Inclusion of High-Dose Treosulfan Followed by Autologous Transplantation in the Tandem Transplantation for Patients with Multiple Myeloma <60 Years.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5098-5098
Author(s):  
Albrecht Reichle ◽  
Nina Burgmayer ◽  
Ernst Holler ◽  
Anna Berand ◽  
Reinhard Andreesen
Keyword(s):  
Multiple Myeloma ◽  
Autologous Transplantation ◽  
Allogeneic Transplantation ◽  
High Dose ◽  
Peripheral Blood Stem Cells ◽  
Intraindividual Comparison ◽  
Best Response ◽  
Patients At Risk ◽  
Blood Stem Cells ◽  
High Dose Melphalan

Abstract High-dose treosulfan followed by autologous transplantation is a tolerable and efficacious regimen in quite different tumor types. Aim of the present study was to proof safety and efficacy of high-dose treosulfan in an intraindividual comparison with melphalan. Between August 2003 and July 2006, 20 patients with multiple myeloma, age< 60 years were enrolled onto an unicentric phase II trial. The median age was 55 years. All patients received pretreatment with 3 to 4 cycles idarubicin and dexamethasone (90%) or CAD (10%). After induction the peripheral blood stem cells were mobilized with a combination of ifosfamide, epirubicin, etoposide (IEV) followed by G-CSF. Stem cell harvest was successful in all patients. Thereafter, the patients received tandem transplantation in an interval of 2 months, first after conditioning with high-dose treosulfan on day −4 to −2, 14g/m2 daily, then after high-dose melphalan 140 mg/m2. Maintenance therapy with interferon-alpha was administered in 30% of the cases. For all patients the completion rate of the first transplantation was 100%, for the second 85%. Three patients did not proceed to the second autologous transplantation due to a severe ischemic colitis (n= 1) or a high-risk profile (allogeneic transplantation in 2 cases). Two patients received an allogeneic transplantation during the further course of the disease. Overall the conditioning regimens were well tolerable. Hematotoxicity grade 4 was observed after each high-dose cycle. Grade 3/4 infections and stomatitis were present in 5%/5% after treosulfan and in 18%/6% after melphalan. An acute coronary heart syndrome occurred after Mel140. The duration of severe leukopenia (< 1.0 leukocytes) was significantly shorter after treosulfan (6.4 days vs. 7.9 days, p= 0.009), whereas time to leukocyte recovery did not significantly differ between the regimens. No treatment related deaths occurred. Best response after transplantation was CR 30%, PR 60%, NC 5%, and PD 5%. In comparison to the preceding chemotherapy a further >50% decline of the paraprotein was achieved by treosulfan in 3 cases, by melphalan in 2 cases. In the intraindividual comparison treosulfan and melphalan, respectively, have shown two times superior response. The median event-free survival was 28 months, and the overall survival at 4 years was 81%. In conclusion, high-dose treosulfan may be more favorable for patients at risk for infections than melphalan, and seems to be as efficacious as melphalan for the treatment of multiple myeloma. Treosulfan should be further investigated in multiple myeloma patients.

Ex-Vivo Expanded Peripheral Blood Stem Cells (EVEC) Compared with Un Manipulated Peripheral Blood Stem Cells (PBSC) Autologous Transplantation for Multiple Myeloma: A Pair Match Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 502-502 ◽  
Author(s):  
Noel-Jean Milpied ◽  
Gerald Marit ◽  
Bernard Dazey ◽  
Jean-Michel Boiron ◽  
Zoran Ivanovic ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
High Dose ◽  
Peripheral Blood Stem Cells ◽  
Cd34 Cells ◽  
Blood Stem Cells

