lenalidomide
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.
Recent Publications Focus
Below is a summary of the newest research publications targeting lenalidomide (sorted by publication date).
Recent studies demonstrate lenalidomide's continued role in treating both lymphoid malignancies and multiple myeloma across relapsed/refractory and newly diagnosed settings. In follicular lymphoma, lenalidomide combined with rituximab (R2) showed sustained clinical benefit in long-term follow-up studies: a 5-year analysis of the AUGMENT trial confirmed improved progression-free and overall survival in relapsed/refractory indolent non-Hodgkin lymphoma [41990300], while the 10-year RELEVANCE trial demonstrated that R2 provided comparable efficacy to rituximab-based chemoimmunotherapy in previously untreated advanced follicular lymphoma, establishing it as a chemotherapy-free alternative [41915772]. When combined with novel agents, R2 showed further promise: epcoritamab plus lenalidomide and rituximab demonstrated superior response rates and survival outcomes compared to lenalidomide, rituximab, and standard chemotherapy in relapsed/refractory follicular lymphoma [42415230], and tafasitamab combined with lenalidomide and R-CHOP is being evaluated for high-risk diffuse large B-cell lymphoma in the frontMIND trial [42217458].
In multiple myeloma, lenalidomide has been incorporated into several novel combination regimens with varying disease contexts. The bortezomib-lenalidomide-dexamethasone (VRd) backbone, a standard induction therapy, was examined for its immunomodulatory effects, revealing that VRd induces expansion of monocytic myeloid-derived suppressor cells that correlate with treatment response depth in newly diagnosed patients [42374568]. Real-world safety surveillance across common lenalidomide-based regimens (Rd, VRd, and daratumumab-lenalidomide-dexamethasone) identified regimen-specific adverse event patterns, with daratumumab combinations associated with elevated infection signals and VRd linked to neurological disorders, supporting tailored monitoring strategies [42171749]. Several emerging lenalidomide-containing combinations demonstrated encouraging clinical activity: zanubrutinib plus lenalidomide in relapsed/refractory diffuse large B-cell lymphoma achieved 58% overall response rate [41824782], belantamab mafodotin combined with carfilzomib, lenalidomide, and dexamethasone produced deep responses in heavily pretreated multiple myeloma [41719502], selinexor combined with VRd achieved high response rates and disease regression in newly diagnosed myeloma with extramedullary disease [41564431], and belantamab mafodotin with lenalidomide and dexamethasone proved effective in transplant-ineligible patients [41346230].
Lenalidomide was also evaluated in less common hematologic malignancies and for mechanistic investigation. A phase 1 study of romidepsin, azacitidine, dexamethasone, and lenalidomide in relapsed/refractory T-cell lymphoma achieved high initial response rates at the maximum tolerated lenalidomide dose of 20 mg [41779512], and structural studies confirmed lenalidomide's functional interaction with the cereblon thalidomide-binding domain, supporting its role as an immunomodulatory and E3 ubiquitin ligase-recruiting agent [42101529]. Meta-analytic evidence pooling outcomes across multiple lenalidomide-containing regimens in follicular lymphoma with early progression of disease demonstrated excellent efficacy for lenalidomide in combination with rituximab or obinutuzumab [41587420].