At ASCO 2012 Jakubowiak, from U of Chicago, shows "high risk" patients responses no different from standard risk patients on carfilzomib [Kyprolis].
Presented by Andrzej J. Jakubowiak, MD, PhD.
In this phase I/II trial, 53 patients with newly diagnosed multiple myeloma were given carfilzomib, lenalidomide, and dexamethasone in induction and maintenance phases to determine the rate of ≥near complete response (CR), which was 78% after 8+ cycles, with no evident difference in response by stage or cytogenetics. At the same time point, more than half of patients (61%) were in stringent CR. Responses appeared durable as all such patients maintained sCR for a median of 9 months. Progression-free survival was 97% at 12 months and 92% at 24 months. There was no grade 3/4 peripheral neuropathy, and no discontinuations occurred from toxicity during maintenance.
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID=100344
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Re: sCR even in High Risk patients on carfilzomib
Hi Suzierose...that is very encouraging news for the 'high risk' sub-group of patients, isn't it? Thanks for volunteering your posts too, on the ASH conference. As a reader, I am trying to grasp the significance of the studies that the Beacon has posted, and your insights help too. One of these days I may be able to get a handle on all of the new research!
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Nancy Shamanna - Name: Nancy Shamanna
- Who do you know with myeloma?: Self and others too
- When were you/they diagnosed?: July 2009
Re: sCR even in High Risk patients on carfilzomib
Hi Nancy!
Yes, it is!
Particularly so, when you consider that 'high risk' patient genetic stratification came out of UAM's trials, since despite throwing every highly toxic multiple four drug combo chemo you could think of at the patient, there was a group that did dismal even with back-back tandem HDT along with multiple 6 drug combo toxic chemo, they were unable to achieve CR.
So, this is very good news indeed!
The best news will be when we have long term PFS and OS which let's us see how enduring the responses are.
But for now, 97% and 92% PFS at 12 and 24 months, respectively, without tandem HDT and multiple drug combo's is a BFD!!!.
Yes, it is!
Particularly so, when you consider that 'high risk' patient genetic stratification came out of UAM's trials, since despite throwing every highly toxic multiple four drug combo chemo you could think of at the patient, there was a group that did dismal even with back-back tandem HDT along with multiple 6 drug combo toxic chemo, they were unable to achieve CR.
So, this is very good news indeed!
The best news will be when we have long term PFS and OS which let's us see how enduring the responses are.
But for now, 97% and 92% PFS at 12 and 24 months, respectively, without tandem HDT and multiple drug combo's is a BFD!!!.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: sCR even in High Risk patients on carfilzomib
Suzierose,
This is wonderful news for newly diagnosed "high risk" patients!!
Like Nancy, I am most grateful for your posts and for Beacon's coverage of the ASH conference.
You are so kind to share the fruits of your reseach with those of us who may not have as much access to, and, more importantly, understanding of the information!
Thank you again!!!
Lisa B.
This is wonderful news for newly diagnosed "high risk" patients!!
Like Nancy, I am most grateful for your posts and for Beacon's coverage of the ASH conference.
You are so kind to share the fruits of your reseach with those of us who may not have as much access to, and, more importantly, understanding of the information!
Thank you again!!!
Lisa B.
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Lisa B. - Name: Lisa B.
- Who do you know with myeloma?: My mother, Barbara Henson
- When were you/they diagnosed?: 10-28-11
- Age at diagnosis: 71
Re: sCR even in High Risk patients on carfilzomib
Suzie,
There are so many abreviations to learn in multiple myeloma. Your last one is certainly my favorite!
There are so many abreviations to learn in multiple myeloma. Your last one is certainly my favorite!
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rumnting - Who do you know with myeloma?: husband
- When were you/they diagnosed?: 4/9/11
- Age at diagnosis: 54
Re: sCR even in High Risk patients on carfilzomib
Hi rum&ting!!
...mine 2!!!....
...mine 2!!!....
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: sCR even in High Risk patients on carfilzomib
I'm asymptomatic but, in a clinical trial with BHQ880. I was never convinced that a SCT was the answer. People get them and still need treatment after. Could this be the alternative until better treatment comes along. I don't like the idea of taking a year of my life with a SCT only to have it not work a year later. What's the point?
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Stan W. - Name: Stan
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: SMM-April 2012
- Age at diagnosis: 58
Re: sCR even in High Risk patients on carfilzomib
Here is some additional information, that provides pharmacological reasons for why carfilzomib is showing deeper responses than bortezomib, and overcoming bortezomib resistance, as well as having success in high-risk patients. It all has to do with the selectivity and specificity of how and where it binds to the proteasome producing a sustained and irreversible inhibition.
In short, it has superior efficacy and tolerability due to where and how it binds to the protesasome.
"It is thought that the selectivity of carfilzomib for the β5 subunit contributes to its improved tolerability profile compared with bortezomib.
