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Latest Data on CELMoDs in NHL
Latest Data on CELMoDs in NHL From the Annual Hematology Meeting 

Released: February 28, 2025

Expiration: February 27, 2026

Nathan Denlinger
Nathan Denlinger, DO, MS
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Key Takeaways
  • CELMoDs bind to cereblon triggering the degradation of key lymphomagenic proteins involved in cell proliferation and survival.
  • Recent data from trials of the CELMoD golcadomide showed promising activity and manageable safety in patients with relapsed/refractory non-Hodgkin lymphoma including those who have previously received CAR T-cell therapy.
  • CARMOD and GOLSEEK-1 are ongoing clinical trials of golcadomide alone or in combination with chemotherapy in patients with B-cell lymphoma.

In this commentary, I provide an overview of the potential role of cereblon E3 ligase modulatory drugs (CELMoDs) in the management of patients with non-Hodgkin lymphoma (NHL) and highlight the latest available data on CELMoDs in lymphomas presented at the American Society of Hematology (ASH) 2024 Annual Meeting.

Overview
CELMoDs such as avadomide, iberdomide, mezigdomide, and golcadomide are oral agents currently under investigation in multiple hematologic malignancies including NHL. These drugs target cereblon, which regulates the expression, assembly, and activities of crucial proteins involved in cell proliferation and metabolism. The chemical structure of CELMoDs is specifically designed to promote binding to cereblon and induce targeted protein degradation of transcription factors. In NHL, CELMoDs promote the destruction of Ikaros and Aiolos, which are lymphomagenic proteins, via their role as key regulators of lymphoid development and differentiation. CELMoDs are being investigated in the management of patients with NHL where they are showing significant promise.

Golcadomide in Previously Treated NHL
CC-99282-NHL-001 is an ongoing nonrandomized, multicenter, phase I/II first-in-human trial of golcadomide for patients with relapsed/refractory (R/R) NHL. Patients aged 18 years or older with R/R NHL who had received at least 2 previous lines of therapy were eligible to participate in the study. In addition, the trial allowed the inclusion of patients with NHL who had received at least 1 previous line of therapy and were ineligible for any other treatment. The patients in the dose-escalation portion of the trial received golcadomide monotherapy at a dose ranging from 0.2 mg to 0.8 mg. Those in the dose-expansion phase received 0.2 mg or 0.4 mg golcadomide alone or in combination with an antilymphoma agent (rituximab, tafasitamab, obinutuzumab or valemetostat) for up to 2 years. The endpoints included the determination of the maximum tolerated dose, recommended phase II dose, efficacy, safety, and tolerability.

At ASH 2024, updated efficacy and safety results from 77 patients who received golcadomide plus rituximab on CC-99282-NHL-001 were presented. Of these, 39 patients received 0.2 mg golcadomide plus rituximab and 38 received 0.4 mg golcadomide plus rituximab. The majority of patients (≥97%) who received either 0.2 mg or 0.4 mg of golcadomide in combination with rituximab had diffuse large B-cell lymphoma (DLBCL). Of note, 54% and 53% of patients who received 0.2 mg golcadomide and 0.4 mg golcadomide, respectively, had received CAR T-cell therapy. The median prior lines of therapy in these patients was 4 (range: 1-11).

In the 69 efficacy evaluable patients with R/R DLBCL, the overall response rate (ORR) was 48%, including 30% who achieved a complete response (CR). Among 34 efficacy evaluable patients with R/R DLBCL who received 0.2 mg of golcadomide plus rituximab, the ORR was 35% vs 60% in the 35 efficacy evaluable patients who received 0.4 mg golcadomide plus rituximab. In the population of 21 patients who had previously received CAR T-cell therapy, the ORR was 50%, including 33% who achieved a CR. Among the 17 patients with CAR T-cell therapy–naive R/R DLBCL, the ORR was 71%, including 53% who achieved a CR. Of importance, the ongoing phase II CARMOD trial is investigating golcadomide shortly after CAR T-cell infusion for patients with R/R large-cell lymphoma (LBCL), including DLBCL, primary mediastinal B-cell lymphoma, high-grade B-cell lymphoma, or any transformed follicular lymphoma or marginal zone lymphoma. To be eligible, patients must have an indication for CAR T-cell therapy as second- to fourth-line therapy (NCT06271057). In the CARMOD trial, patients will receive CD19-directed CAR T-cell infusion on Day 0 followed by the initiation of golcadomide at a dose of 0.3 mg/week. Golcadamide will start on Day 5 post CAR T-cell infusion and continue for a total of six 28-day cycles. The primary endpoint is complete metabolic response. CARMOD will shed more important light on the efficacy of golcadomide after CAR T-cell therapy in patients with R/R LBCL.

