Two Myeloma Experts Debate Role Of Stem Cell Transplantation In The Treatment Of Multiple Myeloma
In a recently published article, two myeloma experts discussed the role of autologous stem cell transplantation as an initial line of therapy in myeloma patients. The debate centered on the limited evidence supporting stem cell transplants in the context of newer, alternative treatment options.
An autologous stem cell transplant is a procedure in which stem cells are collected from a patient prior to high-dose chemotherapy and later re-infused into the body to replace the cells that were destroyed by chemotherapy.
The results of two randomized trials show that patients who underwent stem cell transplantation had a median improved survival time of 12 months to 18 months compared to patients who received conventional chemotherapy. Based on these findings, stem cell transplantation has become a standard treatment for eligible patients.
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However, the role of stem cell transplantation as an initial treatment for multiple myeloma is now in question due to the introduction of novel and commonly used anti-myeloma agents including Revlimid (lenalidomide), thalidomide (Thalomid), and Velcade (bortezomib). Studies have shown that most patients who receive conventional chemotherapy along with combinations of these novel agents demonstrate high responses within a short period of time.
According to Dr. Vincent Rajkumar of the Mayo Clinic in Rochester, Minnesota, stem cell transplantation is one of several available treatment options and the decision to undergo the procedure should be based on the specific needs of the patient.
“Autologous stem cell transplantation is just one of many available [treatment] options, and the decision on the need for stem cell transplantation and its timing must be tailored to meet the needs of the patient. A one-size-fits-all approach is no longer applicable in the disease,” wrote Dr. Rajkumar.
In his opinion, the current data on the outcomes following early stem cell transplantation are not enough to support stem cell transplantation as a default method of initial therapy (see related Beacon news).
On the opposite side of the debate, Dr. Philippe Moreau of University Hospital Hotel-Dieu in Nantes, France, contends that the data currently available support the routine use of stem cell transplantation in the treatment of eligible myeloma patients.
“Autologous stem cell transplantation is a routine procedure and is associated with a mortality rate of less than 2 percent, which is lower than that reported by physicians favoring continuous upfront therapy without stem cell transplantation,” wrote Dr. Moreau.
In his opinion, future studies should concentrate on identifying the patients who would benefit most from this treatment option.
Dr. Rajkumar believes that the evidence conferring a clinical benefit of any procedure is defined by an improvement in overall survival or improved quality of life. Currently, there are many studies that claim results in favor of one method over another based on measures such as complete response or progression-free survival. However, in Dr. Rajkumar’s opinion, these measures are not necessarily indicative of better outcomes as far as the patient and quality of life are concerned.
“As long as overall survival has not been shown to be better with one [treatment] approach over the other, and no validate patient-reported quality of life studies have been done, the decision on what the appropriate timing is should be made based primarily on patient preference, not physician preference,” wrote Dr. Rajkumar.
Dr. Brendan Weiss of the Abramson Cancer Center in Philadelphia who was not involved in the debate, agrees with Dr. Rajkumar’s assessment of measures relevant for outcomes.
“Complete response has not been consistently correlated with overall survival in multiple myeloma. Until we have better biomarkers, clinical benefit should be based on improvements in overall survival and/or quality of life,” said Dr. Weiss.
While Dr. Rajkumar supports the use of stem cell transplantation in clinical trials designed to find an eventual cure for myeloma, he does not believe that the procedure should be used as a default initial treatment for all eligible patients in a clinical setting. This is based on his claim that there is limited work investigating the optimal sequence of therapy involving stem cell transplantation.
According to Dr. Rajkumar, results from the few recent studies comparing early stem cell transplantation to delayed stem cell transplantation show no overall survival benefits that favor either option. However, by delaying stem cell transplantation, he believes patients can extend their time spent leading normal lives.
“A delayed stem cell transplant approach allows a person with newly diagnosed myeloma to live the younger years of their life without feeling like a cancer patient,” wrote Dr. Rajkumar.
Additionally, Dr. Rajkumar believes in tailoring each patient’s course of treatment according to his or her risk factors and needs. While he routinely supports early stem cell transplantation in intermediate-risk patients (characterized by particular chromosomal abnormalities), he offers standard-risk patients a choice between early and delayed stem cell transplantation.
