A Phase IIa, Open-Label, Randomized, Pharmacokinetic Comparative, Cross-Over Studyof Melphalan HCl for Injection (propylene glycol-free) and Alkeran for Injection for Myeloablative Conditioning In Multiple Myeloma Patients Undergoing Autologous Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4525-4525
Author(s):  
Omar Aljitawi ◽  
Siddhartha Ganguly ◽  
Sunil Abhyankar ◽  
J. Daniel Robinson ◽  
J, D. Pipkin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Propylene Glycol ◽  
Median Time ◽  
Autologous Transplantation ◽  
High Dose ◽  
High Dose Therapy ◽  
Open Label ◽  
Dose Therapy ◽  
The Mean ◽  
High Dose Melphalan

Abstract Abstract 4525 High dose therapy and autologous transplantation is considered a standard of care procedure in symptomatic, transplant eligible multiple myeloma patients. The chemotherapy of choice in this situation is high dose melphalan. The later has marginal solubility and limited chemical stability upon reconstitution and dilution. The marginal stability of this compound has limited the use of regimens utilizing higher absolute dosages and/or longer infusions (> 60 minutes) that could potentially lead to improved outcomes. Accordingly, co-solvents are used in the marketed formulation, which are believed to contribute to the side effects of the therapy. A co-solvent used in Alkeran for Injection is propylene glycol, which has been reported to cause renal dysfunction, arrhythmias, hyperosmolality, increased anion gap metabolic acidosis, and sepsis-like syndrome. On the other hand, Melphalan HCl for Injection (Propylene Glycol-Free), a reformulation of Alkeran for Injection, incorporates the Captisol® brand of β-cyclodextrin sulfobutyl ethers, sodium salts (also known as [SBE]7m-β-CD) into a freeze-dried product developed by CyDex Pharmaceuticals, Inc. (CyDex). Captisol improves stability allowing for potentially longer infusion times. Study Design/Goals: In this phase IIa, open-label, randomized, cross-over design, the PK of Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection are assessed in the same MM patients undergoing transplantation. Furthermore, the rates of myeloablation and subsequent engraftment are determined, and any difference in expected safety and tolerability due to high-dose Melphalan HCl for Injection (Propylene Glycol-Free) is assessed in transplanted patients. Results: Seven patients of the planned 24 patients have already enrolled in the study at the University of Kansas Medical Center. All patients achieved myeloablation followed by successful engraftment. Median time to myeloablation, defined as number of days from the start of chemotherapy until absolute neutrophil count dropped below 500/Ul, was 6.4 days (range 5–7 days). Median time to neutrophil engraftment, defined as first day of three consecutive days where ANC was higher than 500/Ul following their nadir, was day +9. Beside expected grade 2–3 toxicities related to high dose melphalan, no additional toxicities were reported. In specific, no renal insufficiency was noted. Preliminary PK analysis has been performed on five patients. Preliminiary parameter estimates (Mean± SEM) are presented in the Table. The mean bioavailability was 113%. The mean half-lifes for the Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection were 70 and 75 min. Following Melphalan HCL for Injection (PropyleneGlycol-Free) and Alkeran for Injection, the distribution volumes were 0.23 and 0.35 L/kg and clearances were 0.29 and 0.34 L/hr per kg, respectively. Conclusion: Melphalan HCl for Injection (Propylene Glycol-Free), administered as half of a high-dose conditioning regimen, appears to result in successful myeloablation and subsequent engraftment at no extra-toxicity, and trending toward higher bio-availability compared to Alkeran. Future studies that are designed to expose patients exclusively to the propylene glycol-free formulation will delineate potential safety and efficacy advantages over the current therapy.ProductN=Cmax (μ g/mL)t½α(min)t½ β(min)Vc (L)Vdss (L)AUC (μ g* min/mL)CL (mL/min)Melphalan HCl for Injection55.5 ± 2.112.9 ± 2.769.6 ± 2.825.5 ± 11.042.0 ± 15.4424 ± 146529 ± 187Alkeran54.4 ± 2.624.2 ± 19.774.8 ± 14.039.3 ± 25.752.3 ± 22.1375 ± 167631 ± 209 Disclosures: Aljitawi: CyDex Pharmaceuticals, Inc.: Research Funding. Off Label Use: Melphalan use in high dose therapy and autologous transplantation. Robinson:CyDex Pharmaceuticals, Inc.: Consultancy. Pipkin:CyDex Pharmaceuticals, Inc.: Employment.

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.

