Multiple Myeloma

Our findings reveal that exosomal tRF-1003 plays a pivotal role in MM angiogenesis by modulating the HIF-1α/VEGF signaling pathway through MAPK1. These insights provide a novel perspective on the mechanisms driving MM progression and highlight the potential therapeutic value of targeting tRF-1003 in managing multiple myeloma.

P1, N=30, Recruiting, Oncotherapeutics | Not yet recruiting --> Recruiting | Initiation date: Jan 2024 --> Dec 2022

Furthermore, MKX upregulated SESN3 and downregulated BCL2L11, which may together underlie decreased etoposide-induced apoptosis...Taken together, our study identified MKX as novel aberrantly expressed homeobox gene in AML and MM, highlighting the function of IRX1 in normal myelopoiesis and B-cell development, and of IRX-related genes in corresponding malignancies. Our data merit further investigation of MKX and its deregulated target genes to serve as novel markers and/or potential therapeutic targets in AML patient subsets.

P2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Mar 2025 | Trial primary completion date: Dec 2024 --> Mar 2025

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.

MTSI involved immunizing BALB/c mice with CFA from Pb18 as a tolerogen and Pl01 as an immunogen, using Freund's adjuvant and cyclophosphamide to induce immune tolerance...The effective generation of P. lutzii-specific antibodies by MTSI demonstrates this technology's promise for the development of accurate PCM diagnostic instruments. These antibodies have the potential to enhance patient outcomes and reduce the incidence of false-negative diagnoses, which could lead to better disease management.

Interestingly, carfilzomib-resistant cells were at least as sensitive to ATX-101 as the wild-type cells, suggesting both low cross-resistance between ATX-101 and proteasome inhibitors and elevated proteasomal stress in carfilzomib-resistant cells. Our multi-omics approach revealed a vital role of PCNA in regulation of proteasomal and ER stress in MM.

Bcl-2 protein ratios predicting sensitivity to venetoclax in vitro were also able to distinguish patients with shorter time to progression after triplet-based induction therapy and ASCT. This is the first study to assess the expression of the most important Bcl-2 family proteins by a quantitative method in a large set of MM patients according to their cytogenetic abnormalities. We shed light on the impact of these proteins on MM prognosis, which could help to consider the levels of proteins involved in apoptosis in the development of new therapeutic strategies.

Both cancers were aggressively treated. The patient received autologous stem cell transplantation (ASCT) for multiple myeloma and tyrosine kinase inhibitor for chronic myeloid leukemia concurrently to achieve the complete response.

In our study, CPI-613 was found to inhibit the proliferation of MM cells, and its combination with bortezomib (BTZ) produced a significant inhibitory effect at lower doses. Furthermore, we found CPI-613 significantly inhibited tumor growth and induced intrinsic apoptosis in the MM mouse xenograft model. This study reveals the mechanism and effect of CPI-613 in MM, which suggests that CPI-613 may be a new drug option for the clinical treatment of MM, but further clinical trials are needed for evaluation.

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

P2, N=20, Recruiting, Northside Hospital, Inc. | Not yet recruiting --> Recruiting

P1, N=125, Recruiting, K36 Therapeutics, Inc. | N=60 --> 125 | Trial completion date: Oct 2025 --> Jun 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

P1/2, N=17, Active, not recruiting, Hackensack Meridian Health | Trial completion date: Nov 2024 --> Sep 2025 | Trial primary completion date: Nov 2024 --> Sep 2025

P1, N=126, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting | N=184 --> 126

Importantly, in a NSD2-dependent MM cellular model, we show that expression of NSD2 mutants, engineered to disrupt the interaction between H3K27me3 and PHDVC5HCH, display in comparison to wild-type NSD2: incomplete loss of H3K27 methylation throughout the genome, decreased activation of adhesive properties and cell adhesion genes, and a decrease of the corresponding H3K27ac signal at promoters. Collectively, these data suggest that the PHDVC5HCH domain of NSD2 plays an important role in modulating gene expression and chromatin modification, providing new opportunities for pharmacological intervention.

The introduction of human CRBN into these models allows for the study of IMiDs and cereblon based PROTACs in mice. New genetically engineered models based on germinal center cell activation of Nsd2 or Ccnd1 together with constitutive NFkB are being developed to model some of the important genetic subtypes of human multiple myeloma.

Molecular docking, molecular dynamics (MD) simulations, and MM/GBSA calculations further confirmed the stable binding of voreloxin to both c-Myc and Bcl-2 G4s, primarily driven by π-π stacking and hydrogen bonding interactions. These findings provide valuable insights for the development of G4-targeting drugs for cancer therapy.

Multi-target approaches, e.g. the bispecific BCMA×CD19 CAR-T product GC012F, are advancing through clinical development with encouraging safety and efficacy data. However, randomized controlled trials will be necessary to confirm the role and positioning of CD19-directed CAR-T cells within the current MM treatment landscape.

