Our data suggest that reduced CSN5 expression leads to abnormalities in the ubiquitination cycle of CRL4A, resulting in the inhibition of LEN-mediated degradation of IKZF1 and IKZF3. These findings delineate an additional mechanism of LEN resistance in MM cells and may contribute to the development of alternative therapeutic strategies to overcome LEN resistance.

P2, N=61, Active, not recruiting, Omar Nadeem, MD | Recruiting --> Active, not recruiting | Trial completion date: Mar 2029 --> Dec 2030 | Trial primary completion date: Mar 2026 --> Dec 2026

P1, N=6, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=20 --> 6

In summary, we report the involvement of ADAR1-regulated dsRNA-sensing in modulating lenalidomide sensitivity in MM. These findings highlight a novel RNA-related mechanism underlying lenalidomide resistance and underscore the potential of targeting ADAR1 as a novel therapeutic strategy.

Lenalidomide, a derivative of thalidomide, is a type of immunomodulatory drug (IMiD) that has been standard therapy for multiple myeloma (MM) and other hematologic malignancies for almost two decades. In addition, treatment with IMiDs is also associated with an increased risk for myelodysplastic neoplasms (MDS), squamous cell carcinoma of the skin, and, less frequently, acute lymphoblastic leukemia (ALL). We present a case of an elderly male with MM and multiple subsequent skin cancers, who presented with pancytopenia and was diagnosed with B-lymphoblastic leukemia (B-ALL) after 10 years of maintenance lenalidomide therapy.

P=N/A, N=65, Recruiting, IRCCS Azienda Ospedaliero-Universitaria di Bologna

P2/3, N=1000, Recruiting, University Health Network, Toronto | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: May 2025 --> May 2026

P2, N=124, Active, not recruiting, University of Leeds | Trial completion date: Jun 2023 --> Jun 2025

P2, N=25, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Jun 2025 --> Nov 2024 | Trial primary completion date: Jun 2025 --> Nov 2024

These interactions are crucial for the observed inhibitory activity. Molecular dynamics simulation revealed the binding event of the most active compound with class I histone deacetylase and the stability of the complex in a biological environment.

Further basic and clinical studies are needed to define the role of these molecules during tumor development and to improve their clinical impact as biomarkers and targets for predicting the efficacy of immunotherapies. This study deepens the understanding of the intricate regulation of the immune checkpoints mediated by soluble factors and allows us to devise new ways to combine conventional treatments with the most innovative anticancer options.

P1/2, N=68, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Sep 2024 --> Dec 2024

The RVd therapy, combining lenalidomide, bortezomib, and dexamethasone, is a mainstay treatment for multiple myeloma. Blocking MHC-I or depleting T cells alleviates the defective erythropoiesis of PRCA, suggesting that the interaction between erythroid cells with elevated MHC-I and T cells in the bone marrow might contribute to PRCA. Taken together, our study implicates a mechanism underlying lenalidomide-induced PRCA in treating cancer patients.

In addition, CA induces apoptosis by enhancing the expression of Bax and caspase-3; and decreased expression of Bcl-2 in prostate cancer cells. Thus, CA might act as a therapeutical application against prostate cancer by targeting the IL-6/JAK/STAT3 signaling axis.

Here, we present the crystal structure of an IL-6 domain-swapped dimer that computational approaches could not predict. The structure explains why the IL-6 dimer is antagonistic to the IL-6 monomer in signaling complex formation and provides insights for IL-6 targeted therapies.

P2/3, N=138, Recruiting, R-Pharm International, LLC | Trial completion date: Dec 2026 --> Dec 2028 | Trial primary completion date: Jun 2026 --> Apr 2027

P1/2, N=101, Active, not recruiting, University of Chicago | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P2, N=54, Completed, Amgen | Active, not recruiting --> Completed

P3, N=10000, Recruiting, Novo Nordisk A/S | Not yet recruiting --> Recruiting

P2, N=150, Completed, Peter MacCallum Cancer Centre, Australia | Unknown status --> Completed

P2, N=215, Recruiting, Memorial Sloan Kettering Cancer Center

MRD testing was performed at 100 days post-autologous stem cell transplant (ASCT) (n=39) and/or after one year of lenalidomide (len) maintenance (n=33)...However, these findings are based on preliminary data from a small cohort, requiring further validation in larger studies. Future research will focus on enhancing sensitivity and validating these findings in a broader patient population.

