Assessment of prolonged proteasome inhibition through ixazomib-based oral regimen on newly diagnosed and first-relapsed multiple myeloma: A real-world Chinese cohort study.

OBJECTIVE: To evaluate the effectiveness, safety, and convenience of in-class transition (iCT) from intravenous bortezomib-based induction to ixazomib-based oral regimens. METHODS: This retrospective real-world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first-line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib-based induction therapy, followed by an ixazomib-based oral regimen for 2 year or until disease progression or intolerable toxicity. RESULTS: The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence in situ hybridization (M-FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib-based treatment spanning 6 months. At the 20-month median follow-up, 53% of patients remained on therapy. The 24-month PFS rate was 84.3% from the initiation of bortezomib-based induction and 83.4% from the start of ixazomib-based treatment. Overall response rate (ORR) was 100% post-bortezomib induction and 90% following 6 cycles of the ixazomib-based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia. CONCLUSION: In the real-world Chinese MM population, NDMM and FRMM patients responded favorably to PI-based continuous therapy, demonstrating substantial response rates. The ixazomib-based iCT allows for sustained PI-based treatment, offering promising efficacy and tolerable AEs.

Assessment and Management of Cardiotoxicity in Hematologic Malignancies.

With the increasing overall survival of cancer patients due to recent discoveries in oncology, the incidence of side effects is also rising, and along with secondary malignancies, cardiotoxicity is one of the most concerning side effects, affecting the quality of life of cancer survivors. There are two types of cardiotoxicity associated with chemotherapy; the first one is acute, life-threatening but, fortunately, in most of the cases, reversible; and the second one is with late onset and mostly irreversible. The most studied drugs associated with cardiotoxicity are anthracyclines, but many new agents have demonstrated unexpected cardiotoxic effect, including those currently used in multiple myeloma treatment (proteasome inhibitors and immunomodulatory agents), tyrosine kinase inhibitors used in the treatment of chronic myeloid leukemia and some forms of acute leukemia, and immune checkpoint inhibitors recently introduced in treatment of refractory lymphoma patients. To prevent irreversible myocardial damage, early recognition of cardiac toxicity is mandatory. Traditional methods like echocardiography and magnetic resonance imaging are capable of detecting structural and functional changings, but unable to detect early myocardial damage; therefore, more sensible biomarkers like troponins and natriuretic peptides have to be introduced into the current practice. Baseline assessment of patients allows the identification of those with high risk for cardiotoxicity, while monitoring during and after treatment is important for early detection of cardiotoxicity and prompt intervention.

Ixazomib - the first oral proteasome inhibitor.

Ixazomib, as a proteasome inhibitor, inhibits the chymotrypsin-like activity of the ß5 subunit of the 20S proteasome. Based on the TOURMALINE-MM1 study, ixazomib was proved by the FDA as the orphan drug in November 2015. With a promising effect in prolonging the progression-free survival compared with placebo treatment (median: 20.6 versus 14.7 months), it was the first oral compound combined with lenalidomide and dexamethasone for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least one prior therapy. The main adverse events include low-grade hematological, digestive, or cutaneous events, which were manageable with care. Overall, ixazomib demonstrated favorable safety profile. Ongoing trials are conducted to define its place in first-line, maintenance, and relapse therapies. In this review, we summarized the clinical pharmacology, efficacy, tolerability, safety, and cost-effectiveness of ixazomib.

MG132 ameliorates kidney lesions by inhibiting the degradation of Smad7 in streptozotocin-induced diabetic nephropathy.

BACKGROUND: Smad7 is the main negative regulatory protein in the transforming growth factor-ß (TGF-ß) downstream signaling pathway, which plays an important role in diabetic nephropathy (DN) and may be related to the ubiquitin proteasome pathway (UPP). AIM: We investigated the role of UPP in regulating TGF-ß/SMAD signaling and explored the therapeutic effect of the ubiquitin proteasome inhibitor MG132 on DN. METHODS: Wistar rats were randomly divided into a diabetes group and a normal control group. Rats in the diabetes group were injected intraperitoneally with streptozotocin. Diabetic rats were then randomly divided into a diabetic nephropathy group (DN group), an MG132 high concentration (MH) group, and an MG132 low concentration (ML) group. After 8 weeks of treatment, 24-hour urinary microalbumin (UAlb), urinary protein/urinary creatinine (Up/Ucr) values, ALT, AST, Bcr, kidney damage, TGF-ß, Smad7, fibronectin (FN), and Smurf2 were detected. RESULTS: The body mass and Smad7 protein expression decreased in DN group, but kidney weight, kidney weight index, UAlb, Up/Ucr, FN and Smurf2 mRNA expression, and TGF-ß protein expression increased. However, these changes diminished following treatment with MG132, and a more pronounced effect was evident in MH group compared to ML group. CONCLUSION: MG132 alleviates kidney damage by inhibiting Smad7 ubiquitin degradation and TGF-ß activation in DN.