Dr Morillo on the Mechanism of Action for Golcadomide in R/R Follicular Lymphoma

[Golcadomide’s] binding is outside the tryptophan pocket, and that [gives] a much more deep and strong inhibition of Ikaros [and Aiolos]. That leads to stronger T-cell activation against the tumor, [as well as] improved T-cell immunity. That’s the main difference [between] this new drug [and others in the field], and what [contrasts] it with lenalidomide is [that it is] stronger, more potent, and more selective.

Daniel Morillo, MD, a consultant hematologist in the Lymphoma Unit and a clinical investigator at the Early Phase Clinical Trials Unit (START Madrid–FJD) at Hospital Universitario Fundación Jiménez Díaz, discussed the mechanism of action of the potential first-in-class oral CELMoD golcadomide (CC-99282), which is under investigation alone and in combination with rituximab (Rituxan) in patients with relapsed/refractory follicular lymphoma in the phase 1/2 CC-99282-NHL-001 trial (NCT03930953).

Golcadomide is a CELMoD designed specifically for lymphoma, Morillo said. Like the immunomodulatory drug lenalidomide (Revlimid), golcadomide binds and modifies cereblon; however, its distinguishing structural feature is that it binds outside the tryptophan pocket of cereblon, which produces a deeper and more potent inhibition of the Ikaros and Aiolos transcription factors, according to Morillo. That deeper degradation translates into stronger T-cell activation against the tumor and improved T-cell immunity, making golcadomide more potent and more selective than lenalidomide, he explained.

Findings from CC-99282-NHL-001 presented at the 2026 EHA Congress showed that at a median follow-up of 17.08 months (range, 2.1-35.1), patients in cohort D treated with at golcadomide 0.4 mg plus rituximab (n = 36) experienced an objective response rate (ORR) of 97%, with a complete response rate of 75%; golcadomide at 0.2 mg plus rituximab (n = 22) generated an ORR of 77%, including a CR rate of 41%.

These findings support the ongoing phase 3 GOLSEEK-4 study (NCT06911502), which is evaluating golcadomide plus rituximab as a fixed-duration option for patients with second-line and beyond follicular lymphoma.