Understanding the implication of increasing MRD burden is particularly relevant in patients with NDMM treated with quadruplet therapy (QUAD, consisting of a PI, an IMiD, an anti-CD38 mAb and dexamethasone) and autologous stem cell transplantation (ASCT), since most will reach MRD negativity...Among the 19 patients with MRD-P, 12 (63%) were on observation at time of MRD-P, 2 were receiving single agent lenalidomide, 5 were receiving a QUAD, 17 (89%) had previously obtained MRD negativity at <10-5 including 10 (53%) who had also achieved MRD negativity at 10-6...Outcomes of patients with MRD-P are similar to those of patients with IMWG-defined PD. These findings challenge the paradigm of IMWG-defined PD and paraprotein measurability as minimal parameters for change in therapy and Introduction of agents with new mechanisms of action.

P3, N=389, Completed, Fondazione EMN Italy Onlus | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jul 2024

Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of IKZF1/3 inhibitor lenalidomide in a mouse model. Thus, YTHDF2 coordinates epi-transcriptional and transcriptional networks to potentiate T cell immunity, which could inform therapeutic intervention.

P2, N=187, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

P1/2, N=32, Not yet recruiting, University of Aarhus

These trials have shown that ziltivekimab does not increase the risk for cytopenia or infectious complications as has been described for other interleukin-6-targeting monoclonal antibodies, like tocilizumab. In addition, ziltivekimab has shown efficacy in improving anemia parameters, including hemoglobin levels and iron studies. Ziltivekimab deserves full scale clinical development, and to this aim, large-scale clinical trials are under way.

Sixteen patients had CRS previously treated with tocilizumab and 17 patients had ICANS previously treated with steroids. Siltuximab appeared to be effective for both CRS and ICANS, including previously treated toxicities. These data support the use of siltuximab in CRS and ICANS as well as provide rationale for future prospective studies.

The original molecular glue degraders (thalidomide, lenalidomide, and pomalidomide) are known to bind to cereblon (CRBN) and alter its surface to induce recruitment, ubiquitination, and degradation of therapeutically valuable neosubstrates (IKZF1, IKZF3, and CK1α). Herein, we describe the medicinal chemistry efforts that resulted in the discovery of SJ3149 as well as other potent and selective CK1α degraders. We report kinetic profiling and parameters of CK1α degradation, ternary complex, antiproliferative effects, in vitro ADME data, and in vivo pharmacokinetic studies with demonstrated oral bioavailability.

P2, N=394, Not yet recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

P1/2, N=37, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed

Lenalidomide (LEN) is widely used immunomodulatory drug (IMiD)...The study included newly diagnosed MM patients (NDMM) and MM patients treated with first-line LEN and dexamethasone (RD) who achieved and least very good partial remission (VGPR)...This should be emphasized because IL-17-related signaling can potentially be targeted, providing the rationale for future research. Establishing the molecular background associated with long-lasting and profound response to LEN may improve LEN-based chemotherapy regimens and facilitate the development of adjuvant therapies to enhance its anti-MM activity.

Optimizing the formulation, for example, enriched fish oil that meets drug concentration standards for EPA and DHA, a continuous infusion rate, reductions in long-chain saturated fatty acids concentrations, and addition of medium-chain triglycerides to improve EPA + DHA utilization and physical stability are key pharmaceutical factors. This may result in a safer and more effective option than targeted abrogation of cytokines and consequent risks of adverse drug reactions, but will require formal study in randomized control trials in humans.

P=N/A, N=96, Completed, iOMEDICO AG | Active, not recruiting --> Completed | N=250 --> 96

P1, N=11, Terminated, Ohio State University | Phase classification: P1b --> P1

MRD testing was performed at 100 days post-autologous stem cell transplant (ASCT) (n=39) and/or after one year of lenalidomide (len) maintenance (n=33)... cfWGS is a promising MRD alternative which is less invasive than MFC and clonoSEQ. It benefits non-secretory and some light chain only patients where EasyM is not currently feasible and uniquely informs of clonal dynamics at progression. Future work will aim to improve sensitivity and validate findings in a larger cohort.

These observations imply that Pomalidomide treatment influences the T-cell repertoire, particularly in the CD4 + subpopulation during the later stages of treatment, raising speculation about the potential involvement of these lymphocyte expansions in mechanisms related to antitumor immunity.

In the whole group H, significantly more patients obtained Clinical Disease Activity Index remission by tumor necrosis factor inhibitors (7/9, 77.8%) than by interleukin-6 inhibitors (1/6 (16.7%); p = 0.04). In patients with rheumatoid arthritis, interleukin-6 inhibitors may be more beneficial for patients with low femoral bone mineral density, whereas tumor necrosis factor inhibitors may be advantageous for those with preserved bone mineral density.

P2, N=204, Not yet recruiting, Peptinov SAS

Even though we could not find any predictive value of CD56, c-myc, and cyclin D1 expression on mobilization, c-myc was found to be associated with low OS. Further studies with large and homogenous study population would be more informative.