For patients with multiple myeloma, the new therapies have made such an impact that a big question is whether patients still need to undergo a hematopoietic stem cell transplant.
This was one of the questions addressed in the Intergroupe Francophone du Myélome (IFM) 2009 trial, published onlineApril 6 in the New England Journal of Medicine.
The results show that after induction with lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Takeda), and dexamethasone (RVD) (multiple brands), survival for patients who received transplants as part of consolidation therapy was similar to that for patients who received transplants following relapse. However, progression-free survival (PFS) and response rates were higher for patients in the early transplant group.
"This benefit must be weighed against the increased risk of toxic effects associated with high-dose chemotherapy plus transplantation, especially since we found that later transplantation might be as effective as early transplantation in securing long-term survival," the investigators concluded.
"We owe a big 'merci' to the IFM investigators" for addressing these issues, comment experts writing in accompanying editorial.
"In summary, transplantation resulted in a deeper and longer initial treatment response than did a nontransplantation approach. However, the benefits of transplantation were more modest than some might have hoped, and it did not appear to be curative," the editorialists, Jeffrey A. Zonder, MD, and Charles A. Schiffer, MD, of the Karmonos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, told Medscape Medical News.
Transplant Still Has Role
Medscape Medical News also approached myeloma expert S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minnesota, who was not associated with the study, for comments.
"The study shows that transplant still has a role in myeloma even in era of new drugs by demonstrating a significant PFS advantage over RVD alone in newly diagnosed myeloma," he said.
He indicated that with respect to timing, the study showed that overall survival was similar for patients who received transplants early or late (at time of relapse).
"This gives patients a choice on timing," Dr Rajkumar said. He noted the remarkable progress made in myeloma. "We now get a 4-year overall survival rate of over 80% in newly diagnosed patients who are transplant eligible," he said.
Implications for Clinical Practice
In one way, the results of the study may well reflect clinical practice.
Dr Schiffer told Medscape Medical News that the study data show no clear advantage with early transplant. "Some patients in the study haven't needed a transplant. There may be a benefit from delaying transplantation," he said.
However, for appropriate patients, early transplant may be preferable. Dr Rajkumar explained that the similar rates of overall survival show that as long as transplant is performed, the timing of early vs late transplant can be made on the basis of patient preferences. "Some patients want to get it over with, and some want to delay transplant as much as possible. This trial shows we can abide by patients' wishes and circumstances, with a few exceptions," he said.
Dr Rajkumar noted that the results of the trial will not change the practice at the Mayo Clinic. "Our group has been following the paradigm shown in this trial for many years. This trial doesn't change our practice but reaffirms what we do and recommend," Dr Rajkumar said.
Dr Rajkumar indicated that with the new drugs available for treating myeloma, there has been a feeling that transplant might not offer much. "That's not the case. The impressive PFS benefit with early transplant shows that the modality still works and is effective," he said.
Dr Rajkumar indicated that early transplant is preferred for all patients except for those at standard risk who prefer the delayed approach. "As far as I know, most myeloma experts would agree with me on this issue," he said.
"For the patients who elect late transplant, we still need to collect stem cells early, and we still need to consider transplant at first relapse," he explained. "That's the way they get same survival as the early transplant arm," he noted.
He indicated that either of the approaches used in the study are applicable to standard-risk patients. "This study cannot be used to dismiss transplant since both arms received transplant. Only the timing varied," Dr Rajkumar said.
However, for intermediate-risk and high-risk patients, on the basis of data from other studies, the Mayo Clinic approach is preferred for early transplant and bortezomib-based maintenance.
Age is also an important factor, Dr Rajkumar noted. "Patients who are closer to 70 years of age are better off with early transplant. If they choose to delay, they may miss out on an active treatment modality," he said. "RVD will always be there. Transplant won't, since one has to be fit to undergo the procedure," he added.
IFM 2009 Study Details
IFM 2009 was an open-label, phase 3 study conducted in 700 patients with newly diagnosed multiple myeloma who were randomly allocated at enrollment to receive transplant or RVD as consolidation therapy.
All patients received three cycles of induction therapy with RVD, after which stem cells were collected from all patients for transplant. Patients who were allocated to consolidation therapy received five additional cycles of RVD (n = 350); those allocated to transplantation (n = 350) received high-dose chemotherapy with melphalan and underwent transplant. All patients received maintenance therapy with lenalidomide for 1 year.
