Melphalan and Amifostine Followed By One or Two Autologous or Syngeneic Stem Cell Transplants and Maintenance Therapy in Treating Patients With Stage II-III Multiple Myeloma

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00217438
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 130
• Locations: 4
• Arms: 2
• Patients Per Site: 32.5

Study Details

Study Description

Brief Summary

RATIONALE: Giving chemotherapy drugs, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemoprotective drugs, such as amifostine, may protect normal cells from the side effects of chemotherapy. Giving chemotherapy with a peripheral stem cell transplant once or twice, using stem cells from the patient or an identical brother or sister, may allow more chemotherapy to be given so more cancer cells are killed. Giving maintenance therapy after a stem cell transplant may kill any cancer cells that remain. It is not yet known which dose of melphalan is more effective in treating multiple myeloma (MM).

PURPOSE: This randomized phase III trial is studying two different doses of melphalan to compare how well they work when given together with amifostine followed by one or two autologous or syngeneic stem cell transplants and maintenance therapy in treating patients with stage II-III MM

Condition or Disease	Intervention/Treatment	Phase
Refractory Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma	Drug: melphalan; Drug: amifostine trihydrate; Procedure: peripheral blood stem cell transplantation; Genetic: fluorescence in situ hybridization; Procedure: bone marrow ablation with stem cell support	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. Compare the complete response (CR) and near CR rate in patients undergoing autologous stem cell transplant (ASCT) using melphalan 280 mg/m^{2 or melphalan 200 mg/m}2.

SECONDARY OBJECTIVES:

1. Compare toxicities between patients receiving amifostine and melphalan 280 mg/m^{2 or melphalan 200 mg/m}2.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

INDUCTION THERAPY:

ARM I (HIGH DOSE MELPHALAN AND AMIFOSTINE): Patients receive amifostine intravenously (IV) over 3-5 minutes on days -3 and -2 followed by high-dose melphalan IV over 15-30 minutes on day 2.

ARM II (LOW DOSE MELPHALAN AND AMIFOSTINE): Patients receive amifostine as in arm I and melphalan as in arm I at a lower dose.

AUTOLOGOUS OR SYNGENEIC PERIPHERAL BLOOD STEM CELL TRANSPLANTATION (PBSCT): At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0.

Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT.

Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.

After completion of study treatment, patients are followed up every 3 months for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-Center Phase III Study of Autologous Transplantation for Patients With Multiple Myeloma Comparing Melphalan 280 mg/m2 + Amifostine With Melphalan 200 mg/m2 + Amifostine
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (high dose melphalan, amifostine trihydrate, transplant) INDUCTION THERAPY: Patients receive amifostine IV over 3-5 minutes on days -3 and -2 followed by high-dose melphalan IV over 15-30 minutes on day 2. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.	Drug: melphalan; Given IV; Other Names: Alkeran CB-3025 L-PAM L-phenylalanine mustard L-Sarcolysin ; Drug: amifostine trihydrate; Given IV; Other Names: ethiofos Ethyol gammaphos WR-2721 ; Procedure: peripheral blood stem cell transplantation; Undergo PBSCT; Other Names: PBPC transplantation PBSC transplantation peripheral blood progenitor cell transplantation transplantation, peripheral blood stem cell ; Genetic: fluorescence in situ hybridization; Correlative study; Other Names: fluorescence in situ hybridization (FISH) ; Procedure: bone marrow ablation with stem cell support; Undergo transplant
Active Comparator: Arm II (low dose melphalan, amifostine trihydrate, transplant) INDUCTION THERAPY: Patients receive amifostine as in arm I and melphalan as in arm I at a lower dose. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.	Drug: melphalan; Given IV; Other Names: Alkeran CB-3025 L-PAM L-phenylalanine mustard L-Sarcolysin ; Drug: amifostine trihydrate; Given IV; Other Names: ethiofos Ethyol gammaphos WR-2721 ; Procedure: peripheral blood stem cell transplantation; Undergo PBSCT; Other Names: PBPC transplantation PBSC transplantation peripheral blood progenitor cell transplantation transplantation, peripheral blood stem cell ; Genetic: fluorescence in situ hybridization; Correlative study; Other Names: fluorescence in situ hybridization (FISH) ; Procedure: bone marrow ablation with stem cell support; Undergo transplant

Outcome Measures

Primary Outcome Measures

1. CR and Near CR Rates [Up to 120 days after transplant]

   Per modified European Group for Blood and Marrow Transplant (EBMT) response criteria for definition of response in patients with multiple myeloma treated by high-dose therapy and stem cell transplantation: Complete Response (CR): Complete disappearance of all clinically measurable disease, complete response requires negative tests for monoclonal proteins in serum and urine by immunofixation, no monoclonal plasma cells in marrow specimen by flow cytometry and no evidence of progressive bone disease by skeletal survey. "Near" Complete Response (nCR): Less than 0.1 gram/dL monoclonal protein detectable in serum by standard protein electrophoresis and less than 50 mg monoclonal protein detectable in urine on 24 hour collection. Less than 5% monoclonal plasma cells detectable in bone marrow by immunohistochemistry. No evidence of progressive bone disease by skeletal survey.

