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Trends In The Use Of Stem Cell Transplantation For Multiple Myeloma (ASH 2012)

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Published: Jan 22, 2013 2:35 pm

Findings from a retrospective study of stem cell transplantation among U.S. and Canadian multiple myeloma patients show that the technique has become more common in the past 15 years.

In addition, the outcomes associated with the procedure have improved over time.

“There was progressively improved survival for multiple myeloma patients managed with autologous stem cell transplantation as an initial therapy,” said Dr. Luciano Costa from the Medical University of South Carolina, who presented the results at the American Society for Hematology (ASH) annual meeting last month.

“Stem cell transplants have also remained safe,” he added.

However, Dr. Costa noted that changes over time in the way stem cell transplants are done are unlikely to have been responsible for the observed increase in survival among myeloma patients undergoing the procedure.

Instead, he argued that improvements in initial, pre-transplant (induction) therapy, combined with more effective post-relapse therapy, have probably contributed the most to improvements in survival among transplant recipients.

Based in part on the study findings, Dr. Costa recommended that stem cell transplantation and novel agents, such as thalidomide (Thalomid), Velcade (bortezomib), and Revlimid (lenalidomide), be combined in the treatment of myeloma patients.

According to Dr. Costa, previous studies have not evaluated the contribution of autologous stem cell transplants to the observed increase in survival rates in myeloma patients.

Therefore, he and his colleagues analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) for 20,278 U.S. and Canadian myeloma patients who underwent autologous stem cell transplantation within 12 months of their diagnosis between 1995 and 2010.

In an autologous stem cell transplant, a patient’s own stem cells are collected before high-dose chemotherapy or radiation therapy. The stem cells are then reinfused into the patients to replace the healthy stem cells destroyed by the high-dose therapy.

Patients in Dr. Costa's study were divided into three groups based on the time when they received their transplant: 1995 to 1999 (2,226 patients), 2000 to 2004 (6,408 patients), and 2005 to 2010 (11,644 patients).

Dr. Costa pointed out that the median age of patients receiving a stem cell transplant soon after their diagnosis has increased over time from 54 years in the first time period to 58 years in the last time period. The share of patients receiving a transplant who were at least 65 years old rose from 8 percent in the first time period to 24 percent in the third time period.

However, the share of newly diagnosed patients over the age of 65 who receive a stem cell transplant soon after diagnosis has remained very low over the years.  The share was close to zero in the initial time period of Dr. Costa's study, and about 7 percent in the last time period.

In contrast, the share of newly diagnosed patients under the age of 65 receiving a stem cell transplant has increased noticeably over the past 15 years.

A Myeloma Beacon analysis of the data in Dr. Costa's presentation show that, in the first time period, about 14 percent of newly diagnosed patients under the age of 65 received a stem cell transplant within one year of diagnosis.  By the final period, this share reached about 30 percent.

There also has been a sizable increase in the share of patients under the age of 65 receiving a stem cell transplant at any point in their therapy (that is, not just within a year of diagnosis).  The Beacon's analysis indicates that this share has increased from about 22 percent in the first period to 40 percent in the last period.

Dr. Costa also noted that the data he and his colleagues collected show – not surprisingly – that the use of novel agents as initial therapy before stem cell transplantation has increased over the three time periods:  thalidomide (from less than 1 percent to 22 percent to 52 percent); Velcade (from 0 percent to 2 percent to 35 percent); and Revlimid (from 0 percent to 1 percent to 21 percent).

According to Dr. Costa, the increased use of novel agents has led to “better disease response prior to the stem cell transplant.”

Another trend regarding stem cell transplantation was the increased use over time of single-agent melphalan (Alkeran) as the high-dose therapy prior to transplantation over the three time periods.

During the first period, 54 percent of patients had single-agent melphalan prior to transplantation.  In the second and third periods, this share increased to 93 percent and 99 percent, respectively.

Dr. Costa explained that melphalan has replaced both total body irradiation-based therapies and multi-drug regimens in recent years.

“To my surprise, there was also a decreased use of maintenance therapy” after transplantation, added Dr. Costa. The share of patients who received maintenance therapy decreased from 46 percent in the first group to 27 percent in the third group.

“However, there was a substantial change in agents [used for maintenance], from predominantly interferon in the first [group] to novel agents in the third [group],” he added.

As to overall survival among the patients in Dr. Costa's study, it increased over time. Five-year overall survival rates among patients receiving a transplant within a year of diagnosis increased from 47 percent in the first period, to 52 percent in the second, and to 55 percent in the third.