The Effect of Bortezomib Containing Induction On the Long Term Outcome of autologous Haemopoietic Stem Cell Transplantation in Multiple Myeloma Patients Outside Clinical Trials - a Single Center Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5050-5050
Author(s):  
Miklos Udvardy ◽  
Remenyi Gyula ◽  
Attila Kiss ◽  
Peter Batar ◽  
Arpad Illes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Practice ◽  
Median Survival ◽  
Induction Therapy ◽  
High Dose ◽  
High Dose Therapy ◽  
Long Term Outcome ◽  
Dose Therapy ◽  
Starting Point ◽  
The Mean

Abstract Abstract 5050 Introduction: We aimed to investigate the effect of bortezomib-based induction therapy for the treatment of transplant-eligible multiple myeloma (MM) patients, as compared to non-bortezomib-based treatments, in daily clinical practice. Patients and methods: All 122 transplant eligible MM patients treated at our center between 2003 and 2011 were reviewed retrospectively without selection. Patients had received induction with or without a bortezomib-based regimen, followed by high dose therapy (single Mel200+APSCT). The group consistend of 64 males and 58 females, mean age: 55, 2±8, 7 year. 45, 9% of the patients had IgGκ (56), 18% IgGλ (22), 10, 6% IgAκ (13), 7, 3% IgAλ (9), 0, 8% IgMκ (1), 3, 2% κ (4), 10, 6% λ (13), and 3, 2% had non secretory (4) MM. Bone marrow FISH analysis revealed del-13q in 2 cases, monosomy 13 in 14, t4:14 in 1, monosomy 13 + del 17p in 1. Plasma cell leukemia (primary and secondary) was found in 2 cases. Induction therapy was applied either in our center, or patients were referred to us to perform high dose therapy after induction therapy given in other regional hematology departments. Due to regulatory reasons, patients mainly received non-bortezomib containing induction (VAD, thal-dex 78%, bortezomib-based 22%) until 2008. Later predominantly bortezomib-based therapy was used (69%, mainly VTD or PAD), the remaining (mainly those referred to our center) cases had thal-dex, or CTD induction. Results: Patients without bortezomib in induction: The mean followup of the 22 patients who did not receive bortezomib as part of induction was 53. 2+21. 9 month, 14 of them died (66, 7%) during followup. Median survival reached at 38 month following induction, or if calculated after completion of high dose therapy median survival was 52 month. Patients with bortezomib based induction. The mean follow-up time of this 100 patients time was 44, 5+ 27, 6 months. 25 pts died (25%) and survival probability at 50 month from the initation of induction was 69. 8 % in these patients compared to the 40. 7% estimated survival for the patients without bortezomib (p<0. 01). Survival probabilty at 50 month after completion of high dose therapy (as a new starting point of followup) was 39, 7% without bortezomib-based induction and 74, 6%, in patients receiving bortezomib-based induction (p<0. 05). Median survival times has not reached following induction and high dose therapy. Conclusions: This retrospective survey clearly supports the important role of that bortezomib containing induction regimens achieving prolonged survival both after induction and following high dose therapy in multiple myeloma clinical practice settings, as compared to regimens without bortezomib. Disclosures: Off Label Use: Rituximab is not authorized for Mantle Cell Lymphoma in Hungary.

Induction Therapy in Multiple Myeloma

Hematology ◽  
2008 ◽  
Vol 2008 (1) ◽  
pp. 306-312 ◽  
Author(s):  
Jean-Luc Harousseau
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Tumor Burden ◽  
Prolonged Treatment ◽  
Induction Treatment ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
High Dose Melphalan

Abstract In most hematologic malignancies the role of induction treatment is to achieve complete remission (CR). In multiple myeloma this has been possible only with the introduction of high-dose therapy plus autologous stem-cell transplantation (ASCT). In the context of ASCT there is a statistical relationship between CR or very good partial remission (VGPR) achievement and progression-free survival or overall survival. High-dose therapy consists of 3 to 6 courses of a dexamethasone alone or combined with vincristine-adriamycin (VAD) to reduce the tumor burden and the plasma cell infiltration followed by 1 or 2 courses of high-dose melphalan plus ASCT. This treatment induces 20% to 40% CR and 40% to 55% CR/VGPR. The introduction of novel agents in the induction treatment is changing this scenario. The combinations of dexamethasone with thalidomide, bortezomib or lenalidomide increase the CR/VGPR rates compared to dexamethasone or VAD. Triple combinations are currently being evaluated, but preliminary results with not more than 3 or 4 cycles show post-ASCT CR/VGPR rates of 60% to 75% In elderly patients who are not candidates for ASCT, combinations of melphalan-prednisone with a novel agent (thalidomide, bortezomib or lenalidomide) yield CR/VGPR rates that are quite comparable to those achieved in younger patients with ASCT. Prolonged treatment with the combination of lenalidomide plus dexamethasone can be administered safely and appears to induce very high (up to 70%) CR/VGPR rates as well.

