Kombinationschemo, periphere Stammzelltransplantation, biologische Therapie, Pamidronat und Thalidomid bei multiplem Myelom
Sequentielle hochdosierte Behandlung mit Melphalan und Busulfan/Cyclophosphamid, gefolgt von der Rettung peripherer Blutvorläuferzellen, Interferon/Thalidomid und Pamidronat für Patienten mit multiplem Myelom
RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow doctors to give higher doses of chemotherapy drugs and kill more cancer cells. Biological therapies, such as interferon alfa, use different ways to stimulate the immune system and stop cancer cells from growing. Thalidomide may stop the growth of cancer cells by stopping blood flow to the tumor. Pamidronate may help to reduce the side effects of treatment for multiple myeloma.
PURPOSE: This phase II trial is studying combination chemotherapy, peripheral stem cell transplantation, biological therapy, pamidronate, and thalidomide to see how well they work in treating patients with stage I, stage II, or stage III multiple myeloma.
Studienübersicht
Status
Bedingungen
Detaillierte Beschreibung
OBJECTIVES:
- Determine the feasibility and toxic effects of high-dose melphalan, busulfan, and cyclophosphamide followed by autologous peripheral blood stem cell rescue, interferon alfa, and pamidronate in patients with responsive or stable, low-bulk multiple myeloma.
- Determine the response rate and progression-free and overall survival of patients treated with this regimen.
- Determine the feasibility of adding thalidomide to interferon alfa and pamidronate in patients who are not in complete remission (CR) 6 months after the second course of high-dose chemotherapy.
- Determine whether administration of thalidomide can increase the CR rate in patients who are not in CR 6 months after the second course of high-dose chemotherapy and determine its effect on progression-free and overall survival of these patients.
- Determine the pharmacokinetics of busulfan and cyclophosphamide and correlate the pharmacokinetics with the toxic effects of these drugs and outcome in these patients.
- Determine the effect of thalidomide on microvascular density of bone marrow and correlate these possible effects with outcome in these patients.
- Determine the cytogenetics, gene rearrangement, and fluorescence in situ hybridization in baseline and post treatment bone marrow and blood specimens and correlate the presence/persistence of these features with treatment outcome in these patients.
OUTLINE: Patients receive cyclophosphamide IV over 2 hours on day 1 and filgrastim (G-CSF) subcutaneously (SC) or IV twice a day beginning on day 2 and continuing until peripheral blood stem cells (PBSCs) are collected. PBSCs are collected beginning on day 10.
Patients receive high-dose melphalan IV on day -1. PBSCs are reinfused on day 0. G-CSF is administered IV or SC daily beginning on day 1 and continuing until blood counts recover. Between 8 and 14 weeks later, patients receive high-dose busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. PBSCs are reinfused on day 0 and G-CSF is administered IV or SC daily until blood counts recover.
Patients with responding or stable disease after chemotherapy receive maintenance therapy with interferon alfa beginning 14-20 weeks after day 0 of the second course of chemotherapy. Interferon alfa is administered SC 3 times a week for 3 years. Patients also receive pamidronate IV every 4 weeks until disease progression. Patients who are not in complete remission (CR) 6 months after completing the second course of chemotherapy receive oral thalidomide daily for a maximum of 1 year or for 3 months after achieving CR.
Patients are followed monthly for 1 year, every 3 months for 1 year, and then periodically thereafter.
PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study within approximately 2.5 years.
