-MDSCs (median +0.98%, p<0.0001), which normalized after ASCT."
• Jun 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."
• 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 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."
• 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)."
• 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."
• 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 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."
• 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."