Multiple Myeloma

Here, we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFN-γ+ TPHEX represent a potential target for immunotherapy of blood cancers.

In addition, we showed unique patterns of miRNA expression in patients experiencing platelet engraftment delay which involved the downregulation of hsa-let-7f-5p and upregulation of hsa-miR-96-5p; and neutrophil engraftment delay which was associated with decreased levels of hsa-miR-125a-5p and hsa-miR-15b-5p. Our findings highlight the significant alterations in serum miRNA levels during AHSCT and suggest the clinical utility of miRNA expression patterns as potential biomarkers that could be harnessed to improve patient outcomes, particularly by predicting the risk of bacteremia during AHSCT.

Our model was also associated with the distribution of immune cells. This novel signature, either alone or in combination with age and β2-microglobulin, showed a good prognostic predictive value and might be used to guide the management of MM patients in clinical practice.

When we knocked down NCOA4 or blocked autophagy using chloroquine, BTZ-induced ferritin degradation and the increase in intracellular free Fe2+ were significantly reduced in MM cells, confirming the role of BTZ in enhancing ferritinophagy. The induction of ferroptosis inhibitor liproxstatin-1 successfully counteracted the synergistic effect of BTZ and RSL-3 in MM cells. Altogether, our findings reveal that BTZ elevates intracellular free Fe2+ by enhancing NCOA4-mediated ferritinophagy and synergizes with RSL-3 by increasing ferroptosisin MM cells.

P2, N=78, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Apr 2024 --> Dec 2024

P2, N=33, Not yet recruiting, Cristiana Costa Chase, DO | Initiation date: Mar 2024 --> Jun 2024

P2, N=50, Active, not recruiting, Ida Bruun Kristensen | Recruiting --> Active, not recruiting

Patients with plasmacytoma who died also had an increased pro-oxidant profile. These data show the profile of inflammatory response markers that are altered in patients with MM who die quickly and serve as a basis for the development of future studies of markers to predict better survival in this disease.

In conclusion, this study showcases the need to study the influence of different CAR architectures based on an identical scFv individually. It indicates that current scFv-based anti-BCMA CAR with clinical utility may already be at their functional optimum regarding the known structural variations of the scFv linker.

These results indicate that NeoTx differentially affects PDAC-infiltrating immune cells and may have detrimental effects on the existing B cell landscape and the formation of TLS. Gaining further insight into the underlying molecular mechanisms is crucial to overcome the intrinsic immunotherapy resistance of PDAC and develop novel strategies to improve the long-term outcome of PDAC patients.

We show that TRIM33 knockdown sensitizes MM cells to the PARP inhibitor Olaparib, and this is synergistic with the standard of care therapy bortezomib, even in co-culture with bone marrow stromal cells (BMSCs). These findings suggest that TRIM33 loss contributes to the pathogenesis of high-risk MM and that this may be therapeutically exploited through the use of PARP inhibitors.

For patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment.

Moreover, GLYR1 transcriptionally activates PER3, and the knockdown of PER3 alleviates the effects of GLYR1 and induces its malignant behavior in MM cells. To conclude, GLYR1 upregulates PER3 and suppresses the aggressive behavior of MM cells, suggesting that GLYR1/PER3 signaling may be a potential therapeutic target for MM.

An unexpected cytoplasmic immunoreactivity for MUM1 was observed in 2 melanocytic tumors. Summarized, MUM1 or melan-A immunomarkers alone are not sufficient to differentiate between CEMPs and amelanotic melanomas and should be part of a larger immunopanel including λ light chain, CD20, and PNL2.

We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma.

P2/3, N=300, Recruiting, Monash University | Not yet recruiting --> Recruiting

P2, N=28, Not yet recruiting, Dickran Kazandjian, MD

P1, N=130, Not yet recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd.

