NEW YORK CITY—Ensuring the best approaches to stem cell mobilization, understanding the often controversial role of autotransplantation and the number of transplants patients should receive, and keeping abreast of the potential of allogeneic transplants or novel agents in clinical trials are all important considerations when treating patients with multiple myeloma—all issues discussed here at the National Comprehensive Cancer Network Annual Congress on Hematologic Malignancies.
Stem Cell Mobilization
Using a growth factor for five to seven days is a common technique for stem cell mobilization in patients with multiple myeloma, said William Bensinger, MD, Professor of Medicine in the Division of Oncology at the University of Washington School of Medicine and Director of the Autologous Stem Cell Transplantation Program at Fred Hutchinson Cancer Research Center, noting that granulocyte colony-stimulating factor (G-CSF, filgrastim) has been the growth factor almost exclusively used for this purpose.
Oncologists may also use combinations of chemotherapeutic agents with filgrastim for 10 to 18 days, he said. However, most recently, filgrastim for five to seven days has been combined with the drug plerixafor, a CXCR4 antagonist, for one to four days beginning on the fourth day of filgrastrim.
In one recent study he cited of about 300 myeloma patients, plerixafor together with G-CSF was more effective than G-CSF alone in mobilizing hematopoietic stem cells for autologous transplant. The addition of plerixafor to G-CSF resulted in higher CD34+ cell collection in fewer days of apheresis.
The data for stem cell content or dose are derived from a variety of earlier trials, he said. For example, a 1995 study that he coauthored showed that the CD34 content was important for predicting platelet recovery. Specifically, the use of postinfusion colony-stimulating factor was associated with a significant delay in platelet recovery in patients who received fewer than 5.0 × 106 CD34+ cells/kg. However, in patients who received more than that there is a rapid and relatively complete recovery in platelet independence, he said.
Data indicate that factors associated with poor mobilization include increasing age, marrow involvement, chemoresistant disease, more than six cycles of conventional-dose chemotherapy, prior use of alkylators, and prior radiotherapy to localized areas.
Using growth factors without chemotherapy is also associated with poor mobilization, although data suggest that when using filgrastim alone, higher doses are associated with better collections, he added.
Schedule dependency can also affect the ability to collect stem cells. For example, G-CSF given at 5 µg/kg twice daily leads to a higher harvest of CD34+ cells and requires fewer apheresis procedures than G-CSF given at 10 µg/kg once daily.
Lenalidomide exposure may also have an impact on the ability to mobilize peripheral blood stem cells, Dr. Bensinger continued. A 2007 study in Leukemia of 562 myeloma patients mobilized with G-CSF alone found a significant decrease in the total CD34+ cells collected, average daily collection, and Day 1 collection, and an increased number of aphereses in those treated with lenalidomide compared with those who received dexamethasone, thalidomide-dexamethasone, or vincristine-doxorubicin-dexamethasone (VAD).
This problem, Dr. Bensinger said, may be overcome with the use of cyclophosphamide plus G-CSF for mobilization.
Overall, although certain factors that can affect stem cell mobilization can't be changed—i.e., patient age, disease stage, baseline CD34, and SDF-1 gene polymorphisms—it is possible to influence prior treatment, including chemotherapy drugs and doses and radiation therapy, he said. “The message is to mobilize relatively early in the course of a patient's disease, even if you're not planning on an immediate transplant. Earlier is better for the collection of stem cells.”
In addition to stem cell mobilization, another key issue is autotransplantation, which has always been controversial in myeloma, said Jayesh Mehta, MD, Professor of Medicine and Director of the Hematopoietic Stem Cell Transplant Program at Robert H. Lurie Comprehensive Cancer Center at Northwestern University.
Unlike the situation with diseases such as acute leukemia, “relapse after autotransplantation is almost inevitable in myeloma, and the procedure is likely not curative in the majority of patients,” Dr. Mehta wrote in a recent article in Bone Marrow Transplant, explaining that in most myeloma patients, however, autotransplantation tends to provide significant benefits in terms of prolongation of survival with normal quality of life.
Data on high-dose therapy and autotransplantation are addressed in several studies, he said. Overall, one of the weaknesses of autotransplantation studies is that data were obtained before the era of novel agents, but their strength is that long-term follow-up data are available.
Some of the literature finds high-dose treatment to be advantageous. For example, the IFM-90 trial found that high-dose therapy and autotransplantation provided a superior response rate, event-free-survival, and overall survival compared with conventional chemotherapy in myeloma patients.
Additionally, the MRC Myeloma VII study found that high-dose therapy and stem cell autotransplantation was superior to conventional low-dose treatment.
