Low-risk intensive therapy for multiple myeloma with combined autologous bone marrow and blood stem cell support

Abstract

To improve the safety of autotransplantation for myeloma, peripheral blood stem cell (PBSC) collection was attempted in 75 previously treated patients after the administration of high-dose cyclophosphamide (HD-CTX; 6 g/m2) with or without granulocyte-macrophage colony- stimulating factor (GM-CSF). Sixty patients subsequently received melphalan 200 mg/m2 (57 patients) or melphalan 140 mg/m2 and total body irradiation (850 cGy) (3 patients) supported by both autologous bone marrow and PBSC; 38 patients received GM-CSF posttransplantation. Among 72 patients undergoing PBSC apheresis, “good” mobilization (greater than 50 colony-forming units granulocyte-macrophage [CFU-GM] per 10(5) mononuclear cells) was achieved when prior chemotherapy did not exceed 1 year and when GM-CSF was used post-HD-CTX; similarly, rapid platelet recovery to 50,000/microL within 2 weeks was associated with “good” PBSC mobilization. These same variables also predicted for rapid engraftment after autotransplantation, so that hematologic recovery (granulocytes greater than 500/microL and platelets greater than 50,000/microL) proceeded within 2 weeks among the 37 patients with “good” PBSC collection. As a result of rapid neutrophil recovery (greater than 500/microL) within a median of 2 weeks, infectious complications both post-HD-CTX and posttransplant were readily manageable, resulting in only one treatment-related death post-HD-CTX. The cumulative response rate (greater than or equal to 75% cytoreduction) for all 75 patients was 68%, with 12-month event-free and overall survival projections of about 85%. Using both bone marrow and PBSC together with GM-CSF, autotransplants are safe and appear effective in myeloma, especially when prior therapy had been limited to less than 1 year. More than 80% of transplanted patients achieved complete hematologic recovery within a median of 1 month posttransplant (granulocytes greater than 1,500/microL; platelets greater than 100,000/microL; hemoglobin greater than 10 g%), thus providing sufficient hematopoietic reserve for further chemotherapy in the event of posttransplant relapse.

Presenting Features and Prognosis in 72 Patients With Multiple Myeloma Who Were Younger Than 40 Years

“…The median survival of our patients younger than 40 years who had normal renal function or low serum 2 -microglobulin levels was about 8 years. This long survival in young patients with MM treated with conventional chemotherapy should be considered when evaluating the results in patients receiving more intensive therapy such as bone marrow transplantation (Gahrton et al, 1991;Attal et al, 1992;Harousseau et al, 1992;Jagannath et al, 1992). Patients who also have a low plasma cell labelling index might have an even longer median survival.…”

“…The effect of chemotherapy in MM is palliative and does not usually result in long-lasting responses, even when intensive regimens such as VAD or high-dose melphalan are used (Gore et al, 1989;Samson et al, 1989;Lokhorst et al, 1992). For this reason, the efficacy of high-dose therapy followed by autologous or allogeneic stem cell support is currently being investigated (Gahrton et al, 1991;Attal et al, 1992;Harousseau et al, 1992;Jagannath et al, 1992;Alexanian & Dimopoulos, 1994). Although a median survival of 54 months is the longest reported so far in long-term studies of MM, it is still unsatisfactory, especially in persons younger than 40 years.…”

“…In patients with MM, conventional chemotherapy results in response rates from 50% to 60%, but in most series the median survival still remains between 2 and 3 years (Salmon et al, 1990;MacLennan et al, 1992;Bladé et al, 1993;Greipp et al, 1993;Oken et al, 1995). Because of this short survival, the efficacy of new therapeutic strategies, such as high-dose therapy followed by stem cell support, is being investigated (Gahrton et al, 1991;Jagannath et al, 1992). This newer therapeutic approach seems particularly indicated in younger patients, who tolerate high-dose therapy better and have, perhaps, better immunosurveillance.…”

Impact of response to treatment on survival in multiple myeloma: results in a series of 243 patients

“…Response to conventional chemotherapy should include either patients achieving the plateau phase or combine both objective and partial or minimal response. The high complete response rate currently obtained with high-dose therapy followed by autologous bone marrow or peripheral stem cell rescue is encouraging (Jagannath et al, 1992: Attal et al, 1992: Harousseau et al, 1992. However, longer follow-up is required to establish the actual impact of this high tumour reduction on survival.…”

High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation

“…The standard melphalan dose in single agent HDM therapy for myeloma is a body surface area (BSA) based dose of 200 mg m -2 , used initially in Arkansas [11], and confirmed by Moreau et al [12] where improved OS was observed for patients receiving 200 mg m -2 compared with melphalan 140 mg m -2 and total body irradiation. Subsequent trials have used 200 mg m -2 as a standard [13][14][15] and comparison of 200 mg m -2 with 100 mg m -2 demonstrated better outcomes with the higher dose in the tandem transplant setting [16].…”