Velcade-Dexamethasone Plus Donor Lymphocyte Infusions In Myeloma Patients Relapsing After Donor Stem Cell Transplantation
Results from a small Italian Phase 2 clinical trial indicate that Velcade plus dexamethasone, followed by donor lymphocyte infusions, may be an important treatment option for patients who relapse after donor stem cell transplantation.
The findings show that almost two-thirds of the patients responded to the Velcade (bortezomib)-dexamethasone (Decadron) combination, and that donor lymphocyte infusions deepened the responses achieved with Velcade-dexamethasone.
The study investigators also note that side effects associated with the treatment were manageable and expected, considering the high likelihood of these patients developing transplant-related complications.
The Italian study is important. Donor stem cell transplants are often viewed as a last line of defense against myeloma. Indeed, in the Italian study, the donor transplant was the second transplant the patients had received. All of them had previously received a stem cell transplant using their own stem cells.
The current study, however, confirms previous research showing that, even if a myeloma patient relapses after a donor stem cell transplant, there are still treatment options that can improve patient survival.
As important as the Italian study is, it also leaves unanswered a key question: For patients like the ones who participated in the study, is Velcade the best option to use with donor lymphocyte infusions, or is it better to use a different anti-myeloma drug, such as thalidomide (Thalomid) or Revlimid (lenalidomide)?
Donor, or allogeneic, stem cell transplantation is a procedure in which a patient receives high-dose chemotherapy followed by an infusion of stem cells from a matched donor in order to replace the cells that were destroyed by the chemotherapy. These stem cells can be from either a related donor, such as a sibling or other relative, or from an unrelated donor.
Once transfused into the patient, the donor stem cells eventually mature into immune cells that hopefully recognize the patient’s myeloma cells as abnormal cells and destroy them. This phenomenon is known as the graft-versus-myeloma effect.
A donor stem cell transplant is different from an autologous stem cell transplant, in which a patient’s own stem cells are collected and returned to the patient following chemotherapy.
Despite its curative potential for multiple myeloma, there is still a high risk of relapse after a donor stem cell transplant. Additionally, donor transplantation is a risky procedure due to the potential for life-threatening complications, such as graft-versus-host-disease (GVHD).
GVHD is similar to the graft-versus-myeloma effect in that the immune cells recognize the patient’s cells as foreign and attack them. However, with GVHD, the immune cells attack the patient’s healthy cells.
Previous research has shown that donor lymphocyte infusions may be an effective therapy for patients who relapse after donor stem cell transplantation. The procedure involves collecting lymphocytes, a type of white blood cell, from the stem cell donor and infusing them into the patient after the stem cell transplant. The lymphocytes are associated with the same graft-versus-myeloma effect as the donor transplant.
According to the Italian researchers, donor lymphocyte infusions induce a response rate of approximately 30 percent. Previous studies have shown that increasing doses of donor lymphocyte infusions had the highest anti-myeloma activity and were associated with a low rate of GVHD.
In an effort to increase the response rate in patients relapsing after donor transplantation, the Italian researchers combined donor lymphocyte infusions with Velcade-based therapy. They argued that Velcade has shown good response rates in patients relapsing after autologous stem cell transplants and that its side effect profile does not overlap with the common donor transplant-related complications.
The Phase 2 study included 19 multiple myeloma patients with a median age of 57 years who had relapsed after donor stem cell transplantation.
Patients had received a median of two prior lines of therapy. All had previously received an autologous stem cell transplant.
The median time between the donor transplant and enrollment in the trial was 55 months.
Between 2007 and 2010, patients received three cycles of Velcade plus dexamethasone, followed by a maximum of four increasing doses of donor lymphocyte infusions.
The median follow-up time was 40 months.
The researchers found that 62 percent of patients responded to the Velcade-dexamethasone combination, with 5 percent of patients achieving a complete response, 31 percent a very good partial response, and 26 percent a partial response.
The overall response rate increased to 68 percent after the donor lymphocyte infusions. The researchers point out that many patients were able to deepen their responses with donor lymphocyte infusions. After donor lymphocyte infusions, 19 percent of patients achieved a stringent complete response, 13 percent a complete response, 31 percent a very good partial response, and 6 percent a partial response.
Patients responded for a median of 17 months. The researchers found that patients who developed chronic GVHD, which occurs after 100 days of the transplant, responded significantly longer (29 months) than patients who did not develop chronic GVHD (8 months).
After three years, the progression-free survival rate was 31 percent and the overall survival rate was 73 percent.
Chronic GVHD also had a positive effect on progression-free survival: patients who developed chronic GVHD had a significantly longer three-year progression-free survival (37 months) than patients who did not develop chronic GVHD (8 months). However, overall survival did not differ between the two groups.
According to the researchers, the safety profile of the treatment was acceptable.
The most common side effects included infections (63 percent), peripheral neuropathy (pain, tingling, or loss of feeling in the extremities due to nerve damage) (59 percent), and weakness (32 percent).
In addition, 31 percent of patients developed GVHD. However, the researchers point out that no patients developed extensive chronic GVHD.
The authors of the current study note that the response and survival rates seen in their trial are similar to those that were seen in a retrospective analysis by Dutch researchers. The Dutch study (full text), which was retrospective, also looked at the impact of Velcade-dexamethasone treatment combined with donor lymphocyte infusions in patients who relapsed after a donor stem cell transplant.
The authors of the Dutch study, however, concluded from their findings that treating patients with Velcade and dexamethasone prior to donor lymphocyte infusions "did not result in durable remissions." Instead, the Dutch researchers suggest that other anti-myeloma drugs, particularly thalidomide, may be a better option for combining with donor lymphocyte infusions.
