Enzymatic activities of circulating plasma proteasomes in newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide and dexamethasone

Manasanch, Elisabet E.; Larrea, Carlos Fernández de; Zingone, Adriana; Steinberg, Seth M.; Kwok, Mary; Tageja, Nishant; Bhutani, Manisha; Kazandjian, Dickran; Roschewski, Mark; Wu, Peter; Carter, George; Zuchlinski, Diamond; Mulquin, Marcia; Lamping, Liz; Costello, Rene; Burton, Deborah; Gil, Lindsay A.; Figg, William D.; Marić, Irina; Calvo, Katherine R.; Yuan, Constance; Stetler‐Stevenson, Maryalice; Korde, Neha; Landgren, Ola

doi:10.1080/10428194.2016.1214953

Cited by 11 publications

(7 citation statements)

References 20 publications

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“…We were also noted higher levels of proteasome ChT-L activity in ISS stage III compared to stage I, although it did not acquire statistical significance. We observed a similar situation in proteasome concentration as Manasanch et al [ 22 ], who examined proteasome activity in newly diagnosed MM patients treated with carfilzomib, lenalidomide and dexamethasone: There were no statistically significant differences with regard to the ISS stage. On the contrary, data from another study showed meaningfully increased ChT-L activity and proteasome concentration in a group of patients in advanced stages of MM [ 7 , 12 ] and other diseases, such as CLL patients [ 16 ], and with solid tumours in stages III/IV [ 20 ].…”

Section: Discussionsupporting

confidence: 87%

High chymotrypsin-like activity in the plasma of patients with newly diagnosed multiple myeloma treated with bortezomib is predictive of a better response and longer PFS

et al. 2018

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Proteasome inhibitors (PIs) such as bortezomib constitute an important part of the modern standard therapy for multiple myeloma (MM). In this study, we set out to assess whether proteasome concentration and chymotrypsin-like (ChT-L) activity could serve as potential biomarkers defining the likelihood of response to treatment with bortezomib, in order to identify patients who are more likely to respond to treatment with PI. We analysed proteasome concentration and ChT-L activity in the plasma of 78 patients with newly diagnosed MM during treatment with or without proteasome inhibitors. Values of all the studied parameters in the group of responders decreased sharply from the initial levels already after the third cycle of chemotherapy and remained significantly lower until the end of treatment. On the other hand, in the group of non-responders, there was an increase in the measured proteasome parameters already after the third cycle, and they remained high during the next cycles of therapy. We also showed that high baseline proteasome ChT-L activity values might prognosticate longer progression-free survival (PFS) in patients treated with PI. Our findings demonstrate that measuring plasma proteasome ChT-L activity can be used as a powerful biomarker for predicting clinical response to treatment and PFS in patients with newly diagnosed MM.

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Section: Discussionsupporting

confidence: 87%

High chymotrypsin-like activity in the plasma of patients with newly diagnosed multiple myeloma treated with bortezomib is predictive of a better response and longer PFS

et al. 2018

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“…Circulating 20S proteasomes (c-20S) are physiologically present in human plasma, and their levels increase significantly under a variety of pathological conditions, including autoimmune diseases, cancerous tumors, trauma, sepsis, and acute respiratory distress [60,61,62,63,64,65]. Electron microscopy studies determined that the complexes are intact [66].…”

Section: The Extracellular 20s Proteasomementioning

confidence: 99%

The Contribution of the 20S Proteasome to Proteostasis

et al. 2019

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The last decade has seen accumulating evidence of various proteins being degraded by the core 20S proteasome, without its regulatory particle(s). Here, we will describe recent advances in our knowledge of the functional aspects of the 20S proteasome, exploring several different systems and processes. These include neuronal communication, post-translational processing, oxidative stress, intrinsically disordered protein regulation, and extracellular proteasomes. Taken together, these findings suggest that the 20S proteasome, like the well-studied 26S proteasome, is involved in multiple biological processes. Clarifying our understanding of its workings calls for a transformation in our perception of 20S proteasome-mediated degradation—no longer as a passive and marginal path, but rather as an independent, coordinated biological process. Nevertheless, in spite of impressive progress made thus far, the field still lags far behind the front lines of 26S proteasome research. Therefore, we also touch on the gaps in our knowledge of the 20S proteasome that remain to be bridged in the future.

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“… 9 Unfortunately, these results were not replicated in a prospective study after initial treatment of myeloma patients with carfilzomib, lenalidomide and dexamethasone. 10 , 11 This lack of association may be due to great efficacy of the combination treatment or the fact that cProteasomes activity is not reflective of the proteasome activity of malignant plasma cells, for example. Presently, there is no validated biomarker able to predict the clinical outcomes after treatment with carfilzomib.…”

Section: Introductionmentioning

confidence: 99%

Carfilzomib boosted combination therapy for relapsed multiple myeloma

Steiner

Manasanch

2017

OTT

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Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome, the proteolytic core particle within the 26S proteasome, resulting in the accumulation of proteasome substrates and ultimately growth arrest and apoptosis of tumor cells. The development and ultimate approval of this medication by regulatory agencies has been an important step toward improving clinical outcomes in multiple myeloma. Although initially approved as a single agent for the treatment of multiply relapsed and/or refractory myeloma, in the USA, it is now widely used in the early relapse setting in combination with lenalidomide and dexamethasone. Carfilzomib has also been studied in combination with second-generation immunomodulatory drugs, histone deacetylase inhibitors, alkylating agents and other novel medications. In this review article, we will discuss the efficacy, safety, tolerability and quality of life of carfilzomib-based combination therapies, as well as novel agents, for relapsed multiple myeloma.

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Enzymatic activities of circulating plasma proteasomes in newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide and dexamethasone

Cited by 11 publications

References 20 publications

High chymotrypsin-like activity in the plasma of patients with newly diagnosed multiple myeloma treated with bortezomib is predictive of a better response and longer PFS

High chymotrypsin-like activity in the plasma of patients with newly diagnosed multiple myeloma treated with bortezomib is predictive of a better response and longer PFS

The Contribution of the 20S Proteasome to Proteostasis

Carfilzomib boosted combination therapy for relapsed multiple myeloma

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