Abstract Abstract 502 Autologous stem cell transplantation with PBSC after high-dose chemotherapy remains standard therapy for patients with symptomatic Multiple Myeloma (MM). Strategies to minimize complications could significantly reduce the morbidity of that procedure. One possibility could be to shorten the duration of induced neutropenia through the injection of an ex-vivo expanded graft. Nineteen patients (pts) received EVEC after high-dose Melphalan (HDM) (200 mg/m2) as the only graft. The ex-vivo expanded procedure has been described elsewhere (Boiron et al. Transfusion 2006 and Ivanovic et al. Transfusion 2006). Briefly, thawed peripheral blood CD 34+ cells collected after G-CSF mobilisation and selected with immunomagnetic devices were incubated for 10 days in a serum free medium (Maco Biotech HP01) with Stem Cell Factor (Amgen), G-CSF (Amgen) and TPO (Amgen: 7 pts; Cellgenix:12 pts). The expanded cells were then thoroughly washed and injected 48h after the HDM injection. The ex-vivo expansion lead to a median fold of 5,4 for CD34+ cells (1,3-11,8); 118 for CD33+ (1-703880); 3386 for CD14+ (4-101075); 28,5 for CD13+ (10-703880) and 13 for CFUs (6-21). The median N° of CD34+ cells injected was 14×10e6/kg (5,3-48). The results of these transplants were compared to those achieved in 38 pts who received unmanipulated PBSC after HDM. Pts and controls were matched for age, sex, stage of the disease, first line chemotherapy ( VAD or VD) status of the disease at time of transplant, year of transplant, time between diagnosis and transplant, CD34+ mobilisation technique (HD cytoxan + G-CSF or G-CSF alone) and the median N° of total nucleated cells and of CD34+ collected. The results are summarized on the table: There was no secondary neutropenia in the patients who received EVEC. With a median FU of the entire cohort of 30 m, the median OS for pts who received their first transplant with EVEC and with PBSC is 69 m and not reached respectively (p=NS), the median PFS is 18 m and 27 m (p = NS) and the median time to progression is 14 m and 15 m (p=NS). Conclusion: EVEC is feasible, safe and reduce significantly the morbidity of autologous stem cell transplantation after HDM for multiple myeloma. Disclosures: Milpied: Amgen France: Honoraria.

Long-Term Results in Multiple Myeloma After High-Dose Melphalan and Autologous Transplantation According to Response Categories in the Era of Old Drugs

2014 ◽  
Vol 14 (2) ◽  
pp. 148-154 ◽  
Author(s):  
Massimo Martino ◽  
Maurizio Postorino ◽  
Giuseppe Alberto Gallo ◽  
Giuseppe Messina ◽  
Santo Neri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Autologous Transplantation ◽  
Long Term Results ◽  
High Dose ◽  
High Dose Melphalan ◽  
Old Drugs

How I Treat Frontline Transplant-eligible Multiple Myeloma

Blood ◽  
2021 ◽  
Author(s):  
Aurore Perrot
Keyword(s):  
Multiple Myeloma ◽  
Randomized Clinical Trials ◽  
Human Monoclonal Antibody ◽  
Autologous Transplantation ◽  
Proteasome Inhibitors ◽  
Standard Of Care ◽  
Adaptive Strategy ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Melphalan

High dose Melphalan supported by autologous transplantation is the standard of care for eligible patients with newly diagnosed multiple myeloma for more than 25 years. Several randomized clinical trials have recently reaffirmed the strong position of transplant in the era of proteasome inhibitors and immunomodulatory drugs combinations, demonstrating a significant reduction of progression or death in comparison with strategies without transplant. Immunotherapy is currently changing the paradigm of multiple myeloma management and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved in the setting of newly diagnosed multiple myeloma. Quadruplets become the new standard in the transplantation programs, but outcomes remain heterogeneous with various response depth and duration. Otherwise, the development of sensitive and specific tools for disease prognostication allows to consider adaptive strategy to a dynamic risk. I discuss in this review the different available options for the treatment of transplant-eligible multiple myeloma patients in frontline setting.

Pegfilgrastim after High-Dose Chemotherapy and Autologous Peripheral Blood Stem Cells Transplantation. A Single-Centre Experience in 15 Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4213-4213 ◽  
Author(s):  
Carole Soussain ◽  
Laure Marec ◽  
Wajed Abarah ◽  
Christian Allard ◽  
Hassina Mallek ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Peripheral Blood ◽  
Central Nervous System Lymphoma ◽  
High Dose Chemotherapy ◽  
Fixed Dose ◽  
High Dose ◽  
Peripheral Blood Stem Cells ◽  
Blood Stem Cells ◽  
Stem Cells Transplantation

