Kyprolis - Which Multiple Myeloma Patients Will Physicians Treat With It?
Physicians in the United States are able to prescribe Kyprolis for their patients now that the drug has been approved for the treatment of multiple myeloma.
The drug's widespread availability, however, raises the important question: For what types of myeloma patients are physicians likely to prescribe Kyprolis?
Last month, the U.S. Food and Drug Administration (FDA) approved Kyprolis (carfilzomib) for the treatment of multiple myeloma patients meeting specific criteria. The patients must have received at least two prior therapies, including Velcade (bortezomib) and an immunomodulatory agent, meaning either Revlimid (lenalidomide), thalidomide (Thalomid), or pomalidomide. The patients must also have demonstrated disease progression on or within 60 days of completing their last therapy.
For more information, see the related Beacon news article announcing the FDA approval as well as a Q&A about the approval.
Although Kyprolis has been approved by the FDA for this specific set of myeloma patients, once a drug is approved in the U.S., physicians have substantial freedom to prescribe the drug as they deem appropriate.
At the same time, Medicare, Medicaid, and private insurance companies may decide to control health care costs by restricting reimbursement of Kyprolis treatment to patients meeting the FDA criteria described above. This may particularly be the case with Kyprolis, given that it is currently the most expensive myeloma treatment available.
So, for which patients are myeloma specialists likely to prescribe Kyprolis?
To gain a better sense of what the answer to this question is likely to be, The Beacon conducted an informal survey with a wide range of myeloma specialists around the country. We asked each of them: "How do you see yourself using Kyprolis in the near future – e.g., for what kinds of patients?"
Below is what the myeloma specialists told us.
Please note that some of the comments have been edited for brevity and clarity. For consistency, comments also have been edited to refer to patent-protected drugs by their brand names.
Amrita Krishnan, City of Hope:
We would use Kyprolis for patients with relapsed myeloma. We are also going to be exploring its use in the post-transplant setting as consolidation in a clinical trial.
We have participated in several of the Kyprolis earlier trials and are very pleased about its approval as our experience with it in clinical trials has been favorable.
Ruben Niesvizky, Weill Cornell Medical College:
We are using Kyprolis upfront (first-line) in our flagship protocol ‘Car-BiRd,’ [which is a Phase 2 clinical trial that will evaluate treatment of newly diagnosed myeloma patients with Kyprolis and dexamethasone followed by treatment with clarithromycin (Biaxin), Revlimid, and dexamethasone (Decadron), and finally Revlimid alone.]
In addition, Kyprolis would be an excellent choice for patients who are intolerant to Velcade by virtue of their neuropathy [pain, tingling, or loss of sensation in the extremities].
Patients who have suffered progression of disease after at least three lines of therapy including Velcade, immunomodulatory drugs, and alkylators will also benefit.
Philip McCarthy, Roswell Park Cancer Institute:
[I see myself using Kyprolis] as part of salvage therapy, especially for patients who have relapsed or progressing disease after Velcade-containing regimens. I would expect to recommend use in combination with Revlimid and dexamethasone for this patient population.
Guido Tricot, University of Iowa Hospitals and Clinics:
The availability of Kyprolis will make it possible to provide a proteasome inhibitor to those patients who do not tolerate Velcade because of neuropathy.
Proteasome inhibitors are probably the most potent anti-myeloma agents given as single therapy, with the exception of high-dose melphalan [Alkeran].
It remains to be shown that Kyprolis is equally potent as Velcade. If that is the case, it may replace Velcade as the preferred proteasome inhibitor.
Jeffrey Wolf, University of California, San Francisco:
The FDA has approved Kyprolis for patients who have had at least two prior regimens which are not now working, and I think that is entirely appropriate. In general that will include patients who have already had Revlimid and Velcade.
Frederic Reu, Cleveland Clinic:
At this point, we will use Kyprolis predominantly for relapsed or refractory patients and patients with neuropathy in any of the schedules that have been found safe.
