P2, N=33, Active, not recruiting, University of Washington | Trial completion date: Jan 2031 --> Jan 2028

P2, N=20, Active, not recruiting, Institute of Hematology & Blood Diseases Hospital, China | Recruiting --> Active, not recruiting

P3, N=11, Terminated, Alliance for Clinical Trials in Oncology

This heterogeneity is derived from differences in the strength and duration of PERK-mediated translational inhibition, which gates downstream translation-dependent IRE1α and ATF6 transcriptional programs. Finally, in multiple myeloma, we show that bortezomib-tolerant cells depend on IRE1α activity for survival, linking UPR state to proteasome-inhibitor resistance and positioning SNUPR to guide branch-selective targeting.

Incorporating early NT-proBNP monitoring, carfilzomib exposure, and refined age categorization may improve risk prediction and support more personalized cardiovascular surveillance strategies in cardio-oncology. However, this refined dynamic model should be regarded as exploratory and requires validation in larger independent cohorts before it can be considered for clinical application.

To address this, we performed proteome and phosphoproteome profiling of 12 MM cell line models, comprising four parental lines (AMO-1, ARH77, L363, and RPMI8226) paired with lines that acquired resistance to bortezomib (BTZ) or carfilzomib (CFZ). Beyond known adaptations such as the overexpression of the PI target PSMB5 and the drug efflux transporter ABCB1, we identified the oxidoreductases NQO1 and NQO2 as significantly upregulated proteins under chronic proteotoxic stress across several models. Pharmacological follow up in PI resistant AMO-1 cells showed that NQO2 inhibition by imatinib fully restored CFZ sensitivity, validating NQO2 as a contributor to resistance formation in this model system.

P=N/A, N=17, Completed, University Hospital, Limoges | Recruiting --> Completed

P1/2, N=300, Active, not recruiting, Australasian Leukaemia & Lymphoma Group | Recruiting --> Active, not recruiting

Functionally, MAGEC2 promoted malignant proliferation and induced resistance to adriamycin and bortezomib. MAGEC2 overexpression also exacerbated bone lesions in vivo. Collectively, these findings identify MAGEC2 as both a prognostic biomarker and a promising therapeutic target in MM, and highlight its role as a multifunctional regulator of the ubiquitin system.

CDKN3 overexpression prevented the effects of si-MYBL2 on ferroptosis and BTZ sensitivity in MM cells by interacting with the PI3K/Akt signaling pathway. In conclusion, knockdown of MYBL2 promoted ferroptosis and enhanced the BTZ sensitivity of MM cells through transcriptional regulation of CDKN3 and inactivation of the PI3K/Akt signaling pathway.

This is the first study to model gastrointestinal side effects of bortezomib in rodents, implicating neuroimmune dysregulation of the vagus nerve. Our data show that the gut microbiota is not a primary driver of bortezomib side effects. However, the absence of a symptom profile in FMT mice suggests that, in GF mice, the gut microbiota beneficially modulates the host to protect against bortezomib side effects. Further studies are required to determine whether this can be harnessed to mitigate clinical complications of bortezomib.

P1, N=21, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: May 2027 --> Jun 2026 | Trial primary completion date: May 2027 --> Jun 2026