P1, N=33, Active, not recruiting, Massachusetts General Hospital | Trial completion date: Jun 2022 --> Jun 2025 | Trial primary completion date: Jun 2022 --> Dec 2024

P=N/A, N=51, Completed, UNC Lineberger Comprehensive Cancer Center | Recruiting --> Completed | Trial completion date: Nov 2024 --> Sep 2023 | Trial primary completion date: Nov 2024 --> Sep 2023

P=N/A, N=27, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting

P2, N=72, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P2, N=57, Active, not recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Feb 2026 --> Aug 2026 | Trial primary completion date: Feb 2024 --> Aug 2024

This phase 1 clinical trial demonstrates that early introduction of immunotherapy after ASCT is well tolerated and shows promising disease control in patients with MM, accompanied by favorable changes in the immune microenvironment.

P1, N=40, Not yet recruiting, Nexcella Inc. | Phase classification: P1b --> P1 | Initiation date: Jan 2024 --> May 2024 | Trial primary completion date: Dec 2025 --> Dec 2026

P1, N=47, Active, not recruiting, Sanofi | Trial completion date: Apr 2024 --> Aug 2024

P=N/A, N=260, Not yet recruiting, Peking University People's Hospital

Overall, this study highlights the potential beneficial effect of a higher BMI on CAR-T cell therapy outcomes.

P2, N=67, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Mar 2024 --> Jun 2024 | Trial primary completion date: Mar 2024 --> Jun 2024

P1/2, N=316, Recruiting, Hoffmann-La Roche | Phase classification: P1 --> P1/2

P2, N=52, Active, not recruiting, Massachusetts General Hospital | Trial completion date: Jun 2022 --> Jun 2025 | Trial primary completion date: Jun 2022 --> Dec 2024

P2, N=120, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting | Trial completion date: Dec 2027 --> Jun 2027 | Trial primary completion date: Dec 2027 --> Jun 2027

P=N/A, N=1000, Active, not recruiting, The First Affiliated Hospital of Soochow University

P2, N=43, Recruiting, Andrew Yee, MD | Trial completion date: May 2025 --> May 2026 | Trial primary completion date: May 2024 --> May 2025

P1, N=30, Recruiting, Massachusetts General Hospital | N=60 --> 30 | Trial completion date: Sep 2022 --> Sep 2024 | Trial primary completion date: Sep 2022 --> Sep 2024

P1, N=19, Active, not recruiting, Massachusetts General Hospital | Phase classification: P1b --> P1 | Trial completion date: Jun 2023 --> Sep 2024 | Trial primary completion date: Jun 2023 --> Sep 2024

While the mechanism underlying SR remains unclear, our findings suggest that host immune response as well as EBV infection may contribute to SR. Further studies are needed to elucidate the clinicopathologic mechanisms of tumor regression in plasma cell neoplasms.

In 2023, no new antibody-drug conjugates, immunocytokines or chimeric antigen receptor-T cells were approved. Of the approved antibodies, two targeted programmed cell death receptor-1 (PD-1) for orphan indications, two targeted CD20 for diffuse large B cell lymphoma, two targeted different receptors (B-cell maturation antigen [BCMA] and G-coupled protein receptor class C, group 5, member D [GPRC5D]) for treatment of multiple myeloma, and one each that targeted amyloid-β protofibrils for Alzheimer's disease, neonatal Fc receptor alpha-chain for myasthenia gravis, complement factor C5 for CD55 deficiency with hyper-activation of complement, angiopathic thrombosis and severe protein-losing enteropathy disease, interleukin (IL)-23p19 for severely active ulcerative colitis, IL-17A-F for plaque psoriasis and respiratory syncytial virus (RSV)-F protein for season-long RSV prophylaxis in infants.

P2, N=32, Recruiting, Massachusetts General Hospital | Not yet recruiting --> Recruiting

P=N/A, N=420, Recruiting, RenJi Hospital | Not yet recruiting --> Recruiting

P=N/A, N=130, Recruiting, Travera Inc | Trial completion date: Jan 2025 --> Jan 2027 | Trial primary completion date: Jan 2024 --> Jan 2026

P=N/A, N=400, Not yet recruiting, Tufts Medical Center