Expression of CRL4-CRBN complex proteins predicts a response to immunomodulatory drugs for patients with multiple myeloma (MM), according to research in the Journal of Clinical Medicine.

Many patients with MM eventually develop drug resistance and relapse. Immunomodulatory drugs provide effective treatment for MM, and studies have shown that these drugs bind to cereblon (CRBN), which contributes to limiting the growth of MM cells.

The cullin-4 RING E3 ubiquitin ligase (CRL4-CRBN) is a complex of multiple proteins, including DNA damage-binding protein 1 (DDB1), cullin-4A (CUL4A), and regulator of cullin-1 (ROC1). In this study, the researchers sought to determine the correlation between the expression of these proteins and response to immunomodulatory drug therapy.

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The authors retrospectively analyzed bone marrow samples from 130 patients with MM in Poland. A total of 81 patients received thalidomide as for newly diagnosed MM, and 49 were treated with lenalidomide for relapsed or refractory MM. Immunohistochemistry (IHC) staining was used to evaluate the protein expression.

Patients who were CRBN positive had better overall response (partial response or better) to treatment than patients who were CRBN negative (73% vs 52%; P =.0126). CUL4A positivity was associated with a better overall response rate compared to patients who were CUL4A negative (38% vs 20%; P =.027), and CUL4A positive patients had a longer progression-free survival after a median follow up of 4.75 years.

Patients who were DDB1 positive had a poorer prognosis and a lower overall survival rate.

The study has some limitations, including the different treatments patients received and that cytogenetic and molecular data were not available for some of the MM patients.

Further studies are needed to better understand the associations between the predictive role of the CLR4-CRBN complex for patients receiving immunomodulatory drugs. This study demonstrated that CUL4A and CRBN may be predictive for a positive response to immunomodulatory therapy. Results also showed that DDB1 expression has prognostic value for patients with MM as well.


Barankiewicz J, Szumera-Ciećkiewicz A, Salomon-Perzyński A, et al. The CRBN, CUL4A and DDB1 expression predicts the response to immunomodulatory drugs and survival of multiple myeloma patients. J Clin Med. 2021;10(12):2683. doi:10.3390/jcm10122683