Reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed multiple myeloma.

Despite recent advances, multiple myeloma (MM) remains incurable, and most patients eventually develop progressive disease. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potentially curative option in 10%-20% of patients with relapsed or refractory disease. We evaluated the outcome of patients undergoing allo-HSCT with reduced-intensity conditioning (RIC) for relapsed and/or refractory MM at our institution. The study cohort included 51 patients with heavily pretreated, relapsed MM who underwent RIC allo-HSCT between 1996 and 2006. The median time from diagnosis to allo-HSCT was 34 months, and median follow-up in surviving patients was 27 months (range, 3-98 months). Cumulative transplantation-related mortality at 1 year was 25%. Progression-free survival (PFS) and overall survival (OS) at 2 years were 19% and 32%, respectively. The incidences of grade II-IV acute and chronic graft-versus-host disease were 27% and 47%, respectively. At the time of this analysis, 12 patients (24%) were alive, 7 of whom (14%) were in remission for up to 6 years after allo-HSCT. A lower beta2 microglobulin level (<3.3) and previous autologous HSCT were predictive of lower nonrelapse mortality and longer PFS and OS. Our findings indicate that allo-HSCT with RIC is associated with acceptable toxicity and durable remission and survival in relapsed or refractory MM. The use of RIC allo-HSCT earlier in the course of the disease may offer the greatest benefit.

Autologous hematopoietic stem cell transplantation may reverse renal failure in patients with multiple myeloma.

Approximately 20% of patients with multiple myeloma (MM) have renal failure at diagnosis, and about 5% are dialysis-dependent. Many of these patients are considered ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) because of a high risk of treatment-related toxicity. We evaluated the outcome of 46 patient with MM and renal failure, defined as serum creatinine >2 mg/dL sustained for >1 month before the start of preparative regimen. Patients received auto-HSCT at our institution between September 1997 and September 2006. Median serum creatinine and creatinine clearance (CrCl) at auto-HSCT were 2.9 mg/dL (range: 2.0-12.5) and 33 mL/min (range: 8.7-63), respectively. Ten patients (21%) were dialysis-dependent. Median follow-up in surviving patients was 34 months (range: 5-81). Complete (CR) and partial responses (PR) after auto-HSCT were seen in 9 (22%) and 22 (53%) of the 41 evaluable patients, with an overall response rate of 75%. Two patients (4%) died within 100 days of auto-HSCT. Grade 2-4 nonhematologic adverse events were seen in 18 patients (39%) and included cardiac arrythmias, pulmonary edema, and hyperbilirubinemia. Significant improvement in renal function, defined as an increase in flomerular filtration rate (GFR) by 25% above baseline, was seen in 15 patients (32%). Kaplan-Meier estimates of 3-year progression-free survival (PFS) and overall survival (OS) were 36% and 64%, respectively. In conclusion, auto HSCT can be offered to patients with MM and renal failure with acceptable toxicity and with a significant improvement in renal function in approximately one-third of the transplanted patients. In this analysis, a melphalan (Mel) dose of 200 mg/m(2) was not associated with an increase in toxicity or nonrelapse (Mel) mortality (NRM).

Arsenic trioxide with ascorbic acid and high-dose melphalan: results of a phase II randomized trial.

Arsenic trioxide (ATO) is synergistic with ascorbic acid (AA) and melphalan against myeloma both in vitro and in vivo. The aim of this randomized phase II trial was to determine the safety and efficacy of a combination of ATO, melphalan, and AA as preparative regimen in 48 patients undergoing autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma (MM). Forty-eight patients received melphalan 200 mg/m2 i.v. over 2 days and AA 1000 mg i.v. over 7 days in 3 treatment arms: no ATO (arm 1), ATO 0.15 mg/kg i.v. x 7 days (arm 2), and ATO 0.25 mg/kg i.v. x 7 days (arm 3). No dose-limiting toxicity, engraftment failure, or nonrelapse mortality (NRM) was seen in the first 100 days post-ASCT. Complete responses (CR) were seen in 12 of 48 patients (25%), with an overall response rate (ORR = CR + PR) of 85%. Median progression-free survival (PFS) was 25 months; median overall survival (OS) has not yet been reached. There was no significant difference in CR, PFS, or OS among the 3 treatment arms, and no adverse effect of ATO on melphalan pharmacokinetics. Addition of ATO + AA to high-dose melphalan is safe and well tolerated as a preparative regimen for MM.

