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Since the advent of “total therapy” for multiple myeloma in the 1990s, about 10% of patients so treated have remained in continuous complete remission for at least a decade. That’s long enough for their physicians to think about using the “C” word, as in “cure,” suggested Dr. Bart Barlogie.
In an analysis provocatively subtitled “The Myth of Incurability,” Dr. Barlogie of the Myeloma Institute for Research and Therapy at the University of Arkansas, Little Rock, proposed that overall survival plateaus such as those seen at 5-6 years in highly proliferative diseases such as childhood acute lymphoblastic leukemia might take longer to achieve in more slowly proliferative, accumulation-type malignancies such as multiple myeloma.
“One must have patience and time, staying at the same institution as I have, to see the results,” Dr. Barlogie said.
The term “total therapy” as applied to multiple myeloma means the application at any given time of all agents and modalities that show efficacy against the disease, with the goal of reducing tumor burden maximally up front.
This concept, said Dr. Barlogie, “is the whole reason for combination chemotherapy—not wait[ing] until relapse occurs, and then using the next [regimen] and third and so on.”
He and his coauthors reviewed outcomes for three successive iterations of total therapy protocols (see accompanying chart) called Total Therapy 1 (TT1), Total Therapy 2 (TT2), and Total Therapy 3 (TT3).
Dr. Barlogie provided updated overall survival data collected prospectively in randomized trials on 231 patients who received TT1 for a median follow-up of 14 years, 668 patients who received TT2 for a median follow-up of 6 years, and 303 patients who received TT3 for a median follow-up of 3 years.
About one-third of the patients in each group presented with multiple myeloma with cytogenetic abnormalities.
Each successive protocol brought steady improvements in each of the four end points, Dr. Barlogie said. For example, stringently defined complete remissions increased significantly from 40% with TT1 to 50% with TT2 to 60% with TT3.
The median duration of complete remissions also increased, from 2.5 years among patients treated with TT1 (with 16% of patients in continuous complete remission for more than a decade) to 5 years among patients treated with TT2. For patients treated with TT3, the 3-year estimate for complete remissions is 90%.
Median event-free survival was 2.6 years with TT1 and 5 years with TT2. Among patients given TT3, it’s estimated that 80% will have 3 years of event-free survival.
Overall survival was 5.7 years with TT1 and 9 years with TT2. The estimated 3-year overall survival rate is 85% with TT3.
The authors found that patients with high-risk myeloma (15% for all three protocols combined), as determined by gene array profiling, had significantly shorter duration of complete or near-complete remissions and event-free survival than did the 85% of patients with low-risk profiles.
Interestingly, TT2-treated patients with the t(4;14) translocation had significantly lower overall and event-free survival rates, compared with patients without the translocation. Among patients treated with TT3, however, patients with the translocation achieved event-free survival nearly identical to that seen in patients without it.
This finding suggests that the addition of bortezomib provided significant additional benefit for patients with high-risk multiple myeloma subsets, Dr. Barlogie said.
Moreover, in low-risk myeloma with the TP53 deletion, the TT3 protocol produced overall and event-free survival rates similar to those in patients who did not have this deleterious deletion. But among patients with high-risk disease, although the initial frequency of remission was similar in patients with or without the TP53 deletion, both groups of patients did poorly, Dr. Barlogie said.
An important lesson from TT2 and TT3, however, is that while complete remission might be readily achieved, especially in high-risk myeloma, the trick is to sustain that remission, according to Dr. Barlogie.
In their analysis of the two protocols, he and his coauthors found that, as expected, the best survival rate was seen in patients who had a complete remission sustained from 3 years.
Patients who lost a complete remission after having attained it within the first 3 years had the worst outcomes, however, whereas patients who took longer than 3 years to achieve complete remissions had intermediate outcomes.
Taken together, the lessons from total therapies 1, 2, and 3, plus potential new iterations, suggest that physicians might soon be able to speak with confidence about a cure for myeloma, Dr. Barlogie stated.
“Cure is a realistic outcome in myeloma,” he said. “The fact that an occasional patient relapses beyond 10 years is often used as an argument against this, but this actually happens in all other diseases, including childhood leukemia as well, so this should not be an argument against the lack of curability.”
Dr. Barlogie “gave a landmark presentation,” said Dr. Kenneth C. Anderson, director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute in Boston, in a discussion that followed.
“The notable result here, and I truly think it’s remarkable,” he said, “is that if you look from Total Therapy 1 to Total Therapy 2 to Total Therapy 3, there’s an improvement in event-free and overall survival and [complete remission] duration, and what’s the difference? The difference, truthfully, is the incorporation of bortezomib into the paradigm.
“When you talk about the kinds of numbers—50% event-free survival, 60% 10-year complete continuous response—I actually agree with [Dr. Barlogie] that the concept of talking about cure in myeloma is actually here.”
The study was funded by the National Cancer Institute, the Multiple Myeloma Research Foundation, and private donors. Dr. Barlogie disclosed that he has been a consultant and adviser, and has received honoraria from Celgene Corp. and from Millennium Pharmaceuticals Inc.
Dr. Anderson is a consultant to and has received research funding from Celgene, Millennium, and Novartis.
Barlogie B. et al. Total therapy (TT) for myeloma—10% cure rate with TT1 suggested by more than 10-year continuous complete remission: Bortezomib in TT3 overcomes poor risk associated with t(4;14) and DelTP53 in TT2. Abstract 8516.
Commentary |
Dr. Bart Barlogie has pioneered over the years the total therapy concept, where patients get aggressive combination chemotherapy before high-dose therapy and tandem transplantation, followed by consolidation and maintenance therapy. There have been several generations of Total Therapy. Total Therapy 2 added thalidomide to Total Therapy 1, and Total Therapy 3, which was reported at an oral session at ASCO, incorporated both bortezomib and lenalidomide treatment. The excitement here is that the addition of bortezomib, especially prior to high-dose therapy and tandem transplantation, and also the use of bortezomib, lenalidomide, and dexamethasone post–high-dose melphalan have resulted in a marked improvement of outcome in Total Therapy 3 vs. prior iterations of total therapy. In particular, the cytogenetic features that predicted adverse outcome, such as chromosome 13 deletion or 4:14 translocation, no longer did so. The projections for Total Therapy 3 included a greater-than-50% 10-year event-free survival rate and a greater-than-60% 10-year continuing complete response rate. The incorporation, therefore, of novel therapies into the total therapy paradigm has overcome adverse cytogenetics and achieved results heretofore not observed in multiple myeloma. These studies have set the stage for going forward and defining high-risk patients who would be candidates for novel high-risk protocols. Alternatively, patients having sustained continuing complete remission would be candidates for trials using less aggressive therapy. — Kenneth C. Anderson, M.D.
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