Credit: Chad McNeeley
NEW YORK—A debate on the pros and cons of upfront transplant in symptomatic multiple myeloma (MM) yielded a split decision from the audience during the NCCN 9th Annual Congress: Hematologic Malignancies.
Sergio Giralt, MD, of Memorial Sloan Kettering Cancer Center in New York, argued for upfront transplant, pointing out that long-term MM survivors have transplant as upfront therapy.
Kenneth Anderson, MD, of Dana Farber/Brigham and Women’s Cancer Center in Boston, took the stance that, in the past 10 years, there has been a
revolution in novel therapies that has significantly improved survival in MM.
For upfront transplant
Dr Giralt cited the 36-month follow-up of the E4A03 landmark analysis of patients who went off therapy after 4 cycles of lenalidomide/dexamethasone to pursue early stem cell transplant and those who continued treatment until disease progression.
Regardless of whether the patients were younger than 65 years or between 65 and 70, the patients who had an early transplant had superior progression-free survival (PFS) and overall survival (OS) compared to those who did not.
Dr Giralt added that bortezomib should be a component of induction therapy prior to autologous stem cell transplant (ASCT). Even though there is no survival benefit with bortezomib-based regimens, he said, there is significant improvement in PFS, as shown in a meta-analysis of phase 3 European studies.
The E4A03 landmark study also determined that the more intense the treatment, the better the outcome. So patients with double ASCT had a significantly longer PFS than patients who only had a single transplant.
This held true for OS as well, and included patients with 17p deletion and/or t(4;14) who failed to achieve complete remission after bortezomib-based induction regimens.
An analysis of 27,987 MM patients with a median age of 68 years (range, 19 to 90) revealed that of the patients who survived 10 years or more, 16.5% had ASCT as part of their initial therapy.
Dr Giralt concluded that the preponderance of evidence supports high-dose melphalan and ASCT as upfront consolidation therapy for MM. And until results of randomized trials investigating combination therapies are reported, melphalan consolidation should be considered the standard of care for all eligible patients with MM.
Against upfront transplant
Dr Anderson countered with data showing limited or no improvement in survival with ASCT, including evidence from studies by Attal, Fermand, Blade, Child, and Barlogie.
ASCT confers only modest PFS advantage, he said, showing results of the Barlogie study in which patients undergoing ASCT had a 25-month PFS, compared with a 21-month PFS with VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone).
“In the last 10 to 15 years, there has been a revolution in myeloma,” Dr Anderson said. “We have a lot of novel agents here today, and we have even more coming. It’s a hugely exciting time.”
Dr Anderson pointed out that since the introduction of novel agents, survival has improved between 2006 and 2010, compared to the period between 2001 and 2005, and particularly in patients older than 65 years (P=0.001).
Transplant has also changed, he said. Novel therapies have been integrated into the transplant paradigm, either before, as induction and consolidation therapy, or after, as maintenance. He indicated that this begs the question as to whether we really need the transplant component.
There has also been unprecedented use of triplets in combination therapy, Dr Anderson said, resulting in overall response rates upwards of 90%. For example, carfilzomib in combination with lenalidomide and dexamethasone prompted an overall response rate of 94%, with a stringent complete response (CR), CR, and near CR of 53%.
“It’s a new day in myeloma,” he said. “It’s taken us a long time, but we’re worrying about minimal residual disease (MRD) now. We’re worried about getting to the endpoint of 1 myeloma cell in 1 million normal cells.”
The point is, he added, that with novel therapies, such as carfilzomib, lenalidomide, and dexamethasone, patients who achieve a complete response can become MRD negative, suggesting an unprecedented extent of response without transplant.
MRD negativity may also be accomplished with oral agents, such as ixazomib. The depth of response with ixazomib increases over the course of treatment, with 27% achieving stringent CR or CR with a median duration of response of 13.8 months, and 82% of patients attaining MRD-negative status.
“In the absence of transplant,” Dr Anderson said, “this is an unprecedented response.”
Dr Anderson also pointed out that in the era of novel agents, there is no difference in outcome between early or delayed transplant. The 4-year OS in transplant-eligible patients who received initial therapy with lenalidomide was 80%, regardless of the timing of ASCT.
And in one trial, patients who received a delayed transplant fared better in OS than those transplanted early.
Dr Anderson said there is a parallel, international phase 3 study underway (IFM/DFCI2009) that will provide an answer to the debate on upfront transplant in the not-too-distant future.
