ORLANDO, FL—Transplant hematologists who believe that allogeneic transplant has a place in multiple myeloma were disappointed with the results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial, reported here at the American Society of Hematology Annual Meeting.
The trial (Abstract 41), comparing tandem autologous hematopoietic stem cell transplant with or without maintenance therapy (auto-auto) versus single autologous transplant followed by HLA matched sibling non-myeloablative allogeneic hematopoietic stem cell transplant (auto-allo) for patients with standard-risk multiple myeloma showed that the auto-allo approach at three years added no benefit to progression-free or overall survival compared with use of auto-auto.
A possible explanation is that the positive graft-versus-myeloma effect with auto-allo transplant was countered by its associated early transplant-related mortality.
“We did see evidence of a graft-versus-myeloma effect [with auto-allo], because those patients who developed chronic graft-versus-host had a significant 60% reduction in risk of disease progression,” said the first author, Amrita Krishnan, MD, Director of the Multiple Myeloma Program at City of Hope in California. “However, that was not enough to offset the transplant-related mortality—it was low at 12% in our study, but not low enough to derive a benefit from the allo transplant.”
Patients in the auto-auto arm of the study randomly assigned to receive thalidomide-dexamethasone maintenance did not have increased progression-free or overall survival, she noted, adding that this was likely due to poor tolerability.
The multicenter Phase III trial biologically assigned patients to auto-auto using melphalan at 200 mg/m2 conditioning, or to an auto-allo approach using melphalan at 200 mg/m2 followed by allo transplant with 2 Gy total body irradiation.
Graft-versus-host disease (GVHD) prophylaxis was cyclosporine and mycophenolate mofetil. The primary endpoint was three-year progression-free survival. Between December 2003 and March 2007, a total of 710 patients from 43 US centers were enrolled. Patients were assigned to the auto-allo arm based on the availability of an HLA-matched sibling donor at time of enrollment.
Among 625 patients with standard-risk myeloma (i.e., the absence of chromosome 13 deletion by metaphase karyotyping and a beta-2 microglobulin level of no more than 4 mg/L), 436 were assigned to auto-auto and 189 to auto-allo.
Patients in the auto-auto arm were further randomized to either one year of thalidomide-dexamethasone maintenance (217 patients) or observation only (219). Progression-free and overall survival between the thalidomide-dexamethasone maintenance and observation patients were equal, and these arms were pooled for the primary analysis.
The complete and near complete response rates at study entry were 24% for both groups. At three-years, the progression-free survival rate was 46% for the auto-auto group, versus 43% for auto-allo. Three-year overall survival was 80% for auto-auto versus 77% for auto-allo.
Dr. Krishnan reported that 82% of patients in each arm received the assigned second transplant. Among 522 patients who received their second transplant, three-year progression-free survival was 47% for auto-auto versus 44% for auto-allo.
At Day 56 after second transplant, disease response rates in the auto-auto group were 50% very good partial response or better and 40% with complete and near complete response; versus auto-allo with 49% with good partial response or better and 48% with complete and near complete response.
Among auto-allo patients, the probabilities of Grades III-IV acute and chronic GVHD were 9% and 47%, respectively.
Philip L. McCarthy Jr., MD, Professor of Oncology and Director of the Blood & Marrow Transplant Program at Roswell Park Cancer Institute, asked later at the meeting to comment on the BMT CTN 0102 trial, agreed that the allogeneic transplant community would likely be disappointed.
Among the negatives, Dr. McCarthy said, the trial showed that an allogeneic conditioning regimen of a single fraction of total-body radiation alone is inadequate.
He also said that the toxicity associated with an allogeneic transplant is still too high, at least in this patient population.
“There is still a fair amount of death, due not to disease but to regimen-related toxicity or graft-versus-host disease. That remains the big issue in this patient population.”
He said the patients best served by allogeneic transplant may be the ultra-high-risk patients who have bad prognostic features—“They don't respond to induction very well, they have maybe two failures, and those are the patients you may want to target for allo-transplant,” he said.
