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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In 2003 it was approved by the FDA under the accelerated approval scheme for use in patients with progressive myeloma following previous treatment and was also approved in Europe in 2004. The data review for the FDA accelerated approval took just four months and was based on two Phase II studies of 256 patients, all of whom had been pretreated with other agents. Across these two trials, objective responses were observed in 23–35% of the patients and complete responses in 7 patients, with a median duration of response of 365 days. Thus, the trials demonstrated that bortezomib was more effective at delaying disease progression than a standard treatment of high-dose dexamethasone. Although certain serious side effects were worse for patients taking bortezomib, more patients taking the drug were alive after one year than those on the standard treatment. Bortezomib is now approved for multiple myeloma in combination with other agents, and also for the treatment of mantle-cell lymphoma.
Multiple Myeloma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Grade III–IV neuropathy with bortezomib has been significantly reduced by switching from intravenous to subcutaneous injection and a weekly schedule without reduced efficacy. Other side effects with bortezomib include gastrointestinal toxicity, thrombocytopenia, herpes zoster, and hypotension. Both thalidomide and lenalidomide are prothrombotic, and all patients must be assessed for thrombotic risk with a view to starting on appropriate prophylaxis which is typically either prophylactic-dose low-molecular-weight heparin or aspirin. Thalidomide also causes constipation, neuropathy, and somnolence. Lenalidomide although derived from thalidomide does not cause these side effects but does cause fatigue and myelosuppression and requires dose reduction in renal failure. With daratumumab the most common side effect is typically a mild infusional toxicity with the first dose.
Proteasome and Protease Inhibitors
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
N. E. Franke, J. Vink, J. Cloos, Gertjan J. L. Kaspers
Several phase II clinical trials have shown the efficacy of bortezomib as single drug. Interim analysis of these studies shows an overall response rate of 18% to 60% in FL and 39% to 56% in MCL. Currently different combination-studies are ongoing to identify the optimal treatment strategy. An overview of these studies can be found in the review of Leonard et al. (77).
Formosanin C induces autophagy-mediated apoptosis in multiple myeloma cells through the PI3K/AKT/mTOR signaling pathway
Published in Hematology, 2022
Ping Chen, Sungui Wu, Xiaoqing Dong, Min Zhou, Peipei Xu, Bing Chen
Additionally, KEGG pathway enrichment analyses identified the PI3K/AKT signaling pathway, a key regulator of cell survival, growth, proliferation, and apoptosis, as a target of Rhizoma Paridis in MM cells. This hinted us that FC, a main component of Rhizoma Paridis, may acts on the PI3K/AKT signaling pathway. Using IGF-1, we revealed that the suppression of the PI3K/AKT/mTOR pathway contributes to FC-induced excessive autophagy, leading to apoptosis in MM cells. It’s known that internal reactive oxygen species is associated with the PI3K/AKT/mTOR pathway, autophagy and apoptosis in MM cells [32, 33]. However, the role of internal reactive oxygen species in FC inhibition of the PI3K/AKT/mTOR pathway-induced autophagy-mediated apoptosis in MM cells is unclear, which deserves further study. In addition, one of the most significant side effects of bortezomib is peripheral neurotoxicity, which occurs in up to 50% of cases; bortezomib may severely reduce patients’ quality of life, and its clinical application is, therefore, significantly restricted [34, 35]. Our recent study demonstrated that bortezomib results in peripheral neurotoxicity via activation of the mTOR pathway [34]. Thus, we speculated that FC can be used to enhance the anti-MM efficacy of bortezomib and relieve bortezomib-induced peripheral neurotoxicity by targeting the mTOR pathway. Apparently, this speculation requires further investigation.
Memory B cells and long-lived plasma cells in AMR
Published in Renal Failure, 2022
Wenlong Yue, Jia Liu, Xiaohu Li, Luman Wang, Jinfeng Li
Moreover, in AMR patients, traditional immunosuppressive agents do not rapidly eliminate DSAs and cannot block the persistent source of antibodies, namely, long-lived plasma cells. Some drugs targeting plasma cells, such as the proteasome inhibitor-bortezomib, can inhibit the function of long-lived plasma cells and reduce the concentration of serum DSAs [100]. However, bortezomib also has corresponding shortcomings. For example, related studies have shown that compared with that in early AMR, the graft function of advanced patients using bortezomib was not obviously improved [101]. Short-term treatment cannot reduce serum DSA levels. On the one hand, this may be due to the negative feedback mechanism generated by the short-term reduction of plasma cells, which leads to the proliferation of B cells and the production of new ASCs; on the other hand, this may be because the half-life of bortezomib is lower than that of serum DSAs. For the inhibition of plasma cells, DSAs showed false negative results in clinical detection [102,103]. Therefore, the combination of mycophenolic acid, rituximab, and plasma exchange before bortezomib treatment can significantly enhance the therapeutic effect of bortezomib. However, bortezomib can cause side effects such as peripheral neuropathy, gastrointestinal reactions, and cytopenia [104]. When combined with traditional immunosuppressants, we should pay attention to the dose of immunosuppressants.
Combination Treatment with Rituximab and Bortezomib in a Patient with Non-Paraneoplastic Autoimmune Retinopathy
Published in Ocular Immunology and Inflammation, 2020
Matthew D. Benson, David J. A. Plemel, Elaine Yacyshyn, Irwindeep Sandhu, Ian M. MacDonald, Chad F. Baker
Subsequently, her treating ophthalmologist referred her to another institution to explore other treatment options given her lack of response to prior therapies. At the institution’s recommendation and with the assistance of a hematologist and rheumatologist, she was started on a combination of rituximab with bortezomib. Starting in January 2017, she received rituximab at a dose of 1000mg intravenously on days 1 and 15. Bortezomib was dosed at 1.5mg/m2 subcutaneously with oral dexamethasone 8 mg on days 1, 8, and 15 out of a 28-day cycle. The treatment course was administered over a total of 6 cycles. Ondansetron was given as an antiemetic and valacyclovir as prophylaxis for Varicella zoster virus. Side effects attributed to bortezomib treatment included epigastric discomfort, fatigue, constipation, and local injection site inflammation.