I am getting shots of Prolia (denosumab) for osteoporosis. However, now that I have been diagnosed with multiple myeloma, the oncologist wants to change that to Zometa (zoledronic acid). I have had zero side effects from Prolia, and wanted to stay on it due to the widespread side effects reported for Zometa, but the oncologist says it doesn't work for multiple myeloma patients. The studies I find on the Internet say Prolia works at least as well, but the doctor somehow feels those studies are no good, or something.
Does anybody have any information about this issue?
Forums
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bodumene - Name: bodumene
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: January, 2017
Re: Zometa vs. Prolia in multiple myeloma patients
Hi Bodumene,
Note that denosumab and zoledronic acid work in very different ways.
But you are right that denosumab has had good results with multiple myeloma and has been shown to be "non-inferior" to zoledronic acid in the prevention of SREs (skeletal related events / damage):
"Amgen Announces Positive Top-Line Results From Xgeva (Denosumab) Phase 3 Trial For Delay Of Bone Complications In Multiple Myeloma Patients," Amgen press release, Oct 20, 2016
Zoledronic acid is pretty widely considered to be the current "standard of care" (a term I dislike when it comes to myeloma treatments) for multiple myeloma patients considered to be at risk of developing SREs. The myeloma trial data for denosumab is very new and it could be that your doctor is simply not aware of some of the latest trial results. But I think if you are doing well on denosumab that it makes sense for you to press your case and to show your doctor the results of some of the recent denosumab trials.
As you delve into this more, you might want to investigate if your dosage needs to be upped if you are utilizing denosumab for the prevention of multiple myeloma SREs. The multiple myeloma trial (referenced above) dose was 120 mg every four weeks, but I believe the standard recommended dose for treating osteoporosis is 60 mg every 6 months.
Lastly, it will be interesting to see in the long term how the incidence of osteonecrosis of the jaw (ONJ) from denosumab usage compares to that of zoledronic acid. ONJ is probably the one thing that scares myeloma patients the most regarding these kinds of SRE-preventative drugs.
Note that denosumab and zoledronic acid work in very different ways.
But you are right that denosumab has had good results with multiple myeloma and has been shown to be "non-inferior" to zoledronic acid in the prevention of SREs (skeletal related events / damage):
"Amgen Announces Positive Top-Line Results From Xgeva (Denosumab) Phase 3 Trial For Delay Of Bone Complications In Multiple Myeloma Patients," Amgen press release, Oct 20, 2016
Zoledronic acid is pretty widely considered to be the current "standard of care" (a term I dislike when it comes to myeloma treatments) for multiple myeloma patients considered to be at risk of developing SREs. The myeloma trial data for denosumab is very new and it could be that your doctor is simply not aware of some of the latest trial results. But I think if you are doing well on denosumab that it makes sense for you to press your case and to show your doctor the results of some of the recent denosumab trials.
As you delve into this more, you might want to investigate if your dosage needs to be upped if you are utilizing denosumab for the prevention of multiple myeloma SREs. The multiple myeloma trial (referenced above) dose was 120 mg every four weeks, but I believe the standard recommended dose for treating osteoporosis is 60 mg every 6 months.
Lastly, it will be interesting to see in the long term how the incidence of osteonecrosis of the jaw (ONJ) from denosumab usage compares to that of zoledronic acid. ONJ is probably the one thing that scares myeloma patients the most regarding these kinds of SRE-preventative drugs.
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Zometa vs. Prolia in multiple myeloma patients
A couple of other things to consider are cost of zoledronic acid versus donosumab and the dosage of Prolia versus Xgeva.
While Prolia and Xgeva utilize the exact same active ingredient (denosumab), they are marketed to different patient populations (e.g. cancer versus osteoporosis) and have different dosage recommendations for those target populations. So, be careful when looking up the various dosage schedules for each.
Zoledronic acid (aka Zometa) is now available in generic form and is probably a lot less expensive than a cutting-edge monoclonal antibody such as denosumab.
