Donor Stem Cell Transplant As Consolidation Therapy May Be Effective And Safe In Myeloma
The results of a small, retrospective study indicate that donor stem cell transplantation may be effective and well tolerated in multiple myeloma patients who have a deep response to initial therapy.
Specifically, the researchers found that for the majority of patients, stem cell transplantation deepened their initial response to a complete or stringent complete response.
Two years following transplantation, three-quarters of the patients were disease-free, which according to the researchers shows that donor transplantation may be a good tool for the prevention of early relapse and progression of the disease.
However, the study investigators point out that a larger number of patients will be needed to evaluate the efficacy of donor transplantation as consolidation therapy (following initial therapy). A Phase 2 study is currently underway to follow up on these findings.
Background
Autologous stem cell transplantation is frequently used as early treatment in myeloma patients up to 65 years of age. In this process, the patient’s own stem cells are collected before receiving high-dose chemotherapy, which destroys the cancerous cells as well as the patient’s healthy bone marrow cells. The stem cells are then returned to the patient following chemotherapy, and the stem cells eventually mature to replace the destroyed cells.
The role of donor (allogeneic) stem cell transplantation in multiple myeloma, however, is still controversial. In this procedure, the patient receives stem cells from a matched donor instead of from his or her own body.
Although donor transplantation gives myeloma patients a better chance for a cure than autologous transplantation, it also carries a greater risk of life-threatening diseases such as graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack the recipient’s cells.
Because of these risks, donor stem cell transplants are mostly done in the context of clinical trials.
Consolidation therapy is a short course of treatment meant to deepen a patient's response to prior treatments. It is different from maintenance therapy, which typically involves a longer regimen meant to prevent disease progression while maintaining a favorable quality of life.
According to the investigators of the current study, the use of donor stem cell transplantation as consolidation therapy has not been well studied.
They therefore sought to investigate the efficacy of donor transplantation as consolidation therapy in patients who had reached a very good partial response or a complete response after initial therapy.
Study Design
Researchers from the Lee Moffitt Cancer Center in Tampa, Florida, retrospectively analyzed data from 22 multiple myeloma patients who, between 2007 and 2012, had achieved a very good partial response or a complete response after initial therapy with Velcade (bortezomib) or Revlimid (lenalidomide) and went on to receive a donor transplant as consolidation therapy. The median patient age was 49 years.
Patients had received either Velcade plus fludarabine (Fludara) and melphalan (Alkeran) or fludarabine and melphalan alone as a reduced-intensity conditioning regimen prior to donor transplantation.
Patients in the Velcade-conditioning group received 30 mg/m2 of fludarabine for four straight days up until the third day before transplantation, 70 mg/m2 of melphalan for two days up until the third day before transplantation, and 1.3 mg/m2 of Velcade immediately after the last dose of melphalan.
Patients who did not receive Velcade as part of their conditioning regimen received 40 mg/m2 of fludarabine for four days up until the third day before transplantation and 70 mg/m2 of melphalan for two days until the third day before transplantation.
The researchers also retrospectively identified 41 myeloma patients with similar characteristics who received an autologous transplant to serve as a comparison group. These patients had a median age of 54 years and had reached their first very good partial response or complete response just prior to transplantation.
Study Results
Prior to receiving a donor transplant, 27 percent of patients achieved a stringent complete response. This measure increased to 68 percent after donor transplantation.
Of the patients who had reached a very good partial response prior to donor transplantation, 33 percent improved their response to a complete response and 42 percent improved to a stringent complete response following donor transplantation.
Among the patients who underwent autologous transplantation, 21 percent of patients reached a complete response and 57 percent reached a stringent complete response after transplantation.
Two years post-transplant, 8 percent of patients in the donor transplant group relapsed, compared to 46 percent in the autologous transplant group.
The estimated two-year progression-free survival rate for patients who underwent donor transplantation was 75 percent, compared to 52 percent for patients who underwent autologous transplantation.
The estimated two-year overall survival rate for the donor transplant group was 78 percent, versus 90 percent for the autologous transplant group.
Graft-versus-host disease (GVHD) was a common side effect among patients undergoing donor transplantation.
Overall, 45 percent of patients experienced moderate to severe acute GVHD, which occurs within 100 days of transplantation. Furthermore, 46 percent of patients experienced chronic GVHD, which occurs 100 or more days after transplantation.
After donor transplantation, 18 percent of patients died of GVHD-related complications and 5 percent died from disease progression.
For more information, please see the study in the journal Bone Marrow Transplantation (abstract).
Related Articles:
- Number And Type Of Stem Cell Transplants Carried Out Each Year For Multiple Myeloma Vary Markedly Across U.S. Cancer Centers
- Stem Cell Transplantation May Be Underutilized In Multiple Myeloma Patients In Their 80s
- ECT-001 Granted Regenerative Medicine Advanced Therapy (RMAT) Designation By U.S. FDA
- 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
It strikes me that if one is one is going to study the efficacy of allo versus auto transplants (which is a great study to do), that one would also naturally want to compare what these results would be if you only continued on with just novel agents and did no transplant whatsoever. I know there are ongoing studies of auto versus novel agents only (which is also a great and much needed study), but it just seems like there would be more consensus and agreement on the end result if one group was looking at the overall big picture (auto versus allo versus novel-only). I worry that we are going to end up with another mess similar to the lack of consensus regarding just what the risk of progression classification is for MM.