Other data have found high-dose treatment with autotransplantation to be comparable to conventional therapy. Specifically, a study by the “Myélome Autogreffe” Group (MAG) confirmed a benefit of high-dose therapy for event-free survival and time without symptoms, treatment, and treatment toxicity, but did not indicate that high-dose therapy was superior to conventional chemotherapy in overall survival for myeloma patients.
Yet other data found high-dose therapy to be inferior, noted Dr. Mehta, citing the InterGroupe Francophone du Myélome (IFM) 99-06 study.
Early vs Late
Early vs late autotransplantion has also been studied—specifically, a MAG trial found that high-dose therapy with peripheral blood stem cell transplantation resulted in a median overall survival of 5+ years in young patients with symptomatic myeloma, whether the procedure was performed early as first-line therapy or later as a rescue treatment.
The average time without symptoms, treatment, and treatment toxicity, however, was better for patients receiving an early transplant. Another study, Intergroup 9321, found early and late autotransplant to be comparable, although data on quality of life were not available.
The issue of tandem transplantation is also controversial but has been addressed in the literature, Dr. Mehta said. For example, another IFM study found that when compared with a single autologous stem-cell transplant after high-dose chemotherapy, double transplantation increased overall and event-free survival in myeloma patients. The benefits from a second transplant “were largely confined to patients who did not achieve at least a very good partial response,” with the first transplant, he said.
The Bologna 96 clinical study (JCO 2007;25:2434–2441) concluded that when compared with a single autologous stem-cell transplant as upfront treatment, double transplant resulted in a better complete response or near complete response rate, relapse-free survival, and event-free survival in newly diagnosed myeloma patients, but did not extend overall survival. The benefits from double transplant were particularly evident among patients who had not had at least a near complete response after one autotransplantation, the authors noted.
Dr. Mehta added that a study from Holland, essentially a tandem-vs-single-transplant study, found that double-intensive therapy provided longer event-free but not overall survival compared with single-intensive treatment.
Moreover, he added, the still unpublished GMMG-HD2 study, presented as an abstract at the 2005 International Myeloma Workshop, found that event-free survival and overall survival for tandem transplant was comparable with a single transplant.
With tandem studies, although the data suggest that oncologists might be able to select patients for the procedure based on the quality of their response to the first treatment, the issue is controversial, said the meeting's Chair, Andrew D. Zelenetz, MD, PhD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center.
“There's a lot of debate about this issue,” Dr. Bensinger agreed. “What we do in Seattle is generally collect enough stem cells for at least two transplants, and we offer a second transplant if a patient is not in a complete response or near complete response. Otherwise, we usually stick with one transplant.”
Allogeneic transplantation for multiple myeloma is also being evaluated in clinical studies. Data indicate that it is possible to safely conduct a mini-allotransplant in patients with myeloma, said George Somlo, MD, Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Cancer Center.
For example, the IFM initiated two trials in 1999 to study patients with high-risk newly diagnosed myeloma. After induction therapy and a first autologous stem cell transplant in both protocols, patients with an HLA-identical sibling received a dose-reduced allogeneic stem cell transplant (IFM99-03 trial), while those without an HLA-identical sibling donor were randomized to a second autologous transplant with high-dose therapy, with or without anti–IL-6 monoclonal antibody (IFM99-04 protocol). While mini-allotransplant following autologous transplant was relatively safe, it did not result in extended event-free survival.
Another study, published in 2007 and using a somewhat similar approach, found that overall survival was superior in patients with newly diagnosed multiple myeloma who received a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling compared with recipients of tandem stem-cell autografts. Although only a fraction of the patients ended up receiving the allograft modality, the results were provocative enough to conclude that in study settings, this approach is reasonable, Dr. Somlo said.
In addition, he noted, the ongoing Phase III, multicenter Blood and Marrow Transplant Clinical Trials Network 0102 trial is evaluating tandem autologous transplants vs autologous transplant followed by HLA-matched sibling non-myeloablative allogeneic transplant.
Researchers are also evaluating whether novel agents will improve the progression-free survival rate in patients with myeloma after they undergo a single autologous stem cell transplant with high-dose therapy.
For example, the Phase III BMT CTN 0702 multicenter study is comparing upfront treatment with tandem autologous transplants with maintenance therapy versus a single autologous transplant plus consolidation with lenalidomide, bortezomib, and dexamethasone, followed by maintenance therapy or a single autologous transplant plus maintenance therapy. All three arms of the trial include lenalidomide as maintenance therapy.
Oncologists are looking forward to the results from this trial, Dr. Somlo said, emphasizing that encouraging patients to participate in such studies is critical to their completion.