Study Suggests Longer Infusion Time Does Not Improve Safety Of Zometa For Myeloma Patients
The results from a clinical trial, called the ZMAX trial, suggest that administering Zometa intravenously over a longer period does not increase the drug’s safety compared to shorter infusion times.
Dr. James Berenson, from Berenson Oncology and lead author of the study, stated in email correspondence with The Myeloma Beacon that he hopes these study results will reassure patients that a 15-minute infusion time is safe. Ultimately, the study authors suggested that infusion duration should be based on individual patient considerations.
Zometa (zoledronic acid) is an intravenous bisphosphonate that reduces bone loss and fractures by inhibiting the cells that breakdown bone. Studies have also explored its potential anti-cancer effects (see related Beacon news).
Treatment of myeloma bone disease is important, since 20 percent of multiple myeloma patients experience a fracture at the time of their myeloma diagnosis, and 60 percent of multiple myeloma patients experience a fracture during their cancer.
Since Zometa is primarily excreted from the body through the kidneys, it and other bisphosphonates can lead to an increased risk of kidney damage. Furthermore, due to the nature of the disease, multiple myeloma patients are at increased risk of kidney failure compared to the general population (see related Beacon news). Approximately 20 percent of all myeloma patients will develop progressive kidney failure sometime during the course of their disease.
Therefore, researchers sought to determine in this study if kidney damage could be minimized in patients receiving intravenous Zometa by slowing the rate at which the drug is administered. This, they hypothesized, would lower the levels of the drug in the patient’s bloodstream, thus lowering its accumulation in the kidneys.
A total of 176 multiple myeloma patients were treated in centers across the United States. Patients were randomly assigned to receive 4 mg Zometa intravenously over a 15-minute or 30-minute time period. Tests were then conducted to measure the amount of Zometa that accumulated in the blood following treatment as well as chemicals released from the kidney that indicate damage.
As researchers expected, the amount of Zometa in the bloodstream was higher at the end of the treatment period for patients who received their dose in 15 minutes as opposed to 30 minutes, 249 ng/mL compared to 172 ng/mL, respectively.
After one year of treatment, slightly fewer patients in the 30-minute treatment group had measurable kidney damage compared to the 15-minute treatment group, 16 percent versus 20 percent, respectively. The differences were not, however, statistically significant.
When tests were performed after two years of treatment, researchers found no difference in the percent of patients experiencing kidney damage in the two treatment groups (28 percent for the 15-minute group and 27 percent for the 30-minute group).
The same side effects were experienced in both treatment groups, the most common of which were skeletal-related events and osteonecrosis of the jaw, a condition that is associated with a loss of blood supply to the jaw resulting in jawbone death.
The researchers noted that since the time of their study, the U.S. Food and Drug Administration has recommended a decreased dose of Zometa be administered to multiple myeloma patients based on the severity of existing kidney damage. The researcers suggested that further studies should be conducted with a larger patient group to determine the effects of increased administration time with the new dosing guidelines.
According to Dr. Berenson, “Longer infusions are more important than lowering the dose, which is likely to impact its effectiveness. However, in most patients, this is not necessary; 15 minutes is fine. However, if the [kidney] function is impaired, it is our practice to slow it down; we do not lower the dose.”
For more information, please see the study in The Journal of Supportive Oncology (pdf).
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- Stem Cell Transplantation May Be Underutilized In Multiple Myeloma Patients In Their 80s
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
The problem for many with a short infusion time is that it makes them feel sick, nauseous, and generally kicked in the teeth. Anecdotally, many patients who suffer these side effects have reported a better experience with Zometa if given over a longer duration. I hope that the docs will continue to offer a longer infusion duration for those experiencing these side effects in an effort to keep the patient willing to endure yet another treatment in their MM.
