The CRBN, CUL4A and DDB1 Expression Predicts the Response to Immunomodulatory Drugs and Survival of Multiple Myeloma Patients

Joanna Barankiewicz,Agata Malenda,Monika Prochorec-Sobieszek,Filip Garbicz,Przemysław Juszczyński,Irena Misiewicz-Krzemińska,Paulina Wieszczy,Ewa Lech-Marańda,Aleksander Salomon-Perzyński,Anna Szumera-Ciećkiewicz

doi:10.3390/jcm10122683

Abstract

Immunomodulatory drugs (IMiDs) are effective in the treatment of multiple myeloma (MM), myelodysplastic syndrome with deletion of chromosome 5q and other haematological malignancies. Recent studies showed that IMiDs bind to cereblon (CRBN), a substrate receptor of the CRL4–CRBN complex, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in MM cells, contributing to their anti-myeloma activity. We aimed to determine whether the CRL4–CRBN complex proteins’ expression predicts the prognosis of MM patients treated with IMiDs. Here, we evaluated the expression of CRL4–CRBN complex proteins and their downstream targets with immunohistochemistry (IHC) staining in 130 bone marrow samples from MM patients treated with thalidomide or lenalidomide-based regimens. We found that the expression of CRBN and CUL4A was associated with the superior IMiD-based treatment response (p = 0.007 and p = 0.007, respectively). Moreover, the CUL4A expression was associated with improved PFS (HR = 0.66, 95% CI 0.44–0.99; p = 0.046) and DDB1 expression showed a negative impact on OS both in the univariate (HR = 2.75, 95% CI 1.65–4.61; p = 0.001) and the multivariate (HR 3.67; 95% CI 1.79–7.49; p < 0.001) analysis. Overall, our data suggest that the expression of DDB1, CUL4A and CRBN assessed by IHC predicts the clinical course of MM patients and identifies patients with a high probability of responding to IMiD-based therapy.

Highlights

We separately evaluated the expression of CRL4–CRBN complex proteins (CRBN, DNA damage-binding protein 1 (DDB1), cullin 4A (CUL4A)) and their downstream targets (IKZF1, IKZF3) with IHC staining, using FFPE bone marrow samples from 130 MM patients treated with IMiDs
DDB1 and CUL4A assessed by routine, diagnostic IHC evaluation of bone marrow samples is associated with the outcome of multiple myeloma patients treated with IMiDs
Our analyses revealed that CRBN expression impacts the superior response to thalidomide or lenalidomide-based treatment in line with previously published data

Summary

Introduction

Multiple myeloma (MM) is the third most common haematologic malignancy in the European Union, with approximately 33,000 new cases and 20,000 deaths annually [1]. Despite the impressive therapeutic progress that has occurred in recent decades, the development of drug resistance is typical during the clinical course of MM, and most patients eventually relapse and require further therapy [2]. The introduction of thalidomide, a firstin-class immunomodulatory drug (IMiD), in 2006 was one of the milestones in MM therapy history. Thalidomide and its newer derivatives such as lenalidomide and pomalidomide, along with proteasome inhibitors, are the backbone of most combination regimens used in the treatment of MM. In Poland and other European countries, thalidomide-based regimens are the most common therapy for young and fit newly diagnosed MM patients; lenalidomide and next-generation IMiDs are available for relapsed/refractory groups of patients

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