[Mark11]

Re: Does a deeper response mean longer overall survival?

by Mark11 on Fri Sep 23, 2016 11:28 am

Hi Mr. Potatohead,

I am going to put the links up to 2 papers that we discussed often here back in 2011. I think you might be thinking in a way Dr. San Miguel cautions against in this paper:

"Nevertheless, it is important to consider that although eradication of cancer stem cells may be necessary to cure most malignancies, in some others, some residual tumor cells may persist under the control of the immune system. This may apply to tumors with a pre-malignant antecedent, such as multiple myeloma and low-grade lymphomas, which are usually preceded by a monoclonal gammopathy of undetermined significance (MGUS) or a clonal benign lymphocytosis phase, respectively.15,16 Thus, although achieving enduring complete remission would be a prerequisite for cure in most multiple myeloma patients, there are some long-term survivors who do not achieve complete remission but revert to an MGUS-like profile. Whether these residual cells represent cancer stem cells or are merely clonal plasma cells without the capacity to develop a malignant disease remains to be determined. Nevertheless, it is important to distinguish these cases from those in which a suboptimal response is the result of a suboptimal treatment.

Another group of patients in whom complete CR may be misleading are those cases with rapid response but early relapse, as was found for Burkitt’s lymphoma; they may benefit from short sequential therapies to avoid tumor cell escape and regrowth.17 With these two exceptions, a pre requisite to obtain a cure would be to achieve and maintain the best response."

http://www.haematologica.org/content/96/9/1246

Quite a few other people in this thread are doing what Dr. Rajkumar mentions in this paper:

"First, it is well known that responders will always appear to do better than nonresponders, regardless of whether or not the treatment works.21 Nevertheless, the habit of comparing survival between those who achieve CR versus those who do not has not diminished. The fact that this type of analysis is fundamentally flawed needs to be recognized; responders should not be directly compared with nonresponders, and they will always appear to do better regardless of whether the treatment works or not.21 Further, attainment of CR is as much a function of tumor biology as it is a reflection of a therapy's value. "

http://www.bloodjournal.org/content/118/12/3205

Accurately assessing disease biology is another weakness we currently have in myeloma. Patients that have posted here in the past said tests showed them as "standard risk" relapsed quickly and had poor outcomes or did not respond well to therapy.

Just as the tests used to determine a patients disease biology, MRD tests are far from 100% accurate. With the exception of the small studies of allogeneic transplant patients, most MRD studies in myeloma show the majority of patients do relapse. A lot of that can be explained by the fact that allogeneic transplant is an accepted curative therapy for myeloma while proteasome inhibitors and IMIDs have no effect on the myeloma stem / progenitor cells, so taking them in never ending cycles obviously will not cure a patient.

Again, great thread and I think you will find those papers interesting. Like I said before, it is interesting that we keep discussing the same topics through the years.

Mark

[Mark11]

Re: Does a deeper response mean longer overall survival?

by Mark11 on Fri Sep 23, 2016 11:42 am

Hi JPC,

That flow chart is from this 2007 paper on myeloma:

"Mini–Midi–Maxi? How to harness the graft-versus-myeloma effect and target molecular remission after allogeneic stem cell transplantation"

http://www.nature.com/leu/journal/v21/n9/full/2404775a.html

You are correct in that this is a method that has been curing blood cancer patients since the 1970's. You can just change the therapies in the boxes before the allogeneic transplant to fit any blood cancer to get the patient to CR. As we all know, a healthy functioning donor immune system Is very effective at maintaining remissions for many blood cancers.

"Allogeneic hematopoietic cell transplantation (alloHCT) is a curative therapy for hematologic disorders including acute lymphoblastic and myeloid leukemia, chronic lymphocytic and myeloid leukemia, Hodgkin's and non-Hodgkin lymphoma, multiple myeloma, and myelodysplastic syndrome."

http://www.bbmt.org/article/S1083-8791(13)00285-1/fulltext

Mark

[MrPotatohead]

Re: Does a deeper response mean longer overall survival?

by MrPotatohead on Fri Sep 23, 2016 9:30 pm

Mark11,

Thanks for the additional information. I don't disagree with these studies (to the extent that I understand them!), nor do I disagree with the points you make here or have made elsewhere concerning the advantages of the treatment strategy you pursued.

