P1/2, N=201, Active, not recruiting, Celgene | Trial primary completion date: Oct 2024 --> Nov 2025

P2, N=28, Not yet recruiting, Roswell Park Cancer Institute | Initiation date: Nov 2024 --> Feb 2025

In this review, we provide a comprehensive overview of the existing work on IMiD resistance in MM, focusing specifically on the emerging evidence of CRBN pathway-independent mechanisms. Finally, we discuss the plausible actionable strategies and outlook for IMiD-based therapies moving forward.

P1/2, N=0, Withdrawn, Kathleen Dorritie | N=34 --> 0 | Recruiting --> Withdrawn

P1, N=30, Recruiting, Celgene | Not yet recruiting --> Recruiting

P1, N=174, Recruiting, Celgene | Trial primary completion date: Sep 2024 --> Dec 2024

P1, N=156, Active, not recruiting, Celgene | Phase classification: P1/2 --> P1 | Trial primary completion date: Aug 2025 --> May 2025

P2, N=65, Recruiting, The Lymphoma Academic Research Organisation | Not yet recruiting --> Recruiting

P2, N=28, Not yet recruiting, Roswell Park Cancer Institute

P1, N=35, Completed, Celgene | Recruiting --> Completed

P1, N=15, Terminated, Celgene | Completed --> Terminated; Replaced it with another clinical trial.

P1/2, N=85, Recruiting, Bristol-Myers Squibb | Trial completion date: Aug 2030 --> Aug 2029 | Trial primary completion date: Jan 2027 --> Dec 2025

P1/2, N=156, Active, not recruiting, Celgene | Trial completion date: Feb 2032 --> Aug 2025 | Trial primary completion date: Feb 2032 --> Aug 2025

Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide (Len), are effective drugs for the treatment of multiple myeloma. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM.

P2, N=90, Recruiting, Celgene | Not yet recruiting --> Recruiting

P1, N=30, Not yet recruiting, Celgene

Using a literature search methodology comprising searches of PubMed (unlimited time-frame) and international hematology/oncology conference abstracts (2019-2023) for terms including IKZF1, IKZF3, Ikaros, Aiolos, CELMoD, IMiD, iberdomide, mezigdomide, and MM, this paper reviews the importance of Ikaros and Aiolos in MM, the mechanism of action of the IMiDs and CELMoD agents and their relative potency for targeting Ikaros and Aiolos, and preclinical and clinical data on iberdomide and mezigdomide. Emerging data suggest iberdomide and mezigdomide have promising activity, including in IMiD-resistant settings, and, pending phase 3 findings, may provide additional treatment options for patients with MM.

P1, N=16, Completed, Celgene | Active, not recruiting --> Completed | Phase classification: P1b --> P1 | N=50 --> 16 | Trial completion date: May 2025 --> May 2024 | Trial primary completion date: Nov 2024 --> May 2024

P1, N=32, Recruiting, Celgene | Not yet recruiting --> Recruiting

In addition, pomalidomide only overcomes lenalidomide refractoriness in a subset of patients. We will discuss the biological aspects of these agents, including their mechanisms of action, efficacy, and toxicity profile, and provide a comprehensive review of current literature. Special attention will be paid to ongoing and future clinical trials that provide insights into the potential of these novel therapies in the management of MM.

We adopted BioID2-dependent proximity labelling (BioID2-CRBN) to characterise the CRBN interactome in the presence and absence of various IMiDs and the proteasome inhibitor, bortezomib...Here we identify Non-Muscle Myosin Heavy Chain IIA (MYH9) as a putative CRBN neointeractor that may contribute to the haematological toxicity of IMiDs. These studies provide proof of concept for proximity labelling technologies in the mechanistic profiling of IMiDs and related E3-ligase-modulating drugs.

P3, N=850, Recruiting, Celgene | Not yet recruiting --> Recruiting

P2, N=36, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P1/2, N=156, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

P1/2, N=64, Completed, Kangpu Biopharmaceuticals, Ltd. | Active, not recruiting --> Completed | Phase classification: P1b/2a --> P1/2 | Trial completion date: Dec 2023 --> Aug 2023

P2, N=90, Not yet recruiting, Celgene

Furthermore, with the deep penetration of two-photon excitation, Ru-Poma achieved drug-resistant circumvention in a 3D tumor cell model. Thus, we describe the first sample of the CRBN-targeting Ru(II) complex active in PDT.

P1, N=36, Recruiting, Celgene | Not yet recruiting --> Recruiting

P1/2, N=424, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

However, thalidomide and its approved derivatives remain plagued by several shortcomings, such as structural instability and poor solubility. Herein, we present a review of strategies for mitigating these shortcomings and highlight contemporary drug discovery approaches that have generated novel thalidomide analogs with enhanced efficacy as cereblon effectors and/or anticancer agents.

Altogether, compound 1 is a valuable chemical biology tool to study the role of PRC1 in cancer. Importantly, we show that CRBN can be utilized to develop bridged PROTACs, expanding the bridged PROTAC technology for degrading undruggable proteins.

P1, N=36, Not yet recruiting, Celgene

P3, N=850, Not yet recruiting, Celgene

The vast majority of current cereblon (CRBN) ligands is based on the thalidomide scaffold, relying on glutarimide as the core binding moiety...In this new orientation it forms additional hydrophobic interactions and is not available for direct interactions with the canonical neo-substrates. We therefore propose this chemotype as an attractive building block for the design of PROTACs.

P1, N=30, Recruiting, Kangpu Biopharmaceuticals, Ltd. | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: Jan 2024 --> Oct 2024

Preclinical studies of mezigdomide have demonstrated its anti-proliferative and apoptotic effects in MM, along with its immune-stimulatory effects and its synergistic activity with other antimyeloma agents, including in lenalidomide-/pomalidomide-resistant MM cell lines and mouse xenograft models. Early-phase clinical trial data indicate notable activity in heavily pretreated patients with RRMM, including those with triple-class-refractory disease, together with a tolerable and manageable safety profile. This review summarizes current preclinical and clinical findings with mezigdomide and its potential future roles in the treatment of MM.

P1, N=32, Not yet recruiting, Celgene

P1/2, N=156, Recruiting, Celgene | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2027 --> Feb 2032

P2, N=65, Not yet recruiting, The Lymphoma Academic Research Organisation

P1, N=15, Recruiting, City of Hope Medical Center | Initiation date: Dec 2023 --> Mar 2024

P1/2, N=220, Recruiting, Bristol-Myers Squibb | Phase classification: P1b/2a --> P1/2

Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL.