Golcadomide exhibited rapid, deep, and sustained degradation of transcription factors IKZF1 and IKZF3, surpassing the anti-tumor activity of the IMiD® agent lenalidomide in preclinical models. Pharmacological and CRISPR screening further revealed genes and pathways underlying golcadomide's antitumor efficacy. These findings supported golcadomide as a promising drug candidate for DLBCL, providing a strong rationale for future golcadomide-based regimens.

P1/2, N=49, Active, not recruiting, Mayo Clinic | Trial primary completion date: May 2027 --> Mar 2026

P1/2, N=49, Active, not recruiting, Mayo Clinic | Recruiting --> Active, not recruiting

P2, N=68, Recruiting, Emory University | Trial completion date: Oct 2025 --> Sep 2029 | Trial primary completion date: Sep 2025 --> Sep 2027

The addition of anti-PD1 and pomalidomide reduced the T cell exhaustion that occurs in response to TCE in high tumor burden settings. This was accompanied by more favorable T cell profiling, with limited expansion of regulatory T cells and exhaustion. In total, administering TCE following dexamethasone and iberdomide treatments provided deeper and more durable responses with reduced risk of CRS.

P2, N=40, Active, not recruiting, Olivia Newton-John Cancer Research Institute | Recruiting --> Active, not recruiting

P2, N=47, Recruiting, Fondazione Italiana Linfomi - ETS | Not yet recruiting --> Recruiting

Building on the success of immunomodulatory agents, CRBN E3 ligase modulators (CELMoDs), iberdomide (CC-220) and mezigdomide (CC-92480), have been designed as promising and more selective agents. Combining CELMoDs with cellular therapies significantly improves the response rate in MM patients. In this paper, based on the literature presented at the Annual Meeting of the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), the International Myeloma Society (IMS), and the European Hematology Association (EHA) in the 2020-2025 timeframe, we explore the rationale and emerging evidence of combining CELMoDs with immunotherapies, and their use as a bridge to transplant or as post-ASCT maintenance therapy in MM.

An isogenic subline of MM.1S cells with acquired lenalidomide resistance remains sensitive to GCK inhibition-induced IKZF1/3 downregulation and cell growth inhibition. These findings underscore GCK as a promising therapeutic target for bypassing IMiD resistance in MM. Combining GCK inhibition with iberdomide could provide a novel strategy to manage relapsed or refractory patients with multidrug resistance, especially after the exhaustion of immunotherapy.

Cereblon-binding immunomodulators (CBIs), such as pomalidomide (Pom), show in vitro efficacy and clinical activity against certain of these lymphomas. Next generation CBIs, such as golcadomide (Golc) and iberdomide (Iber), have increased affinity to the primary cellular target, cereblon, making them potentially better anticancer agents...The novel CBIs had relatively little activity in Pom-resistant cell lines with low levels of cereblon, suggesting that binding to cereblon is also important for the functions of the novel CBIs. These data show that the newer CBIs are more potent and effective against PEL and BL lines than Pom, and therefore, are worth investigating clinically in patients with these tumors.

P3, N=400, Recruiting, Celgene | Not yet recruiting --> Recruiting

P2, N=63, Recruiting, University College, London | Not yet recruiting --> Recruiting | Trial completion date: Sep 2030 --> Nov 2032 | Trial primary completion date: Sep 2029 --> Nov 2032