Kepivance May Increase The Tolerability Of Higher Doses Of Melphalan For Multiple Myeloma
The results of a Phase 1 study show that Kepivance reduces the severity of melphalan-related mouth ulcers in multiple myeloma patients. Due to better tolerability, the melphalan dosage could be safely increased to 280 mg/m2 prior to a stem cell transplant.
Almost two-thirds of the patients, who all had normal kidney function, had responded to the regimen at 100 days post transplant. The study investigators point out, however, that a Phase 2 trial will be necessary to better determine the efficacy of this regimen.
High-dose chemotherapy followed by autologous stem cell transplantation is the standard course of treatment for multiple myeloma patients under the age of 65. Patients with normal kidney function typically receive a preparative regimen of 200 mg/m2 of melphalan (Alkeran) before a transplant.
Previous attempts to increase the melphalan dose to improve treatment outcomes have been limited by the development of dose-limiting side effects, such as severe mouth ulcers and disrupted heart rhythms. Severe mouth ulcers can cause patients to require hospitalization in order to receive nutrition intravenously.
Kepivance (palifermin) is a drug that stimulates the growth of cells lining the mouth and intestinal tract. In a previous study, it was found to reduce mouth ulcers in myeloma patients receiving a standard dose of melphalan (see related Beacon news).
Researchers led by Dr. Muneer Abidi at the Karmanos Cancer Institute in Detroit, Michigan, designed a study to identify the maximum tolerated dose of melphalan in multiple myeloma patients who also received Kepivance. The researchers hypothesized that a higher dose of melphalan could be tolerated if taken in combination with Kepivance, which could potentially lead to improved disease outcomes.
While Kepivance is costly, the study authors believe the cost could be justified if its use improves response to treatment, decreases time in the hospital, and reduces the need for supportive care for patients with severe mouth ulcers.
Nineteen patients with a median age of 49 years were enrolled in this study between May 2007 and September 2009. They each received 60 µg/kg of Kepivance for three days before the transplant and for three days after the transplant. Patients received between 200 mg/m2 and 280 mg/m2 of melphalan two days before the transplant.
Overall, 18 patients completed the study and were assessed 100 days after the transplant.
At 100 days post transplant, 61 percent of patients had responded to the treatment, including 17 percent who achieved a complete response, 17 percent a very good partial response, and 27 percent a partial response.
Overall, 44 percent of the patients developed severe mouth ulcers for a median duration of five days. Out of the six patients who received the highest dose of melphalan, only 17 percent developed severe mouth ulcers. Twenty-eight percent of the patients did not experience any mouth ulcers.
According to the investigators, the overall rate of severe mouth ulcers is comparable to that of a previous study, which showed that severe mouth ulcers occurred in 42 percent of newly diagnosed myeloma patients receiving 200 mg/m2 of melphalan.
Since the median duration of the severe ulcers in the current study was only five days, no patients required intravenously administered nutrition.
The most common Kepivance-related side effects included mild to moderate rash (100 percent), elevation of enzymes including amylase (56 percent) and lipase (28 percent), and mild to moderate swelling (61 percent).
Irregular heartbeat, which may have been a melphalan-related complication, occurred in 17 percent of patients treated with 280 mg/m2 of melphalan.
The researchers did not observe any treatment-related deaths.
For more information, please see the study in Biology of Blood and Marrow Transplantation (abstract).
Related Articles:
- Stem Cell Transplantation May Be Underutilized In Multiple Myeloma Patients In Their 80s
- Selective Digestive Decontamination May Reduce Risk of Infection In Myeloma Patients Undergoing Autologous Stem Cell Transplants
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Sustained Complete Response To Initial Treatment Associated With Substantial Survival Benefit In Multiple Myeloma
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
How sad that researchers are so devoid of new ideas that they are wasting time on researching if they can use more melphalan for autos. They must have patients lining up for that "exciting" study -lets find the maximum tolerated dose of melphalan!