Studientyp
Einschreibung (Tatsächlich)
Phase
- Phase 2
Kontakte und Standorte
Studienorte
-
-
Arizona
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Phoenix, Arizona, Vereinigte Staaten, 85006
- Banner Good Samaritan Medical Center
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California
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Duarte, California, Vereinigte Staaten, 91010-3000
- City of Hope Comprehensive Cancer Center
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Teilnahmekriterien
Zulassungskriterien
Studienberechtigtes Alter
Akzeptiert gesunde Freiwillige
Studienberechtigte Geschlechter
Beschreibung
DISEASE CHARACTERISTICS:
-
Histologically proven stage I-III multiple myeloma
-
Less than 18 months since diagnosis
-
Smoldering myeloma allowed if there is evidence of progressive disease requiring therapy
- At least 25% increase in M protein levels or Bence Jones excretion
- Hemoglobin no greater than 10.5 g/dL
- Hypercalcemia
- Frequent infections
- Rise in serum creatinine above normal on 2 separate occasions
-
Nonquantifiable monoclonal proteins allowed if other criteria for multiple myeloma or smoldering myeloma are met
-
-
Response/status after induction therapy:
- Responding or stable disease AND no greater than 40% myelomatous involvement of bone marrow
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No Waldenstrom's macroglobulinemia
PATIENT CHARACTERISTICS:
Age:
- 65 and under
Performance status:
- Karnofsky 80-100%
Life expectancy:
- Not specified
Hematopoietic:
- See Disease Characteristics
- Absolute neutrophil count greater than 1,500/mm^3
- Platelet count greater than 100,000/mm^3
Hepatic:
- Bilirubin no greater than 1.5 mg/dL
- Serum glutamic axaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) less than 2.5 times upper limit of normal
- Hepatitis B antigen or hepatitis C ribonucleaic acid (RNA) negative
Renal:
- See Disease Characteristics
- Creatinine no greater than 1.4 mg/dL
- Creatinine clearance greater than 65 mL/min
Cardiovascular:
- Cardiac ejection fraction at least 50% by multigated acquisition scan (MUGA) or echocardiogram
Pulmonary:
- Forced-expiratory volume in one second (FEV_1) greater than 60% of normal
- Diffusing capacity for carbon monoxide (DLCO) greater than 50% of predicted lower limit
Other:
- Not pregnant
- Negative pregnancy test
- Fertile patients must use effective contraception
- Human immunodeficiency virus (HIV) negative
- No other medical or psychosocial problems that would increase patient risk
- No other malignancy within past 5 years except nonmelanomatous skin cancer or carcinoma in situ of the cervix
- No known hypersensitivity to filgrastim (G-CSF) or Escherechi coli-derived proteins
PRIOR CONCURRENT THERAPY:
Biologic therapy:
- Not specified
Chemotherapy:
- See Disease Characteristics
- No more than 3 prior chemotherapy regimens
- At least 4 weeks since prior chemotherapy
Endocrine therapy:
- Not specified
Radiotherapy:
- At least 4 weeks since prior radiotherapy
Surgery:
- Not specified
Studienplan
Wie ist die Studie aufgebaut?
Designdetails
- Hauptzweck: Behandlung
- Zuteilung: N / A
- Interventionsmodell: Einzelgruppenzuweisung
- Maskierung: Keine (Offenes Etikett)
Waffen und Interventionen
Teilnehmergruppe / Arm |
Intervention / Behandlung |
|---|---|
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Experimental: HD chemotherapy followed by PBPC Rescue
Patients receive high-dose (HD) melphalan intra-venously (IV) on day -1. Peripheral blood progenitor cells (PBPCs) are reinfused on day 0. Filgrastim (G-CSF) is administered IV or SC daily beginning on day 1 and continuing until blood counts recover. Between 8 and 14 weeks later, patients receive IV high-dose busulfan every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. PBPCs are reinfused on day 0 and G-CSF is administered IV or subcutaneously (SC) daily until blood counts recover. |
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Was misst die Studie?
Primäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
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Best Response Prior to Tandem Autologous Stem Cell Transplant
Zeitfenster: From enrollment in the study until day -8: before dilantin given pre-first high-dose chemo preceeding first cycle of tandem autologous cell transplant
|
Response gradations are specified in the "Blade criteria", Br J Haematol 1998; 102: 1115-1123. Serum myeloma protein is measured 2x at least six weeks apart, and urine M-component is measured 2x at least 3 weeks apart. Complete response (CR): less than 3% plasma cells in bone marrow or blood. Very good partial response (VGPR): Greater than 90% decrease in myeloma protein, and urine M-component less than 0.1 gm/day. Partial response (PR) Greater than 50% decrease in myeloma protein; urine M-component less than 0.2 gm/day. Lytic skeletal lesions must not increase, and serum calcium level must remain normal. Stable disease (SD): 25-49% decrease in protein and 25% decrease in urine M-component. Progressive disease (PD): Greater than 25% increase in myeloma protein, or hypercalcemia. Relapse: 1) increase greater than 100% of myeloma protein; 2) More than 25% increase of myeloma protein; 3) reappearance of the myeloma peaks; 4) increase in lytic bone lesions on radiographs. |
From enrollment in the study until day -8: before dilantin given pre-first high-dose chemo preceeding first cycle of tandem autologous cell transplant
|
|
Response After Tandem Autologous Stem Cell Transplant
Zeitfenster: After second cycle of tandem autologous stem cell transplant: Day 0 of second transplant to 12 weeks post-cycle 2 cell infusion of the tandem transplant.
