I had asked the question in a previous post about the role of the allo transplant in the treatment continuum for Multiple Myeloma. The Allo, (allogenic transplant), is probably one of the most misunderstood of the current arsenal of myeloma treatments. Basically, the difference in these transplant techniques is that the autologous stem cell transplant uses your own stem cells to repopulate your bone marrow once it has been destroyed by the use of high dose chemotherapy, and the allogeneic uses someone else’s stem cells to replace your bone marrow.
There are also different kinds of allogeneic transplants. One is the related donor transplant, which the stem cells for transplant come from a relative or sibling, and the unrelated donor, which is exactly what it sounds like. The stem cells come from a non related donor. The rest of the significant information about the pros and cons of the allo and differences of treatment types, I will leave to the expert Dr. VIj.
So what were some of the key points that I learned from this Allogeneic broadcast?
1) Apparently the RIT(Reduced Intensity Allogeneic Transplant), has a first year mortality of 10 to 15% vs. 30 to 50% for the published data currently available. This is 2 to 5 times better than the published data, and would indicate to me that the very first thing you need to ask any allogeneic doctor is what is your ONE YEAR SURVIVAL RATE? He knows so, if he does not tell RUN LIKE HECK! Find one that has great experience and not one of the ones that make up the 30 to 50% morbidity group.
2) The myeloma allogeneic transplant has a much higher morbiity than it does in other blood cancers, and some doctors relate that to the older average age of the myeloma patient and their comorbidities. Younger patients may have much better outcomes with the allo than the average myeloma patient.
3) High Risk patients and those that have had a rapid relapse after first treatment may be more likely to benefit from new allogeneic clinical trials that are under developement.
And of course, in order to get an adequate match for a donor stem cell transplant, you first have to have donors. Robin Roberts of ABC News had found that there is a critical need for donors, and you can learn about the donor registry and become a donor if you CLICK HERE!
Would you be Mine?
Dr. Vij started with stating that this topic is still a very relevant for discussion of the myeloma treatments. The allogeneic transplant, which includes not only obtaining stem cells for replacement after high dose chemotherapy from a sibling or unrelated donor, has been under investigation for going on 2 to 3 decades. It has never become mainstream for myleoma treatment and left to the realm of clinical trials. The allogeneic transplant sources have expanded to include alternative donor transplant sources, which includes cord blood and haploidentical donor. A haploidentical, or half matched related donor, could be a sister, brother, mother, or father.
The use of the RIT ( Reduced Intensity Transplant) has taken off in the last decade and a half, and uses the donor’s immune system to fight the cancer in the myeloma patient instead of relying on chemotherapy exclusively. This has resulted in significant reduction in morbidity and mortality in allo stem cell transplantation. It now has improved to the point it can be used in older patients in their late 60’s to early 70’s. However, despite these advances the allo stem cell transplant in multiple myeloma is more the exception than the rule. This is because of the contradictory results obtained from clinical trials. Clinical trials have been being conducted for over 2 decades and originally involved what we call fully myeloablative stem cell transplants. This is where we relied on the chemotherapy and radiation administered to the patient prior to the transplant to eradicate the disease quickly, and the stem cell source’s main function was to provide fresh bone marrow to allow blood cell production. That experience provided a 10 to 20% disease free survival suggesting that this set of patients is cured of their disease. The issue at that time was the upfront mortality that was between 30 and 50% in the first 6 months after transplant. It was felt after several trails that although the allo had curative potential, it in fact harmed more people than it helped. Those people who died may have had a long term disease free control, and some perhaps extended control if they had been treated with conventional treatment or with an autologous transplant.
What contributed to this high initial mortality for the myeloma patient is still not clear, and mortality is much greater than that for other disease states. This has been contributed by some people to organ impairment ( like the kidney) ,comorbidity, frailty, and the advanced age of the myeloma population and these factors may have put the myeloma patient at a higher risk of complication. At that time a clinical trial that was being conducted, comparing the allogeneic transplant to the auologous transplant was terminated early because it was felt to be unethical to even conduct the trial given the high mortality that ensued with the allogeneic stem cell transplant.
More recently in the last 10 to 15 years, we have really started to do the reduced intensity transplants (RIT), and this has really brought down the up front toxicity of this procedure. Instead of the 30 to 50% mortality, we are now down to perhaps 10% at 6 months post transplant, and 10 to 15% at 1 year from transplant. With the RIT (Reduced Intensity Transplant) , it relies more on the donor’s graft to provide the anti myeloma activity, The immune cells in the donor graft attacks the cancer in the recipient. and relies less on the chemotherapy and radiation that was given to the patient prior to transplant to control the disease. By reducing the chemotherapy and radiation at the outset we are able to reduce the toxicity of the procedure, The issue therein is that the graft vs. tumor response or the immune effects of the donor graft is slower in developing. It often takes weeks to months to exert its full impact. So if we have a disease that is progressing at a rapid rate at the time of transplant, or have a very active disease at the time of transplant, it will often require faster disease control than that offered by the RIT. So even now some patients will have a fully myloablative transplant if the disease burden is high at the time of allogeneic transplant.