I wanted to throw a quick shout out to Dr. Shain and his colleagues for initiating this study. I truly appreciate Doctors that attempt to cure their patients. Lets hope some patients in this study get cured of myeloma!
Hi Multibilly,
It would be almost impossible to do a randomized trial like the one you suggest to give a definitive answer to that question. For example, I would never go into a trial where I could possibly not get an allo in first CR. Most patients are just the opposite - they would not go into trial if allo was a possibility. Also, the novel agents and both allos and autos are meant to compliment each other and hopefully work more effective in combination. They are not competing against one another to see which is "better". IMO that is one of the reasons we are not moving closer to a cure outside of allo transplant in myeloma. I constantly hear Doctors saying things like lets see if Kyprolis/Rev/DEX can get the same mediocre outcome as an auto used to. Who cares? How about we try and improve things for all patients and make cure possible without allo transplant?
Mark
All good points and a good perspective Mark. I agree that it would be impractical to do a new 3-way trial given the points your raise. However, this kind of analysis could be done via a retrospective study, just as this study was. I also don't believe that most of the current novel agents approved for use in MM treatment were developed specifically to be complementary drugs to allos and autos, although they are often used that way. I could be wrong, but I never came across this specific design goal when reading up on novel agents.
In any case, don't get me wrong, I'm not trying to take away from what Dr. Shain is doing here. It's most commendable. I'm obviously just one of those with a novel-only bias that continues to look for data to support that choice.
Multibilly and Mark, the web site for the CIBMTR has a summary of the results of stem cell transplants allo and auto for myeloma on the slide 44 of the downloaded presentation at: http://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/Pages/index.aspx#DownloadSummarySlides
For the 500 transplant center in the study they show that at least in the first 6 years the auto has a better life expectancy than the allo. I don't know what this would show for say 10 years. Moffitt seems to be one of the very best at the allo and they say they have a first year GVHD death of 18% vs 35 to 50% for the 500 transplant centers of the CIBMTR. So Moffitt is doing something very right. Gary
Thanks Gary P. Great slides. I personally find slide 44 to be quite sobering, to say the least. I personally wouldn't be signing up for any of these transplant options based on this graph. Let's just take the 3 year stats as a middle-of-the-graph reference point. Morbidity rates are as follows: Auto: 27%; Sibling: 48%; Donor: 70%. Unless I was very high risk and I had exhausted the new novel treatment options out there, I just can't see why I would want to sign up for any of these options.
Hi Gary P.,
First of all, Happy Mothers Day to your wife and all the Mothers that may be reading this. Great weather here in the Northast to get out today.
I have to first quote one of the most informed bloggers/myeloma patients out there:
"Multiple Myeloma - Save Yourself!!!!" - "As I have stated time and time again a multiple myeloma specialist can double and triple your life expectancy and survival rate."
Most myeloma Docs are not allo specialists. If you are going to do an allo, you need to see an allo specialist, not just the "run of the mill" myeloma Doc. Being a myeloma specialist does not make you an allo expert.
This is something you can relate to as someone that did "total therapy". Do you think a lot of patients that have never done it overestimate the risks? It sure seems like it to me. Likewise my experience actually doing an allo is that it is nothing like what the people that have never done one seem to think it is.
The big advantage to the allo is after 5 years. Short term studies (5 years or less) will not likely show any advantage to allo transplant. Both myself and another poster here are up to our 2 year mark in remission from allo transplant. Here is a stat from a study about allo transplants in general. All blood cancer patients are included.
"Most deaths after HCT occur within the first 2 years as a result of relapse, acute or chronic graft-versus-host disease (GVHD), infection, or other acute or subacute toxicities of HCT. Death beyond 2 years is infrequent."
"These data indicate that long-term prospects for survival are excellent, with 80% to 92% of 2-year survivors surviving at 10 years after HCT.'
http://jco.ascopubs.org/content/29/16/2230.long
That is a stat no other myeloma therapy can match. Some risks early, but they go away as time goes on. As we know, myeloma therapy is a marathon and not a sprint. IMO it is wise to do therapies early that show great benefit years down the road.
Mark
Hi Multibilly,
Actually those statistics are not "sobering" at all. Check out Gary P's blog. The latest update to the SEER database shows only 50% of all myeloma patients diagnosed in 2006 surviving at 4 years. Newsflash - patients with cancer die. The new drugs lift all boats. We know Revlimid works better for patients that did allos than those that do not. The antibodies will likely do the same. I am actually very upbeat about my future. I never let negative people pull me down!
Mark
"After donor transplantation, 18 percent of patients died of GVHD-related complications and 5 percent died from disease progression."
It is this stat - almost one out of 5 that dying from GVHD complications that is sobering. Yes 77% did not die and perhaps as many as 50% will go cancer free - possibly cured.
So you have to decide to roll the dice. Are you willing to risk a one in 5 chance of death for a possiblity of a cure?
If they can get the death from the GVHD complications down to something that is not statistically significant, then Allo transplants will become the gold standard in so far as treatment. Until then, it will remain confined to a secondary role.
I agree with Ron and would also like to add the following to the 'sobering' list.
"Overall, 45 percent of patients experienced moderate to severe acute GVHD, which occurs within 100 days of transplantation.
Furthermore, 46 percent of patients experienced chronic GVHD, which occurs 100 or more days after transplantation."
It was an excellent article by Virginia Li but I think the headline, which includes the words "And Safe In Myeloma", is not accurate.
--Steve
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