P=N/A, N=5000, Recruiting, University of Alabama at Birmingham | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

P1, N=12, Recruiting, Shanghai Cell Therapy Group Co.,Ltd

P=N/A, N=30, Completed, Nepean Blue Mountains Local Health District | Recruiting --> Completed

Nevertheless, when co-segregation was eliminated, the detrimental effect of +1q or del(1p) was no longer observed. In conclusion, this study confirms the prognostic significance of high-risk cytogenetic abnormalities in MM and highlights the importance of considering co-occurrence for accurate prognosis assessment.

In this respect, RB1 loss has been implicated in the progression of MM through its influence on interleukin-6 (IL-6) secretion and cell proliferation. This review comprehensively summarizes the role of RB1 in MM and expounds on the potential of targeting RB1 as a therapeutic strategy for this malignancy.

P1, N=24, Not yet recruiting, The First Affiliated Hospital of Soochow University

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

P2, N=75, Recruiting, Canadian Myeloma Research Group | Not yet recruiting --> Recruiting

Concomitant NAMPT inhibition further compounded the effects of NAPRT KO, effectively sensitizing MM cells to the chemotherapeutic drug, melphalan; NAPRT added-back fully rescues these phenotypes. Overall, our results propose comprehensive NAD+ biosynthesis inhibition, through simultaneously targeting NAMPT and NAPRT, as a promising strategy to be tested in randomized clinical trials involving transplant-eligible MM patients, especially those with more aggressive disease.

Altogether, our findings indicated that SFN inhibits MM cell-induced osteoclast differentiation and macrophage proliferation by elevating FPN1 levels. SFN could be a promising therapeutic strategy for MM-associated osteolysis.

All mAB-treated patients with malignancies developed polyfunctional immunity humoral and T-cell immunity to SARS-CoV-2 even in the setting of B-cell deficiency. The evolution of this immunity, including new variant-specific antibodies, without secondary illnesses suggests that patients were protected from symptomatic re-infection, and mAB therapy did not blunt the development of host immunity. Future studies are warranted to better characterize immunologic memory over time with exposures to new viral variants, evaluate prolonged viral shedding and the continued use of appropriate mAB for infection in high-risk patients.

P=N/A, N=26, Completed, University of Oklahoma | Recruiting --> Completed | N=60 --> 26 | Trial completion date: Jul 2025 --> Sep 2024

P=N/A, N=50, Recruiting, Pack Health | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Oct 2024 --> Aug 2025

P=N/A, N=26, Completed, University of Turin, Italy | Recruiting --> Completed | N=100 --> 26 | Trial completion date: Sep 2022 --> Dec 2024

P=N/A, N=1272, Completed, Universitätsklinikum Hamburg-Eppendorf | Active, not recruiting --> Completed

P=N/A, N=100, Recruiting, Pack Health | Trial completion date: Jun 2025 --> Dec 2025 | Trial primary completion date: Mar 2025 --> Aug 2025

P=N/A, N=40, Completed, University of Turin, Italy | Active, not recruiting --> Completed | Trial completion date: Jul 2025 --> Dec 2024 | Trial primary completion date: Jul 2025 --> Jul 2024

[18F]AlF-NOTA-SC exhibited CXCR4-specific uptake in vitro and in vivo, with fast and persistent tumor accumulation, making it a strong candidate for clinical translation as an 18F-alternative to [68Ga]PentixaFor.

P1, N=11, Terminated, Guenther Koehne | Active, not recruiting --> Terminated; The study met criteria for stopping due to lack of efficacy per protocol specifications.

Notably, SP-A exhibits strong synergistic effects when combined with the proteasome inhibitor bortezomib...In the case of drug intervention, SP-A attenuates the binding of SSRP1 and USP10 by inhibiting protein interactions between TRIB3 and SSRP1 and promoted SSRP1 protein degradation, leading to significant inhibition of MM development. Visual abstract created with Biorender.

Using the NOD-scid IL2Rgammanull (NSG) mouse based xenograft model and intra-bone MM growth model, we validated that target SENP3 enhanced the killing effect of GPX4 inhibitor RSL3, thereby reduced tumor burden, prolonged survival of mice, and alleviated bone disruption of mice bearing MM tumors. Our study deciphers the mechanism of BMSCs preventing MM cells from spontaneous ferroptosis, and clarifies the therapeutic potential of non-apoptosis strategies in managing refractory or relapsed MM patients.

The poor correlation observed between these two measures prompted evaluation of those with discordant results, identifying that those with low sBCMA and high MTV frequently had low/absent BCMA expression on plasma cells and suboptimal response. Our findings highlight the potential utility of sBCMA and MTV to facilitate more personalized treatment strategies in the management of RRMM eligible for BCMA directed CAR-T.

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.