|
Response gradations are specified in the "Blade criteria", Br J Haematol 1998; 102: 1115-1123. Serum myeloma protein is measured 2x at least six weeks apart, and urine M-component is measured 2x at least 3 weeks apart. Complete response (CR): less than 3% plasma cells in bone marrow or blood. Very good partial response (VGPR): Greater than 90% decrease in myeloma protein, and urine M-component less than 0.1 gm/day. Partial response (PR) Greater than 50% decrease in myeloma protein; urine M-component less than 0.2 gm/day. Lytic skeletal lesions must not increase, and serum calcium level must remain normal. Stable disease (SD): 25-49% decrease in protein and 25% decrease in urine M-component. Progressive disease (PD): Greater than 25% increase in myeloma protein, or hypercalcemia. Relapse: 1) increase greater than 100% of myeloma protein; 2) More than 25% increase of myeloma protein; 3) reappearance of the myeloma peaks; 4) increase in lytic bone lesions on radiographs. |
After second cycle of tandem autologous stem cell transplant: Day 0 of second transplant to 12 weeks post-cycle 2 cell infusion of the tandem transplant.
|
|
Three-year Overall Survival
Zeitfenster: Estimate reported at three years after day 0 of the first cycle of infusion of cells of the tandem transplant.
|
Kaplan-Meier estimate at three years post-first transplant of survival. Outcome is death or alive at follow-up (censored). 95 percent confidence interval of the point estimate is calculated using Greenwood's variance. |
Estimate reported at three years after day 0 of the first cycle of infusion of cells of the tandem transplant.
|
|
Progression-free Survival
Zeitfenster: Estimate reported at three years after day 0 of the first cycle of infusion of cells of the tandem transplant.
|
Kaplan-Meier estimate at three years post-first transplant of survival. Event of interest is the first of Death or Progression. Censoring is Alive in Continuous Complete Remission at date of last follow-up. 95 percent confidence interval of the point estimate is calculated using Greenwood's variance. |
Estimate reported at three years after day 0 of the first cycle of infusion of cells of the tandem transplant.
|
|
Best Response at 6 Months Post Tandem Autologous Stem Cell Transplant
Zeitfenster: Six months after day 0 of the first cycle of the tandem autologous stem cell transplant. This will be used to determine administration of thalidomide.
|
Response gradations are specified in the "Blade criteria", Br J Haematol 1998; 102: 1115-1123. Serum myeloma protein is measured 2x at least six weeks apart, and urine M-component is measured 2x at least 3 weeks apart. Complete response (CR): less than 3% plasma cells in bone marrow or blood. Very good partial response (VGPR): Greater than 90% decrease in myeloma protein, and urine M-component less than 0.1 gm/day. Partial response (PR) Greater than 50% decrease in myeloma protein; urine M-component less than 0.2 gm/day. Lytic skeletal lesions must not increase, and serum calcium level must remain normal. Stable disease (SD): 25-49% decrease in protein and 25% decrease in urine M-component. Progressive disease (PD): Greater than 25% increase in myeloma protein, or hypercalcemia. Relapse: 1) increase greater than 100% of myeloma protein; 2) More than 25% increase of myeloma protein; 3) reappearance of the myeloma peaks; 4) increase in lytic bone lesions on radiographs. |
Six months after day 0 of the first cycle of the tandem autologous stem cell transplant. This will be used to determine administration of thalidomide.
|
|
Best Response After Tandem Autologous Stem Cell Transplant and Maintenance
Zeitfenster: Response after six months after day 0 of the first cycle of the tandem transplant, after administration of maintenance thalidomide if necessary, until three years post-day 0 of the first cycle of the tandem transplant.
|
Response gradations are specified in the "Blade criteria", Br J Haematol 1998; 102: 1115-1123. Serum myeloma protein is measured 2x at least six weeks apart, and urine M-component is measured 2x at least 3 weeks apart. Complete response (CR): less than 3% plasma cells in bone marrow or blood. Very good partial response (VGPR): Greater than 90% decrease in myeloma protein, and urine M-component less than 0.1 gm/day. Partial response (PR) Greater than 50% decrease in myeloma protein; urine M-component less than 0.2 gm/day. Lytic skeletal lesions must not increase, and serum calcium level must remain normal. Stable disease (SD): 25-49% decrease in protein and 25% decrease in urine M-component. Progressive disease (PD): Greater than 25% increase in myeloma protein, or hypercalcemia. Relapse: 1) increase greater than 100% of myeloma protein; 2) More than 25% increase of myeloma protein; 3) reappearance of the myeloma peaks; 4) increase in lytic bone lesions on radiographs. |
Response after six months after day 0 of the first cycle of the tandem transplant, after administration of maintenance thalidomide if necessary, until three years post-day 0 of the first cycle of the tandem transplant.