Irrespective of cell type, brief exposure (1 hour) to carfilzomib resulted in greater cytotoxicity (particularly to hematologic tumor cell lines) in terms of cell viability, apoptosis, and cell cycle progression, compared with bortezomib.[22] Sustained inhibition of the proteasome with carfilzomib may explain the greater cytotoxic response.[22] It is important to note that in vitro studies confirm that the sustained binding of carfilzomib to the proteasome does not significantly affect the rate of recovery of proteasomal activity (50% to 100% recovery within 24 hours in all tissues), which was only moderately slower than with bortezomib, suggesting that proteasomal recovery involves de novo protein synthesis.[22]
However, these results for carfilzomib cannot be generalized to whole blood; less than 50% recovery was observed after 1 week, compared with complete recovery after 48 hours in bortezomib-treated samples.[22]
The binding profile of carfilzomib results in accumulation of ubiquitin-protein conjugates and proteasome substrates, as well as inhibition of myeloma cell proliferation via induction of apoptosis. carfilzomib demonstrated potent antiproliferative and pro-apoptotic effects in myeloma cell lines and in patient-derived models of myeloma. Like bortezomib, carfilzomib-induced apoptosis occurs through intrinsic and extrinsic caspase pathways that converge on the effector caspase-3. However, in preclinical models of multiple myeloma, carfilzomib demonstrated increased activity against multiple myeloma cell lines, enhanced JNK phosphorylation, and greater potency in increasing caspase-3, caspase-8, and caspase-9 activity (1.5-fold, 1.8-fold, and 2.0-fold increases, respectively), compared with bortezomib.
Of note, in both cell-line models and clinical samples, carfilzomib overcame primary and secondary resistance to bortezomib. The researchers suggest that this may be due to the sustained inhibition of the ChT-L subunit, which potentially requires the cell to synthesize and reassemble new proteasomes. This may overcome the cell’s attempt at resistance by overproduction of proteasome subunits and other ubiquitin-proteasome pathway proteins—a characteristic displayed by cells resistant to bortezomib."
Good news!
http://www.cancernetwork.com/supplements/onc-nov-2011/content/article/10165/1983417?pageNumber=2
In short, it has superior efficacy and tolerability due to where and how it binds to the protesasome.
"It is thought that the selectivity of carfilzomib for the β5 subunit contributes to its improved tolerability profile compared with bortezomib.
Irrespective of cell type, brief exposure (1 hour) to carfilzomib resulted in greater cytotoxicity (particularly to hematologic tumor cell lines) in terms of cell viability, apoptosis, and cell cycle progression, compared with bortezomib.[22] Sustained inhibition of the proteasome with carfilzomib may explain the greater cytotoxic response.[22] It is important to note that in vitro studies confirm that the sustained binding of carfilzomib to the proteasome does not significantly affect the rate of recovery of proteasomal activity (50% to 100% recovery within 24 hours in all tissues), which was only moderately slower than with bortezomib, suggesting that proteasomal recovery involves de novo protein synthesis.[22]
However, these results for carfilzomib cannot be generalized to whole blood; less than 50% recovery was observed after 1 week, compared with complete recovery after 48 hours in bortezomib-treated samples.[22]
The binding profile of carfilzomib results in accumulation of ubiquitin-protein conjugates and proteasome substrates, as well as inhibition of myeloma cell proliferation via induction of apoptosis. carfilzomib demonstrated potent antiproliferative and pro-apoptotic effects in myeloma cell lines and in patient-derived models of myeloma. Like bortezomib, carfilzomib-induced apoptosis occurs through intrinsic and extrinsic caspase pathways that converge on the effector caspase-3. However, in preclinical models of multiple myeloma, carfilzomib demonstrated increased activity against multiple myeloma cell lines, enhanced JNK phosphorylation, and greater potency in increasing caspase-3, caspase-8, and caspase-9 activity (1.5-fold, 1.8-fold, and 2.0-fold increases, respectively), compared with bortezomib.
Of note, in both cell-line models and clinical samples, carfilzomib overcame primary and secondary resistance to bortezomib. The researchers suggest that this may be due to the sustained inhibition of the ChT-L subunit, which potentially requires the cell to synthesize and reassemble new proteasomes. This may overcome the cell’s attempt at resistance by overproduction of proteasome subunits and other ubiquitin-proteasome pathway proteins—a characteristic displayed by cells resistant to bortezomib."
Good news!
http://www.cancernetwork.com/supplements/onc-nov-2011/content/article/10165/1983417?pageNumber=2
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: sCR even in High Risk patients on carfilzomib
I agree with you StanW.
I have always beleived that the benefit of HDT does not outweigh it's long-term effects. It takes a lifetime to build up an immune system, and given the complexity of it, it just seems irreplaceable. Having to take all the immunizations again, is simply a start, there is much that our immune system does from simply warding off everyday pathogens, that I suspect is loss, given how susceptible SCT patients are to infections, colds, flu etc.
And you are right, there is a 50% failure rate, so to quote you 'what's the point'.
I have always beleived that the benefit of HDT does not outweigh it's long-term effects. It takes a lifetime to build up an immune system, and given the complexity of it, it just seems irreplaceable. Having to take all the immunizations again, is simply a start, there is much that our immune system does from simply warding off everyday pathogens, that I suspect is loss, given how susceptible SCT patients are to infections, colds, flu etc.
And you are right, there is a 50% failure rate, so to quote you 'what's the point'.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: sCR even in High Risk patients on carfilzomib
Perhaps there should be a poll: How long after SCT did you relapse and need treatment? There's a poll regarding happiness with the SCT. That doesn't answer the question. Yes, one could be happy but, still need treatment because of a relapse a year later. I wouldn't be happy if I gave up a year of my life only to need treatment the next year. In fact, I'd be miserable.
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Stan W. - Name: Stan
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: SMM-April 2012
- Age at diagnosis: 58
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