Is anyone having cardiac issues and wondering if it is the bortizomib or carfilzomib?
This article reviews how the proteasome inhibitors work on the ubiquitin-protesome system(UPS) which was discovered by the nobel prize winning team Rose, Herschko and Ciechanover.
"The development of several categories of proteasome-specific inhibitors further delineated a role for the UPS in multiple forms of heart disease, such as ischaemia/reperfusion, cardiac hypertrophy, cardiomyopathies, and heart failure. In the vasculature, it was initially shown that proteasome activity affects angiogenesis7 and, subsequently, that the proteasome participates in nitric oxide metabolism, oxidative stress, and atherosclerosis. Descriptions of a dysfunction of the UPS in human heart disease also began to emerge in the literature.8–10 Recently, several clinical case reports have mentioned potentially cardiotoxic side effects of proteasome inhibitors, for example, in patients treated for solid tumours and haematological malignancies.11,12"
http://cardiovascres.oxfordjournals.org/content/85/2/251.full
Here is another excellent review of most commonly used oncology agents and their cardiotoxicity..... excerpt for bortezomib:
"Proteasome Inhibitor
Bortezomib
In a pivotal clinical trial, 669 multiple myeloma patients were treated with bortezomib or high-dose dexamethasone (17). The incidence of cardiac disorders during treatment with bortezomib was 15% versus 13% in those patients treated with dexamethasone. HF events occurred in 5% of bortezomib-treated patients and in 4% of dexamethasone-treated patients. Two percent of patients in each of the treatment groups developed HF (10,17).
....snip...."The mechanism of HF associated with bortezomib is unknown, but it has been proposed that it may cause cardiotoxicity through proteasome inhibition (46). In chronic CMP, it is thought that the ubiquitin–proteasome system may be activated, and that this may be an adaptive mechanism for maintaining a normal stroke volume. In addition, susceptibility to cardiovascular disease has been attributed to an age-related decrease in proteasome activity. Therefore, in patients who possess a baseline presence of subclinical CMP, the ubiquitin–proteasome system is activated, and this may predispose them to bortezomib cardiotoxicity (46).
http://content.onlinejacc.org/cgi/content/full/53/24/2231?ijkey=0bb38cddd67807c64e539ac33e1575edbcbee48e
HF = heart failure.
CMP= cardiomyopathy
The trial authors concluded that the risk of HF with bortezomib was no different than it is with high-dose dex.
Alternatively, the review author, Dr Yeh (Celgene consulte) speculates that if you have subclinical (unsymptomatic) CMP prior to therapy that the body may have upregulated the UPS to compensate for CMP and that the proteasome inhibitors inhibit that upregulation thus creating more susceptibility to cardiotoxicity from borezomib.
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Re: Proteasome Inhibitors and the Cardiovascular System
Hi Suzierose...thanks for the links to the interesting articles about proteasome-specific inhibitors and the cardiac system. I suppose that any chemotherapeutic drugs as powerful and effective as the ones mentioned, could also have severe side effects. This would be a reason for heart monitoring of patients, wouldn't it? The thread of research papers also points to a use of bortezomib in the treatment of a type of lung cancer. There was a reversible case of heart problems in one patient. The authors warned that patients with a history of heart problems should be carefully monitored when on the drug. Many patients with lung cancer also have heart problems, according to the paper.
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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: Proteasome Inhibitors and the Cardiovascular System
Hi Nancy,
Sorry, but I did not read the trail on lung cancer. Often times I will if the trial cited is not specific for multiple myeloma patients. Yes, while uncommon, sometimes HF is reversible.
The concern is that patients may not be aware that HF can occur on proteasome inhibitors, especially given that it could be subclinical when they initially start therapy. Even more confounding is that some of the clinical signs of heart failure..fatigue, cough/wheeze, muzziness occur as a common side effect of other chemo agents as well as bortezomib.
Having cardiac monitoring is as you mentioned a good thing to request.
Having a history of heart problems is usually does not go unnoticed and monitoring is usually status quo.
It is those patients who have subclinical cardiac issues that need most to request monitoring. Particularly, if they notice shortness of breath or that they are walking a lot more slowly. Never feel rested. It may not just be bortezomib either it could be the steroid or lenalidomide.
Somewhat like when they give concomittant myelosuppressive agents...steroids/lenalidomide and bortezomib all can cause cardiac issues.
At least though we should know to suspect that it could be the proteasome inhibitor as well as the other agents that we could be taking.
Presently, it seems many may not consider the proteasome inhibitor as a possible cause of HF as well.
Sorry, but I did not read the trail on lung cancer. Often times I will if the trial cited is not specific for multiple myeloma patients. Yes, while uncommon, sometimes HF is reversible.
The concern is that patients may not be aware that HF can occur on proteasome inhibitors, especially given that it could be subclinical when they initially start therapy. Even more confounding is that some of the clinical signs of heart failure..fatigue, cough/wheeze, muzziness occur as a common side effect of other chemo agents as well as bortezomib.