Noting that approximately 90% of patients across each arm completed their assigned treatments, "in the IFM 2009 trial, the planned treatments were realistic," Dr Schiffer and Dr Zonder write.
The rate of complete or very good partial responses after induction were similar for both groups of patients: 45% for RVD alone, and 47% for the transplant group. Rates after consolidation and maintenance were significantly higher for the transplant group. After induction and consolidation, complete or very good partial responses were reported for 88% of patients in the transplant group and for 77% in the RVD group (P = .001).
The median PFS at 4 years (the primary endpoint) was higher for the transplant group: 50 vs 36 months for patients who received RVD as consolidation therapy (hazard ratio, 0.65; P < 0.001). Four-year incidence of disease progression was lower for the transplant group (49% vs 65% for the RVD group), and complete responses were higher (59% vs 48% for the RVD group).
Minimal residual disease (MRD), as measured by flow cytometry, was not detected in a higher proportion of patients in the transplant group: 79% vs 65% for RVD (P < 0.001). Although patients in whom MRD was not detected had better outcomes compared with those in whom MRD was detected, in 50% of patients, disease progression was reported, the editorialists point out. "More sensitive tests for MRD may prove to be more discriminating," they state
Of the 207 patients in the RVD arm who experienced disease progression, 172 received second-line treatment; of these, 136 patients (79%) received a salvage transplant. In the transplant group, 149 experienced disease progression, and 123 patients received second-line treatment; of these, 21 (17%) received a second transplant.
Adverse events were higher for patients in the transplant group. Treatment discontinuation was higher (11% vs 9% for the RVD group), as were treatment-related deaths (six vs two patients). The rate of grade 3/4 neutropenia was also significantly higher (92% vs 47% for the RVD group), as was the rate of grade 3/4 gastrointestinal disorders (28% vs 7% for the RVD group).
Four cases of acute myeloid leukemia were reported in the transplant group; one case was reported in the RVD group.
"Although acute myeloid leukemia is part of the natural history of myeloma and its treatment, particularly in the context of melphalan use, the patients in the transplantation group will require longer follow-up to accurately quantify this important risk," the IFM 2009 investigators write.
The editorialists agree. "[The] incidence of acute myeloid leukemia is likely to increase, since therapy-related acute myeloid leukemia-myelodysplastic syndrome continues to occur up to 10 years after transplantation," they write. "It is likely that maintenance lenalidomide also contributes to the risk of this disease," they add.
The Role of Maintenance Therapy Questioned
An aspect of this study and clinical practice that may be questioned is the role of maintenance therapy following consolidation. In IFM 2009, all patients received lenalidomide maintenance for 1 year.
"The price of 1 year of maintenance lenalidomide is more than $120,000 in the United States; it is perhaps lower in other countries with more thoughtful and competitive pricing programs, but it is still formidable," Dr Schiffer and Dr Zonder write in their editorial.
"The added 'value' of extended maintenance therapy will be dubious unless an improvement in overall survival is established," they add.
Dr Schiffer and Dr Zonder indicate that "given the prices of new drugs, the price of transplantation, which was once considered to be prohibitively expensive, now represents a relatively small part of the overall monetary cost of the treatment program." In a cost-analysis study, the median cost of transplant was estimated at ~$30,000 (Mishra V et al. Clin Lab Haematol. 2003;25:179-184).
Next Steps
The editorial also noted that an ongoing US trial (NCT012008662) that was prospectively planned as a companion to IFM 2009 has a nearly identical design, with the exception that maintenance lenalidomide was provided until disease progression.
"The combined results of these two trials will be of interest, particularly within biologically defined risk groups and among patients in whom minimal residual disease is not detected," Dr Schiffer and Dr Zonder note.
"The two studies together will expand the number of patients in different risk groups and may identify patients who do not need a transplant," Dr Schiffer told Medscape Medical News.
The study was partially supported by grants from Celgene and Jannsen. Several study authors reported ties with industry, details of which are provided in the journal article. Dr Rajkumar has disclosed no relevant financial relationships. Dr Schiffer has received grant support and personal fees from Celgene, personal fees from Takeda/ Millenium, Coherus. Spectrum, Astellas, Ambit, Ariad, Pfizer, Pharmacyclics, Juno, and Teva outside the submitted work. Dr Zonder has ties with pharmaceutical companies, as listed in the journal article.
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