Ravi Vij, Washington University in St. Louis:
In the immediate future, I will be using Kyprolis in patients with relapsed and refractory multiple myeloma who have been exposed to Revlimid and Velcade and are needing alternative therapies.
Sergio Giralt, Memorial Sloan-Kettering Cancer Center:
[I see myself using Kyprolis for] patients with relapsed and refractory myeloma intolerant to Velcade or with neuropathy, as part of combination therapy for relapsed and refractory myeloma, and upfront for patients with neuropathy.
Ken Shain, Moffitt Cancer Center:
Much of the excitement surrounding the use of this new agent [Kyprolis] is that we now have an additional agent with which to treat our relapsed and refractory patients.
Kyprolis has been approved as a single agent in relapsed/refractory multiple myeloma and should currently be used only in this setting. However, there are ongoing clinical trials both in the relapsed/refractory and previously untreated patient settings in combination with Revlimid, cyclophosphamide [Cytoxan], and other agents that bear watching.
For instance, the Phase 2 study, PX-171-006, which is examining the combination CRd (Kyprolis, Revlimid, and low-dose dexamethasone) in relapsed patients, has demonstrated very promising results.
Preliminary data [has also been presented] on the same combination in previously untreated patients. These results suggest unprecedented disease control in the upfront setting.
However, all of these studies are early in analysis and development, and the results need to be validated prior to off-study utilization in these settings and combinations.
As these clinical trials mature, the use of Kyprolis will likely expand and be used in combination with other therapeutics. To date, however, it should be used as approved.
Adam Cohen, Fox Chase Cancer Center:
In the near future I will likely be using Kyprolis in patients who have progressed after previous Velcade and Revlimid, or for those who are unable to tolerate Velcade due to neuropathy or other reasons.
Eventually, I think we’ll be using it earlier in the disease course, and there is a proposed cooperative group trial comparing Kyprolis, Revlimid, and dexamethasone versus Velcade, Revlimid, and dexamethasone for newly diagnosed patients that will hopefully open in the next six months. This will provide more data about using it in the front-line setting and about how it compares to Velcade head-to-head.
Seema Singhal, Northwestern University:
I expect to use [Kyprolis] in patients with relapsed disease. I have already had experience with enrollment of approximately 50 patients in clinical trials with Kyprolis.
Peter Voorhees, University of North Carolina at Chapel Hill:
The recent FDA approval of Kyprolis is an important step forward for patients with myeloma.
In the short term, Kyprolis is now an important option for those patients who have received at least two previous therapies for their myeloma (including Velcade and thalidomide or Revlimid) and have relapsed disease that is resistant to the most recently used therapy. This is the FDA indication as it stands now.
Patients who are particularly likely to benefit from Kyprolis are those with Velcade-sensitive disease who cannot tolerate Velcade due to peripheral neuropathy. That being said, responses in Velcade-resistant disease are also seen.
Moving forward, ongoing studies will help pave the way for the use of Kyprolis in combination therapy, both in the relapsed and newly diagnosed settings.
Vincent Rajkumar, Mayo Clinic:
We are testing Kyprolis in all stages of myeloma, including newly diagnosed disease and as part of pre-transplant conditioning. We hope to activate an NCI cooperative group Phase 3 study in newly diagnosed myeloma this year in which all the major groups are expected to participate.
Outside of trials, I would use it in patients who are refractory to Velcade- and Revlimid-containing regimens, consistent with the approved indication. In addition, I would consider it in patients who are unable to tolerate Velcade and have previously failed other available options.
The Myeloma Beacon would like to thank the above physicians who participated in the survey for their assistance and expertise.