While Prolia and Xgeva utilize the exact same active ingredient (denosumab), they are marketed to different patient populations (e.g. cancer versus osteoporosis) and have different dosage recommendations for those target populations. So, be careful when looking up the various dosage schedules for each.
Zoledronic acid (aka Zometa) is now available in generic form and is probably a lot less expensive than a cutting-edge monoclonal antibody such as denosumab.
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Zometa vs. Prolia in multiple myeloma patients
Hi Bodumene.
To add another spin to the above: As Multibilly says, the 2 drugs work in different ways, and denosumab may be "non-inferior" to zoledronic acid for the prevention of (skeletal related events / damage), but it is also thought (and cited in many papers) that bisphosphonates (like zoledronic acid) have separate anti-tumor effects on myeloma cells. This may be his or her reason for suggesting the change.
Some research suggests that denosumab may also have anti-tumor effects (and it should via its action on the RANKL pathway - but those may be less robust), and I'm not aware of any study examining it's effect on multiple myeloma cells specifically.
you may want to read :
Zwolak, P, and Dudek, AZ, "Antineoplastic Activity of Zoledronic Acid and Denosumab", Anticancer Research 33: 2981-2988 (2013) (full text of article)
Their conclusion:
"Many patients and physicians may prefer to use denosumab, because of its subcutaneous application compared to intravenous injections of ZA [zoledronic acid]. Furthermore, an initial evaluation showed that denosumab causes fewer complications related to treatment e.g. osteonecrosis of the jaw, and hypocalcemia. In addition, there are no limitations in the use of denosumab for patients with renal impairment.
>>> On the other hand, ZA demonstrates superiority in terms of its direct antineoplastic activity demonstrated both in vitro and in vivo compared to denosumab. <<<
Further pre-clinical and clinical evaluation is needed for both agents to fully assess the antineoplastic mechanisms of activity of both agents."
To add another spin to the above: As Multibilly says, the 2 drugs work in different ways, and denosumab may be "non-inferior" to zoledronic acid for the prevention of (skeletal related events / damage), but it is also thought (and cited in many papers) that bisphosphonates (like zoledronic acid) have separate anti-tumor effects on myeloma cells. This may be his or her reason for suggesting the change.
Some research suggests that denosumab may also have anti-tumor effects (and it should via its action on the RANKL pathway - but those may be less robust), and I'm not aware of any study examining it's effect on multiple myeloma cells specifically.
you may want to read :
Zwolak, P, and Dudek, AZ, "Antineoplastic Activity of Zoledronic Acid and Denosumab", Anticancer Research 33: 2981-2988 (2013) (full text of article)
Their conclusion:
"Many patients and physicians may prefer to use denosumab, because of its subcutaneous application compared to intravenous injections of ZA [zoledronic acid]. Furthermore, an initial evaluation showed that denosumab causes fewer complications related to treatment e.g. osteonecrosis of the jaw, and hypocalcemia. In addition, there are no limitations in the use of denosumab for patients with renal impairment.
>>> On the other hand, ZA demonstrates superiority in terms of its direct antineoplastic activity demonstrated both in vitro and in vivo compared to denosumab. <<<
Further pre-clinical and clinical evaluation is needed for both agents to fully assess the antineoplastic mechanisms of activity of both agents."
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rick - Name: rick
- Who do you know with myeloma?: husband
- When were you/they diagnosed?: nov 2015
- Age at diagnosis: 50
Re: Zometa vs. Prolia in multiple myeloma patients
I had been taking twice yearly injections of Prolia prior to my multiple myeloma diagnosis. I was osteoporotic at the time. However, once I was diagnosed with myeloma, I was told to stop Prolia and to go on monthly infusions of pamidronate (Aredia) instead. I tried to find out why this change of medicine was necessary, but I had no luck.