With regard to safety, Dr. Costa and his colleagues found that transplants were safe throughout the entire study period. Treatment-related mortality after 100 days, for example, was consistently low among patients in all three time periods, on the order of 1 to 2 percent.

For more information, please refer to abstract 596 at the ASH 2012 meeting website as well as Dr. Costa's presentation slides, which he and the CIBMTR have made available for download and viewing as a courtesy to the Beacon’s readers.

Photo by Nissim Benvenisty on Public Library of Science – some rights reserved.
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20 Comments »

  • Jan Stafl MD said:

    Thank you for another great summary! Although the technique specifics may not be responsible for the improved OS statistics after ASCT (I agree that pre-transplant use of novel agents are), I am sure that they have reduced the side effects and co-morbidities of these transplants. Is there any comparable data for allo transplants over time? Of course, differentiating mini, partial and full allo's is important for comparison.

  • nancy shamanna said:

    That was a study with a really large no. of participants, retrospectively. I found I was exactly in the norm for the last group studied, since my ASCT was in 2010. Interesting to see the results, and that the five year survival rates were gradually rising...10% difference between groups 1 and 3. Hope that they will continue to monitor this way and update the results too. It seems that the novel agents have improved survival rates, and also that the stem cell transplants can be done more safely now than when they were first introduced. Hope the trend of progress continues! There will probably be other studies for patients who don't do transplants, but do have the newer drugs, for comparison purposes too.

  • Maike Haehle (author) said:

    Thanks for your comments, Jan and Nancy.

    There was a similar study done a few years ago that looked at trends in allogeneic transplantation. The study was published in the journal Blood in 2011. Unfortunately, it only covers the period from 1989 to 2005.

    The full text of the article can be viewed online (at no cost) here:

    http://bloodjournal.hematologylibrary.org/content/early/2011/06/20/blood-2011-02-337329.full.pdf

  • Maike Haehle (author) said:

    Jan - We've also received permission from Dr. Shaji Kumar, the lead author of the Blood article I mentioned in my previous comment, to make available to our readers a slide deck summarizing the key findings that were later published in the article. Here's a link to the slide deck (PDF): http://bit.ly/VoW09p

    The slides are for a presentation Dr. Kumar did at the 2009 American Society of Hematology meeting.

  • NotEinstein said:

    More pretzel logic from an irrelevant study:

    “Stem cell transplants have also remained safe,”

    Uh huh-- no one disputes that deaths from an ASCT are rare. The problem is the long-term devastating effects from stem cell transplanst on the bone marrow - which certainly is not safe. As well as the fact that most ASCTs have no benefit whatsoever.

    "However, Dr. Costa noted that changes over time in the way stem cell transplants are done are unlikely to have been responsible for the observed increase in survival among myeloma patients undergoing the procedure."

    So therefore WHAT is the benefit of an ASCT? No indication here.

    "Instead, he argued that improvements in initial, pre-transplant (induction) therapy, combined with more effective post-relapse therapy, have probably contributed the most to improvements in survival among transplant recipients."

    OK - so why does this say about the need for stem cell transplantation? Once again -- nothing!

    "Based in part on the study findings, Dr. Costa recommended that stem cell transplantation and novel agents, such as thalidomide (Thalomid), Velcade (bortezomib), and Revlimid (lenalidomide), be combined in the treatment of myeloma patients."

    Even though the discussion preceding this paragraph provides no indication - and in fact, defies the logic -- of any benefit of an ASCT, he is still advocating this toxic procedure here.

    Why can't hematologists admit the simple truth? ASCTs developed decades ago - when the available drugs rarely led to a good response - to deepen the response. This need is simply no longer APPLICABLE today - and yet they continue to shove these hundred thousand dollar treatments down scared patient's throats.

    This seem to counter a physician's responsibility "to do no harm." Enough already!

  • Jan Stafl MD said:

    With all due respect, I strongly disagree with the conclusions "NotEinstein" made based on the article, and his bias. I underwent an ASCT one year ago, had no complications, and have no long term side effects. My research points to a doubling of both PFS and OS in patients who had ASCT after initial novel agent induction. My QOL is better than ever! So I just add my experience so that others faced with the difficult decision of whether to proceed with a transplant are not swayed by his biased opinion.

  • TerryH said:

    There is some truth to what NotEinstein says in terms of Dr. Costa's study not really giving any insight into how much early stem cell transplantation improves patient survival in the age of novel therapies.

    However, there is no contradicting the fact that high dose chemo followed by stem cell transplantation still deepens response even in the age of novel therapies. I am at a loss as to why people claim that it doesn't.