Symptom burden after autologous stem cell transplantation for multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is the most common indication for high-dose chemotherapy with autologous stem cell transplantation (ASCT) in the U.S. and can be associated with substantial morbidity. Thorough assessment and understanding of symptoms and risk factors for symptom development after ASCT are logical first steps toward developing strategies aimed at reducing the symptom burden associated with this procedure. METHODS: The authors performed a prospective evaluation of symptom burden among 64 patients with myeloma who underwent ASCT. Symptom data were collected using the M. D. Anderson Symptom Inventory (MDASI) at 4 time points: baseline, the day of stem cell infusion (Day 0), nadir of counts, and Day 30. Univariate analysis was performed to correlate pretransplantation variables with post-transplantation symptom burden at these time points. RESULTS: MDASI scores increased significantly throughout transplantation, with most patients returning to baseline by Day 30 after the procedure. Patients with the highest MDASI scores at baseline had the highest MDASI scores at nadir (P= .02). Patients with prolonged time to transplantation and women had a trend toward higher nadir global symptom severity scores. These groups, as well as patients aged >60 years, had a trend toward higher nadir interference scores. CONCLUSIONS: ASCT for MM was associated with significant but reversible symptom burden during the first 30 days, and the baseline symptom burden was the most important predictor of symptom burden after transplantation. The MDASI was useful as a tool for following the symptom burden associated with ASCT and may be used to evaluate interventions aimed at reducing transplantation-related morbidity in these patients.

Results of a retrospective single institution analysis of targeted skeletal radiotherapy with (166)Holmium-DOTMP as conditioning regimen for autologous stem cell transplant for patients with multiple myeloma. Impact on transplant outcomes.

(166)Holmium-DOTMP is a beta-emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high-dose radiation to the bone marrow. Phase I/II trials showed feasibility and tolerability when combined with high-dose melphalan with or without total-body irradiation (TBI) in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). The purpose of this study was to define the potential impact of (166)Holmium-DOTMP on outcomes in patients with MM undergoing ASCT. Retrospective review of transplant outcomes among patients with MM who received an ASCT between January 1998 to December 2001 with either melphalan 200 mg/m(2) or a (166)Holmium-DOTMP containing regimen as part of their initial therapy. Univariate analysis was performed for response, overall survival (OS), and event free survival (EFS). One hundred four patients were identified, of which 41 received a (166)Holmium-DOTMP containing regimen and 63 received melphalan alone. The (166)Holmium-DOTMP patients were divided into 2 groups according to the dose received (<2400 mCi versus > or = 2400 mCi). The (166)Holmium-DOTMP group had a trend towards a higher complete remission (CR) rate compared to patients receiving melphalan alone (51% versus 32%). The median EFS for the low-dose (166)Holmium-DOTMP, the high-dose (166)Holmium-DOTMP, and melphalan alone was 30, 23, and 19 months, respectively; the OS rate at 5 years for the 3 groups was 61%, 40%, and 43%, respectively. (166)Holmium-DOTMP, in combination with high-dose melphalan, can result in higher CR rates when given in optimal doses (<2400 mCi) when compared to melphalan alone, and should be further tested in phase III trials in patients with MM undergoing ASCT.

Deletion of the short arm of chromosome 1 (del 1p) is a strong predictor of poor outcome in myeloma patients undergoing an autotransplant.

Several chromosomal abnormalities detected by conventional cytogenetic analysis have an adverse impact on the outcome in myeloma patients. A wide spectrum of abnormalities involving chromosomes 1, 13, 14, and 17 has been described. We analyzed the outcome of 83 patients with clonal cytogenetic abnormalities, who underwent high-dose therapy and autologous stem cell transplantation for multiple myeloma at our institution. Clonal abnormalities were detected at diagnosis by conventional cytogenetic analysis in 83 patients. Patients underwent a single autologous transplant between April 2000 and May 2005. Preparative regimen was high-dose melphalan alone (73), or a combination of topotecan, melphalan, and cyclophosphamide (TMC=10). The most commonly observed chromosomal abnormalities were deletion of chromosome 13 (32%), hyperdiploidy (21%), deletion of chromosome 1p (18%), and t (11; 14) in 7% patients. Median follow-up among surviving patients was 25.5 months. Median interval from diagnosis to autotransplant was 7.7 months (range: 2.5-52). Median progression-free survival (PFS) for the entire group was 19 months and the median overall survival (OS) was 52 months. On univariate analysis, both PFS and OS were significantly shorter in patients with deletion 1p (P=.001 and <.0001, respectively). Thirty-two patients whose cytogenetic abnormalities returned to normal prior to autotransplant had longer PFS and OS than patients with persistent abnormalities (P=.02 and .08, respectively). Deletion 1p is associated with a significantly shorter remission and survival in patients undergoing high-dose therapy and a single autologous transplant for myeloma.