Dr. Moreau, on the other hand, views stem cell transplantation as a routine, cost-effective procedure that will likely remain the standard of care for eligible myeloma patients.
“The argument of cost does not support the use of continuous novel agent-based therapy upfront in comparison with early stem cell transplantation, which is less expensive than two years of therapy,” he wrote.
He notes preliminary data from a recent study that appears to favor early stem cell transplantation over standard chemotherapy in combination with novel agents. However, the overall survival was not significantly different between the patient groups, and final results have not yet been published.
While not against the idea of limiting stem cell transplantation to a specified group of patients, Dr. Moreau asserts that the relationship between individual risk factors and the most beneficial treatment options have not yet been adequately identified. Thus, the best approach would be to offer the most effective treatment for all patients, regardless of their risk level.
“Although we are progressing towards a consensus regarding the definition of high-risk disease, no cooperative group is currently able to propose a risk-adapted strategy based on well-defined biological and/or clinical characteristics,” wrote Dr. Moreau.
Dr. Weiss agrees with Dr. Moreau that risk-adapted approaches have not yet been confirmed in clinical trials.
“Unlike the case in acute leukemias, we have not performed appropriate clinical trials to validate risk-adapted approaches, as suggested by the Mayo Clinic. Until these studies are performed, these biomarkers of risk are important in informing discussions of prognosis with patients, analyzing current clinical trials, and generating hypotheses to test in future trials,” added Dr. Weiss.
Additionally, Dr. Moreau argues that in delaying stem cell transplantation, a patient could run the risk of not being able to receive a transplant at all due to disease progression or additional health complications. He references a study in which only 77 percent of patients in a delayed stem cell transplantation group could actually receive a transplant by the time they relapsed.
Dr. Moreau added that ongoing trials evaluating the role of stem cell transplantation in the context of the current understanding of myeloma will hopefully surface with results in the near future.
For more information, please see the article in Leukemia Research (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
- Number And Type Of Stem Cell Transplants Carried Out Each Year For Multiple Myeloma Vary Markedly Across U.S. Cancer Centers
- Sustained Complete Response To Initial Treatment Associated With Substantial Survival Benefit In Multiple Myeloma
I was delighted that Dr. Rajkumar believes that "one size fits all" is not the way to treat patients. Specifically, a one-size-fits all approach to dosing melphalan should rejected. It is almost incomprehensible that a discussion of this sort should be devoid of any mention of the amount of melphalan to use and that maybe, just maybe, the amount of melphalan should be personalized to the patient. I know that we need to maximize the amount of melphalan that is used in order to get the residual myeloma level as low as possible to delay disease progression....but this maximum amount is different for each patient! When we exceed this maximum the side effects can be catastrophic resulting in permanent quality of life issues. Thankfully, we have one enlighted oncologist at least who is planning studies to determine melphalan dosage maps which can be individualized to the patient. Until they are prepared and in use by the myeloma community I suggest all patients considering stem cell transplant proceed with caution.
Thanks Ms Li for writing this article. I found it to be very thought provoking, and reassuring in a way that there are more treatment models available than before. I have been through differing chemotherapies, before and after stem cell transplant. If possible, I would not undergo a second SCT, because it is very time consuming in the sense of recovery, and loss of immunities. The one I did have has seemed to be very effective in helping to remit the myeloma though, and I don't regret having one SCT.
When SCT's were first studied, survival times were increased by a matter of 12 - 18 months, now we seem to be talking in terms of years. The combination of all the different therapies seems to be more effective now, but of course side effects and toxicities are always an issue to be very careful about. I am sure that more studies of the recent treatments combined with and without SCT's must be ongoing....nice to see that Dr. Rajkumar favours a variety of approaches to treatments.
when Dr. Moreau considers the costs of SCT's as being lower than 2 years of chemotherapy, is he taking into account that many patients continue on to 'Maintenance Chemo'? Also, if there are complications and a patient is hospitalized because of the SCT, that is not a cost benefit either. I noticed that the availability
of an oral med, such as Revlimid, is actually somewhat cost effective, since no hospital facilities outside of the pharmacy are needed at all! The drug itself is really expensive, but that seems to be the main cost of that therapy.
