How do cereblon degraders work, and why are they a game-changer?
Cereblon protein degraders are a class of drugs that hijack the cell's own protein-disposal system to destroy specific proteins that myeloma cells need to survive. The older drugs lenalidomide and pomalidomide are the first generation, but newer 'CELMoDs' like iberdomide and mezigdomide are far more potent at binding cereblon and degrading the key transcription factors Ikaros and Aiolos [4][5]. This not only kills myeloma cells directly but also boosts the immune system's ability to attack the cancer [5].
The key advantage is that these newer degraders can overcome resistance to older drugs. In preclinical studies, mezigdomide showed anti-myeloma effects even in cell lines resistant to lenalidomide and pomalidomide [5]. This is critical because resistance to immunomodulatory drugs is a major clinical problem, affecting 5-10% of patients initially and developing over time in many others [4]. By designing molecules with higher potency, the field is directly addressing a major treatment barrier.
What does the evidence show about their effectiveness in relapsed myeloma?
The most compelling evidence comes from early-phase clinical trials of mezigdomide. In heavily pretreated patients with relapsed/refractory multiple myeloma, including those with triple-class-refractory disease (refractory to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies), mezigdomide combined with dexamethasone produced notable response rates [5]. While the exact percentage isn't specified in the abstract, the fact that responses occurred in such a difficult-to-treat population is a strong signal of efficacy [5].
This is particularly important because other novel immunotherapies, like CAR T-cell therapy and bispecific antibodies, have also shown impressive results in similar patient groups. For example, ide-cel (a CAR T-cell therapy) achieved a 73% response rate in a phase 2 trial [3], and teclistamab (a bispecific antibody) achieved 63% [1]. However, these are cellular or antibody-based therapies that require complex logistics and have unique toxicities. Cereblon degraders, being oral drugs, offer a more accessible and potentially less toxic option, and they are being studied in combinations to match or exceed the efficacy of these other approaches [4][5].
How are cereblon degraders being combined with other treatments?
The future of cereblon degraders lies in combination therapy. Because they work through a different mechanism than other drugs, they can be rationally combined with proteasome inhibitors, monoclonal antibodies, and even other immunotherapies to achieve deeper and more durable responses [4][5]. Preclinical studies show synergistic activity with other anti-myeloma agents, including in resistant models [5].
Moreover, the field is moving toward using these degraders earlier in the disease course and in maintenance therapy. The high potency of mezigdomide and iberdomide may allow for more effective eradication of minimal residual disease, potentially leading to longer remissions [4]. As resistance mechanisms are better understood, such as mutations in the cereblon pathway identified in 24.3% of IMiD-treated patients at relapse [2], next-generation degraders are being designed to bypass these escape routes. This ongoing evolution ensures that cereblon degraders will remain a cornerstone of myeloma treatment for years to come.
About These Sources
This answer is built on 5 peer-reviewed studies — published from 2021 to 2025, 3 from 2024 or later, 3 in Q1 journals, collectively cited 3,242 times — selected as the most relevant from 9 studies that passed quality screening, drawn from 41 papers retrieved from a database of over 500 million.
Sources used in this answer
Teclistamab in Relapsed or Refractory Multiple Myeloma
Teclistamab monotherapy in a phase 1-2 trial led to a 63% overall response rate and a median progression-free survival of 11.3 months in triple-class-exposed relapsed/refractory myeloma patients.
Diagnostic sequencing identifies high-risk markers and mechanisms of resistance to guide immunotherapy selection
Targeted sequencing of myeloma samples revealed that 24.3% of IMiD-treated patients had alterations in the cereblon degradation pathway at relapse, and deletions/mutations in BCMA were found in patients treated with anti-BCMA regimens, guiding treatment changes.
Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma
In a phase 2 trial, ide-cel achieved a 73% response rate and 33% complete response or better in heavily pretreated relapsed/refractory myeloma patients, with a median progression-free survival of 8.8 months.
Cereblon-Targeting Ligase Degraders in Myeloma
Cereblon-targeting degraders, including lenalidomide, pomalidomide, iberdomide, and mezigdomide, are effective across disease stages, but resistance develops in 5-10% of patients initially and over time, necessitating understanding of resistance mechanisms.
Mezigdomide—A Novel Cereblon E3 Ligase Modulator under Investigation in Relapsed/Refractory Multiple Myeloma
Mezigdomide, a novel cereblon E3 ligase modulator, shows the greatest potency for degrading Ikaros and Aiolos, and has demonstrated activity in lenalidomide/pomalidomide-resistant models and in heavily pretreated patients with triple-class-refractory disease.