[hopeful27]

Why not do either an allo transplant or continuous therapy?

by hopeful27 on Wed Jun 11, 2014 2:13 pm

For the past few weeks I keep reading all over about stem cell transplants-auto, tandem, etc.

However, I think I have come to the conclusion that an allo, or remaining on meds and hoping that the numbers stay constant, is the best way to go in our situation. I don't I ever want my mom to get an auto done unless it's a salvage resort. Her doctor is in agreement ... said he treated one patient for 19 years who lived a good life on and off meds his whole life.

Does anyone else agree with this thinking? An auto just sounds like a waste of time and energy up front. Anyone else in agreement or speak from experience?

[Mark]

Re: Why not do either an allo transplant or continuous thera

by Mark on Wed Jun 11, 2014 5:35 pm

Hi Hopeful27,

It is great that you are doing so much reading/research for your mother. She is lucky to have a daughter like you.

I agree basically with what your thought process. I was not planning on doing an auto prior to my allo. You have also figured out that an allo is meant to be consolidation and maintenance therapy as opposed to "therapy of last resort", as many patients seem to think of it.

Autos are just a high dose of melphalan (an alkylator). Alkylators can be given in standard doses as well (ex. Cytoxan, melphalan, bendamustine). They are an important drug class for myeloma patients, but they do not have to be given in a high dose to be effective.

As I have mentioned in other posts, it really depends on what the patients goal of therapy is and what they are comfortable with. Since cure was my objective and I was uncomfortable taking long cycles of proteasome inhibitors and IMIDs due to the long term side effects of taking them are not known an allo was a great therapy choice for me. Most patients seem comfortable taking long cycles of those drugs so that is the best choice of therapy for them. No myeloma therapy is without side effects and how a patient deals with them is critical. Note Paul Jakubowskis column on March 30 and the importance of doing what the patient is comfortable with, because it is the patient that deals with the effects/outcomes of the therapies they do or do not do.

I had a couple of different doctors and BMT nurses mention to me that they thought I was the only patient that seemed to recover quicker after my full allo as compared to my auto. I think that was a classic case of "attitude being everything". I was in a positive frame of mind coming in for my allo as I viewed it as my chance of getting my "old life" back. I was not in as positive frame of mind prior to my auto as my doctor thought I could get to CR with a few more cycles of a Velcade-based combo and that I did not need to do an auto to get me to CR prior to my allo.

Best of luck with your decisions going forward. Sounds like you are fortunate to have a doctor that listens to the patient and has them involved in the therapy decision process.

Mark

[dnalex]

Re: Why not do either an allo transplant or continuous thera

by dnalex on Wed Jun 11, 2014 6:23 pm

The only thing is that the side effects of the meds may at some point become intolerable, even though they appear to be effective still. This happened to my mom with Revlimid and Velcade. She tolerated both just fine did not have any issues until about 18 months into her maintenance routine, at which point she made the decision to end the maintenance treatment.

[Christa's Mom]

Re: Why not do either an allo transplant or continuous thera

by Christa's Mom on Thu Jun 12, 2014 8:13 pm

Allo's seem like they should work, which is why they intrigue so many doctors and patients. My understanding is that 10% of the people, like Mark, will do very well on them, 10% will die, and the rest can suffer a lot from graft-versus-host disease. The outcomes are poor enough that allos are often not covered by insurance plans. Sadly, as with most myeloma treatments, you don't know where you will end up on this spectrum until you are through treatment.

I think there very much is a place of an auto transplant, and they are not a waste of time, especially if you don't have one of the high-risk variants of multiple myeloma. But it does depend on what you want from your treatment. Quality of life should not be taken for granted.

EJ was 54 when he underwent his stem cell transplant (auto) three years ago this month. He's had an M-spike of 0.1 since then, although it has crept up to 0.3 over the past year, but has been holding steady for the past six months. During the past three years, we've gotten married, spent a two week honeymoon in Europe, two weeks at the beach, and he's traveled to New Orleans for Voodoo Fest.

EJ also is an avid volleyball player and plays competitively at least once a week. He's held a full time job, is guardian for his disabled sister, and is working on the plans for renovating our house. He's had an excellent quality of life and I've loved seeing him happy and "healthy."

The articles I've seen on continuous therapy have been intriguing, but I have a lot of questions about it. None of the drugs for myeloma are without risks -- and I don't think EJ would have been able to have such a normal life for the past three years if he had been on treatment. I know that he will have to start treatment again at some point in the future, but with all of the new drugs available, I am hopeful that he will be with me for a long time.