scholarly journals Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4039-4047 ◽  
Author(s):  
Heinz Ludwig ◽  
Brian G. M. Durie ◽  
Vanessa Bolejack ◽  
Ingemar Turesson ◽  
Robert A. Kyle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Risk Factor ◽  
Conventional Therapy ◽  
Autologous Transplantation ◽  
Young Patients ◽  
Poor Performance Status ◽  
High Dose ◽  
High Dose Therapy ◽  
Prognostic Features ◽  
Dose Therapy

Abstract We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P < .001) both after conventional (median, 4.5 years vs 3.3 years; P < .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.

scholarly journals Double-intensive therapy in high-risk multiple myeloma

Blood ◽  
1992 ◽  
Vol 79 (11) ◽  
pp. 2827-2833 ◽  
Author(s):  
JL Harousseau ◽  
N Milpied ◽  
JP Laporte ◽  
P Collombat ◽  
T Facon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
High Risk ◽  
Autologous Transplantation ◽  
High Dose ◽  
High Dose Therapy ◽  
Hematopoietic Stem ◽  
Dose Therapy ◽  
Group 2 ◽  
Group 1

A high remission rate is achieved with high-dose melphalan (HDM) in multiple myeloma (MM), and autologous transplantation of hematopoietic stem cells allows a prompt hematologic recovery after high-dose therapy. We treated 97 patients with high-risk MM (group 1:44 advanced MM including 14 primary resistances and 30 relapses; group 2: 53 newly diagnosed MM) with a first course of HDM. For responding patients a second course of high-dose therapy with hematopoietic stem cell support was proposed. After the first HDM, the overall response and complete remission rates were 71% and 25% with no significant difference between the two groups. The median durations of neutropenia and thrombocytopenia were significantly longer in group 1 (29.5 days and 32 days, respectively) than in group 2 (23 days and 17 days, respectively). This severe myelosuppression led to eight toxic deaths and the fact that only 38 of the 69 responders could proceed to the second course (three allogenic and 35 autologous transplantations). Among the 35 patients undergoing autologous transplantation (10 in group 1, 25 in group 2), 31 received their marrow unpurged collected after the first HDM, and four received peripheral blood stem cells. The median durations of neutropenia and thrombocytopenia after autologous transplantation were 24 days and 49 days, respectively. Two toxic deaths and nine prolonged thrombocytopenias were observed. The median survival for the 97 patients was 24 months (17 months in group 1, 37 months in group 2) and the median duration of response was 20 months. The only parameters that have a significant impact on the survival are the age (+/- 50 years) and the response to HDM. The median survival of the 35 patients undergoing autologous transplantation is 41 months, but the median duration of remission is 28 months with no plateau of the remission duration curve. Patients responding to HDM may have prolonged survival, but even a second course of high-dose therapy probably cannot eradicate the malignant clone.

scholarly journals Double-intensive therapy in high-risk multiple myeloma

Blood ◽  
1992 ◽  
Vol 79 (11) ◽  
pp. 2827-2833 ◽  
Author(s):  
JL Harousseau ◽  
N Milpied ◽  
JP Laporte ◽  
P Collombat ◽  
T Facon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
High Risk ◽  
Autologous Transplantation ◽  
High Dose ◽  
High Dose Therapy ◽  
Hematopoietic Stem ◽  
Dose Therapy ◽  
Group 2 ◽  
Group 1

Abstract A high remission rate is achieved with high-dose melphalan (HDM) in multiple myeloma (MM), and autologous transplantation of hematopoietic stem cells allows a prompt hematologic recovery after high-dose therapy. We treated 97 patients with high-risk MM (group 1:44 advanced MM including 14 primary resistances and 30 relapses; group 2: 53 newly diagnosed MM) with a first course of HDM. For responding patients a second course of high-dose therapy with hematopoietic stem cell support was proposed. After the first HDM, the overall response and complete remission rates were 71% and 25% with no significant difference between the two groups. The median durations of neutropenia and thrombocytopenia were significantly longer in group 1 (29.5 days and 32 days, respectively) than in group 2 (23 days and 17 days, respectively). This severe myelosuppression led to eight toxic deaths and the fact that only 38 of the 69 responders could proceed to the second course (three allogenic and 35 autologous transplantations). Among the 35 patients undergoing autologous transplantation (10 in group 1, 25 in group 2), 31 received their marrow unpurged collected after the first HDM, and four received peripheral blood stem cells. The median durations of neutropenia and thrombocytopenia after autologous transplantation were 24 days and 49 days, respectively. Two toxic deaths and nine prolonged thrombocytopenias were observed. The median survival for the 97 patients was 24 months (17 months in group 1, 37 months in group 2) and the median duration of response was 20 months. The only parameters that have a significant impact on the survival are the age (+/- 50 years) and the response to HDM. The median survival of the 35 patients undergoing autologous transplantation is 41 months, but the median duration of remission is 28 months with no plateau of the remission duration curve. Patients responding to HDM may have prolonged survival, but even a second course of high-dose therapy probably cannot eradicate the malignant clone.

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