Nancy S.
I think the cost of an Auto Transplant is between $75k and $150k here in the US. Costs vary a lot based on geography and if it is done in or out patient. Revlimid costs around $12k per month. The typical IV push of Velcade is in the $3,500 range (1.3 mg/m2) - at least that was the cost when I used it in late 2010. Therapies that involve long cycles of Revlimid and Velcade are very expensive over the long run. If a patient has good Insurance here in the US, they do not look at costs since they do not view themselves as paying for it. You will rarely see a US based Doctor discussing the outrageous cost of Revlimid since most of the big name Doctors are on a Celgene Board or they are a paid consultant of Celegene.
Mark
Hi Mark....if I could just add to your comments a bit....an SCT is not really a 'stand alone' treatment in many cases any more. There is additional treatment by novel agents before and after it, so that adds to the cost. Also, Revlimid comes in differing doses, so one just hopes that the lower doses are not at the same price. I calculate it to be $600 per pill, if you were taking 20 a month (three weeks on, one week off cycle), by your estimates. The whole thing is so expensive, no matter which treatments you are on, that it just boggles the mind sometimes! I am indeed very fortunate to live in a country where we have universal health care...my treatments were all covered. But we are all concerned about costs, since we pay the taxes to float this system. I am not a health care economist, or a 'bean counter' at all really, and am very grateful to be living here where i get good treatment.
But the bortezimib is also expensive, and that is from a different drug company than Celgene. Do you think that any new drugs will be inexpensive? Given the amount of research that goes into developing a new cancer drug, and given the low likelihood of any particular line of research translating into a new drug, I am pretty sure that all novel agents will be expensive, at least for a few years. I don't know what we can do about that really, even if we feel that the drugs are in some cases over-priced. Eventually they may revert to 'generic' versions, but that seems to take a long time to occur. And I suppose that in the greater arena of cancer drugs, ones specific to treating myeloma only represent a small market.
Nancy S.,
I am one of the fortunate ones that has great insurance and I have a great Doctor/Transplant center that is a 45 minute drive for me. It infuriates me when I read stories about my fellow patients here in the US that have to drain savings to pay for the cost of these drugs because they do not have as good Insurance as I have. I do not mind if the Drug compaines make a profit, that is their duty to their shareholders, but many Myeloma patients suffer financial hardship in addition to the challenges they face as a Cancer patient. I tend to mention Celgene more because more Myeloma patients have pay a larger amount of the cost of Revlimid then Velcade.
The cost of items tend to go down when demand drops. I am probably one of the few patients diagnosed in the US in 2010 that has never taken Thal or Revlimid. If the Doctors here in the US stopped prescribing it unnecessarily the cost could potentially drop. I am surprised the Insurance companies approve on-going cycles of Revlimid maintenance. There is no clear cut data that shows Revlimid maintenance improves OS for patients. It is also being prescribed as maintenance and there is no measurement showing it killing any Myeloma cells.
Mark
hi Mark...it saddens me when people write in about their financial hardships vis a vis Myeloma. You get mad, but I just get sad about it. It happens all over the world...cancer is not a good diagnosis to have. It drains many people's savings and worse too. My mother-in-law died of stomach cancer and we were the caregivers in the last year of her life so I know all about it. I guess that here we are at least sheltered from the costs of the treatments and meds used, for the most part. I am not saying that everyone in Canada is as lucky as I have been...and luck is a part of this. It was definitely Bad Luck to have myeloma, but since then I have been luckier than many.
I was thinking kind of the opposite about supply and demand...if the cost of certain drugs were to be lowered, then they could be used by more patients. More drugs would be sold, and so the profit to the manufacturers could actually increase. When you think of the world market, that could be huge! Revlimid is not even approved for use in certain provinces here, and from reading the Beacon, is also not approved in certain other countries....we couldn't know why for sure, but I suspect that cost is the main issue.
As for your statement about Revlimid's effectiveness, I couldn't comment, except to say that it worked for me as maintenance chemo. I was on several sorts of treatments, so it's difficult to pinpoint which ones really were the most effective. I am certainly grateful for all the help to get me well again.
Mark,
I think you know from previous comments I have made about information you have shared with us here that I respect your opinion and I think you add a lot to the discussion here at the Beacon.