Abstract The efficacy of Pegfilgrastim (PF) in decreasing the duration of neutropenia has been proved after standard dose of chemotherapy. Results of PF after high dose chemotherapy (HDC) and autologous peripheral blood stem cells transplantation ASCT) are lacking. We studied the efficacy of PG in patients receiving HDC and ASCT for lymphoproliferative disease. Fifteen consecutive patients (8 males; 7 females) were onrolled in the study from September 2003 through March 2004. Median age of the patients was 56 years. Diseases were multiple myeloma in 5 patients, diffuse large cell non-Hodgkin’s lymphoma (NHL) in 3 patients, follicular lymphoma in 4 patients, mantle cell lymphoma in one patient, and primary central nervous system lymphoma PCNSL) in 2 patients. All patients were eligible for HDC and ASCT per institutional criteria. Stem cells were collected with peripheral blood pheresis after high dose cyclophosphamide (7 cases); high dose Ara-c (5 cases); ifosfamide (1 case); CHOP-like chemotherapy (1 case); or in steady state (1 case). All the patients received daily G-CSF (5 to 10 mcg/kg). Three different conditioning regimens were used. Patients with multiple myeloma received high dose melphalan (200 mg/m²), patients with PCNSL received a combination of high dose Thiotepa (750 mg/m²), Busulfan (12 mg/kg), and Cyclophosphamide (120 mg/kg), and patients with NHL received a BEAM chemotherapy. PF was administered as a single subcutaneous injection of 6 mg at day +3 after stem cell infusion, except for one patient whose injection was done on day 4. No adverse event attributable to PF was observed. There were no toxic death on study. All patients engrafted neutrophils and platelets. The median time to neutrophils engraftment (&gt; 500/mm3) was 7 days (range, 4–12). Febrile neutropenia was almost constant (14/15) but never exceed OMS grade 2. Median number of days with IV antibiotics was 7 days (range 5–22). These preliminary data show that a fixed dose of 6 mg of PF given subcutaneously at day +3 after HDC and ASCT is safe and effective. A cost efficacy study is warranted to compare PF and daily dose of standard G-CSF after ASCT.

Phase IIa, Open-Label, Randomized, Pharmacokinetic Comparative, Cross-Over Study of Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4512-4512
Author(s):  
Omar S. Aljitawi ◽  
Sunil Abhyankar ◽  
Siddhartha Ganguly ◽  
Karen Wolfe ◽  
Kelly Daniels ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Propylene Glycol ◽  
Autologous Transplantation ◽  
High Dose ◽  
University Of Kansas ◽  
Off Label Use ◽  
Open Label ◽  
Off Label ◽  
High Dose Melphalan ◽  
The University

Abstract Abstract 4512 Background: Though high-dose melphalan and autologous transplantation is a standard procedure in transplant eligible multiple myeloma patients, the use of melphalan in this setting is considered an off-label use. The marketed formulation of melphalan, Alkeran for Injection (Alkeran), has marginal solubility and limited chemical stability upon reconstitution. Alkeran uses propylene glycol as a co-solvent, which has been reported to cause complications including renal dysfunction, arrhythmias, and a sepsis-like syndrome. Propylene Glycol-Free Melphalan HCL for Injection (PG-free Melphalan) is a reformulation of Alkeran developed by CyDex Pharmaceuticals, Inc. (A Ligand Company). It incorporates Captisol®, a specially modified cyclodextrin, to replace the co-solvents and improve stability, potentially allowing for alternative dosing such as longer infusion times. In an interim analysis of this study, PG-free Melphalan, compared to Alkeran, appeared bioequivalent, yet was associated with marginally higher blood drug levels. This abstract summarizes the final findings from this study after enrollment of all planned patients. Methods: This is a phase IIa, open-label, randomized, cross-over design bioequivalence study. In this study, the pharmacokinetics (PK) of PG-free Melphalan and Alkeran were assessed in the same MM patients undergoing transplantation. Patients received both drug products in alternating dosing day fashion and were their own control for PK comparison. The PK measures were determined using WinNonLin 6.1 and bioequivalence assessed per FDA guidance. Furthermore, the safety and tolerability of high-dose melphalan HCL and rates of myeloablation and subsequent engraftment were determined in all patients. Results: 24 patients, 11 females and 13 males, were enrolled between 2/4/2010 and 05/16/2011 at The University of Kansas Medical Center and The University of Kansas Cancer Center. Median age of enrolled subjects was 58 years old (range: 48–65). All had ECOG performance status of 0–1. All patients achieved myeloablation followed by successful engraftment. Median time to myeloablation was 6 days post the start of preparative regimen (range 3–8 days). Median time to neutrophil engraftment was day +9.5 post transplant (range: 9–12). No additional toxicities were reported with PG-free Melphalan. The following events occurred more frequently (>2 difference) when Alkeran was given first (edema, fluid retention, headache, dysguesia, Pollakiuria, rash, bundle branch block,) and the following events occurred more frequently (>2 difference) when PG-free Melphalan was given first (dizziness). PK analysis showed PG-free Melphalan was bioequivalent with Alkeran (Table-1) and also revealed that Cmax and AUC were higher (∼10%) after PG-free Melphalan. Interestingly, plasma concentrations of PG-free Melphalan were higher than Alkeran for up to 3 hours post-administration. Conclusions: PG-free Melphalan, administered as half of a high-dose conditioning regimen, resulted in successful myeloablation and subsequent engraftment with no immediate infusion-related toxicity and no additional overall transplant-related toxicity. PG-free Melphalan met the guidance requirements for bioequivalence with Alkeran while also demonstrating a marginally higher systemic drug exposure. Estimated values are based on an ANOVA on the log transformed PK parameters with fixed effects of sequence, formulation, and period and patient nested within sequence as a random effect. Disclosures: Off Label Use: I will discuss the use of high-dose melphalan for autologous transplantation. Pipkin:CyDex Pharmaceuticals, Inc (A Ligand Company): Employment.