Lyn

[ivanm]

Re: Why not do either an allo transplant or continuous thera

by ivanm on Fri Jun 13, 2014 10:29 am

I second what Mark has said and I believe that you have the gist of it in the short time you have been familiarizing yourself with the disease. It took me a long time to reach the same realization, and I reached it post factum, i.e. after I did an auto transplantation which I believe was a royal waste of time, not to mention I almost kicked the bucket in the process and that it was one of the most dire and challenging times in my otherwise challenging life. Others may have different experiences.

For a younger person, and to me a younger person when it comes to myeloma is someone 55 or less, the logical choice seems to be allo v continuous therapy. Choosing an allo is matter of risk tolerance and logistical considerations. To me, the risk was too high. I couldn't bear the fact that I could perish too early (at that time my son was 3 yrs old). I knew that with auto and maintenance I would probably have at least 5 years sticking around to where he'll have a lasting memory of me. If I was single, however, or my kids were grown up, I'd probably have chosen otherwise.

If you make the choice for allo, the question is whether your insurance will cover it. This is where logistics come in. You also may have to relocate because allos are not a standard fare. I am fortunate to be in NYC, but others may not be similarly situated.

Before you go further down this path, you need to make sure that the allo is covered by your mom's insurance. Also, you need to find out whether she can find a match. This is by no means guaranteed. For example, I have salvage allo process in place for when my continuous therapy hits a block. For months of searching, I believe I've had only 1-2 8/10 HLA matches. So, it takes time ...

Best of luck to you and your mom.

[Mark]

Re: Why not do either an allo transplant or continuous thera

by Mark on Fri Jun 13, 2014 11:27 am

Hi Lyn,

Glad to hear that EJ is doing so well.

I really have to write to discuss this comment:

"My understanding is that 10% of the people, like Mark, will do very well on them, 10% will die, and the rest can suffer a lot from graft-versus-host disease. The outcomes are poor enough that allos are often not covered by insurance plans. Sadly, as with most myeloma treatments, you don't know where you will end up on this spectrum until you are through treatment."

Where did you get those statistics from? I am going to concentrate on this thought that "the rest" suffer with GVHD. Over the long term, extensive chronic GVHD is what can cause a lower quality of life. Two of the Beacon Medical Advisors, Dr. Shain and Dr. Landau published studies that show the following extensive chronic GVHD rates.

The study Dr. Landau was co-author of:

34 pts with a median follow up of 31.6mos (range: 7.6 – 65.1 mos) of survivors are reported, median age 56 years (range 32 – 69). All pts engrafted promptly (median d+10, range d+9 to +12).TRM and acute GvHD (grade II-IV) at 12mos is 9% (95% CI: 2% – 23%) and 6% (95% CI: 1% – 17%). CHRONIC GvHD WAS NOT OBSERVED IN ANY PT.
https://myelomabeacon.org/resources/mtgs/ash2013/abs/2115/

The study Dr. Shain co-authored.

"The cumulative incidence of grades 2-4 acute GVHD at day 100 was 41% (95% CI: 20 – 65) and the cumulative incidence of moderate to severe chronic GVHD at 1 year was 8.0% (95% CI: 0.0 – 29)."
https://myelomabeacon.org/resources/mtgs/ash2013/abs/3390/

Acute GVHD typically occurs between days 30-90 and chronic GVHD starts at around day 90. In these two studies "all the rest" is 0% and 8%. It depends on how and when the transplant is done. I used a polyclonal antibody called antithymocyte globulin (ATG). Rates of extensive GVHD are typically low when ATG is used. It was used in the study Dr. Landau is co-author of. The study used Velcade (bortezomib) and that also seems to work very well in preventing extensive GVHD. I had Grade 1 acute GVHD for about a month. I had a skin rash and sore gums.

I would be interested if Dr. Landau or Dr. Shain could comment on the long term QOL of patients that do either T cell depleted allos or allos done with Velcade used to prevent extensive chronic GVHD. My QOL is outstanding (I am 3 years out) and there are studies that show I am certainly not in the minority. Obviously there is a time commitment and can be some difficulty in the short term but there are long term benefits. Note this study on blood cancer patients shows that 5 year plus t cell depleted allo survivors are having QOL on par with the general population. HRQL is health-related quality-of-life.

"Most survivors beyond 5 years had an excellent performance status with no difference in physical and mental health and higher HRQL scores (P = .02) compared with population norms. Although physical and psychologic symptom distress was low, those with higher symptom distress experienced inferior HRQL. These results show that 5 or more years after T cell-depleted HSCT for hematologic malignancy most individuals survive disease free with an excellent performance status, preserved physical and psychological health, and excellent HRQL."

http://www.ncbi.nlm.nih.gov/pubmed/20302959

There are reasons to not do an allo transplant in first complete response/early in disease course, but IMO in 2014 a high probability of extensive chronic GVHD/poor long term QOL is not one of them if using methods used in the studies above.

Also, my insurance company does pay for upfront tandem auto-allo and I do know others whose insurance companies paid for their allos.