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As someone who is presently benefiting greatly from Kyprolis/carfilzomib in a newly diagnosed patient trial (VGPR after just one cycle; cumulative kappa light chain decrease from 16,200mg/l to 150mg/l after three cycles), it is nice to see that many doctors are planning to prescribe the drug for all classes of patients once more data becomes available from ongoing trials (NIH, Univ. of Michigan) much like Revlimid has been prescribed. Terry L.
Interesting article/paper on off label drug use that is relevant to myeloma patients.
"Litigation documents reveal that pharmaceutical companies have paid physicians to promote off-label uses of their products through a number of different avenues. It is unknown whether physicians and scientists who have such conflicts of interest adequately disclose such relationships in the scientific publications they author."
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001280
"Directly promoting drugs for purposes outside those approved by the US Food and Drug Administration (FDA), so-called “off-label” use, is illegal for drug companies. However, it is not illegal for physicians and scientists to discuss off-label use with colleagues, deliver lectures, and author peer-reviewed studies. But according to a new study, published today (August 7) in PLoS Medicine, only 15 percent of physicians and scientists involved in such promotion adequately disclosed relevant relationships they maintained with pharmaceutical companies in published studies."
http://the-scientist.com/2012/08/07/off-label-drug-disclosure-inadequate/
Hello Terry and Mark,
Thanks for your comments.
Our informal survey makes it clear that many myeloma specialists are open to the idea of prescribing Kyprolis beyond the FDA-approved group of patients. But it's also clear that, in most cases, the specialists intend to stick to the approved group of patients, at least for the immediate future.
This approach is likely to be enforced in many cases by healthcare payers, who now face paying for a drug that is 25 percent more expensive than twice-weekly Velcade, and 150 percent more expensive than once-weekly Velcade.
We are very aware, Mark, of the concerns raised in the paper you have cited. Those concerns play a big part in who we reach out to when we ask for physician input for the articles we write. They definitely played an important role in who we selected for participation in the survey summarized in this article.
Have a great weekend!
Hi Mark, thanks for those links. It is disturbing to find out how prevalent the web of conflicts of interests prevades the medical community. Actually, as a public interest attorney, it isn't so shocking. I see it all the time in court, pleadings, etc. Also, unless I am mistaken, isn't Revlimid still only approved by the FDA for relapsed patients? Yet, it is commonly used all the time in the newly diagnosed and insurers universally or, at least, generally pay for it? Why would Kyprolis be any different over time...I also take comfort in the fact that my NIH doctors never have conflicts to declare and are strictly forbidden by law from engaging in the practices outlined in the links. Terry
Hello again Terry,
The FDA six years ago approved Revlimid for the treatment of multiple myeloma patients who have received one prior therapy.
Since then, myeloma specialists have also started using it in newly diagnosed patients, partly based on their increasing experience with the drug, and partly because of a number of large trials that looked at the drug's use in newly diagnosed patients.
And, as you said, it is now commonly used in newly diagnosed patients, even though its FDA approved use is still the same as it was when it was first approved in 2006.
I wonder if the way the use of Kyprolis changes over time will be different from what happened with Revlimid. Maybe it will be used in relapsed patients longer than Revlimid.
If I recall correctly, Revlimid was approved based on results from two different trials, and they were the "gold standard" kind of trials -- placebo-controlled and Phase 3.
In comparison, Kyprolis was approved based on just a single trial, and it was a Phase 2 trial without any placebo-controlled group of patients.
Doctors didn't hesitate to use lenalidomide. It still doesn't have an indication for first line use either and they used it because thalidomide caused more side effects. Insurers are still paying too. The answers from Mayo, UNC, were the most encompassing of how drug use decisions for 'off label' typically are handled.
Regarding this Beacon article:
This whole"survey" thing about when are the doctors going to use the drug is nice and professional on the record. No health professional would say they were going to use a drug 'off label' they simply do so. After all if they say they are going to use the drug 'off label' that could be perceived as 'promoting' the off-label use which brings with an whole other set of 'ethical/legal' issues. standard for medical use of therapy/drugs is simply 'standard of care' ..what is the the majority of the medical community doing. NOT what did the FDA approve.