Having cardiac monitoring is as you mentioned a good thing to request.
Having a history of heart problems is usually does not go unnoticed and monitoring is usually status quo.
It is those patients who have subclinical cardiac issues that need most to request monitoring. Particularly, if they notice shortness of breath or that they are walking a lot more slowly. Never feel rested. It may not just be bortezomib either it could be the steroid or lenalidomide.
Somewhat like when they give concomittant myelosuppressive agents...steroids/lenalidomide and bortezomib all can cause cardiac issues.
At least though we should know to suspect that it could be the proteasome inhibitor as well as the other agents that we could be taking.
Presently, it seems many may not consider the proteasome inhibitor as a possible cause of HF as well.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Proteasome Inhibitors and the Cardiovascular System
Hi Suzierose...it seems that some of the symptoms of HF could also be associated with myeloma itself, since many patients report a 'slowing down' as a sign that things were not going well, and later got a diagnosis of multiple myeloma. sO, it is all quite confusing, and a challenge to us to try to sort out just what is wrong. The experiences of being slower and less physically capable than before would probably also be associated with the heart somehow, or at least the circulatory system. Anemia can certainly cause problems that way.
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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: Proteasome Inhibitors and the Cardiovascular System
......But of course anyone who suspects heart issues should get it checked out! Or, if it becomes apparent that HF could be a side effect of PSI's, then that would become routine testing. in my case, after the bortezomib cycles, I was thoroughly tested for heart issues because I was having a stem cell transplant. Everything appeared OK, and haven't been back on those meds since then..... Thanks for bringing up this important research, Suzierose!
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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: Proteasome Inhibitors and the Cardiovascular System
I have found that I have increased heart rate for 1-2 days with my CRD treatment. However, it varies by week depending on whether it's a CRD, RD, or just D week (I'm on CRD weeks 1 and 3 of the cycle, RD week 2, and just D week 4) . My normal rate is around 55-60. On CRD weeks, it's in the mid 80s, on the RD week it's in the lower 80s, and on the D week it's upper 70s to low 80s. Given this, I think the majority of the increase is due to the Dex, but the Revlimid and Carfilzomib seem to bump it up a bit more, though we speculate this could also be due to increased fluid retention those weeks too. Other than this I've experienced no other cardiac related issues.
I also went back and reviewed my consent forms for the study, which also include possible side-effects. The only one of the three drugs that lists potential heart issues or increased heart rate is the Dex.
I also went back and reviewed my consent forms for the study, which also include possible side-effects. The only one of the three drugs that lists potential heart issues or increased heart rate is the Dex.
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Kevin J - Name: Kevin J
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: Jan 2011
- Age at diagnosis: 52
Re: Proteasome Inhibitors and the Cardiovascular System
Hi Kevin!
Fluid retention is common with dex and would be considered suspect in terms of cardiac changes especially if you are on more than 5mg of Dex. Data from human trials is just beginning to be reported on cardiac impact of carfilzomib, which is why it was not a likely side effect listed in your consent form. The incidence appears to be low as it is with dex (similiar to bortezomib) but it is always good to know that it can occur. My harvesting was pushed back a week due to cardiac echoscan changes. I sometimes think God intervenes for a reason, since I was so overwrought and focused on pain, delay was good. Now, I have more pain info and will approach the harvest less fearful. Neupogen shots start this Thurs now...
You write:
" (I'm on CRD weeks 1 and 3 of the cycle, RD week 2, and just D week 4)"
I don't think I realized that your trial had such a different dosing schedule.
I wondered if you feel less fatigue when it is just an RD vs CRD week? Having this time off all drugs to prepare for harvest, I noticed a huge difference in how tired I was. It feels like I have dropped a decade of life, I have way more pep in my step vs. when on therapy and I felt like I was carrying a 25 lb weight on my back then vs now without the drugs.
You take D for a solid week? How much D, how often that week?
Your C is every other week, interesting. During that week do you have C on 2 sequential days?
My trial C is 2 back-to-back days for 3 weeks sequentially. Based on this schedule I get more C on a monthly basis than you do. You get 4 days a month and I get 6 days a month of C. But then our total doses overall will be 48 does of C since you have 12 cycles and I have 8.
Interestingly, they have not determined a maximum limiting dose for C.
I wonder if Jakobuwiak was worried about neuropathy when he wrote the protocol, so they dosed it every other week to minimize that AE.
I noted that we both had CR after 5 cycles so efficacy may be same with fewer AE's with your dosing.
When these trials are reported on it is going to provide some excellent comparative data in terms of outcomes, not just for AE's but efficacy in terms of CR's, VGPR, etc. You will be able to compare outcomes in terms of cytogenetic profile with dosing schedule as well. Do you know what doses of C and R you are on? My C is 38mg/m squared and the R is 25mg. I also noted we both had CR following 5th cycle as well, so the dosing comparison may show if one has greater duration of response.
How many BM's are you obligated to provide in your trial? I had one pre-trial, after first 2 infusions, after CR and one going forward at end. The BM after first 2 doses was option. I did it for science.