Mark

[ivanm]

Re: Why not do either an allo transplant or continuous thera

by ivanm on Fri Jun 13, 2014 12:58 pm

Mark,

If you do not mind me asking, to put some of these things in context, what was the statistic NRM [non-relapse mortality] for the type of allo you did? I am sure before you did it, you carefully considered that. In medicine, as is in life, things often boil down to risk/benefit. I will take the liberty to post several NRM tables from Dr. Koehne's most recent paper which summarizes historical studies on allo.

The other point I am curious about, and which the original poster should be curious about, is whether the type of allo you did is still common practice and offered by medical centers. If I recall correctly, you did a standard, i.e. non-RIC transplant without a DLI and without T cell depletion. Correct me if I am wrong. Does anybody do those anymore? There is no substitute for reading Dr. Koehne's entire article, but here are the tables.

Table 1 Results of allogeneic HCT for multiple myeloma using myeloablative
Conditioning

Reference N NRM 3-year OS
[4] 334 (1983–1993) 46 % 35 %
356 (1994–1998) 30 % 55 %
[5] 18 16 % 77 %
[6] 80 44 % 24 %
[7] 66 24 % 39 %

And for RIC,

Table 2 Results of phase II trials with RIC allografts in multiple myeloma

Regimen NRM
Mel FM/TBI 30%
FM 40%
Mel 100 FM/TBI 38%
FM 21%
FbuATG 17%
FM/ATG 23%
TBI 15%

NRM of course is constantly improving via various approaches, but my understanding is that this is at the cost of the probability of cure. Hence the various continuing outstanding allo trials. Thanks.

Moderator's Note: NRM, or non-relapse mortality, is the share of patients who die after receiving a treatment for reasons other than a relapse of the disease being treated. It is often used as a measure of how risky a treatment (such as allo transplantation) is, since, in many cases, non-relapse deaths are due to treatment-related complications.

[Mark]

Re: Why not do either an allo transplant or continuous thera

by Mark on Fri Jun 13, 2014 3:33 pm

Hi IvanM,

Let me first say that I was diagnosed in 2010 so allo stats from 1994-1998 and 1983-1993 were meaningless in my decision. The doctors have done an outstanding job of improving the procedure through the years. When you talk to a newly diagnosed myeloma patient do you discuss the survival statistics from the 90's or do you discuss them with updated figures including novel agents?

Statistics from the 80's and 90's are meaningless IMO because patients did not have drugs to get them into remission prior to the transplant. Allo transplants are risky for patients that are not in first CR or at minimum first VGPR. Does this paper mention how many of those patients were in first CR at the time of transplant?

It does not sound like you know what ATG is judging by you asking me if I used t cell depletion.

"Polyclonal antithymocyte (antilymphocyte) globulin (ATG) preparations are extensively used in organ transplantation and in allogeneic stem cell transplantion mainly due to their T-cell-depleting potential. As part of reduced intensity conditioning regimens, ATG preparations have been shown to improve engraftment and reduce the incidence of severe graft-versus-host disease (GvHD).13,14 ATG preparations are produced by immunizing rabbits or horses with human thymocytes or the Jurkat T-lymphoblastic cell line and contain antibodies targeting a broad spectrum of epitopes expressed on various hematopoietic cells. Irrespective of their mode of preparation, various ATG preparations have been shown to possess potent anti-B-cell activity.15 We and others have recently shown in vitro anti-myeloma cytotoxicity of two commercially available ATG preparations, namely ATG-Fresenius® and Thymoglobulin®.16,17 These findings are further supported by the results of a xenograft model.18 The anti-myeloma effect of ATG is due to complement-mediated cytotoxicity as well as caspase-dependent apoptosis.16,17 ATG therefore not only targets a variety of epitopes, but may also induce several pathways for cell death."

From the same paper the GVHD rates.

"The incidences of overall and extensive chronic GvHD were significantly lower in the ATG group than in the no-ATG group (23% vs. 65% and 3% vs. 37% respectively; p<0.001). In a separate analysis of patients who received a graft from a sibling, there was a trend to less grade II-IV acute GvHD in the ATG group compared to in the no-ATG group (21% vs. 43%; p=0.08). The incidence of chronic GvHD was significantly lower in the ATG group than in the no-ATG group (p<0.001) (Table 2B and Figure 1)."

That is right, a 3% chance of extensive chronic GVHD while I view limited chronic GVHD as a great thing because patients that have limited chronic GVHD have less chance of relapsing.

