Value-Based Care in MyelomaTM (VBM) asked transplant specialist
Sergio A. Giralt, MD, Chief of the Adult Bone Marrow Transplant Service at Memorial Sloan-Kettering Cancer Center, New York, to discuss his transplant strategy for patients with multiple myeloma, and where the field is heading.
VBM: Stem-cell transplant (SCT) has become an integral part of the management of multiple myeloma. Which patients do you consider for SCT?
Dr Giralt: Any patient with symptomatic myeloma should be considered a candidate for transplant as long as he or she wants this treatment, can provide adequate stem cells, and demonstrates an appropriate performance status. By this I mean a candidate for transplant is not frail and can independently perform most activities of daily living. We no longer limit patients according to age, and this is an important message for clinicians.
VBM: Are patients with adverse cytogenetic features treated differently?
Dr Giralt: Transplant does not produce as good results in patients with adverse cytogenetic features as in those without such features, but SCT is still an important component of the treatment strategy in this patient population. We encourage these patients to participate in clinical trials.
VBM: What is your preferred induction regimen?
Dr Giralt: Three randomized controlled trials have shown that bortezomib-based induction regimens are associated with improved outcomes after transplant; therefore, bortezomib-based induction has become the standard of care. The National Comprehensive Cancer Network (NCCN) guidelines recognize that lenalidomide-based inductions are also frequently used. A recent retrospective analysis of E4A03 showed that patients who underwent autologous SCT after 4 cycles of lenalidomide/dexamethasone had a 3-year overall survival (OS) rate of 94% and progression-free survival (PFS) of 64%.
So far there have been no head-to-head comparisons of these 2 strategies. We do know that lenalidomide-based inductions are associated with high response rates and very good partial responses after transplant, so this should also be considered a reasonable option for induction. Further intensification of the induction regimen has been shown to improve response rates before SCT, but the impact on survival has not been established.
VBM: There is emerging concern about secondary cancers related to lenalidomide, but does this apply to the induction setting?
Dr Giralt: Not at all. Secondary cancers are an issue only seen in the context of maintenance therapy, and there, again, the benefit of using lenalidomide outweighs the risk of second malignancies. The concern about using lenalidomide for induction pertains to stem-cell collection, but adequate numbers of stem cells can usually be obtained with stem-cell mobilization using plerixafor or chemomobilization. Lenalidomide-based induction with SCT produces very good outcomes, and the NCCN guidelines accept it.
VBM: What is the preferred conditioning regimen?
Dr Giralt: Melphalan 200 mg/m2 remains the standard of care. Many new conditioning regimens are being explored, mostly combining melphalan with other agents, but these are topics of randomized controlled trials only.
VBM: The value and specifics of maintenance therapy are strongly debated. How do you use maintenance in your practice?
Dr Giralt: This area is one of the biggest unknowns in myeloma care. First, results from the randomized trials with lenalidomide have not yet been published. But when they have been presented at meetings, they have shown significant benefits in PFS, but no OS benefit, at least not yet. For bortezomib, one randomized trial showed some benefit, but more studies are needed.
With lenalidomide maintenance, the CALGB-100104 (Phase III Randomized Study of Lenalidomide as Maintenance Therapy After Autologous Stem Cell Transplantation in Patients with Multiple Myeloma) trial showed a significant improvement in time to progression (43.4 months vs 21.5 months for placebo), and significantly fewer deaths at a median follow-up of 18 months, despite crossover. The IFM 2005-02 trial, at a median follow-up of 34 months, also favored lenalidomide maintenance for PFS (42 months vs 24 months for placebo).
So, for clinical practice today, outside of a clinical trial I generally wait 4 months after transplant and then decide whether to start maintenance based on the patient’s response. If there is minimal residual disease, a persistent paraprotein peak, I start maintenance with lenalidomide, and continue until disease progression.
VBM: Is there a place for allogeneic transplant?
Dr Giralt: We know that a graft-versus-myeloma effect exists with allogeneic transplant, but we have not been able to exploit it effectively. The data from large trials are conflicting. The latest national trial in North America did show some benefit, but the
VBM: What are your thoughts on total therapy and tandem transplant?
Dr Giralt: Long-term disease control will be obtained with effective induction, consolidation with 1 high-dose therapy, and some posttransplant therapy. What is the exact type of posttransplant therapy that is needed for each patient is uncertain. Studies are needed to compare approaches. The national STAMINA trial will evaluate single autologous SCT with or without lenalidomide/bortezomib/dexamethasone consolidation versus tandem transplant and maintenance therapy. Patients having 1 autologous transplant will be randomized to a second, to 4 cycles of consolidation, or to lenalidomide maintenance alone. It requires looking at all the elements of total therapy to determine which is essential for long-term disease control. This should provide helpful information.
VBM: Finally, what are the important unanswered questions about transplant in 2012?
Dr Giralt: The key question is how we stratify patients by risk and tailor maintenance therapy accordingly. Should all patients receive this, or only those not achieving complete remission? The other important question for us is what to do with our patients with high-risk cytogenetics, especially del(17p). They do not respond as well to our current treatments, and we need better strategies for them. Additional issues to consider include:
1. Reducing the burden of treatment:
- Does every patient need triple-therapy induction?
- Would a doublet be sufficient for standard risk disease?
- Is bortezomib, lenalidomide, and dexamethasone the new standard? No randomized data are available.
- What is the optimal duration of induction? Two cycles versus 4 cycles versus “best response.”
2. The timing of SCT:
- Is SCT optional for patients achieving a complete response?
- Should salvage SCT be offered to all relapsing patients, SCT-naïve or not?
3. Improving therapy:
- How do we incorporate new agents into conditioning regimens?
- Can we reduce morbidity?
- How do we prevent relapse?