    Look at any study that reports CR, PR, or overall response rates across a patient population prior to, and after, stem cell transplantation, and you'll find that response rates are higher after stem cell transplantation.

    That doesn't mean that transplantation will improve survival versus delayed (or perhaps even no) transplantation.

    But if your goal is to deepen response, the transplant process will do it.

    No, Dr. Costa's study doesn't settle the "transplant early" vs. "transplant later" vs. "transplant hardly at all" debate. But it does provide some very useful data about how transplantation in the U.S. and Canada has changed over the past 15 years.

  • nancy shamanna said:

    I think that it would be nice if there were a data bank of all patients and their data. Then the numbers could be 'crunched' for any number of questions, such as the one that Einstein infers. The treatments are changing year by year, and so it would be nice to have recent data, aside from very basic survival data, to look at. Maybe this is already available to statisticians? Don't know!

    Like Jan, I have already had the ASCT, and have have induction chemo, maintenance...the WORKS! But have also been in a remission for quite awhile too. So I am very grateful for that time so far, although am not at the five year mark yet. But I take Einsteins points about not being able to differentiate how effective all the treatments have been. it is a combination of treatments, after all. Look forward to learning more, although my 'newbie' days are long gone now!

  • Terry L said:

    Hi NotEinstein, your comments were very intriguing and I was just curious as to your own history of treatments. When I progressed to active myeloma in April, 2012, I had to make a scary and heart-wrenching decision as to treatment. I was offered standard induction with a SCT at UPenn and at the NIH I was offered a slot in the CRD
    (carfilzomib/rev/dex) trial. The latter harvests stem cells, but one does not proceed to a SCT. It is 8 months of CRD, followed by 2 years of low dose rev. My NIH doctor is not a proponent of SCT. I chose the latter and am doing great (now on maintenance) but often wonder if I made the right choice, etc. Thanks for your help. Terry

  • Jan Stafl MD said:

    And thank you Maike for the helpful link and presentation! I do think that in the last 8 years since that study ended, progress has been made with allos for MM. Dr. Arnie Goodman (fellow columnist) has done his research, and seems to be recovering well from a "salvage" allo; I hope he will continue to do well, and be a long term success story!

  • Mark said:

    Hi Terry L,

    NotEinstein is in the same clinical trial you are at the NIH.

    Mark

  • Terry L said:

    Hi Mark, thanks for the update/info and it is good to hear from you! What a small world! NotEinstein, maybe you could drop me a private message. I am registered in the forum as terryl1. Thanks Terry L.

  • NotEinstein said:

    Nah.... I am not in any clinical trial....and I am not opposed to stem cell transplants for certain people at certain times. If we could only predict that subset of patients for who it truly benefits. But hey, I am not a doctor, so this only an opinion. But I personally will avoid stem cell transplants at all costs. The one exception could be an allo transplant -- only because it is curative for some. But even that seems remote. But in the end, I may have no choice....but right now I have plenty and being a human test tube is not one I embrace. Sorry.

    I was also not aware, by the way, of any conclusive findings (suggested by Jan) showing a doubling of OS in patients who had ASCT after novel agent induction. Is this compared to patients who had novel agent induction only? That would be the only valid comparison.

  • nancy shamanna said:

    I looked at the presentation slides in the study discussed and still only less than 30% of newly diagnosed patients took an ASCT. Also, the data was from SEER. I have read of SEER before...it IS a data base of patients in the US, isn't it?

    I think that a retrospective study, which describes treatments and outcomes, is very interesting. This study was on a very large scale, as far as MM goes. It is like a snapshot of medical history over a 25 year span (1995 - 2010). That time period stretches back to when novel agents were not yet on the scene. Since stem cell transplants improved outcomes in those days, they wouldn't just be arbitrarily dropped in favour of the newer drugs, until newer data supported that direction of treatment. Thus a patient like me, in 2009, was being offered quite an array of treatments, in hope of eliminating the myeloma cells.

    So i for one look forward to seeing new studies involving what choices are being made now for treatment.

    NotEinstein...because patients need to be close to a remission and in relatively good health before having a stem cell transplant, comparison studies of patients who did not have them compared to those who did might be skewed too, in the sense that patients who did not have the transplants were in many cases in poorer health than those who did get them. It's a matter of 'relativity', nest-ce pas? Would you like to share any of your 'journey' with us too?

  • Lys2012 said:

    Not Einsten Makes a valid point, Auto SCT is a great option for some people but not others. My new MM doc is big in research for genetics and customized medicine. I didn't have any of the bad cytogenics personally, but I don't like the term "low risk" as it implies a benign disease, and we all know MM is anything but!