Hi Mark,
You know from previous comments I've made that I respect your perspective on myeloma-related topics. However, in this case, I think you're off base.
I don't know the exact figures, but probably 30% of all myeloma patients end up getting a transplant at some point. Maybe even more.
So, if you think about it, improving the effectiveness of transplants is probably one area of research that could have a noticeable effect on patient outcomes in the very near future.
Sure, research of this sort may not be as "sexy" as doing research on potential new treatments. But I think it's good that some researchers are taking the time to looking into different ways of improving the high-dose therapy part of the overall transplant process.
I wonder how much Dr. Muneer Abidi is being paid by the manufacturer of "expensive" Kepviance to carry out these investigations.
I had Kepi as part of my stem cell regimen last fall (I don't know what dosage of melphalan I was given), and it worked... no oral or upper digestive issues whatsoever.
However, as to "mild rash": mine was maddening. I'm a year out now, and STILL itch, tho at a much reduced level. I saw a dermatologist regularly for months about the rashes and itches, and he was basically unsuccessful in controlling the issue.
it's not a small side-effect, I assure you. It was worse, tho seems less permanent, than the neuropathy I got from the Velcade.
Oh... and the Melphalan gave me permanent heart damage: 20% loss of function of the lower left ventrical muscle. On beta blockers, blood pressure meds, and cholesterol control because of it.
ASCT is not trivial, that's for sure.
Having said all that: I'm still here and in VGP remission... so yay!
You can pour a liter of mephalan into someone, but it will still not kill myeloma cells if they are not dividing. But yes, it will kill even more effectively every other dividing cell in your body. How nice.
If you really want to improve mephalan action, you need to add an agent that synchonizes cell division of the myeloma cells, so that all are dividing and hence susceptible at the same time to the otherwise lethal -- save for the the transplant - alkylating agent. And as I recall, there have been some innovative approaches in this area. (But I don't have time to look them up right now). Regardless, approaches like that DO represent creative and promising clinical advances to treat this shitty disease, which seems to be all about waiting for the other shoe to drop. And such new approaches would probably REDUCE the required amount of mephalan while increasing its efficacy.
So I am with Mark on this one.
Hi Dan,
I join you and Mark. Yes, there are far more innovative and less toxic therapeutic options available.
The real deal is how can the manufacturer still use an old highly toxic drug to generate revenues. It is a travesty that they are able to promote the product for continued use!! But if they provide the funding for the research, someone WILL take them up on it..and garner unsuspecting MM patients to experiment on.
There are far more effective and less toxic agents available. Unless a patient has exercised all those options, melphan should not be on the list as the risks/toxicities clearly outweigh the benefits.
Hopefully, high dose chemo with melphalan and cyclophosamide are on their last leg...stem cell salvage was created due to their toxicity...it salvages patients form the toxicity of those agents...it is NOT therapy.
I agree with Terry. Since Melphalan is still one of the best agents at killing mm cells and is still widely used, it makes sense that tweaking it so that it can kill an even higher percent of MM cells is a good use of research dollars.
Suzie-As far as it being a travesty that the company is promoting melphalan for continued use, don't most MM specialists agree that using melphalan/SCT is still one of the primary avenues to remission? Why would you consider it wrong to experiment with it? Maybe they'll also discover that using the current rate of melphalan with an added product can kill the same number of MM cells with fewer side effects. It seems obvious to me their research will provide more options for patients.
Terry H., Stan,
Hope all is well with both of you. Dan points out the proper issue, IMO. While there is no definitive "myeloma stem cell" or cell identified that everyone agrees is the reason for patients relapsing, clearly there is a cell that the drugs we currently use do not kill. That is why allos are considered the only cure - it is the immunotherapy from the donor cells/immune system that can kill the group of cells that cause relapse. For example, Dr. Shain was part of some research that was just published that was attempting to identify the myeloma progenitor cells that said this:
"B cell progenitors showed resistance to melphalan, lenalidomide, and bortezomib."