My point was that reaching a complete response (CR) or even achieving negative minimal residual disease (MRD) is not the only way to survive with multiple myeloma. In the case of CR, the treatment that elicits a deep response (specifically, a CR) may wipe out a more benign myeloma clone that keeps a more aggressive clone under control. So one then may face more aggressive disease that becomes dominant and shortens one's OS. Do you think that's wrong?

It looked to me as if your treatment, after eliciting a very deep response as measured by MRD readings, gave you a new immune system that was able, via a (relatively) mild graft-versus-host effect, to hold whatever clones remained at bay. Hence, you are likely cured. And you don't need a maintenance protocol, which would compromise your quality-of-life in any case, and moreover may not (in the absence of an allo) overcome Darwinian adaptation to the main­tenance drug by any remaining myeloma, which would lead to relapse. Do I have that right?

I wish I had the option of doing what you did, but my age, insurance constraints, and other factors make that unrealistic. On the other hand, just doing one autologous transplant (which is all my insurance would cover) does not appeal to me. The alternative is combination drug / chemo therapy, which is probably what I will continue doing. I understand that it compromises quality of life, and is not a route to a cure, but if it sustains me for 4-5 years, I think I would be happy with that (famous last words).

As you have said more than once, decisions on myeloma treatment depend to a degree on one's goals. Blasting my body with high dose melphalan and then hoping for a long remission, when the evidence is that I may gain a year over what drug/chemo therapy will give me, is not appealing. And that's what my transplant route would look like.

On the other hand, if circumstances were different, I would do what you did – no question!

Please let me know where I am (if I am) going astray or misunderstanding something in any of the above.

I applaud you for doing the research and thinking that led you to the therapy you pursued and the excellent outcome you achieved. I also agree that many of the current "thought leaders" on myeloma are prejudiced in favor of drug treatment. But I think that applies as well to many of those who push for autologous stem cell transplants as the "standard of care".

I hope things will be clearer concerning how best to treat multiple myeloma for everyone in a few years. It all seems quite murky to me at present, despite the many intelligent and dedicated scientists and physicians working on the issue.

[Mark11]

Re: Does a deeper response mean longer overall survival?

by Mark11 on Fri Sep 30, 2016 11:48 am

Hi Mr. Potatohead,

You wrote:

I applaud you for doing the research and thinking that led you to the therapy you pursued and the excellent outcome you achieved.

While a motivated patient is important for a great outcome, it really takes a group effort for a patient to have an unexpectedly good outcome like I am having. A doctor skilled in the use of immunotherapy and an incredibly special person willing to go through a battery of tests and donate bone marrow were essential. You also have to have a great group of caregivers and of course all the medical personnel, particularly the transplant nurses, to have this kind of out­come. It really is a special feeling knowing all of those people did all of that for me to live with such a good quality of life.

My reason for posting about my experience / treatment plan in this thread was not to en­cour­age others to pursue it. It was to show the difference between using minimal residual disease (MRD) data to make treatment decisions, as opposed to just taking the test and using it to predict which patients are likely to do better. It also was to show that most myeloma doctors / patients do not believe they really have a "deep response". Patients with a truly deep response to therapy do not need maintenance. I was using myself as an example. Patients with my pres­en­ta­tion have a median overall survival of 18 months. I have a deep response. The MRD test allowed me to go off therapy, but it is indeed the drug-free remission period that proves I had a deep response to my therapy.

You are a smart patient with a great understanding of the issues. You have to remember that I used the most aggressive therapy early and am having a great outcome, so you have to realize when you ask about theories of clonal evolution, etc. I am likely to go with the thought that using therapies that have the ability to provide a patient a long treatment free period early in disease course is the right way to go. For me, having a novel agent to help get me to CR did not just help increase my overall survival and progression-free survival, it may have con­trib­uted.to the best possible outcome for a myeloma patient.

But I think that applies as well to many of those who push for autologous stem cell transplants as the "standard of care".

