Limits...
Proteasome inhibition and its therapeutic potential in multiple myeloma.

Chari A, Mazumder A, Jagannath S - Biologics (2010)

Bottom Line: Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years.In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease.We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

View Article: PubMed Central - PubMed

Affiliation: Mount Sinai School of Medicine, New York, NY, USA.

ABSTRACT
Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

No MeSH data available.


Related in: MedlinePlus

Median levels of alkaline phosphatase levels of patients with multiple myeloma who responded to treatment with bortezomib and dexamethasone in the APEX trial. Reproduced with permission from Zangari M, Esseltine D, Lee CK, et al. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol. 2005;131(1):71–73.14 Copyright © 2005 John Wiley and Sons.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2990320&req=5

f4-btt-4-273: Median levels of alkaline phosphatase levels of patients with multiple myeloma who responded to treatment with bortezomib and dexamethasone in the APEX trial. Reproduced with permission from Zangari M, Esseltine D, Lee CK, et al. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol. 2005;131(1):71–73.14 Copyright © 2005 John Wiley and Sons.

Mentions: Bortezomib therapy also appears to have beneficial effects on the bone. When alkaline phosphatase levels were compared with responders and nonresponders in the APEX study, the most powerful predictor of a response was a 25% increase in alkaline phosphatase at week 6 (P < 0.0001) (Figure 4).14 Laboratory work has confirmed the ability of bortezomib to not only inhibit osteclast mediated bone destruction, but also directly induce bone formation.15,16 Interestingly, as shown in Figure 4, the increase in alkaline phosphatase was not observed on the dexamethasone arm, even in the responders.14 This increase has also been recently found to be associated with improved time to progression. 17


Proteasome inhibition and its therapeutic potential in multiple myeloma.

Chari A, Mazumder A, Jagannath S - Biologics (2010)

Median levels of alkaline phosphatase levels of patients with multiple myeloma who responded to treatment with bortezomib and dexamethasone in the APEX trial. Reproduced with permission from Zangari M, Esseltine D, Lee CK, et al. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol. 2005;131(1):71–73.14 Copyright © 2005 John Wiley and Sons.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2990320&req=5

f4-btt-4-273: Median levels of alkaline phosphatase levels of patients with multiple myeloma who responded to treatment with bortezomib and dexamethasone in the APEX trial. Reproduced with permission from Zangari M, Esseltine D, Lee CK, et al. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol. 2005;131(1):71–73.14 Copyright © 2005 John Wiley and Sons.
Mentions: Bortezomib therapy also appears to have beneficial effects on the bone. When alkaline phosphatase levels were compared with responders and nonresponders in the APEX study, the most powerful predictor of a response was a 25% increase in alkaline phosphatase at week 6 (P < 0.0001) (Figure 4).14 Laboratory work has confirmed the ability of bortezomib to not only inhibit osteclast mediated bone destruction, but also directly induce bone formation.15,16 Interestingly, as shown in Figure 4, the increase in alkaline phosphatase was not observed on the dexamethasone arm, even in the responders.14 This increase has also been recently found to be associated with improved time to progression. 17

Bottom Line: Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years.In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease.We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

View Article: PubMed Central - PubMed

Affiliation: Mount Sinai School of Medicine, New York, NY, USA.

ABSTRACT
Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

No MeSH data available.


Related in: MedlinePlus