This is an issue the Italian investigators do not address in their study. It therefore is one that myeloma specialists will need to investigate further in future research.
For more information on the Italian study, please see the related journal article in Biology of Blood and Marrow Transplantation (abstract).
Related Articles:
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- 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
I find it interesting that those who developed GVHD had longer progression free survival! Any insights as to why having GVHD is beneficial in keeping myeloma in check?
Thanks
Eric
Eric, GVHD tends to go hand-in-hand with the graft-versus-myeloma effect, in which the donor cells attack and kill the patient's myeloma cells. Therefore, patients who experience some GVHD tend to have longer remission. The key is to figure out how to reduce GVHD while maintaining or enhancing the graft-versus-myeloma effect.
Navneet and Maike - Thanks for the article. All of us allo recipients appreciate everyone at the Beacon for providing us info on allos. From what I have been told patients that do not have any extensive chronic GVHD would use Revlimid or thalidomide with DLI's or Revlimid monotherapy for treatment if needed after transplant. Patients with extensive chronic GVHD would use Velcade with or without DLI's. I am not sure why they felt the need to use DEX with the Velcade. Velcade can be used to prevent/minimize GVHD on its own. Maybe the DEX nullified some of the GVM effect since DEX is so immunosuppressive.
I was fortunate that I only needed steroids during my 4 cycles of Induction. Long term steroid use can cause long term health challenges. IMO it is best to try and minimize DEX use. I really think Pomalyst should work great after allo. Hopefully we will start seeing some data now that it is approved here in the US. Hopefully no DEX will be used/needed when using Pomalyst after allo.
Thanks for the additional information and perspective, Mark. It's always useful to get your thoughts on studies like this one.
We know, by the way, that studies like this one will be of particular interest to patients who already have had an allo transplant. However, we also think patients who haven't had an allo transplant also should be aware of this sort of research, since they someday may need to get an allo transplant.
I had an allo in August, 2011 at the age of 45 and achieved a nearCR. It has been so close to a stringentCR that sometimes the protein band has been so faint as to be undetectable. Yet it is then rediscovered the next month. Last October my doctor put me on a low dose of Revlimid to deepen the response. She says that she has not wanted me on Dex because while it may help with gvhd (which I do not have) it will suppress the graft vs. myeloma effect. Because I had a half-match transplant, she is hesitant to use a DLI (chronic gvhd rates with a 1/2 match can be as high as 50-70%). Instead, the team at Johns Hopkins has given me the option of having a second 1/2 matched allo, using my other brother or one of our older children (ages 16, 19, 22). They believe this is a safer option for me than the DLI and that it has a 20% chance of a cure. But I have to do it soon, while I'm in such a deep remission. It's hard to "choose" to have an allo when life is good and I don't have any problems, yet the presence of any myeloma cells is an enormous problem in itself. My onc has not been pushy, has not tried to persuade me, and has reminded me that there are no guarantees--I might not sail through this allo like I did last time, and I might be in the same place a few years from now whether I have the allo or not. She said most of her patients would not choose to do this. In fact, I will be the first mm patient to do it at JH (it has been done with some other blood cancers). But they have an excellent success rate at JH and my doctor is a believer in allo therapy. She is calling this consolidation therapy since I have not technically relapsed, just haven't reached that molecular response. I am electing to have it this summer... Will keep you posted!
Thanks for sharing your story, Dana ... and what a story it is! Please do keep us posted on how things go. We're wishing you all the best.
Hi Dana,
I am glad to hear that you are feeling so well. I am not so happy to hear that you are still making tough decisions with respect to myeloma therapy. Like you are now, I felt very good when I went in to do my allo. I looked at it like a temporary inconvenience to hopefully get a long remission and get back to a drug free life. Almost made it on the drug free part - I am still on Zometa for my bones. You are definitely an inspirational patient. You are as determined as anyone to try and beat this disease. I am sending all positive energy and prayers your way.
Mark
Dear Mark (and Beacon Staff!),
Thank you so much for the encouraging words. My post-allo time off drugs was amazing, and I truly don't think I had felt so well in three or more years. It was easier (though a lengthier process) on me than the auto that I had for induction. My doctor knows how much I want to be drug-free, and that is why she is giving me this chance. If it doesn't produce that magical, elusive "cure", at least it will still (likely) keep me off the drugs for a longer period of time. I had a very difficult time at diagnosis (8 fractures) but have been blessed to tolerate all the meds very well--no neuropathy or issues to speak of, but I have seen so many young, disabled patients from aggressive drug therapy that I will continue to take my chances with the allo. Other allo patients on this forum have also helped me to weigh the costs re: chronic gvhd. I don't think I could forgive myself for not taking the chance, especially when I have so much family praying that they will be the "chosen" donor. My older brother, who was my last donor, still says it was the greatest thing he's ever done in his life. I really don't want one of my kids to have to go through it, but maybe God has a different/greater plan for them that I can't appreciate as a mother who always wants to protect them! I am just so grateful for a doctor who has tailored my treatment to my personal philosophy as a younger patient (I.e., pursuing cure vs the more gentle, palliative approach I was presented with at our local hospital) and who is willing to let me be her "trailblazer", as she affectionately calls me. She is one of my dearest friends, and I hope that every myeloma patient finds a specialist with as much heart and who offers as much hope. And Mark, thank you for always taking the time to support the allo patients. it has meant so much to me. I have brought many of your informative emails to my doctor who reads them with interest. She said she is glad to see a "poster boy" for allos, as they often get a bad rap! Thank you for helping others to know about this treatment option. And I would love to hear from others who have had more than one! (Hopefully they are out there?!). Best regards, Dana
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