However, I think you're a bit off base when it comes to your statements about maintenance therapy, particularly Revlimid maintenance therapy.
The three or four major trials looking into the potential benefit of Revlimid maintenance therapy have shown without a doubt that it improves progression free survival. One of the trials also has shown that it improves overall survival.
So there certainly is reasonable evidence in favor of maintenance therapy.
Now, it is also true that long-term Revlimid treatment has been shown to increase the risk of secondary cancers, and this is something that has to be taken into account when considering such therapy.
But to suggest or imply, as you do, that it is foolish to prescribe Revlimid maintenance therapy simply does not have any basis in the data that are out there.
As I said, I really value and look forward to the comments you make on this site, and I hope you don't take this comment personally. I just want the discussion to be as fair and objective as possible.
Interesting viewpoints ...particularly:
“Complete response has not been consistently correlated with overall survival in multiple myeloma. Until we have better biomarkers, clinical benefit should be based on improvements in overall survival and/or quality of life,” said Dr. Weiss."
So the question is QOL, NOT overall survival based on current evidence. What is each patient willing to do if they know that BSCT does not increase survival. Do they want to submit to BSCT or do they want to take the time they have and live it fully? That is soooo personal. And perhaps for young patients it is worth the risk.
"Dr. Moreau, on the other hand, views stem cell transplantation as a routine, cost-effective procedure that will likely remain the standard of care for eligible myeloma patients.
“The argument of cost does not support the use of continuous novel agent-based therapy upfront in comparison with early stem cell transplantation, which is less expensive than two years of therapy,” he wrote.,,,snip ... However, the overall survival was not significantly different between the patient groups, and final results have not yet been published."
So, if it is a cost issue, the question is to Dr. Moreau, if cost was NOT an issue...what would he recommend?
Given that life and QOL are priceless to a patient with MM. Economics is NOT the issue for those with MM. It may be an obstacle but as an issue...there is no question..we would spend our last dime!!
And based on current data, the jury is still out.
Which means each patient much choose what they believe is best and choose wisely, often from the heart
vs. the data.
Mark,
I wholeheartedly agree with you!! The cost is outrageous. Many would say unethical at best and immoral at worse.
There is not a lot research involved in modifying a drug structure vs. developing a wholly different chemical entity, and in that regard, lenalidomide is definitely very much excessively overpriced, as all they did was modify thalidomide. The cost is obscene compared to the negligible research cost involved. GMAB..pleease!!
When you take a drug and get a toxicity that is a incurable maliganancy as untreatable as what you started with? My grandmom called that going from the frying pan to the fire. hmmmmm
We are all individuals making choices, no one can say what any one person should do..but certainly all the risks should be known.
What is PFS when you get a new malignancy?
Hi Terry!
you write:
...., "that it is foolish to prescribe Revlimid maintenance therapy simply does not have any basis in the data that are out there."
How so? Can they treat that secondary malignancy? Or are you now subjected to new chemo/radiation? That is not known to cure your new problem on top of the disease (MM) you had to start with? How is that a good risk? BOTH of which require therapy and those therapies are not the same and have additional toxicities. What type of choice is that.
As far as evidence goes...let's be clear, those parameters are based on RESPONSE, with criteria that are geared towards approval (profit) for the company...not efficacy for the patient.
Right not PR plus CR equal OR....and PR is defined as relapsing in less than 6 months, CR response equals response for greater than 6 mos. as defined that means 6 mos and 1 day equals CR...so what does that mean for patients?
Patients need to be clear the definitions were made to get FDA approval, not efficacy for the patients. There is nothing magical about 6 mos other than, most chemotherapy is not effective enough to last BEYOND 6 months..so if the industry had to PROVE efficacy beyond that they couldn't. Since the majority of patients do relapse after 6 months. Thus the 6 month cut off.
So, let's be hopeful, but also understand how these terms were developed for FDA approval. The majority of chemotherapeutic agents would not be on the market if they had to prove efficacy longer than 6 months.
Let's make our decisions wisely and informed.
It's no secret that I agree with Dr. Rajkumar, believing there should be no such thing as a "standard treatment regimen." Instead, standard tools from which to select the appropriate agent(s) in reply to demonstrated need or patient response to existing therapy.