Joe
Joe
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Wobbles - Name: Joe
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: June 2016
- Age at diagnosis: 67
Re: Zometa vs. Prolia in multiple myeloma patients
I know that a lot of myeloma specialists believe that Zometa may have, or definitely does have, an anti-myeloma effect. This belief is usually based on the results of a large UK clinical trial where multiple myeloma patients who received Zometa had longer overall survival than patients in the trial who received a weaker, first-generation bisphosphonate (clodronate), which is approved in some parts of the world, but not in the U.S.
However, if you speak to myeloma specialists who also specialize in myeloma bone disease, you'll often hear doubts as to whether Zometa has a direct anti-myeloma effect. Instead, these specialists will note the Zometa's impact on overall survival in the UK trial was probably due to two effects:
If Zometa or Aredia had a clinically significant anti-myeloma effect, they would have delayed the progression of smoldering myeloma to active myeloma. That's what any anti-myeloma drug will do. But the bisphosphonates did not delay progression.
The trials were a key test of how bisphosphonates might affect multiple myeloma because, in smoldering patients, bones are still strong, and the bone marrow microenvironment is not particularly damaged. So the main impact bisphosphonates can have on myeloma is a direct effect on the disease.
All of this relates back to the original question in the sense that, if Prolia / Xgeva is equally as good as Zometa at building back bone in multiple myeloma patients, then I would expect Prolia and Xgeva to have the same sort of effect on overall survival in multiple myeloma patients as has been seen with Zometa. And, of course, vice versa.
However, if you speak to myeloma specialists who also specialize in myeloma bone disease, you'll often hear doubts as to whether Zometa has a direct anti-myeloma effect. Instead, these specialists will note the Zometa's impact on overall survival in the UK trial was probably due to two effects:
- Zometa was better at reducing serious bone fractures, which themselves tend to reduce survival
- Zometa was likely better at improving the bone microenvironment, which enabled the myeloma therapies and the patients' own immune systems to better fight their disease.
If Zometa or Aredia had a clinically significant anti-myeloma effect, they would have delayed the progression of smoldering myeloma to active myeloma. That's what any anti-myeloma drug will do. But the bisphosphonates did not delay progression.
The trials were a key test of how bisphosphonates might affect multiple myeloma because, in smoldering patients, bones are still strong, and the bone marrow microenvironment is not particularly damaged. So the main impact bisphosphonates can have on myeloma is a direct effect on the disease.
All of this relates back to the original question in the sense that, if Prolia / Xgeva is equally as good as Zometa at building back bone in multiple myeloma patients, then I would expect Prolia and Xgeva to have the same sort of effect on overall survival in multiple myeloma patients as has been seen with Zometa. And, of course, vice versa.
Re: Zometa vs. Prolia in multiple myeloma patients
Having just joined this forum, I am amazed at both the depth of knowledge and the compassion of its members. Thank you so much for your responses to my question. The information you gave was very helpful.
I saw the doctor today, and he explained in more detail the reasoning behind his choice of Zometa over Prolia, and some of the relevant research. I guess I do trust his knowledge and judgment. He took care of my wife some years ago for breast cancer, and helped us decide which drugs she should take after the surgery. He made recommendations, but in the end, was supportive of our decision even though it wasn't his first choice.
I saw the doctor today, and he explained in more detail the reasoning behind his choice of Zometa over Prolia, and some of the relevant research. I guess I do trust his knowledge and judgment. He took care of my wife some years ago for breast cancer, and helped us decide which drugs she should take after the surgery. He made recommendations, but in the end, was supportive of our decision even though it wasn't his first choice.
