[Mark11]

Re: Allo transplantation - what are your thoughts?

by Mark11 on Wed Oct 29, 2014 3:13 pm

Hi Grant,

The risk is influenced by multiple factors. One is the patients overall health and disease status. One common way to assess patients risk is the EBMT risk score. The main factors considered are age (the younger the recipient the better), disease stage (first complete response is best), time interval between diagnosis and transplant (less than one year is best), and donor type/sex mismatch. If interested here is a recent paper about the EBMT risk score.

A Gratwohl, "The EBMT risk score," Bone Marrow Transplantation (2012) 47, 749-756 (full text).

Here are the non relapse mortality risk from the abstracts about allo transplant from ASH from 2013. I went to the abstracts here at the Beacon and typed in "allogeneic transplant" and this what came back. These do not seem "high" or "scary" to me. Unfortunately patients with myeloma/blood cancer are at risk to die no matter what therapy they use. The NRM for patients using novel agents/autos is not zero.

"Only 1 (2.5%) patient died from complications related to alloBMT." (abstract 3407)

"Non-relapse mortality was 0% at 1 year and 6% overall." (abstract 2129)

"Cumulative incidences of NRM and progression were 10% (95%CI: 3-22) and 47% (37-58; Fig. 1)." (abstract 3353)

'Manageable chronic GVHD occurred in 19/31 (61%) evaluable patients, there were no transplant-related deaths by day 100 and 2 patients died of infection (microbiologically-unconfirmed sepsis at day 240 and disseminated nocardia infection at day 1025), resulting in a TRM of 6%." (abstract 2128)

"The cumulative incidence of non-relapse mortality was 6% (95%CI: 0.0 – 22) at 100 days and 13% (95%CI: 1 – 34) at 1 year, respectively." (abstract 3390)

This is a trial of relapsed patients only. 9% is very low considering these are heavily pretreated / relapsed patients.

"TRM and acute GvHD (grade II-IV) at 12mos is 9% (95% CI: 2% – 23%) and 6% (95% CI: 1% – 17%)." (abstract 2115)

This study includes patients from 1996-2013, so it has a mix of older and newer data.
"The non-relapse mortality (NRM) rates were lower in the auto-allo group as compared to RIC: 1 yr and 3 yr NRM were 8.1% and 14.1% in the auto-allo and 20.3% and 27.4% in early RIC group, p<0.001." (abstract 920)

Note this study for the difference in outcomes between patients doing an allo for consolidation of (newly diagnosed) as opposed to relapsed patients.

"Results of allo transplant study at John Theurer Center," Beacon forum discussion started Oct 23, 2014.

There is non relapsed mortality for all myeloma patients, mainly due to infection risk. I would not do an allo unless I was in a complete response. My read of the data is that they do a good job of upgrading myeloma patients that are MRD positive to MRD negative and than main­tain­ing that response long term. They do not seem to be a good therapy to try and treat active disease or as "therapy of last resort".

Good luck with your decision.

Mark

[Grant]

Re: Allo transplantation - what are your thoughts?

by Grant on Thu Oct 30, 2014 2:13 am

Thanks Mark. That is really useful and I will spend the proper amount of time digesting it! But, at first glance, the risk does not seem as high as I imagined.

Ta

Grant

[Lev]

Re: Allo transplantation - what are your thoughts?

by Lev on Fri Oct 31, 2014 2:44 am

Hi everybody here,

I have followed this discussion with great interest. My private summing up came to this result:

• Autologous SCT = not too dangerous, can give good results with myeloma, but it will come back. Maybe after a month or two or, more realistically, after some years. For a few it may even work as a cure.
• Allo SCT = more problematic in itself, you will need medication to suppress the immune system to avoid rejection. But there is a real chance that the allo transplant may cure your myeloma.

I am just listening, reading and trying to find a way through this jungle, and yesterday I came across this article from Oncology Times, which refers to this article:

ML Donato et al., "The Graft-Versus-Myeloma Effect: Chronic Graft-Versus-Host Disease but Not Acute Graft-Versus-Host Disease Prolongs Survival in Patients with Multiple Myeloma Receiving Allogeneic Transplantation," Biology of Blood and Marrow Transplant, August 2014, Volume 20, Issue 8, Pages 1211-1216.