As to expense: I think the drugs are too expensive and a reduction in end user cost should be sought. Yet looking at the big picture I also know that even the analogs are tremendously expensive to develop, certify, and market. In a better economic climate, it would be easier to ask the developers to recover their investment and develop a profit profile over a longer period of time. But the instabilities and high cost of investment dollars is realistic justification for a faster investment recovery and profits to reinvest in new directions. It makes a great case for the single payer model of health care: a country buying in volume and attaining a discount for that volume makes for a significantly lower retail price. We do have to keep it in mind that while there are way too many people with MM, we are still a minority on the health care stage. It's a difficult question, that's for sure. No easy answers.
Great comments y'all!
Compliments to Virginia Li for an excellent summary.
TerryH,
No offense taken - just a difference of opinion. That is what forums are for! I should have put an IMO in front of the comment - If the Doctors here in the US stopped prescribing it unnecessarily the cost could potentially drop. That is clearly an opinion based on the very different (and very much in the minority) philosophy that is the basis of my treatment.
It seems like the data that you point out actually supports my comment that Revlimid does not improve OS. I am guessing the study you refer to that shows OS improvement for Revlimid maintenance is the one summarized in this article.
http://www.clinicaloncology.com/ViewArticle.aspx?d=Hematologic%2BMalignancies&d_id=149&i=June%2B2011&i_id=734&a_id=17222&ses=ogst
If one out of four trials shows an OS difference of 90% vs 83% at a median of 28 months since transplantation on Rev maintenance vs Placebo and the others show no OS advantage, I would think most people would say the balance of the evidence shows that Revlimid maintenance does not improve OS. My interpretation of the data is that long term Revlimid maintenance increases PFS at the cost of making the patient resitant to Revlimid and in the majority of cases, IMID's as a class. I know there were studies at ASH as well, this one from ASCO 2011 showed a 35% response (best was a VGPR - no CR's) to Pomalidomide in patients that has already used Revlimid.
http://www.medpagetoday.com/MeetingCoverage/ASCO/26985
If you view Myeloma therapy as a sprint and that upfront PFS is the most important statistic, then long term Revlimid maintenance is a good idea. The only evidence that I am aware of that supports long term Revlimid maintenance is the one I mentioned above. It is not enough to convince me, considering the others do not show an OS advantage, that it will turn this into a marathon for me, so I have chosen not to use it. I am definitely in the minority when it comes to my opinion on maintenance therapy. Come to think of it, I am in the minority on just about every issue when it comes to Myeloma therapy!
Mark
Give me a break: the flimsy arguments of Moreau (who practices in a country with socialized medicine) are (1) that ASCT is quite routine (ONLY 1 in 50 die); and (2) it is cost-effective. Where is the actual clinical benefit and substance behind his position?
He further grasps at straws when he asserts that waiting until relapse to get an ASCT is itself a risky proposition because there is a 23 percent chance you would not qualify at that time. But this assumes that this small fraction of patients would otherwise benefit from an early ASCT -- and I see NO indication of that in this summary.
Because NO ONE knows in this current era:
But in this regard, I do agree with Moreau - as does Rajkumar -- that future studies should concentrate on identifying the patients who would benefit most from ASCT. Any competent oncologist who is honest will point out to a patient that most people will receive NO benefit from an ASCT or do worse after an ASCT. If they can tell a patient that with an ASCT, the chance of say 5 year disease free remission is greater than 80 percent, then we might be getting somewhere. I, for one, am waiting ....
When discussing the possible effect of maintenance therapy in general and of Revlimid in specific, perhaps one has to use a slightly different terminology the TTP (Time To Progression) and its TTT (Time To Treatment). According to my MM specialist, based on his long time experience, patients that relapsed during maintenance do it more aggressively then patients that relapsed w/o maintenance (no clinical evident though) and though needs treatment sooner. According to him, when comparing TTT and not TTP, even the slight advantage of maintenance may vanish.