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bodumene - Name: bodumene
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: January, 2017
Re: Zometa vs. Prolia in multiple myeloma patients
Cheryl raises some good points (as usual). My specialist is one of those folks who has at least sometimes in the past mentioned the potential anti-myeloma properties of Zometa. However, recent studies have suggested otherwise. In particular, see this study:
Garcia-Sanz, R, et al, "Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial," Haematologica, Sep 2015 (full text of article)
Abstract:
This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse. One hundred patients were randomized to receive either zoledronic acid (4 mg iv/4 weeks, 12 doses) (n=51) or not (n=49). Experimental and control groups were well balanced for disease and prognostic features. Zoledronic acid did not show an antitumor effect according to changes in M-component. However, there were fewer symptomatic progressions in the experimental group than in the control group (34 versus 41, respectively; P=0.05) resulting in a median time to symptoms of 16 versus 10 months (P=0.161). The median time to next therapy was also slightly longer for the treated group than the untreated, control group (13.4 versus 10.1 months), although the difference was not statistically significant (P=0.360). The pattern of relapses was different for treated versus control patients: progressive bone disease (8 versus 20), anemia (24 versus 18), renal dysfunction (1 versus 2), and plasmacytomas (1 versus 1, respectively). This concurred with fewer skeletal-related events in the treated group than in the control group (2 versus 14), with a projected 4-year event proportion of 6% versus 40% (P<0.001). In summary, zoledronic acid monotherapy does not show an antitumor effect on biochemical relapses in multiple myeloma, but does reduce the risk of progression with symptomatic bone disease and skeletal complications.
Garcia-Sanz, R, et al, "Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial," Haematologica, Sep 2015 (full text of article)
Abstract:
This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse. One hundred patients were randomized to receive either zoledronic acid (4 mg iv/4 weeks, 12 doses) (n=51) or not (n=49). Experimental and control groups were well balanced for disease and prognostic features. Zoledronic acid did not show an antitumor effect according to changes in M-component. However, there were fewer symptomatic progressions in the experimental group than in the control group (34 versus 41, respectively; P=0.05) resulting in a median time to symptoms of 16 versus 10 months (P=0.161). The median time to next therapy was also slightly longer for the treated group than the untreated, control group (13.4 versus 10.1 months), although the difference was not statistically significant (P=0.360). The pattern of relapses was different for treated versus control patients: progressive bone disease (8 versus 20), anemia (24 versus 18), renal dysfunction (1 versus 2), and plasmacytomas (1 versus 1, respectively). This concurred with fewer skeletal-related events in the treated group than in the control group (2 versus 14), with a projected 4-year event proportion of 6% versus 40% (P<0.001). In summary, zoledronic acid monotherapy does not show an antitumor effect on biochemical relapses in multiple myeloma, but does reduce the risk of progression with symptomatic bone disease and skeletal complications.
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Zometa vs. Prolia in multiple myeloma patients
Thanks for pointing out that Spanish study, Multibilly. I recall seeing it when it came out, but had forgotten about it in the interim. It certainly reinforces previous evidence suggesting that Zometa does not have a direct anti-myeloma effect.
Of course, the Spanish study results makes one wonder what was different in the UK study that led to the survival advantage among the patient who received Zometa.
Is it possible, for example, that clodronate has a pro-myeloma effect?
Or do bisphosphonates, and perhaps other bone-building drugs, have an anti-myeloma effect only when they are used together with myeloma therapies, in the way that Empliciti really doesn't have much of an anti-myeloma unless it is used with other myeloma drugs?
(Many of the patients in the UK trial were treated with Zometa and clodronate while they also were receiving other myeloma therapies.)
Of course, the Spanish study results makes one wonder what was different in the UK study that led to the survival advantage among the patient who received Zometa.
Is it possible, for example, that clodronate has a pro-myeloma effect?
Or do bisphosphonates, and perhaps other bone-building drugs, have an anti-myeloma effect only when they are used together with myeloma therapies, in the way that Empliciti really doesn't have much of an anti-myeloma unless it is used with other myeloma drugs?
(Many of the patients in the UK trial were treated with Zometa and clodronate while they also were receiving other myeloma therapies.)
Re: Zometa vs. Prolia in multiple myeloma patients
Here's another study that came out recently that suggests that Zometa does not have an anti-myeloma effect. The participants in the study were newly diagnosed myeloma patients. One group got Zometa for 4 years after diagnosis. The other group got Zometa for just 2 years after diagnosis. Patients were randomly assigned to one of the two groups.