Regarding patients with follicular lymphoma (n = 59) on the phase I/II CC-99282-NHL-001 trial, the addition of rituximab to golcadomide, especially when combined with the higher dose of golcadomide (0.4 mg), increased response rate compared with golcadomide monotherapy. In the 25 patients treated with 0.4 mg golcadomide plus rituximab, the ORR was 92%, while in the 22 patients treated with 0.2 mg golcadomide plus rituximab the ORR was 72%. This is comparable with an ORR of 67% reported among the 12 patients treated with golcadomide alone at the 0.2 mg or 0.4 mg dose. Of note, among the 8 patients with prior exposure to lenalidomide, 0.4 mg golcadomide plus rituximab resulted in an ORR of 100%.

With regard to the safety outcomes from the CC-99282-NHL-001 trial, neutropenia was the most common adverse event reported with golcadomide plus rituximab. All-grade neutropenia was reported in 19 (49%) patients with R/R DLBCL who received 0.2 mg golcadomide plus rituximab (grade ≥3: 46%) vs 29 (76%) of those who received 0.4 mg golcadomide plus rituximab (grade ≥3: 74%). All-grade anemia and thrombocytopenia occurred in less than 27% of patients regardless of golcadomide dose. Febrile neutropenia, fatigue, constipation and pneumonia were also reported with golcadomide plus rituximab. However, aside from neutropenia, all other adverse events were infrequent. No grade ≥3 fatigue, constipation or pneumonia was reported with either dose of golcadomide. Overall, the adverse events were mostly grade 1 or 2.

Golcadomide in Previously Untreated NHL
There is a phase I trial (CC-220-DLBCL-001) that is investigating the efficacy and safety of iberdomide or golcadomide in combination with R-CHOP-21 for patients with previously untreated aggressive B-cell lymphoma (NCT04884035). Data from patients who received golcadomide at 0.2 mg (n = 35) and 0.4 mg (n = 37) in this trial were presented at ASH 2024. In the cohort of patients who received 0.2 mg golcadomide, 80% had DLBCL compared with 87% in the cohort of patients who received 0.4 mg golcadomide. In either of these cohorts, approximately 50% had the GCB subtype of DLBCL. Regardless of the cell of origin, 0.4 mg golcadomide plus R-CHOP-21 elicited durable complete metabolic response, with a 1-year progression-free survival rate of 85% and a 1-year overall survival rate of 91%. Among 31 patients with high-risk disease, the 1-year progression-free survival and overall survival rates were 86% and 93% respectively. Treatment with 0.4 mg of golcadomide plus R-CHOP-21 yielded significant reductions in the circulating tumor DNA levels as well as a high measurable residual disease negativity rate at the end of treatment. These data form the basis for the ongoing phase III GOLSEEK-1 trial of R-CHOP with or without golcadomide for patients with previously untreated high-risk LBCL (NCT06356129). GOLSEEK-1 will further define the role and utility of golcadomide in patients with previously untreated NHL.

My Final Thoughts
These are exciting times, and I am very enthusiastic about the response rates seen with golcadomide in patients with NHL in these studies. The potential benefits of augmenting the immune system with this type of therapy are huge, particularly for patients previously treated with CAR T-cell therapy or bispecific antibodies. The use of CELMoDs in this manner will hopefully eradicate cancer cells and mediate durable remission. That CELMoDs are well tolerated and that they can be used as an add on to CAR T-cell therapy with manageable safety is significant. Sometimes in the post–CAR T-cell therapy space, there are patients who do not achieve a good response, and these patients may not be able to tolerate aggressive chemotherapy. Therefore, the safety profile seen with golcadomide makes its potential utility exciting in the management of patients with multiply-relapsed NHL. The ongoing clinical trials will further define the utility of CELMoDs in NHL.

Your Thoughts?
What questions do you have about the potential utility of CELMoDs for patients with NHL? Answer the polling question and join the conversation in the discussion box below. 

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