But he thought that idea might change because the survival benefit of an auto-auto over an auto-allo regimen might take years to emerge. “You may need to wait long enough to see that benefit, because the tandem auto is very good at keeping patients in remission.”
No Definitive Answer
In an interview after the session, co-moderator Edward A. Stadtmauer, MD, Professor of Medicine and Director of the Bone Marrow and Stem Cell Transplant Program at the University of Pennsylvania, noted that prior studies have suggested a benefit to the non-myeloablative approach, although BMT CTN 0102 is the largest of all the studies and therefore may have a greater power to express it.
“But the definitive answer is still not there”, Dr. Stadtmauer said. “Meanwhile, the data suggest that the routine use of a non-myeloablative allogeneic transplant is not yet indicated in standard-risk patients.”
He noted that in the discussion period after Dr. Krishnan's presentation, someone in the audience had said that because the trial was not randomized to transplant or no transplant there was some selection bias.
Another comment from the audience offered the possibility that with further follow-up, more of the long-term benefit of the graft-versus-myeloma effect from allogeneic transplant might be seen, while the autologous transplant-treated patients continue to have their relapse.
BMT CTN 0102 was sponsored by the National Institutes of Health and the National Heart, Lung, and Blood Institute.
In a separate session, Dr. Stadtmauer presented his own data from BMT CTN 0102, focusing on a subset of high-risk myeloma patients (Abstract 526).
He said this planned secondary analysis of a cohort of high-risk myeloma patients demonstrated equivalent three-year progression-free and overall survival for auto-auto and auto-allo in both intention-to-treat and as-treated analyses.
“However, trends in late progression-free survival and time to progression/relapse suggest that further follow-up is needed before final conclusions regarding the utility of auto-allo in this high-risk cohort can be made,” Dr. Stadtmauer said.
He reported three-year progression-free survival rates of 33% for auto-auto versus 40% for auto-allo; and three-year overall survival rates of 67% and 59% respectively.
Regarding disease response at Day 56 after second transplant, the auto-auto group had a 57% very good partial response or better and a 37% complete response or near complete response; in the auto-allo group, 48% had a very good partial response or better, and 41% had a complete response or near complete response.
He said this study does show the feasibility of an allogeneic stem cell transplant approach for high-risk myeloma patients, and that it may serve as a platform for future studies seeking to enhance graft-versus-myeloma effects.
He added that there is an even higher risk group of myeloma patients that has not been studied, and given the limited other options, there might be more enthusiasm about using an allogeneic transplant because of the demonstrated poor outcome with either novel or conventional therapies.
Interestingly, Dr. Stadtmauer said that the use of autologous-allogeneic transplant in standard-risk myeloma patients has diminished in the US to the extent that BMT CTN 0104 may have accounted for its largest use in recent years.
Another transplant specialist, Don Benson, MD, PhD, Assistant Professor of Internal Medicine at Ohio State University Medical Center, who not involved in BMT CTN 0102, was asked to comment on the trial for this article.
“I'm a transplanter, and I have a personal belief in allo-transplant for the right patients,” he admitted. “But whether one is pro- or anti-allogeneic transplant, this trial has been interpreted that it's too early to make a definitive statement.”
Looking forward, he said the BMT CTN is starting a study comparing a tandem auto-auto to a single auto, adding lenalidomide maintenance to the single-auto arm because of results from the Cancer and Leukemia Group B 100104 study, also presented at the ASH meeting, which showed an advantage for lenalidomide maintenance over observation.
“If we can get high-quality, long-term remissions without the risk of an allo transplant, then that would be preferable to putting patients at the short-term risk of toxicity, and especially graft-versus-host disease,” Dr. Benson said. “In BMT CTN 0102, I think the rate of chronic GVHD in the allo arm was about 50%—you're alive and disease-free, but you're fighting other battles then.”
He said currently, allogeneic transplant is reasonable in the setting of a clinical trial. “But with these data coming out on long-term remissions with low-dose lenalidomide maintenance after a single autologous transplant, that's really going to become the benchmark that allogeneic transplant or any other form of therapy has to be.”