However, one other strategy that has evolved is the tandem transplant where the first transplant is autologous, and then followed in three to six months by a second allogeneic transplant (preferably sibling matched). What we have is rapid disease control from the autologous transplant along with the potential curative characteristics of the allogeneic transplant. We have been able to accomplish this treatment regimen without excessive morbidity and mortality, but we have not been able to conclusively show that this is better than a single autologous or dual autologous transplant. There have been numerous studies in this regard, perhaps a half a dozen large randomized trials. Two of these trials showed that the tandem autologous transplant had an OS (overall survival) advantage and possibly some patients are being cured of their myeloma. The problem is that for most studies the followup is short. Four of the studies also show no survival advantage of the autologous/allogeneic over the tandem autologous transplant. The critics of this assertion who favor allogeneic transplants point out that the these 4 studies are the shortest in duration and that more time is required to show a survival advantage for the auto/allo. This may in fact be true, because it has been noted in the past that a survival advantage may emerge with long followup. So Dr. Vij believes we still do need longer term followup of the allogeneic studies which have been conducted in the era of RIT(Reduced Intensity Transplant).
However, we must look at what other treatment options we have for myeloma patients, and in this case we have seen a plethora of options which have emerged over that last 10 plus years. Autologous transplant, not often offered as a curative therapy, however is meant to be a life extending therapy. The data from two large groups of patients, one in the United States and one in Europe, with long term follow up suggests that up to 30% of patients that obtain a complete remission(CR) after an autologous transplant are alive and disease free for 12 plus years from transplant. Now we are having more and more patients who achieve complete remission, and complete remission after autologous transplant is not in the 50 to 60% range. So now if we have 30% of those patients alive and disease free 12 plus years out we will have many more patients living long term with just autologous transplants. The auto is a much safer procedure, which in the best of hands has only a 1 to 2% mortality rate. We are making great progress with the newer drugs being incorporated into the autologous transplant paradigm which will let more people be disease free 10 to 15 years out. Do we think that these people are cured? We hope that they are, having been disease free that far out, however we still will not find many myeloma specialists who will talk about the autologous transplant as being curative.
As said, our armamentarium of drugs is expanding, and even with the transplant ineligible patients, we are seeing better results. Within the last year we have had two new drugs approved, Carfilzomib and Pomaldomide, added to Bortezomib, Revlimid, and Thalidomide which were approved in the first decade in this millennium. We certainly have made major strides. Now we have antibodies that are in development that seem to be very promising, which include Elotuzomab and Daratumumab and other CD38 antigen directed antibodies, with some people now feeling that the best is yet to come. Some people are conflicted with whether we should be subjecting patients to a high risk procedure with curative potential, rather than going with our increasingly more effective chemotherapy drugs.
This Allogeneic transplant is left to be in more of the realm of investigation. There are moves afoot to do large Allogeneic transplant studies. The two groups of patients where this is thought to be worth investigating further are those that have high risk chromosomal abnormalities, where using it as an upfront procedure would be appropriate, or with people who have had early relapse after either transplant or conventional therapy. Dr. Vij believes that the Allogeneic transplant will continue to be an area of active research, and in the future may become applicable to more patients, however right now caution is advised.
We often have different Allogeneic approaches at different centers. Dr. Vij is often asked whether he would conduct an allo on a younger patient. He explained to us that we physicians all, in such patients, have a discussion about the treatment options. They sometimes see patients in their 20’s, but not often, but in those cases he thinks doctors ,and especially transplant doctors, are willing to explore the use of the allogeneic transplant outside the context of the clinical trial. He also said that different physicians have varying comfort levels of conducting the allogeneic transplant outside the clinical trial format.
Dr. Vij then asked to go into the Q & A section of the program. If you want to listen to his excellent conversation of the Pros and Cons with the Cure Panel and the listeners, it begins at the 20 min. and 15 second time of his presentation. You can again go to this presentation if you CLICK HERE. The Q & A session included some unique incites into the Graft vs Host disease, more in depth explanation of the mini allo (RIT), and an expanded explanation of the reason morbidity in myeloma is greater than in MDS or leukemia.
I would like to thank Dr.Ravi Vij, Priya and the Cure Talk Crew, the Myeloma Panel members and our listeners for another great educational experience for the myeloma patient community. And as always may God Bless your myeloma journey. Gary Petersen firstname.lastname@example.org
For more information on multiple myeloma go to the web site www.myelomasurvival.com or you can follow me on twitter at: https://twitter.com/grpetersen1
P.S. – After the broadcast Dr. Robert Orlowski of M.D. Anderson was kind enough to send the following tweet: About use of allo in high risk patients. MD Anderson data: same factors that predict for early relapse post-auto apply to allo. He included the attached article from Blood that provided a M.D. Anderson study showing the benefit of the RIP over the full allo in relapsed and refractory patients. To view this excellent article CLICK HERE. Thank you Dr. Orlowski for your confirming data, and your obvious commitment to the myeloma patient community.