In the real world, doctors use the drugs that work best. It is not a good thing AT ALL for patients to get neuropathy it alters their quality of life. Anytime a life-limiting side effect can be avoided it is best to do so and that means using the most effective drug with the least amount of side effects as demonstrated in clinical trials.
There are several well controlled trials where newly diagnosed MM patients have been treated with carfilzomib and they provide all MM specialists with the clinical evidence they need to use the drug in the newly diagnosed MM and this evidentiary based medicine is what supports 'off label' use of drugs. Or what will establish 'standard of care' as to how MM specialists treat the newly diagnosed. Oftentimes the easiest route is to do their own clinical trial with patients in their practice.
As far as the cost issue with insurers, the same thing holds. They cannot withold therapy on the basis of cost IF the drug they will pay for has KNOWN side effects greater than the one they are denying coverage for ..afterall, let's be clear they would have to pay additional money to treat the side effects!!
Bottomline this whole issue even being raised is from the competition to limit the use of carfilzomib as it diminishes their market share.
This is good old competitive marketing seeking to limit the use of a new agent so they do not lose revenues.
Mark, The key word in the articles you cited is promote. The pharmaceutical industry cannot 'promote' use however they can 'discuss' use IF the physician solicits information. (don't you just love lawyerly semantics) The company cannot initiate the discussion as that falls under 'promotion'. Doctors establish standards of practice, by discussing therapy and drug use at their professional meetings, such as ASCCO, ICAAC, etc where the clinical trials demonstrate a drugs efficacy or non-efficacy. See how difficult it becomes to differentiate "discussion vs promotion" medical scientists have to be able to discuss amongst their peers the outcomes of their therapies.
There are those who could call that 'promotion' given that typically a majority of the most brilliant minds with the best expertise are in the audience as the new therapies are discussed and the trial outcomes are presented.
PotaTOE PoTAToe...you decide
Great discussion everyone,
You are correct, CherylG. Revlimid's approval in myeloma was based on two placebo-controlled Phase 3 trials. Also, as you suggest, no data from a Kyprolis Phase 3 trial have yet been published (as far as we're aware). The recently published data on Kyprolis in combination with Revlimid and dexamethasone in newly diagnosed myeloma patients was a Phase 1/2 trial with 53 patients.
In regard to your feedback, suzierose, we carried out this survey because we know that Kyprolis, and how it will be used, is a topic of major interest to our readers. Because we do not have the resources to conduct a large-scale survey, we conducted a small survey with specialists we felt from experience would not be biased toward any particular treatment.
We also expected honest feedback about the expected use of Kyprolis, based on at least two considerations. First, we have received frank feedback in the past from most of the survey participants. Second, there is nothing illegal or unethical in the U.S. about a physician prescribing a drug off label or saying, in response to a survey, that they will do that. (This is clearly evidenced by the fact that some physicians actually told us they would consider using the drug off label.)
All that having been said, we expect that this survey overstates, if anything, the extent to which Kyprolis will be used in patients other than the FDA-approved patient population. The question we asked physicians ignored reimbursement restrictions (more on that in a moment). Even more importantly, the physicians we consulted are mainly at major cancer centers, and such physicians are more likely to use off-label treatment regimens than, say, community oncologists.
Finally, reimbursement restrictions on the prescribing of myeloma treatments do exist. There are insurance companies, for example, that restrict the prescribing of Revlimid to its FDA-approved patient population. Such restrictions are particularly common immediately after a drug is approved, and, as we have said, they may well be especially prevalent, and especially persistent, in the case of Kyprolis given its cost relative to Velcade.
If the data from the clinical trials involving patients who were newly diagnosed being treated initially with carfilzomib, reaches a phase 3 level, and is indicative of Kyprolis being effective and safe for patients, woulnd't another approval be sought by Onyx for that situation? Thus the drug would be indicated for new patients, and their wouldn't need to be 'off label' prescribing at all!