Could you explain what you mean by that? I would think it would be pretty irresponsible for a doctor to not at least discuss an autologous transplant with a transplant-eligible patient. The reality is that high-dose melphalan is the myeloma drug with the highest single agent activity, it increases overall survival for patients that do them compared to those who do not, and it ap­pears to be the only treatment that has the ability to give the patient a deep enough re­sponse to enjoy a long treatment-free period and the good quality of life that comes with that time period. It is up to the patient if they do the transplant and most choose not to do it, but I am not sure why you have a negative view of a doctor who gives their patient the opportunity to do an auto. What would you think of a doctor who stated he/she did not use IMIDs because he/she "did not believe in them"?

I hope things will be clearer concerning how best to treat multiple myeloma for everyone in a few years. It all seems quite murky to me at present, despite the many intelligent and dedicated scientists and physicians working on the issue.

My only advice would be to go with what the peer reviewed studies tell you, as opposed to what you hear in YouTube videos or the like. The main peer-reviewed papers I relied on to make my therapy choices proved to provide accurate information, and they were all published in 2010 and earlier. Newly diagnosed patients have much more data to work with than I did.

The other advice would be to know what type of myeloma you have. I knew what the studies showed my outcome would be using the standard approaches, and I accepted my diagnosis.

Also, have a goal for your therapy and a long-term treatment plan. I have known for the last 5 years what my next line of therapy would be if I needed it. Those things made my therapy decisions easy for me.

Good luck and keep starting these types of threads!

Mark

[MrPotatohead]

Re: Does a deeper response mean longer overall survival?

by MrPotatohead on Tue Oct 04, 2016 1:08 am

Hi Mark

I can understand the need to have the help of a great medical team to achieve the kind of results obtained in your case. I'm sure it also takes great insurance coverage or, lacking that, a very healthy account balance.

I also understand your point about using minimal residual disease (MRD) measures to guide therapy as opposed to using them to predict outcomes. That certainly is not common practice (as far as I know), but it makes eminent good sense.

I don't think I was very clear when I referred to "those who push for autologous stem cell trans­plants." I was trying to make a point based on my own experience seeking second and third opinions on the best treatment options for myself. One place I went to frankly char­acterized themselves as a place that is likely to recommend transplants, all things being equal, apparently due to their experience doing them and their sunk costs in having the facilities and staff to optimize their success. But the same thing applies, I think, to experts who favor drug / chemo regimens over transplants. No one is trying to be malicious, and certainly it is not the case that a blind eye is deliberately being turned to one alternative over the other. It's just what a given clinician or myeloma center may be comfortable with.

Applying your advice to my own case. I have kappa light chain myeloma, with FISH analysis show­ing deletion 13 and translocation 11:14. I was initially rejected for an autologous trans­plant, and have had drug / chemo treatments consisting of Revlimid and prednisone, sub­cu­taneous Velcade and dex, as well as (my latest regimen consisting of) Cytoxan (cyclo­phos­pha­mide), Kyprolis, and dex. I relapsed after about two months on the Revlimid, did not respond at all to the Velcade, and have just relapsed on the Kyprolis, after obtaining a complete response to it. My pattern appears to be either no response to novel agents, or else a short-lived re­sponse. My oncologist tells me that this is indicative of aggressive disease. And while I can't tell you where I read what I am about to say, I do remember finding a paper that stated that if the pattern I described characterized how myeloma behaved with novel agent induction regimens, it was likely to do the same thing when subjected to an autologous stem cell transplant (and vice versa).

So right now I am completely at sea concerning what my next steps should be. My pre­occu­pations with the importance / non-importance of getting a CR, as well as the possibilities of one's disease consisting of. multiple clones, are all related to my current dilemma and trying to put together a strategy for dealing with it. I think my situation was not helped by the fact that it took four years to get an accurate diagnosis, and that when it finally arrived, my bone marrow biopsy showed a 90% infiltration by malignant plasma cells. I also had hundreds of lytic lesions, along with kidney damage and four fractured vertebrae. Multiple myeloma enjoyed quite the party at my expense.