I always insist on an hour for my wife after hearing a fellow patient tell of an error in setting the timing for her Zometa to five minutes instead of fifteen. She suffered kidney damage as a result. We also refrain from taking Zometa on a day when Velcade is administered as it seems the flu like symptoms are worse. Considering the possible risks and discomfort why not take a cost free precaution? Jim and Jane in Florida
I agree, Lori. My husband suffered such horrible side affects which lasted the whole weekend of his "rest" week after the 15 minute infusion of Zometa(102.5 fever, weak, etc). The subsequent infusion was prolonged to 45 minutes to an hour and there were no side affects. We will continue to take our time with Zometa.
Every patient is different, and it could well be that for some, increasing infusion from the standard 15 minutes to 45 or 60 minutes may be the key.
I had my first dose on Monday (for 15 minutes). While I felt fine that night, for the next three days, I felt as if the drug honed in and amplified every local ache, twist, and pain that I have ever had in my life.
I went in with no pain anywhere - and the drug triggered achiness in about a half dozen places that bothered me once or more over the past decades. And curiously, none of that triggered pain was it an area in which a lesion was suspected. I did not experience fever. It was more like being thrown from a bicycle onto concrete.
A powerful and strange drug.
But after three days, all the pain all went away.
I have heard that this acute reaction is not uncommon the first time. So I am not convinced I have to increase the infusion time in three weeks. But I am wondering ....I also read somewhere that taking a few tylenol right before the infusion can be a prophylactic.
Hi DanD,
I do not know the reason, but clinicians have stated empirically they find that patients on pamidronate (Aredia)seem not to contract ONJ at the same rate/frequency as those on Zometa. No reason has been given...or I should again say..reason unknown.
Personally, I think it does have to do with the concentration of the drug over time of infusion. Zometa (zoledronic acid) is usually given in 30 mins vs. 2 hours for pamidronate. Why that would make a difference given they are both bisphosphates is not known..but it is something that clinicians have noted.There also appears to be a relationship in terms of length of time on the therapy.
I wanted zoledronic acid at first, simply based on infusion time, but I acquiesced to the MD's and their clinical experience. So I am on pamidronate. Sometimes when data/evidence is unknown..clinical experience is best.
Hi SR
Aredia was mentioned to me by the oncologist, along with the long infusion time. But I am on Zometa for now.
While the jury is still out, there is some scientific evidence (as you know) that Zometa may independently have anti-tumorigenic activity. I don't know if that is suspected to be the case for Aredia.
But you seem to raise a provoactive point - one that I am sure has not been clinmically addressed: the short infusion time of Zometa is based on the risk of renal impairment. BUT...what if a longer infusuion time reduced the risk of ONJ. Seems unlikely -- as this seems to take many months to develop -- but you never know.
Regardless, I will be monitoring the situation, including the ONJ risk, vigilantly. This IS a marathon.
Hi Dan,
"While the jury is still out, there is some scientific evidence (as you know) that Zometa may independently have anti-tumorigenic activity."
Yes, I too heard that information, but it is unproven...thus I went with pamidronate based on least likelihood of jaw necrosis. I thought the severity of that side effect warranted a safe bet. If there is SOME 'anti-tumorgenic" activity...it has yet to be proven. Plus, if so you can always switch while having avoided the ONJ.
At present, I am not all that confident if a bisphosphate has anti-tumorgenic effect it will not ALSO apply to pamidronate, as I suspect it would be a class-effect. Only time will tell.
But my point is that I also took that into consideration, along with the fact that the bone that bisphosphates rebuild is not equal to the bone structure that occurs naturally. So, if I am not going to have remodeled bone comparable to that which occurs naturally AND I run the risk of ONJ, I believed erring on the side of no ONJ was more important. After all, if the therapy you take contols the MM there is less likelihood that you will need the bone saving impact of bisphosphates. IOW's do you have a lot of bone lesions, is your therapy abating that? If the therapy is abating that and you do not remodel bone the same..the bet is on pamidronate...and overtime (if they do the studies) we may learn it has the same IF ANY anti-tumorgenic effect.
IMHO
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