Everyone,
Excellent discussion. I just wanted to point out that while Revlimid is commonly prescribed off label for patients here in the US, Celgene has no data that shows using it for newly diagnosed patients improves Overall Survival. OS is the "gold standard" by which all therapies are judged. The European Medicines Agency was recently reviewing Revlimid for use as Induction therapy.
"Based on the review of the data and the company’s response to the CHMP lists of questions, at the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Revlimid could not have been approved to treat newly diagnosed multiple myeloma patients.
The Committee was concerned that, while there was a clear benefit in terms of delaying the progression of the disease in newly diagnosed multiple myeloma patients, this did not lead to a meaningful improvement of symptoms and longer survival. Furthermore, since Revlimid was associated with an increased risk of developing new cancers, the CHMP could not rule out that the lack of a longer survival could be due to death caused by new cancers. Therefore, more mature survival data and follow-up would be needed to conclude on the benefit-risk balance for this indication.
Therefore, at the time of the withdrawal, the CHMP was of the opinion that the benefits of Revlimid in newly diagnosed multiple myeloma patients did not outweigh its risks."
"In its official letter, the company stated that its decision to withdraw the application was based on the CHMP's view that the data provided so far require follow-up with more mature data to allow the Committee to reach a clear conclusion on the benefit-risk balance."
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000717/wapp/Post-authorisation/human_wapp_000140.jsp&mid=WC0b01ac058001d128
The EMA is just a little less biased when reviewing drugs from "Big Pharma" than US based physicians like Andrzej Jakubowiak that meet at ASCO.
Jakubowiak: Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria.
https://ash.confex.com/ash/2011/webprogram/Paper37217.html
Mark
"In regard to your feedback, suzierose, we carried out this survey because we know that Kyprolis, and how it will be used, is a topic of major interest to our readers. Because we do not have the resources to conduct a large-scale survey, we conducted a small survey with specialists we felt from experience would not be biased toward any particular treatment.
We also expected honest feedback about the expected use of Kyprolis, based on at least two considerations. First, we have received frank feedback in the past from most of the survey participants. Second, there is nothing illegal or unethical in the U.S. about a physician prescribing a drug off label or saying, in response to a survey, that they will do that. (This is clearly evidenced by the fact that some physicians actually told us they would consider using the drug off label.)
All that having been said, we expect that this survey overstates, if anything, the extent to which Kyprolis will be used in patients other than the FDA-approved patient population. The question we asked physicians ignored reimbursement restrictions (more on that in a moment). Even more importantly, the physicians we consulted are mainly at major cancer centers, and such physicians are more likely to use off-label treatment regimens than, say, community oncologists.
Finally, reimbursement restrictions on the prescribing of myeloma treatments do exist. There are insurance companies, for example, that restrict the prescribing of Revlimid to its FDA-approved patient population. Such restrictions are particularly common immediately after a drug is approved, and, as we have said, they may well be especially prevalent, and especially persistent, in the case of Kyprolis given its cost relative to Velcade."
Let me say, I agree, this is a major topic of interest to those who visit The Beacon. Additionally, I do not think there is anything unethical or illegal about off-label use. However, it is also true that until 'standard of practice' is established, all medical specialists would, conservatively, not simple state they will do so. The history of chemotherapy use in America demonstrates that is true. There will be, as there should, ongoing discussion and consideration of use, which will need to have demonstrated clinical efficacy before any clinician will simply stand out from the community and state " I will use this drug off-label" Off-label use accrues overtime..and lenalidomide is a good example. Had this same survey been conducted when lenalidomide was first released we would hear the same conservative responses, despite it now being a standard of practice, AND having not ever been given FDA approval for first line use. This is how it should be.