Authors conclusion from abstract:

"Inclusion of antithymocyte globulin in allogeneic stem cell transplantation protocols for patients with multiple myeloma may increase remission rates and at the same time prevent graft-versus-host disease with no increase of relapses."
http://www.haematologica.org/content/93/9/1343.full

A simple way of assessing an individual patients risk is the European Bone Marrow Risk score. The main factors considered are: Patient age, time interval between diagnosis and transplant, donor type/gender mismatch, and disease stage.
http://www.nature.com/bmt/journal/v47/n6/full/bmt2011110a.html

According to this assessment my only significant negative was gender mismatched unrelated donor but the ATG took care of the GVHD as I only had Grade 1 acute GVHD and limited chronic GVHD for one month.

I used the same amount of melphalan that is used for an auto and 210 mg/m2 of fludarabine plus ATG. That is common conditioning though the amounts are usually lower. Remember I was in my early 40's and high risk at diagnosis. It is common for otherwise healthy blood cancer patients in their early 40's to use myeloablative conditioning for allo transplant. Most myeloma patients would not be candidates for full allos so obviously they are rarely used for myeloma. The typical 70 year old standard risk myeloma patient does not need to do an allo transplant so no, it is not nor ever will be "common" practice.

With respect to NRM, in my opinion that is just as much the patients responsibility to lower NRM as it is the doctors/nurses. NRM is typically from infection and it is up to the patient to avoid that after leaving the hospital. I have an awesome group of caregivers and I followed all directions from the doctors/nurses. Unfortunately every patient does not have as great of a support system that I have and do not follow doctors instructions. FWIW my doctor thought my chance of NRM was about 5-6%. I am not sure why that is relevant to anyone else since all cases are different.

I did not need a DLI as I achieved and maintained a molecular response after my transplant. Why use unnecessary therapy? Note these patients used ATG.

"Those patients, who achieved molecular remission, have a high probability of long-term disease-freedom and of cure."

"The study underlines the importance of the depth of remission and shows that achieving molecular remission as determined by myeloma-specific IgH gene rearrangements and plasma cell chimerism is associated with long-term freedom from disease and potential cure of multiple myeloma in an auto-/allo SCT approach."
https://ash.confex.com/ash/2011/webprogram/Paper42900.html

For patients that do not achieve a molecular response a DLI is definitely a great next therapy option.

Mark

[LauraScot]

Re: Why not do either an allo transplant or continuous thera

by LauraScot on Sat Jun 14, 2014 9:06 am

Hi Hopeful27,

In response to your question, "are autos a waste of time and energy upfront," I don't think so.

My goal has been drug free remission, as I think that gives a better QOL over maintenance drugs. I had a tandem auto-RICallo (I'm at +D22 for the allo), and, after the auto, I recovered very well and may have had a long drug free remission from it, and, potentially, a second autoSCT could have extended that.

I was not at all concerned about having an auto and knew I would get through it okay, even if it was tough at times.

At the time I was thinking and worrying mostly about doing the allo (which so far is going very well, but a long way to go). I took the view that people who have long lives with minimal drugs were the exception, and while I could hope for that, it was not likely. That's why I made the decision for upfront allo, to give myself the best chance of having a long drug free remission and possibly cured

I agree with Ivan that it depends on your personal circumstances on whether or not to take on the risks of allo. The decision was easier for me as I don't have any kids to consider.

Laura

[ivanm]

Re: Why not do either an allo transplant or continuous thera

by ivanm on Mon Jun 16, 2014 10:36 am

Thanks for your thorough answer Mark. I didn't mean to sound sardonic in asking about the NRM in your case. It seems many people here value your opinion and they can be swayed by your views about allo transplantation. However, mortality is rarely discussed here.

As I said in my post the older NRM is a historical statistic. Whether it is important, I think patients can decide for themselves. The RIC NRMs are obviously new. I did not give annual ranges, but they are as new as 2004, 2005. The City of Hope study that shows that remission in allo may be illusory is from 2013 and has a 1-yr NRM of 8.3% and 5 and 7 yr NRM of 12%.

As to ATG, two of the studies I quoted are relatively new studies with ATG showing NRM of 17% and 23% (sorry I did not recall exactly what you did, so I asked to correct me if I was wrong, which you did).

As to NRM, considering that big part of it is aGVHD, I am not sure whether anything you do at home can change that. Also, it is a bit presumptuous to think that other patients are sloppy in their infection avoidance at home and hence, they die (which is basically what you are saying).

Anyways, as I've said before, the most reasonable course would be for each person to discuss with their doctor. If Mark and I going at it here is somewhat educational, all the better. NRM is only part of the story. The other story is how lowered NRM relates to relapse, PFS and OS.

Lastly, as I've mentioned before, think how an allo can affect your chances of enrolling in a trial, if God forbid you need to down the line.

Thanks again Mark and good luck. Hopefully you stay in remission many, many years...

Ivan

Moderator's Note: We discuss what the "City of Hope study" is that Ivan mentions above in this posting later in this discussion thread.