I have tried to read the articles, and my impression is that this will be an open discussion for the years to come.

There are some interesting findings:

• Negative reactions/attacks by the new white T cells may actually give better results when it comes to curing the myeloma.
• Whether the donors are siblings or foreign is not as important as I thought.

The number of patients involved was pretty low, and new trials are planned. But maybe allo transplantations could all together be less risky, compared to not doing them??

I am used to reading scientific articles and books, but before June this year I never really read about health care issues. And except from having lived with a physician for nearly 30 years, I have no health care-scientific background. So please read the articles yourselves if you want to avoid any misunderstanding I may have caused.

[Mark11]

Re: Allo transplantation - what are your thoughts?

by Mark11 on Sun Nov 02, 2014 4:16 pm

Hi Lev,

I think you summed it up very well. Just a couple of comments.

"The number of patients involved was pretty low, and new trials are planned"

The average myeloma patient is diagnosed at 70 years old and allo transplant is not a therapy that is appropriate for those patients. Many younger patients also are not interested in doing allo transplant as part of upfront therapy. Therefore the number of patients doing allo transplant as upfront therapy in studies will always be low. Note in this thread there are 2 patients in their 40's that did an allo as part of upfront therapy, one that is planning on doing one, and one that is considering it. We are far from the typical myeloma patient. I was not involved in a clinical trial when I did mine.

"But maybe allo transplantations could all together be less risky, compared to not doing them??"

For a younger patient (less than 50) I agree that it is more risky not to do one than it is to do one early in disease course. Overall survival is estimated to be around 10 years or so for a younger patient. IMO that is a terrible prognosis for a patient diagnosed in their 40's. Doing the allo was actually a very easy decision for me. As soon as I was responding well to my induction therapy I decided I was going to do an allo in first complete response.

"I have tried to read the articles, and my impression is that this will be an open discussion for the years to come."

Unfortunately allos work best in first complete response. While the doctors debate younger patients like me do not have another curative option, so it really does not matter to me if the majority of doctors think younger patients should do them or not as part of upfront therapy. I am very happy with my decision to do an allo as part of my upfront therapy.

Mark

[vicstir]

Re: Allo transplantation - what are your thoughts?

by vicstir on Mon Nov 03, 2014 3:48 am

Thanks to everyone for their thoughts and information. I must admit that if it were up to me to decide on my treatment then I would be inclined to do an allo. Even though I did not and unlikely will reach complete response in my disease. In Australia as patients we have little say in our treatment paths except to go ahead with what is offered or deny treatment. When it comes to cancer treatment of any sort it is through the public system unless you can afford megabucks to seek out alternatives. Which the average Joe Blow could not afford. Well call me Joe. Lol

None the less at least with my new found knowledge on the subject I can put it up for discussion with my doc and see where that takes us.

So thanks again
Vicki

[Lev]

Re: Allo transplantation - what are your thoughts?

by Lev on Mon Nov 03, 2014 11:50 am

A Danish perspective on the right to choose treatment.

The Danish system is 100% public and free. It is a tiny country with less than 10 major hospitals and a lot of smaller ones, some of them satellites of the few large centers.
5 million inhabitants. Most of them within 5 minutes to 2 hours from a major hospital with myeloma specialists. No room for large national parks here.
This is why I am very hesitant to tell other people what to do. But it may be comparable to living in Los Angeles or another metropolitan area with 4-10 million people within a limited area.

There are general treatment plans that are automatically offered to everybody. And if you want something else you will have to come up with good arguments. And if you need support for your point of view, you can ask for a second opinion from other sources.
One thing that I guess will be difficult is to get support/payment for a very alternative treatment that is not supported by recognized science.
If it is in use at other well known hospitals like the Mayo Clinic, then there is a chance, but you may have to put up a stand for it, something that most patients may not be ready for.

I am thinking a lot about this. I am presently at the hospital for three days having stem cells harvested. The plan is ASCT in December after cyclophosphamide-Velcade (bortezomib)-dexamethasone (CyBorD) initializing.