After five years, there was no statistical difference in progression-free survival between the two groups of patients, and overall survival was exactly the same (68 percent) for both groups.
However, the patients in the 4-year group were noticeably less likely to experience bone fractures and other kinds of "skeletal related events" (SRE). The SRE rate was about half in the 4-year group than in the 2-year group.
So longer Zometa dosing does seem to reduce the likelihood that patients will experience fractures, but it doesn't seem to have an appreciable effect on time to relapse or overall survival.
Here's the reference:
Avilès, A, et al, "Prolonged Use of Zoledronic Acid (4 Years) Did Not Improve Outcome in Multiple Myeloma Patients," Clin Lymphoma Myeloma Leuk., 2017 Feb 16 (abstract)
And here's the complete abstract:
Background: Bisphosphonates, especially zoledronic acid (ZA), show antitumor effects in multiple myeloma and other neoplasms. The standard time for ZA administration has been 2 years. However, with improvement in overall survival (OS) in multiple myeloma with new agents, it unclear whether ZA could be administered for a prolonged time to improve OS.
Patients & Methods: A total of 170 patients with untreated, symptomatic multiple myeloma were randomly divided into a group to receive ZA for 4 years, with a control group to receive ZA for 2 years. All patients were treated with the same induction therapy and stem-cell transplantation.
Results: Actuarial curves at 5 years, showed that progression-free survival was 75% (95% confidence interval [CI], 64%-82%) and OS was 68% (95% CI, 60%-76%) in the 4-year group, which was not statistically significantly different compared with the control group: 72% (95% CI, 62%-78%) and 68% (95% CI, 60%-75%; P = .67). However, the 4-year group showed reduced skeletal events (21% occurrence rate); this was statistically significant compared with the control group: 43% (P < .001).
Conclusion: Although ZA did not improve OS in patients with multiple myeloma; it continued to be useful to reduce skeletal events, and thus improve better quality of life for patients.
After five years, there was no statistical difference in progression-free survival between the two groups of patients, and overall survival was exactly the same (68 percent) for both groups.
However, the patients in the 4-year group were noticeably less likely to experience bone fractures and other kinds of "skeletal related events" (SRE). The SRE rate was about half in the 4-year group than in the 2-year group.
So longer Zometa dosing does seem to reduce the likelihood that patients will experience fractures, but it doesn't seem to have an appreciable effect on time to relapse or overall survival.
Here's the reference:
Avilès, A, et al, "Prolonged Use of Zoledronic Acid (4 Years) Did Not Improve Outcome in Multiple Myeloma Patients," Clin Lymphoma Myeloma Leuk., 2017 Feb 16 (abstract)
And here's the complete abstract:
Background: Bisphosphonates, especially zoledronic acid (ZA), show antitumor effects in multiple myeloma and other neoplasms. The standard time for ZA administration has been 2 years. However, with improvement in overall survival (OS) in multiple myeloma with new agents, it unclear whether ZA could be administered for a prolonged time to improve OS.
Patients & Methods: A total of 170 patients with untreated, symptomatic multiple myeloma were randomly divided into a group to receive ZA for 4 years, with a control group to receive ZA for 2 years. All patients were treated with the same induction therapy and stem-cell transplantation.
Results: Actuarial curves at 5 years, showed that progression-free survival was 75% (95% confidence interval [CI], 64%-82%) and OS was 68% (95% CI, 60%-76%) in the 4-year group, which was not statistically significantly different compared with the control group: 72% (95% CI, 62%-78%) and 68% (95% CI, 60%-75%; P = .67). However, the 4-year group showed reduced skeletal events (21% occurrence rate); this was statistically significant compared with the control group: 43% (P < .001).
Conclusion: Although ZA did not improve OS in patients with multiple myeloma; it continued to be useful to reduce skeletal events, and thus improve better quality of life for patients.
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