My quibble is in projecting limited use based on off-label being the obstacle. That has not, historically, been the case with chemotherapy, simply because if the disease is incurable..everything is used. In that sense the survey does not overstate..it UNDERstates. Which is why I replied, that UNC and Mayo response were most encompassing, as those responses reflect the true utilization of off-label use. Not 'promoted' but definitely an equal opportunity for usage.
I respectfully disagree, that major medical centers are most likely to engage in off-label use. Generally,that is not the case. In fact, major medical centers may, if anything, be far more conservative. At least that is what the pharmaceutical industry has seen. When you have major studies done by top experts and the community oncologist sees those results, they are MORE likely to use the drug than not, as it is the work of highly respected experts in their field. They will assess the study and the outcomes. After all the community oncology is also generating revenues and willing to do what will improve the outcome for their patients. AS LONG AS the work is valid, and they will have physician to physcian communication learn the caveats and then proceed to treat the patient. BECAUSE it is beneficial to the patient.
Yes, I agree restrictions on reimbursement exist, what I reject is the premise that they will not pay due to the cost and it being off-label. The insurers understand the costs of side effects and the liability associated with using less effective thereby based on cost particularly when it means the patients health or QOL is compromised. So these 'restrictions' based on 'recent approval' are NOT common!! The insurer has no ground to stand on based on the clinical evidence of superior therapy and they do not want that liability.
Ergo, I repeat, this specious reasoning is nothing more than competitive marketing scare tactics to maintain market share.
Drugs are BIG business. Competitors seek to maintain there market share and this is one of the most common issues they raise to diminish their loss of market share.
No different than the pre-release negative hype for approval of Krypolis...all that was also shown to be nothing but competitive marketing hype, The FDA approved the drug in line with what they traditional do.
My overall point is, this will not be a big deterrent to the use of the product, as the VAST majority of chemotherapy is OFF-label. And I feel that is a service to the readers of the BEACON to make these views known as well.
They will have access, it will be paid for, and anyone who needs Krypolis should not be frightened into believing they won't on the basis of OFF-label use.
I reiterate, UNC and MAYO gave the most honest answers to the survey.
Hi Mark!
re: "Celgene has no data that shows using it for newly diagnosed patients improves Overall Survival. OS is the “gold standard” by which all therapies are judged."
Neither does lenalidomide.
Golds standards are simply that 'gold'. In the real world patients are treated without 'gold standards' because the patient has run out of treatment options OR there are less side effects with a new therapy.
"The Committee was concerned that, while there was a clear benefit in terms of delaying the progression of the disease in newly diagnosed multiple myeloma patients, this did not lead to a meaningful improvement of symptoms and longer survival."
Now, this sounds all flowery and scientific BUT as a patient do you want to delay progression in hopes of overall survival? Yes. And we need longitudinal studies to establish overall survival, particularly with a disease such as MM, where the median age is 60 plus. Those patients may not live long period, but let's say the patient in 50 or 45 ..well we are not going to be able to determined OS for at least a decade. So, would you NOT treat on the basis of unproven OS? Or would you treat in hopes of establishing OS? No different than hypertension, and the long term Framingham studies we now have demonstrating OS! Those studies took a long time..but I would not nor should any MM patient, refrain from using the drug UNTIL OS is demonstrated. Rather, you treat and the patient hopes to be one of those who DOES demonstrate OS. But that can take decades as it did with hypertension, the Framingham studies were started in the 60s by the 80s they HAD demonstrated increased survival along with decrease morbidity and mortality due to cardiovascular disease.
Until the CHMP has evidentiary clinical data, they can wait, before saying the benefits outweigh the risks, but can you as a patient? NO. You have to be the trailblazer and you have nothing to lose. You were going to die without the therapy so any longer life you get is a plus. "Mature data" is a luxury for those without the disease.