BTW, I'm also biased against ASCT as up front routine treatment based on personal experience. When my MM progressed 2.5 years ago, all my doctors recommends ASCT because that's the norm! Because I was a great physical shape and I didn’t want to be "off" for few months, I choose not to do ASCT and to go for VD and later VTD regime (its free in my country) and after 1.5 years of treatment (almost a year ago) I found myself in CR. I know this will change in the future and probably ASCT will cross my way but for sure, I don’t think that it needs to be regarded as a mandatory, up front treatment.
Shay
To Shay
Thanks for sharing your personal experience regarding an ASCT. Like you, I am in good physical shape (and have not begun any treatment yet). I am anemic, though, although even that appears to be stabilizing (any may be improving). In fact, I have no fatigue, which is why I am resisting taking any drugs -- much less drugs that can cause cancer!
My long-term view is that if and when ASCT does come our way, it will have less toxic and targeted protocols and other attributes (perhaps the addition of an antibody) to increase the likelihood of long-term remission - if not a functional cure.
My oncologist is not jamming an ASCT down my throat -- but it was certainly his first recommendation: 4 cycles of VVRD following by an ASCT - and hope for the best.
DanD,
I hear you about the argument Moreau put forth!!
To me the critical points are these:
1) ASCT is not curative in myeloma, it has become the mainstay of treatment for patients who are younger than 65 years, based largely on an improvement in progression-free survival (PFS). NOT SURVIVAL
2) Only two randomized trials showed an overall survival advantage of 12 to 18 months for ASCT plus chemotherapy vs chemotherapy alone. So, the question is how many of those 12-18months were spent hospitalized or with diminished QOL?
3) In addition, among three randomized studies examining when ASCT should be performed, none showed improved survival with early ASCT.
As Rajukumar notes, ASCT is subject to overuse based on over-interpretation of positive clinical trials, ignoring the negative data, and over-reliance on surrogate endpoints.
Which to me is the real issue, how these data are interpreted based on the endpoints they design into the trials which for the most part are to meet FDA approval standards to get the drug on the market with as many indications as possible.
The endpoint criteria are not design for OVERALL patient SURVIVAL.
While ASCT is a choice for newly diagnosed myeloma, it is one of several options and there is not a one-size -fits-all approach for every patient.
Let's be informed and choose wisely based on our own lives, hopes, dreams and desires. Not on someone saying this is what is routinely done, especially when what is 'standard of care' does not mean survival.
Thanks for elaborating SR -- especially about the outcome of studies evaluating the impact of ASCT on survival. I would like to see the actual breakdown of these studies according to patient factors:
What FRACTION of the patients who received ASCT plus chemo actually fared better than those who received just chemo?
And what chemo agents were used in these studies? Did they include modern agents,such as Velcade and revlimid?
Related to the preceding point, what fraction of the patients were in CR prior to ASCT? In the 1990s, when ASCT began, it was to deepen the response in patients, the majority of whom did not reach a CR or near CR because of the older agents being used.
And yes, I am a cynical bastard; but the word myeloma expert is an oxymoron. This disease is highly individualized -- and must be dealt with case by case.
And yes -- transplant centers rely on myeloma patients to keep their "business" alive: myeloma patients are their biggest customer.
At my last appt, the oncologist twice pushed me to meet with the transplant coordinator (just in case). I have declined so far.
And he also tried two somewhat strange tactics: (1) telling me that the center does not generally like to freeze stem cells after inital treatment; and (2) that insurances does not generally cover such freezing anyways, so once I begin treatment, heading to an ASCT ASAP was pretty much set.
Of course, he backed down when we discussed the actual reality. But this was disconcerting.
I just read an interesting quote from Andrew Weil about integrative cancer treatment and the difference between western obcology and integrative oncology. I think it speaks volumes about the risk of stem cell transplant:
"I tell my patients that I think of cancer as a weed. Modern western oncology is focused on destroying the weed while integrative oncology concentrates on the soil the weed grows in and on making the soil as inhospitable as possible to the growth and spread of the weed."
Think about a a stem cell transplant. Not only does it fail to completely pull the weeds. It completely destroys the soil as well. No wonder that the results are unpredictable and more often than not, of little benefit.
I truly believe that an integrative approach (at least for early stage or assymptomatic MM) may offer the most positive, long-term benefit by stabilizing the disease. And it certainly makes me feel optimistic rather than fearful.