Cell-Freezing Devices Are Not Strictly Needed to Start an Autologous Hematopoietic Transplantation Program: Non-Cryopreserved Peripheral Blood Stem Cells Can be Used to Restore Hematopoiesis after High Dose Chemotherapy: A Multicenter Experience in 268 Autografts in Patients with Multiple Myeloma or Lymphoma. Study on Behalf of the Latin-American Bone Marrow Transplantation Group (LABMT)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 849-849 ◽  
Author(s):  
Amado J Karduss-Urueta ◽  
Guillermo J. Ruiz-Arguelles ◽  
Rosendo Perez ◽  
Guillermo J Ruiz-Delgado ◽  
Angelica Maria Cardona ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Median Time ◽  
Latin American ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Peripheral Blood Stem Cells ◽  
Cd34 Cells ◽  
Transplantation Program ◽  
Blood Stem Cells

Abstract Storage of peripheral blood stem cells (PBSC) at 4ºC is a simple and inexpensive alternative to cryopreservation for preserving the clonogenic capacity of progenitors cells in the autologous transplant setting, however it has been perceived as unsafe and has deserved little attention. We present the experience of two Latin-American centers using refrigerated, non-cryopreserved stem cells after conditioning with high dose melphalan, CBV or BEAM in a large group of lymphoma and myeloma patients Materials and Methods PBSC were mobilized with filgrastim 5 mg/kg/BID for three to six days.One to three apheresis procedure were employed; the cells were stored at 4ºC for 5 to 6 days in patients who received BEAM or CBV and for 3 days in those given melphalan. All of the conditioning regimens were administered preserving the full intensity of dose (Table 1). After the autograft all patients received filgrastim or pegfilgrastim Table 1 BEAM D-5 D-4 D-3 D-2 D-1 BiCNU 300 mgs/m2 X Etoposide 200-400 mgs/m2 X X X X Citarabine 300-400 mgs/m2 X X X Melphalan 140 mgs/m2 X CBV BiCNU 300 mgs/m2 13 patients received carboplatin 900 mgs/m2 instead BiCNU X Etoposide 300 mgs/m2 X X X Ciclophosphamide 2.000 mgs/m2 X X X Melphalan Melphalan 200 mgs/m2 X Melphalan 100 mgs/m2 X X Results 102 lymphoma patients: 48 Hodgkin`s lymphoma (HL) and 54 non-Hodgkin´s lymphoma (NHL) received BEAM (71) or CBV (31). A median of 3.3 millions/kg of CD34 was infused; the median viability of the cells after 5-6 days of refrigeration (trypan blue exclusion) was 82%. 101 out of 102 patients engrafted, median time to achieve 500/ul neutrophil or more was 12 days, 100 were evaluable for thrombopoiesis, 99 of them had a self- sustained platelet count of 20.000 or more at a median of 17 days. The OS at 5 years was 59% and 42% for patients with Hodgkin and lymphoma respectively 151 patients with multiple myeloma received melphalan 200 mgs/m2. After 72 hours of refrigeration, a median of 2.6 millions/kg of CD34 cells were infused, the viability in all cases being > 90%. Three patients were not evaluable because early death. Median time to achieve 500 neutrophil or more and 20.000 platelets was 12 (9-50) and 15 (7-50) days. The OS at 5 years was 50% 21 patients with NHL and HL received as conditioning regimen melphalan 200 mgs/m2. After 72 hours of storage, a median of 1.75 millions/kg of CD34 cells were transplanted, 100% of them engrafted, median time to 500 neutrophils and 20.000 platelets was 11.9 and 15 days respectively There were no cases of secondary engraftment failure in any of the three groups Conclusion In this series of 268 patients, we have shown that autologous PBSC can be kept at 4ºC in a conventional blood bank refrigerator for up to six days and use them to rescue high-dose chemotherapy in both multiple myeloma and lymphoma patients. Avoiding freezing procedures results in substantial cost savings. The availability of freezing devices for hematopoietic stem cells is not anymore an obstacle to start a an autologous transplantation program This observation is critical in areas of underprivileged economic circumstances, where more than 50% of the inhabitants of the world live. Disclosures No relevant conflicts of interest to declare.

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