"Conclusions: We propose that antigen-independent B cell differentiation stages are involved in disease origination and progression in myeloma. Further investigations of myeloma putative stem cell progenitors may lead to novel treatments to eradicate the potential reservoir of minimal residual disease."
http://www.ncbi.nlm.nih.gov/pubmed/22988056
What the researchers in Detroit are doing is just adding more melphalan. IMO the research shows melphalan is a good "debulker" for active disease, but it is not a good "closer" to get the minimal residual disease. That is what the research Dr. Shain's group is showing above. It was also shown in older research that shows molecular responses at 50% for patients that did allos and only 7 - 16% of patients that did autos. Dan and Stan are correct IMO in stating that they need to find something new (drug, immunoptherapy) to add to the auto process. Snip's experience with heart problems due to the high dose melphalan is something that cannot be just ignored. The researchers note 17% showing irregular hearbeat after using 280 - that is no trivial issue.
Mark
Hi Stan!!
"As far as it being a travesty that the company is promoting melphalan for continued use, don’t most MM specialists agree that using melphalan/SCT is still one of the primary avenues to remission? "
The data shows that 50% of patients do NOT get CR with melphalan..which necessitates the need for SCT to salvage them!!
"Why would you consider it wrong to experiment with it?"
My reasoning is, not that it is wrong, but it has not the most effective choice AND has significant long lasting adverse effects. What I object to is using a drug, which has been so toxic withOUT benefits that justify that toxicity. Sure, some patients do well, but at what costs? There was a time when that risk was acceptable. It no longer is with all of the new therapies. However, unless they combine it with other new drugs it will fall by the way side. And these new studies are simply being done to continue a revenue stream for a very old & toxic drug. Right now they are conducting trials where there is no melphalan used and showing the results are comparable withOUT it.
It is critical to know that SCT is not therapeutic, it is salvage.
So, I am speaking from a historical perspective of MM therapy, melphalan was NEVER a GOOD choice but it was all that was available. Now, there are better more effective less toxic choices.
"Maybe they’ll also discover that using the current rate of melphalan with an added product can kill the same number of MM cells with fewer side effects. It seems obvious to me their research will provide more options for patients."
Melphalan, always kills more of normal than MM cells.
Options? This study simply claims to reduce side effects of melphalan. My point is why even use melphalan to need Kepivance since there are more efficacious drugs without the side effects that warrant use of kepivance.
However, you are right...if you choose to use melphalan..kepivance will reduce the mouth issues..but what about all the other toxic effects?
Hi Suzie!!
Hope all goes well with you.
"The data shows that 50% of patients do NOT get CR with melphalan..which necessitates the need for SCT to salvage them!!"
You say "salvage" I say "rescue". You say tomato-ha.
50% in CR sounds good to me. MM specialists would not recommend SCT's if they didn't think the reward outweighed the risks.
I used one SCT to reduce my numbers since VDPACE, Revlimid and Velcade weren't doing the trick (wasn't even trying for CR). I used the second SCT to try for CR. I am close to CR and am very, very, very happy with the results. No real side effects either. I'm not in CR (low and stable) but to call these SCT's a failure would be incorrect. On top of that, it appears as if the melphalan may have resensitized my blood to revlimid.
Thalidimide could have been abandoned after it was found to cause birth defects in the 60's. But the "greedy" company kept at it and experimented with it for different purposes. Hence, we now have thalidimide, revlimid and pomalidomide, the work horses against multiple myeloma. The makers of Kepivance would not be putting money into this research if they thought there was no chance of it creating opportunities for MM patients.
If Monsanto wants see if Roundup kills MM cells, I wish them success.
The bottom line is that the more tools we have in the myeloma tool shed, the better. Even if some of the tools aren't the shiny, new ones.
Dan--Wouldn't this research be applicable for patients who cannot tolerate the standard concentration of melphalan? Maybe this will allow SCT's to be used on older or more compromised patients?
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