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

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.

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.

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.

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

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

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.

The duration and value difference for CRP normalization between anti-tumor necrosis factor agents, ustekinumab, and vedolizumab were statistically insignificant...Treatment with 5-aminosalicylic acid (HR 2.77; 95% confidence interval &lsqb;CI] 1.26-6.11) and high albumin level (HR 1.64, 95% CI 1.04-2.61) favored early CRP normalization, whereas structuring behavior less likely than inflammatory behavior (HR 0.43, 95% CI 0.19-0.96). We have provided the actual rate of achieving CRP normalization and its appropriate timeframe as an initial target in CD treatment.

P1/2, N=6, Completed, National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting --> Completed | N=20 --> 6

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.

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.

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.

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.

Here, we report a comprehensive analysis of baseline MCH mutational landscape in pts enrolled in the Fondazione Italiana Linfomi (FIL) MCL0208 phase 3 trial (NCT 02354313), evaluating lenalidomide maintenance vs observation after chemoimmunotherapy and ASCT in untreated MCL pts ≤ 65 years...In conclusion, we provided the M-CH mutational landscape at baseline in younger MCL pts and we showed for the first time the unfavorable clinical impact of large CH clones on MCL progression. Figure 1.

Multiple myeloma (MM) first-line treatment algorithms include immuno-chemotherapy (ICT) induction, high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) consolidation, followed by lenalidomide maintenance...Clinical outcomes were inferior in the PPM1D-mutated (PPM1Dmut) subset with median progression-free survival (PFS) of 15 vs. 37 months (p = 0.0002) and median overall survival (OS) of 36 vs. 156 months (p = 0.001) for the PPM1Dmut and PPM1Dwt population, respectively. Our data suggest that the occurrence of PPM1D gene mutations in peripheral blood cells correlates with inferior outcomes after ASCT in patients with multiple myeloma.

PD-1 inhibitor combined with lenalidomide regimen may be a new treatment for relapsed CD5+ DLBCL.

Our observations suggest that SOX9 expression may serve as a putative indicator of TO formation, indicating a critical role of Sertoli cells in promoting organoid formation, seminiferous tubule integrity, and testicular function in pre- and peri-pubertal testicular tissue.

P3, N=384, Completed, Biocon Biologics UK Ltd | Active, not recruiting --> Completed | Trial completion date: May 2024 --> Nov 2023

P2, N=10, Active, not recruiting, Ciusss de L'Est de l'Île de Montréal | Trial primary completion date: Jan 2024 --> Jan 2026

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.

We compare and contrast our methodology with recent DLBCL classifiers to contextualize our clusters and show improved prognostic utility. Finally, using pre-clinical models, we demonstrate a mechanistic rationale for IKZF1/3 degraders such as lenalidomide to overcome the low immune infiltration phenotype of A7 by inducing T-cell trafficking into tumors and upregulating MHC I and II on tumor cells, and demonstrate that TCF4 is an important regulator of MYC-related biology in A7.

ATL relapse was not observed at 13 months into lenalidomide treatment. Our results suggest that lenalidomide is an effective option for the treatment of post-transplant relapsed ATL.

In the frontline high-dose phase 3 FIL-MCL0208 trial (NCT02354313), 8% of enrolled mantle cell lymphoma (MCL) patients could not be randomised to receive lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) due to inadequate hematological recovery and 52% of those who started LEN, needed a dose reduction due to toxicity...A long lasting G4 neutropenia after ASCT (> 10 days) was associated with a worse outcome, both in terms of PFS and OS. In conclusion, although the harvesting procedures proved feasible for younger MCL patients, long-lasting cytopenia following ASCT remains a significant issue: this can hinder the administration of effective maintenance therapies, potentially increasing the relapse rate and negatively affecting survival outcomes.

P3, N=402, Completed, Fondazione EMN Italy Onlus | Active, not recruiting --> Completed | Trial completion date: Jun 2025 --> Jul 2024

P3, N=210, Completed, Fondazione EMN Italy Onlus | Active, not recruiting --> Completed

IL-4 and IL-6 levels increased during disease progression. In conclusion, this study provides a better understanding of the association between cytokines and the efficacy of Ld therapy as well as the unique changes in cytokines related to inflammatory and immune responses during Ld therapy.

Immunohistochemical analysis revealed that these ATLL cells had reduced CCR4 expression. The present case suggests that treatment should be carefully determined in ATLL with reference to a history of lenalidomide use and CCR4 expression.

Thus, while MSCs support the presence of these immature cell populations, they simultaneously inhibit their maturation. This finding provides novel mechanistic insights into lenalidomide- and pomalidomide-induced cytopenia, and could guide therapeutic strategies for its mitigation.

Furthermore, DC-TNFR2KO mice exhibited reduced levels of interleukin-12 (IL-12), a Th1 cell activator, as well as diminished Th1 cells, and interferon-gamma (IFN-γ) levels in the serum compared to controls following MOS stimulation. In summary, our study provides compelling evidence supporting the role of TNFR2 in promoting PsA-like inflammation through cDC1/Th1 activation pathways.

P1/2, N=12, Terminated, National Health Research Institutes, Taiwan | N=33 --> 12 | Trial completion date: Dec 2025 --> Mar 2024 | Not yet recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Mar 2024; The resolution of DSMB

P3, N=422, Active, not recruiting, AO GENERIUM

P2, N=108, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Aug 2024 --> Aug 2025