I am very strong, 100% well etc. Should I stop treatment and ask to be admitted into one of the trials or should I go for an allo?

The chief phycisian at Herlev Hospital heamatologic department is a myeloma specialist who has worked with myeloma for more than 20 years. She spoke at a myeloma conference in September, about 100 patients attended, and got a splendid lunch at a conference center supervised by Jamie Oliver.
She said that the treatment they are giving at the moment is what they still believe in, for "younger" patients as a first line (full treatment and ASCT with follow up by being included in trials). But she was pretty certain that in a not far future a less aggressive treatment based on new medication will maybe replace the transplant for most patients.
A large trial is already running with many countries and 1,500 patients involved.
The next conference is on this Friday and covering new treatments and trials. The leading Danish myeloma specialists will attend and speak together with international specialists. One of the speakers is Angela Dispenzieri from the Mayo Clinic.

Myeloma is a very small specialty in Denmark, and while there is a lot of research in myeloma here, much of it is done with an international perspective. And many of the trials are x-national.

So, having a public system may or may not be limiting you when it comes to auto, allo or no transplant. But many of us do probably tend to believe what our personal myeloma specialist believe in.

And that leaves the question open: Should I go for an allo, auto or medication-only?
I have chosen the paved road, ASCT. But knowing what I know, from reading all articles I can find and even more from the Myeloma Beacon, I will not give an advise to anyone else. The answer is blowing ...

This is definitely why I need a site like The Myeloma Beacon!

And if I knew what I will know in a year or two, then ... who knows?

Reading about the more private system in the US and the "free" system here, it is my impression that it is up to us as patients to be awake and aware. Maybe the difference is not so big at all.

[Ginger99]

Re: Allo transplantation - what are your thoughts?

by Ginger99 on Fri Jan 02, 2015 12:13 am

Mark11,

My husband, age 27 at diagnosis, now 28, had an auto stem cell transplant (SCT) in February 2014. He did not achieve complete remission. In fact, at day 100, his numbers were increasing. His doctor feels an allo is the best plan, so chemo has been going to attempt CR. When asked about the T-cell depletion option, doctor said when there is less chance of GVHD, there is less chance of myeloma vs. host.

Did your doctor talk at all about this?

Thanks in advance for your response or anyone else who cares to respond.

[CindyBrown]

Re: Allo transplantation - what are your thoughts?

by CindyBrown on Fri Jan 02, 2015 11:30 am

I am going to have an allo and the doctor said it is important to have some myeloma vs host to reduce/remove the myeloma burden.

At age 49, my myeloma has been resistant to many treatments and is down now as I head into my auto transplant but is certainly not a complete response.

My team wants to follow quickly with the allo because I have had such a hard time with chemo being effective and have used almost every drug available already. One of my brothers is a 99% match so he will be my donor.

[Mark11]

Re: Allo transplantation - what are your thoughts?

by Mark11 on Fri Jan 02, 2015 12:03 pm

Hi Ginger99,

I am sorry to hear about your husband current situation. It has to be very disappointing to relapse so quickly off an auto.

I will try and answer this question as best I can. I actually do not view GVHD as a "bad thing". It is the side effect of the curative graft vs myeloma effect. I consider limited chronic GVHD as a great thing, as patients who have it can have long remissions/be cured of myeloma. Here is a video of well known allo transplant expert Dr. Sergio Giralt (Robin Roberts transplant doctor) discussing GVHD:

http://www.mskcc.org/multimedia/graft-versus-host-disease

Note his comments about the doctor trying to give the patient the amount of GVHD / graft vs. leukemia that he/she needs to stay in remission. He mentions multiple times that not being in remission likely means the patient will need more GVHD / GVL effect. Your husband may not be in remission at the time he potentially does the transplant, so t-cell depletion may not be the proper method of doing the allo in his case. That is up to the expert that you choose to do your transplant.

Another factor that influenced my doctor to do a partially t-cell depleted allo was that I had a graft from an unrelated female donor. The pair of female donor to male recipient is known to have a high chance of extensive chronic GVHD, but also the lowest chance of relapse in myeloma and other blood cancers as well. Here is an older study that shows this.