    I am the text book best outcome for ASCT. I was very young, had no pre-existing conditions other then MM, had a very high M-protien that managed to get to a very good response with novel induction, but was still detectable. I had the best response to transplant (stringent complete response) and have been in remission for 2.5 years, no maintence, and feel great. mostly normal for someone my age (30 something) a few long term things I live with, but no regrets!

  • Luciano Costa said:

    In fact the study does not evaluate the merit of AHSCT on itself since all inicluded patients received transplant. Instead it analyzes the changes in its utilization and outcomes. The stepwise improvement in survival over time seen in the study was mostly due to better post relapse/progression survival, speaking for the better efficacy of novel agents, available in the last period but not in the first one. The impact of AHSCT in survival is backed by US and european populational studies showing a sharp increase in MM survival in mid 1990s and early 2000s, prior to widespread use of "novel" agents and coinciding precisely with the popularization of AHSCT. This is further endorsed by the fact the such improvement happended almost exclusively in patients <60 or <65, the age groups more likely to get AHSCT. Our study build on this knowledge by showing on a large scale that there is improvement in survival beyond what is accomplished by AHSCT, likely by the incorporation of novel agents in the threatment plan.

  • NotEinstein said:

    My only treatment so far is what they call BiRD: Biaxin plus Revlimid plus low-dose dex. I did not have any symptoms (other than worsening anemia - which honestly was not affecting me in an obvious way) before starting this regimen. I had normal light chains - only an M spike (about 5) and no high risk cytogenetics (I am hyperdiploid).

    After 4 months, the M spike fell by more than 90%, my blood counts returned to normal (Hb is greater than 13), and I collected stem cells. BTW: it took me almost 3 months to get all my blood counts back to normal after the low-dose cytoxan treatment that preceded collecting stem cells - which tells me a lot about the toxicity of this one agent.

    Since collecting stem cells, I have continued on BiRD and the M-spike is still declining slowly. So I will see how low it goes, and then I will probably go on low dose revlimid as maintenance. The median PFS with this treatment is 4 years -- not bad: twice that of rev and dex alone.

    But coupled with low dose rev, I also plan to use an integrative approach as a long-term maintenance strategy. So this will involve supplements and other natural agents and may eliminate the need for any drugs. My plan is to minimize chemical intervention to keep my options as broad as possible, and yes, last long enough to go for a long-term plan. I am also the same age as Terry L, so I do have that option.

    If you read the blog by Cancer Girl, what I like is that she has been fine for 7 years now - even with a steady M spike - following a plan that seems to use rev and dex (or rev alone) as needed. Until I have faith in a long-term plan, I believe less is much more. Maybe in 3 years, we will know that something like CRD plus an Ab will allow this disease to be chronically managed. The knockout punch cannot be far off.

  • nancy shamanna said:

    Thanks Dr. Costa for pointing out some features of the study. I can see that the middle 'era' did show an improvement in survival after the transplant, but not with the novel drugs. I realized that if I was in the reporting to CIBMTR, from the US and Canada, my data was probably included in this study! I was in a partial remission before the transplant, and later after the transplant and a few months of maintenance chemo, achieved a CR. I think it is a SCR, based on serum free light chain assays and other tests. So it is interesting to read the follow up to all the data gathering that goes on from cancer centres!

    Not Einstein, thanks very much for sharing your treatment history! I have heard of BIRD before actually. It is so interesting that a basic antibiotic like Biaxin can be used to enhance an expensive drug such as Revlimid, which is pretty much exclusive to treating myeloma. (Correct me anyone if I am wrong...are there other cancers treated with Revlimid?). i wonder if the BIRD regime is also used to treat relapse? Lots of us might be interested to know that! Myeloma patients are always looking over their shoulder for relapse! But I was very grateful to get into a CR a few years ago, due to the treatments I had then.

  • NotEinstein said:

    I think there are current studies on relapsed patients - with promising results - using BirRD - in particular those substituting revlimid with pomalidomide. I also read of an intriguing study called Car-BiRD, in which newly diagnosed patients first get carfilzomib and then proceed to BiRD to get the deepest possible response. So to the extent you have not been treated with Carfilzomib or pomalidomide, there may be some excellent options upon relapse.

  • Debby Smith said:

    I appreciate the insights and personal reports of all who commented here. This is my first visit, having just found the website yesterday. My husband, diagnosed in October, just this week declined to move forward with transplant, at least for now, and we are encouraged and relieved. He is a healthy 70 years old and is responding well to CyBorD combination regimen. I look forward to learning much more.