Phase I–II evaluation of rapid sequence tandem high-dose melphalan with peripheral blood stem cell support in patients with multiple myeloma

Summary:The overall survival of patients with advanced multiple myeloma (MM) undergoing high-dose chemotherapy and autologous stem cell transplantation (SCT) depends mainly on the quality of response. Thus, to improve the response rate, a new intensified high-dose chemoradiotherapy was evaluated in a phase I/II study. After induction chemotherapy, 89 patients (median age 51 years, range 32-60 years) with MM stage II/III received a conditioning regimen with total marrow irradiation (9 Gy), busulfan (12 mg/kg) and cyclophosphamide (120 mg/kg) followed by SCT. Regimen-related toxicity according to WHO criteria and response rates defined by EBMT/IBMTR were analyzed. The main toxicity was mucositis grade III/IV in 76%, and fever grade 4I in 75% of patients. Three patients developed reversible venoocclusive disease. Transplant-related mortality was 2%. Among patients with de novo and pretreated MM, a CR rate of 48 and 41%, respectively, was documented. With a median follow-up of 45 months, the actuarial median durations of event-free survival (EFS) and overall survival (OS) after transplant were 29 and 61 months for the whole group, 36 and 85 months for patients with de novo MM, respectively. Thus, administration of this intensified conditioning regimen was associated with tolerable toxicity, a high response rate and long EFS and OS.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A new conditioning regimen involving total marrow irradiation, busulfan and cyclophosphamide followed by autologous PBSCT in patients with advanced multiple myeloma

Einsele

Bamberg²,

Budach³

et al. 2003

“…In particular, the non-relapse mortality rates have been low while the CR rate has been reported to increase after each transplant. 9,32 Similarly, our second study involved the pre-harvest administration of CY at a sufficiently high dose that it could be considered the first of two dose-intensive regimens, with GM-CSF 'substituting' for ASCT. Of note, six of the seven long-term progressive-free survivors, and all of those remaining in continuous CR had received such 'double' dose-intensive therapy.…”

Section: Discussionmentioning

confidence: 99%

Prolonged survival after intensive therapy and purged ABMT in patients with multiple myeloma

Reece

Brockington

et al. 2000

Summary:Despite numerous strategies, the cure of multiple myeloma remains a difficult challenge. Recent approaches have involved dose-intensive therapy followed by stem cell transplantation, most often with autologous stem cells (ASCT). Although ASCT is of benefit, it is not considered curative. Between 1988 and 1995, we utilized an aggressive three-drug conditioning regimen followed by ABMT using marrow purged with either 4-hydroperoxycyclophosphamide (4-HC) or mafosphamide (MAF). Twenty-nine of 42 patients who had first received VAD (14 patients) or VAD followed by cyclophosphamide (

“…29 The following HDC regimens were administered to 126 patients: cyclophosphamide, thiotepa, and carboplatin (CTCb, n = 87), 27 carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC, n = 25), 30 busulfan, melphalan, and thiotepa (BuMelTT, n = 13), 31 or a single high dose of melphalan (n = 1). 32 All patients received filgrastim 6 g/kg/day beginning on day 1 after PBSC infusion and continuing until the absolute neutrophil count (ANC) was Ͼ0.5 ϫ 10 9 /l for 3 consecutive days.…”

Section: Methodsmentioning

confidence: 99%

Mobilization of peripheral blood stem cells following myelosuppressive chemotherapy: a randomized comparison of filgrastim, sargramostim, or sequential sargramostim and filgrastim

Weaver

Schulman

Buckner

2001

Self Cite

Summary:Myelosuppressive chemotherapy is frequently used for mobilization of autologous CD34 + progenitor cells into the peripheral blood for subsequent collection and support of high-dose chemotherapy. The administration of myelosuppressive chemotherapy is typically followed by a myeloid growth factor and is associated with variable CD34 cell yields and morbidity. The two most commonly used myeloid growth factors for facilitation of CD34 cell harvests are granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colonystimulating factor (GM-CSF). We performed a randomized phase III clinical trial comparing G-CSF, GM-CSF, and sequential administration of GM-CSF and G-CSF following administration of myelosuppressive chemotherapy. We evaluated CD34 yields, morbidity, and cost-effectiveness of the three cytokine schedules. One hundred and fifty-six patients with multiple myeloma, breast cancer, or lymphoma received cyclophosphamide with either paclitaxel or etoposide and were randomized to receive G-CSF 6 g/kg/day s.c., GM-CSF 250 g/m 2 /day s.c., or GM-CSF for 6 days followed by G-CSF until completion of the stem cell harvest. Compared with patients who received GM-CSF, patients who received G-CSF had faster recovery of absolute neutrophil count to 0.5 × 10 9 per liter (median of 11 vs 14 days, P = 0.0001) with fewer patients requiring red blood cell transfusions (P = 0.008); fewer patients with fever (18% vs 52%, P = 0.001); fewer hospital admissions (20% vs 42%, P = 0.13); and less intravenous antibiotic therapy (24% vs 59%, P = 0.001). Patients who received G-CSF also yielded more CD34 cells (median 7.1 vs 2.0 × 10 6 kg per apheresis, P = 0.0001) and a higher percentage achieved 2.5 × 10 6 CD34 cells per kilogram (94% vs 78%, P = 0.21) and 5 × 10 6 CD34 cells per kilogram (88% vs 53%, P = 0.01) or more CD34 cells per kilogram with fewer aphereses (median 2 vs 3, P = 0.002) and fewer days of growth factor treatment (median 12 vs 14, P = 0.0001). There were no significant differences in outcomes between groups receiving G-CSF alone and the sequential regimen. After high-dose chemotherapy, patients who had peripheral blood stem cells mobilized with G-CSF or Correspondence: Dr CH Weaver, CancerConsultants.com the sequential regimen received higher numbers of CD34 cells and had faster platelet recovery with fewer patients requiring platelet transfusions than patients receiving peripheral blood stem cells mobilized by GM-CSF. In summary, G-CSF alone is superior to GM-CSF alone for the mobilization of CD34 + cells and reduction of toxicities following myelosuppressive chemotherapy. An economic analysis evaluating the cost-effectiveness of these three effective schedules is ongoing at the time of this writing. Bone Marrow Transplantation (2001) 27, Suppl. 2, S23-S29.