This study clearly demonstrates that transplantation of a male patient with a graft from a female donor involves a graft vs myeloma effect. This donor gender-specific effect has not been seen in previous studies of myeloma transplants, probably because of lack of detectable advantageous effect on OS, masked by increased transplant-related mortality, and inadequate follow-up. Before 1994, there was even a highly significantly poorer OS in F → M than in M → M due to this higher NRM hiding the impact of a reduced REL. However with the decrease in this mortality after 1993, unmasking the reduced REL, the OS was improved and became similar in M → M and F → M.

The lower REL in F → M corroborates with more cGVHD in these patients compared to M → M. An association between graft vs myeloma and GVHD has previously been reported.13, 30, 31, 32

http://www.nature.com/bmt/journal/v35/n6/full/1704861a.html

If I had a male donor, I probably would not have used ATG (antilymphocyte globulin). ATG is a polyclonal antibody that is used to induce in vivo T-cell depletion to facilitate engraftment and lower graft-versus-host disease. In this particular study, relapse rate was not increased for patients who used ATG and patients who used ATG had a higher CR rate.

To minimize the impact of a graft-versus-myeloma effect on response, we evaluated response to treatment on day 100 post-allografting. In all, 93% of the patients in the ATG group and 78% in the no-ATG group showed an objective response (complete or partial remission) after allografting (p=0.03). The rate of complete remission was also significantly higher in the ATG group than in the no-ATG group (59% vs. 39%; p=0.04), (Table 2A). It is worth noting that administration of ATG led to an increase in the complete remission rate after allografting from 39% in the no-ATG group to 57% in those who received ATG ≤30 mg/kg body weight and 63% in those who received ATG >30 mg/kg body weight (p=0.03). Likewise the rate of objective responses (partial and complete remissions) increased from 78% to 91% and 96%, respectively (p=0.02). Among the subgroup of patients who received a graft from a sibling, there were trends to better response in terms of overall responses (86% vs. 78%) and complete remission rates (55% vs. 39%) for patients who received ATG compared to those who did not (Table 2B); however, given the low number of patients, these differences did not attain statistical significance.

When the best response after allogeneic stem cell transplantation was analyzed, the rate of objective responses (complete and partial remissions) remained 93% in the ATG group and 78% in the no-ATG group, while the rate of complete remission increased from 39 to 43% in the no-ATG group and from 59 to 60% in the ATG group. Since response can only be measured in patients not in complete remission at the time of allografting, we performed a separate analysis for these patients. In the uni-variate analysis only partial remission prior to allografting, unrelated donor and ATG were prognostic factors for achieving complete remission. In the multivariate analysis ATG was the only significant prognostic factor for achieving complete remission (RR: 2.57; 95% CI: 1.17–5.64; p=0.02).

http://www.haematologica.org/content/93/9/1343

Sorry for the long response, but the question you are asking is not a simple one. If a patient thinks an allo is in their future, I always say the patient should get a second opinion on how to do their allo since there are so different ways to do an allo.

Also, do not forget that I did my allo in first complete response, so my allo was designed for consolidation and maintenance. I had no active disease at the time of my allo, but I was MRD (minimal residual disease) positive. That is a much different situation than a patient who relapsed in less than one year after an auto.

Best of luck moving forward. Positive energy being sent your way for a much better 2015.

Mark

[Ginger99]

Re: Allo transplantation - what are your thoughts?

by Ginger99 on Fri Jan 02, 2015 3:03 pm

Thanks for your replies. My husband was never in remission so therefore didn't relapse. When he went in for his auto, he also was not in remission. The lowest his M-spike has ever been is 0.4 (which is what it is now).

Although I'd love for him to have a second opinion, I worry that if he gets a second opinion and the other doctor feels they should do the allo in a different way, that Josh will have the added stress of choosing who to trust. If he chooses one or the other and it doesn't work out in his favor, I will feel guilt that I pushed him to get a second opinion. Does that make sense?

We're really just so worried. Josh's doctor works at Siteman in St. Louis on Dr. Vij's team (you may have heard of him), and we really like him. He's kind, up front, and easy to talk to, but I sure would like to speak to someone at UAMS.

Thanks again for your replies.