The EMA is not less biased, they focus on cost much moreso than the FDA, we are capitalistic and the European Medical Association is dealing with socialized costs. Do they make sound reasoning reasoning yes, but it is driven by cost. It is not beneficial to patients to wait until there is 'definitive' proof..the EMA moves based on the use in America. AND the FDA is a far more rigorous regulator body than EMA as proved by the thalidomide baby fiasco. WE, in America declined that use.
I stand with the FDA anyday. Lots I do not agree with. But overall this system has proven to be far more patient oriented and regulatory than ANY European body, biased to costs.
HI Nancy!
you write:
"If the data from the clinical trials involving patients who were newly diagnosed being treated initially with carfilzomib, reaches a phase 3 level, and is indicative of Kyprolis being effective and safe for patients, woulnd’t another approval be sought by Onyx for that situation? Thus the drug would be indicated for new patients, and their wouldn’t need to be ‘off label’ prescribing at all!"
Carfilzomib is in phase 3 trials..they are conducting trials in NDMM and have completed trials in relapsed/refractrory patients. The only thing carflizomib could look to have now, having clearly demonstrated efficacy in both these populations is a comparator arm that is NOT placebo..i.e. bortezomib vs. carfilzomib arms.
Now, let me ask you as a MM patient who knows that bortezomib has lots of neuropathy, would you sign up to be randomly assigned to a bortezomib vs carfilzomib trial? Both drugs work, so it would be ethical.
As it stands now, carfilzomib has demonstrated efficacy in NDMM patients, if you were the mfgr would you pay millions to prove greater efficacy? That is the dilemna. AND the real world cost decision not to mention QOL patient decision.
Which is all to say, that is why lenalidomide has not and will not run trials to get a first line indication, it is cost prohibitive. More importantly..that is the benefit of 'off-label' use. Clinicians already know that lenalidomide is effective therapy so why would Celgene ever submit to fund such a trial?
IOW's just like lenalidomide did not need an FDA approved indication, because of off-label use..neither will carfilzomib.
My point is that it costs to set up studies for FDA approval and if the drug is already being used without those FDA studies and approval, there is no cost benefit to the mfgr.
Which is all to say..that is why the vast majority of chemotherapy use is off-label.
Hi Suzierose...I have to say I find all this quite fascinating. Who would have known how circuitous is the world of chemotherapy drugs before they got diagnosed with myeloma (certainly not me!)? I guess what puzzles me now is why a new drug such as carfilzomib would have to be in a trial with bortezimib for comparative purposes. Would they not both be considered to be good drugs, although different in some ways. I can't understand why they would not both be approved, if they met the other criteria. Which just goes to show that I don't know that much about these issues!
As to your question about which drug I would rather have taken in a 2 drug clinical trial, I have to say that since bortezimib worked really well for me, about as well as carfilzomib has worked for some of you in the clinical trials, I wouldn't be able to answer that question. I only needed four cycles to get close to a remission. I did get neuropathy from it and also from the revlimid, but now, 16 months on from taking any chemo drugs, I don't have much in the way of neuropathy anymore. Thank goodness!! I have met people who had very severe neuropathy from taking the only drugs available previous to the bortezimb and revlimid...that's why I consider that I am really fortunate to have been treated in the more recent era, and to have responded well to therapies.
As far as I know, we cannot get 'off label' drugs in Canada through our health care system (and it would be difficult to afford these sorts of drugs otherwise!). There are clinical trials ongoing though,and I did notice that there are some new carfilzomib trials opening up in Canada. But it is good to know that Kyprolis has now been approved in the US for some categories of relapsed patients, and as you say, probably lots more patients also will be able to try it!
Hi Nancy!
re:"Who would have known how circuitous is the world of chemotherapy drugs before they got diagnosed with myeloma (certainly not me!)?"
Lol, lol..ICAM...I think it isn't to know, especially when most of us believe that health is precious and not a financial commodity.Unfortunately, when capitalism is involved there are lots of twists and turns, not to mention boundaries that can be puzzling.