Fluid retention is common with dex and would be considered suspect in terms of cardiac changes especially if you are on more than 5mg of Dex. Data from human trials is just beginning to be reported on cardiac impact of carfilzomib, which is why it was not a likely side effect listed in your consent form. The incidence appears to be low as it is with dex (similiar to bortezomib) but it is always good to know that it can occur. My harvesting was pushed back a week due to cardiac echoscan changes. I sometimes think God intervenes for a reason, since I was so overwrought and focused on pain, delay was good. Now, I have more pain info and will approach the harvest less fearful. Neupogen shots start this Thurs now...
You write:
" (I'm on CRD weeks 1 and 3 of the cycle, RD week 2, and just D week 4)"
I don't think I realized that your trial had such a different dosing schedule.
I wondered if you feel less fatigue when it is just an RD vs CRD week? Having this time off all drugs to prepare for harvest, I noticed a huge difference in how tired I was. It feels like I have dropped a decade of life, I have way more pep in my step vs. when on therapy and I felt like I was carrying a 25 lb weight on my back then vs now without the drugs.
You take D for a solid week? How much D, how often that week?
Your C is every other week, interesting. During that week do you have C on 2 sequential days?
My trial C is 2 back-to-back days for 3 weeks sequentially. Based on this schedule I get more C on a monthly basis than you do. You get 4 days a month and I get 6 days a month of C. But then our total doses overall will be 48 does of C since you have 12 cycles and I have 8.
Interestingly, they have not determined a maximum limiting dose for C.
I wonder if Jakobuwiak was worried about neuropathy when he wrote the protocol, so they dosed it every other week to minimize that AE.
I noted that we both had CR after 5 cycles so efficacy may be same with fewer AE's with your dosing.
When these trials are reported on it is going to provide some excellent comparative data in terms of outcomes, not just for AE's but efficacy in terms of CR's, VGPR, etc. You will be able to compare outcomes in terms of cytogenetic profile with dosing schedule as well. Do you know what doses of C and R you are on? My C is 38mg/m squared and the R is 25mg. I also noted we both had CR following 5th cycle as well, so the dosing comparison may show if one has greater duration of response.
How many BM's are you obligated to provide in your trial? I had one pre-trial, after first 2 infusions, after CR and one going forward at end. The BM after first 2 doses was option. I did it for science.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Proteasome Inhibitors and the Cardiovascular System
I probably should have described my treatment schedule in normal terms - the way I stated it was admittedly confusing.
I am on the standard CRD schedule, with C on days 1,2 and 15,16, R on days 1-21, and D on days 1, 8, 15, and 22. I was trying to emphasize that on any given week I'm taking a different set of the three drugs - all three on weeks 1 and 3, just the R and D on week 2, and just the D on week 4.
I originally had the C on days 8,9 too, but they went to just weeks 1 and 3 after 8 cycles. I believe this is standard protocol for the trial. I'll be on the trial for 24 cycles, at which time they are recommending I continue with Revlimid maintenance.
The heart rate, queasiness, and fatigue all tend to vary a bit based on which I receive each week. I also receive zometa on week 1, which seems to make things worse. The fatigue is about the same for weeks 1 - 3, and not quite as much week 4 when I've only taken dex, but the difference is not significant.
As noted, I only take dex the first day of each week in the cycle, and the dose is 20mg. It was originally 40mg, but dropped to 20mg after the 8th cycle. The R dose is 25mg, and C dose is 36mg/m-squared.
I reached VGPR after three cycles, but did not reach CR until the 11th cycle. You may have confused the 5 cycles with when I had my stem cell harvest done.
I was required to do BMB at the beginning of the trial and at CR, and I think there will be one more at the end of the trial.
I am on the standard CRD schedule, with C on days 1,2 and 15,16, R on days 1-21, and D on days 1, 8, 15, and 22. I was trying to emphasize that on any given week I'm taking a different set of the three drugs - all three on weeks 1 and 3, just the R and D on week 2, and just the D on week 4.
I originally had the C on days 8,9 too, but they went to just weeks 1 and 3 after 8 cycles. I believe this is standard protocol for the trial. I'll be on the trial for 24 cycles, at which time they are recommending I continue with Revlimid maintenance.
The heart rate, queasiness, and fatigue all tend to vary a bit based on which I receive each week. I also receive zometa on week 1, which seems to make things worse. The fatigue is about the same for weeks 1 - 3, and not quite as much week 4 when I've only taken dex, but the difference is not significant.
As noted, I only take dex the first day of each week in the cycle, and the dose is 20mg. It was originally 40mg, but dropped to 20mg after the 8th cycle. The R dose is 25mg, and C dose is 36mg/m-squared.
I reached VGPR after three cycles, but did not reach CR until the 11th cycle. You may have confused the 5 cycles with when I had my stem cell harvest done.
I was required to do BMB at the beginning of the trial and at CR, and I think there will be one more at the end of the trial.
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Kevin J - Name: Kevin J
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: Jan 2011
- Age at diagnosis: 52
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