Tandem Transplants Increase CR, Reduce Treatment Mortality in Multiple Myeloma

SEATTLE-A two-stage procedure that combines high-dose chemotherapy with autologous stem cell transplantation (SCT) with an immunosuppressive (but not myeloablative) allogeneic SCT in multiple myeloma improves complete response rate and decreases treatment-related mortality. In a plenary presentation at the 43rd Annual Meeting of the American Society of Hematology, David G. Maloney, MD, PhD, presented data for 41 patients treated with this approach (abstract 1822). "The reduced mortality allows treatment of older patients. We feel our method should now be studied in comparison to conventional autografting for the treatment of patients with myeloma," said Dr. Maloney, who is an associate member of the Fred Hutchinson Cancer Research Center in Seattle. Treatment-Related Mortality an Issue In introducing this paper, Stephen Mackinnon, MD, pointed to treatment-related mortality as a major flaw in conventional transplants. "We are still losing one out of three of our transplant patients to transplant-related causes. In addition, conventional transplants are generally not applicable to older patients, because age is associated with increased risk. That is a problem, as most multiple myeloma patients are elderly." Dr. Mackinnon is a consultant in hematology at University College in London. The lower-intensity regimen Dr. Maloney used to prepare patients for the allogeneic SCT is myelosuppressive rather than myeloablative. It has limited antitumor efficacy but is immunosuppressive enough to permit transplant engraftment, according to Dr. Mackinnon. The main difference compared to conventional regimens is in the use of low-dose total-body irradiation. Dr. Maloney said that although myeloablative allogeneic SCT is potentially curative for myeloma (due to the graft-vs-myeloma effect), his group has been concerned about high transplant-related mortality due to regimen-related toxicities and graftvs- host disease. "The alternative of high-dose therapy with autologous stem cell rescue induces cytoreduction of the disease with a low transplantrelated mortality, but nearly all patients eventually relapse or develop disease progression," he said. Therapy Could Be Curative The investigators reasoned that curative therapy might be possible if the safety and cytoreduction of high-dose melphalan(Drug information on melphalan) (Alkeran) and autologous SCT could be combined with the graft-vs-myeloma potential of nonmyeloablative allogeneic SCT from human leukocyte antigen (HLA)-matched sibling donors. "By separating the high-dose conditioning regimen from the immunotherapeutic effect of the allograft, we hoped to decrease the transplantrelated mortality yet maintain the graft-vs-myeloma effect," Dr. Maloney said. Median Follow-up Dr. Maloney reported median 13- month follow-up data on 41 patients with a median age of 52 years (range: 39-71), with previously treated stage II (n = 11) or stage III (n = 30) myeloma but no previous transplant. Forty- nine percent of patients had refractory or relapsed disease, 36% had partial responses to prior treatment, and 15% were in CR at study entry. The patients were given granulocyte colony-stimulating factor (16 μg/kg/d x 4 days) and stem cells were collected. Patients then received melphalan at 200 mg/m² followed by autologous stem cell rescue. At a median of 62 days later (range: 40-120 days), patients received 2 Gy of total-body irradiation (7 cGy/min), immunosuppression with mycophenolate mofetil (CellCept) for 28 days, cyclosporine (Neoral, Sandimmune) (for a minimum of 56 days), and unmodified peripheral blood stem cell allografts from HLA-identical siblings. Of the 41 patients, 40 received nonmyeloablative allogeneic SCT. The majority of patients did not require hospitalization. Granulocyte and platelet nadirs after allograft were 736 cells/μL and 97,000 cells/μL, respectively. Dr. Maloney reported that all patients had successful engraftment, with medians of 90% of donor T-cell chimerism by day 28 after allograft and 99% by day 84. With median follow-ups of 423 days after autologous and 328 days after nonmyeloablative SCT, overall survival was 85%, progression-free survival was 83%, and 1-year treatment-related mortality was 12%. The response rate was 88%, with 61% complete response and 27% partial response and only two progressions to date. "Patients continue to move from partial to complete response," Dr. Maloney said (see Table 1). Graft-vs-host disease was the most serious complication, as 19 of 41 patients developed acute cases. This included 16 patients with grade II, 1 with grade III, and 2 who developed fatal grade IV graft-vs-host disease. Fortyfive percent of patients developed chronic disease requiring therapy. Potent Antitumor Activity "Despite being used in an older group of patients with multiple myeloma, this novel two-step allografting approach has dramatically reduced the acute toxicities of allogeneic SCT, while maintaining potent antitumor activity. This study provides the rationale for a comparative study between this two-step allogeneic approach and standard autologous SCT for the therapy of myeloma," Dr. Maloney concluded.