Both drugs are approved and they are both effective. The thing is there does not have to be a trial that compares one to the other, and the manufacturers likely would prefer that. Somewhat like the conundrum we have with Zometa and Aredia. There are no head to head trials. That's OK, but there will not be definitive scientifically valid way of deciding which drug is better. We can speculate and use clinical judgment based on how patients do on each separately, but no one can say without a double blind randomized controlled trial (DBRCT) if one agent works better than the other. Unfortunately, DBRCT's are very expensive and unless the manufacturer believes they will gain (market share) and offset the cost with additional revenues, often times those trials simply are not done.
What happens in lieu of those trials is that the mfgrs compete by raising skepticism of the other agent, such as saying they do not have an indication and using it for NDMM patients is 'off label". The hype around that could make some physicians and or patients reluctant to use the drugs. That happens far more often with non oncology drugs than with them simply because the other therapeutic areas are not generally life-threatening diseases, which makes the risk of use higher than in patients who have cancer and often are facing terminal illness without it. Which is a long way of saying that the benefit outweighs the risk far more with cancer than someone with say asthma or hypertension. Huge difference.
When I was asking about which drug, I was trying to demonstrate if you knew you had a far higher risk of neuropathy with one drug over another would you risk that side effect, when both agents had been shown independently to be as effective? Sorta like asking if you had to take a drug for hay fever during the day and you knew one would make you drowsy and the other wouldn't which would you choose, if it was not bedtime. Now granted drowsiness goes away, but many times neuropathy does not. You are fortunate/blessed in that your neuropathy was transient, often times it is not and that can change the quality of life for the patient. Also when given the choice, your physician would not be able to say with any certainty that the neuropathy would end. He/she would only be able to say that one was less likely to cause neuropathy than the other based on clinical experience.
I think you are right that 'off label' use is more of an USA thing. The medical profession and the pharm industry lobbied for that and overall, it is a good thing. Without that exception relying on medical judgment many patients might not be treated.
I suppose the another way to put it is..do you think that a drug that works in relapsed/refractory patients who likely have greater cellular resistance is LESS likely to work in a NDMM patient? So, why would that population be denied a more effective or less side effect agent simple because the manufacturer had not received FDA approval and YET they did have clinical trials that demonstrated efficacy and less side effects.
Overall, I agree with you..the more choices we have as patients with an incurable disease is best for all patients. Having a choice is soooo important and that is why carfilzomib receiving approval for ANY indication was a major benefit. Patients with myeloma now have access to another effective drug without being in a clinical trial. Which means they do not have to leave their community for therapy ...that is a GOOD thing.
MM patients have more options...and that is indeed a blessing.
Hi Suzierose, Thanks for your reply. Of course no one can predict just how a particular patient may react to a drug, and certainly there is a problem with Velcade and neuropathy. Since the time when I was treated, I read that now sometimes it is administered just once a week instead of twice a week, and also there is the sub-cutaneous route. I WAS very lucky to get through my initial therapy quickly, so as not to accumulate toxic type side effects. of course the goal in my case was to have the ASCT and then later I had more treatment with Revlimid. The whole package worked well for me...my physicians were brilliant in working with the treatments available to get me through this with the least possible side effects, and back to a healthy state (hope it lasts a long time!!). And I was just lucky to be getting treated right after these new drugs were approved here.
I looked up the carfilzomib studies being done in Canada. They are the type you referred to... DBRCT. One arm is carfilzomib plus dex, and the other arm is Velcade plus dex. They are being sponsored by Onyx and are offered at cancer centres in BC, AB, ON, PQ, NS and NB. The name of the study is ENDEAVOR, in case anyone here is interested. (Not sure if they are for newly diagnosed or relapsed patients).
I think that after going through an experience like the MM diagnosis and treatments, one is left with an interest in this subject which will be ongoing! Glad that you are doing well too! Let us hope that with the new developments, we can stay one jump ahead of MM.