|
Mitarbeiter und Ermittler
Sponsor
Mitarbeiter
Ermittler
- Hauptermittler: George Somlo, MD, City of Hope Medical Center
Publikationen und hilfreiche Links
Allgemeine Veröffentlichungen
- Long-term Progression-free (PFS) and Overall Survival (OS) with Tandem Autologous Transplant (TASCT) After High-dose Induction With Melphalan (MEL) and Busulfan/cyclophosphamide (BU/CY), or a Novel Regimen of MEL and Total Marrow Irradiation (TMI), Followed by Maintenance With Interferon A-2 (IF) and/or Thalidomide (THAL). Haematologica 96(s1), 2011, s103. G. Somlo, J. Palmer, A. Dagis, M. O'Donnell, D. Snyder, F. Sahebi, N. Kogut, A. Brown, R. Spielberger, P.Parker, C. Karanes, L. Popplewell, A. Stein, A. Krishnan, J. Alvarnas, J. Wong, S. Forman.
Studienaufzeichnungsdaten
Haupttermine studieren
Studienbeginn (Tatsächlich)
Primärer Abschluss (Tatsächlich)
Studienabschluss (Tatsächlich)
Studienanmeldedaten
Zuerst eingereicht
Zuerst eingereicht, das die QC-Kriterien erfüllt hat
Zuerst gepostet (Geschätzt)
Studienaufzeichnungsaktualisierungen
Letztes Update gepostet (Tatsächlich)
Letztes eingereichtes Update, das die QC-Kriterien erfüllt
Zuletzt verifiziert
Mehr Informationen
Begriffe im Zusammenhang mit dieser Studie
Schlüsselwörter
Zusätzliche relevante MeSH-Bedingungen
- Gefäßerkrankungen
- Herz-Kreislauf-Erkrankungen
- Neubildungen
- Erkrankungen des Immunsystems
- Neubildungen nach histologischem Typ
- Hämatologische Erkrankungen
- Lymphoproliferative Erkrankungen
- Immunproliferative Erkrankungen
- Hämostasestörungen
- Paraproteinämien
- Bluteiweißstörungen
- Hämorrhagische Störungen
- Hämische und lymphatische Krankheiten
- Multiples Myelom
- Neubildungen, Plasmazelle
- Peptide
- Aminosäuren, Peptide und Proteine
- Proteine
- Schwefelverbindungen
- Organische Chemikalien
- Heterocyclische Verbindungen, 1-Ring
- Heterocyclische Verbindungen
- Heterocyclische Verbindungen, 2-Ring
- Heterocyclische Verbindungen, Fusionsring
- Therapeutika
- Chirurgische Eingriffe, operativ
- Kohlenwasserstoffe, acyclisch
- Kohlenwasserstoffe
- Biologische Faktoren
- Kohlenhydrate
- Carboxylsäuren
- Transplantation
- Piperidine
- Aminosäuren
- Alkane
- Alkohole
- Butylenglykole
- Glykole
- Mesylate
- Alkanesulfonate
- Alkanesulfonsäuren
- Sulfonsäuren
- Schwefelsäuren
- Genomkomponenten
- Genom
- Genetische Strukturen
- Genetische Phänomene
- Phosphoramid -Senf
- Stickstoffsenfverbindungen
- Senfverbindungen
- Kohlenwasserstoffe, halogeniert
- Phosphoramide
- Organophosphorverbindungen
- Interzelluläre Signalpeptide und Proteine
- Glykoproteine
- Glykoconjugate
- Zelltransplantation
- Zell- und Gewebe-basierte Therapie
- Biologische Therapie
- Phenylalanin
- Aminosäuren, aromatisch
- Aminosäuren, zyklisch
- Organophosphonate
- Phthalimides
- Phthalsäuren
- Säuren, carbocyclisch
- Piperidones
- Isoindolen
- Koloniestimulierende Faktoren
- Hämatopoetische Zellwachstumsfaktoren
- Zytokine
- Stammzelltransplantation
- Interferon Typ i
- Interferonen
- Hämatopoetische Stammzelltransplantation
- Diphosphonate
- Genkomponenten
- Gene
- DNA, intergenisch
- Pamidronat
- Cyclophosphamid
- Melphalan
- Busulfan
- Thalidomid
- Interferon-alpha
- Granulozyten-Kolonie-stimulierender Faktor
- Filgrastim
- Periphere Blutstammzelltransplantation
- Introns
Andere Studien-ID-Nummern
- 99021
- P30CA033572 (US NIH Stipendium/Vertrag)
- CHNMC-IRB-99021 (Andere Kennung: City of Hope Institutional Review Board)
- NCI-G99-1583 (Andere Kennung: National Cancer Institute)
- CDR0000067301 (Registrierungskennung: NCI PDQ)
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