Secondary Outcome Measures

1. Relative Toxicities Between Melphalan 280 mg/m^2 or Melphalan 200 mg/m^2 [Up to day 56 after transplant]

   Number of Grade 3-4 adverse events observed in each group from enrollment through the Day 80-120 evaluation. Grade 3-4 events are defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients who have MM undergoing autologous or syngeneic hematopoietic transplantation

• Patients must meet Salmon and Durie criteria for initial diagnosis of MM

• Transplant will be offered to patients with stage II or III MM

• Measurable disease, defined as serum monoclonal protein >= 0.2 g/dl or Bence Jones protein >= 200 mg/24 h

• Karnofsky >= 70 or Eastern Cooperative Oncology Group (ECOG) 0-2

• Life expectancy is not severely limited by concomitant illness

• Left ventricular ejection fraction >= 50%

• No uncontrolled arrhythmias or symptomatic cardiac disease

• Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and diffusion capacity of carbon monoxide (DLCO) >= 50%

• No symptomatic pulmonary disease

• Human immunodeficiency virus (HIV) negative

• Bilirubin < 2 mg/dl

• Serum glutamic pyruvate transaminase (SGPT) < 2.5 x normal

• Creatinine clearance >= 60 cc/min, estimated or measured

• Signed informed consent

Exclusion Criteria:

• Pregnant or lactating females

• Uncontrolled infection

• Planned tandem autologous/reduced intensity allograft

• Insufficient PBSC for an autologous transplant (< 3.0 x 10^6 CD34+ cells/kg total)

• Prior autologous transplant

• Non-secretory myeloma and patients who are in a complete response or near complete response after conventional therapy

• Patients unwilling to practice adequate forms of contraception if clinically indicated

• Male patients on study need to be consulted to use latex condoms, even if they have had a vasectomy, every time they have sex with a woman who is able to have children

• Patients with history of seizures

• Patients receiving antihypertensive therapy that cannot be stopped for 24 hours preceding amifostine treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
2	University of Rochester	Rochester	New York	United States	14642
3	VA Puget Sound Health Care System	Seattle	Washington	United States	98101
4	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: William Bensinger, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00217438
• Other Study ID Numbers: 2004.00; NCI-2009-01543
• First Posted: Sep 22, 2005
• Last Update Posted: Aug 21, 2015
• Last Verified: Aug 1, 2015

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Melphalan; Amifostine

Study Results

Participant Flow

Recruitment Details	This trial opened for enrollment September 2005 and completed enrollment in June 2012. Patients were enrolled at 4 centers: University of Washington, Seattle, WA; Veteran's Administration Puget Sound Healthcare Administration, Seattle, WA; Cedars Sinai Medical Center, Los Angeles, CA; and James Wilmot Cancer Center in Rochester, NY.

Arm/Group Title	Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant)	Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant)
Arm/Group Description	INDUCTION THERAPY: Patients receive amifostine IV over 3-5 minutes on days -3 and -2 followed by high-dose melphalan IV over 15-30 minutes on day 2. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.	INDUCTION THERAPY: Patients receive amifostine as in arm I and melphalan as in arm I at a lower dose. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.
Period Title: Overall Study
STARTED	66	64
COMPLETED	66	63
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant)	Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant)	Total
Arm/Group Description	INDUCTION THERAPY: Patients receive amifostine IV over 3-5 minutes on days -3 and -2 followed by high-dose melphalan IV over 15-30 minutes on day 2. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.	INDUCTION THERAPY: Patients receive amifostine as in arm I and melphalan as in arm I at a lower dose. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.	Total of all reporting groups
Overall Participants	66	64	130
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	57 86.4%	55 85.9%	112 86.2%
>=65 years	9 13.6%	9 14.1%	18 13.8%
Sex: Female, Male (Count of Participants)
Female	23 34.8%	23 35.9%	46 35.4%
Male	43 65.2%	41 64.1%	84 64.6%
Region of Enrollment (participants) [Number]
United States	66 100%	64 100%	130 100%

Outcome Measures

1. Primary Outcome

Title	CR and Near CR Rates
Description	Per modified European Group for Blood and Marrow Transplant (EBMT) response criteria for definition of response in patients with multiple myeloma treated by high-dose therapy and stem cell transplantation: Complete Response (CR): Complete disappearance of all clinically measurable disease, complete response requires negative tests for monoclonal proteins in serum and urine by immunofixation, no monoclonal plasma cells in marrow specimen by flow cytometry and no evidence of progressive bone disease by skeletal survey. "Near" Complete Response (nCR): Less than 0.1 gram/dL monoclonal protein detectable in serum by standard protein electrophoresis and less than 50 mg monoclonal protein detectable in urine on 24 hour collection. Less than 5% monoclonal plasma cells detectable in bone marrow by immunohistochemistry. No evidence of progressive bone disease by skeletal survey.
Time Frame	Up to 120 days after transplant

Outcome Measure Data

Analysis Population Description

Per protocol, patients who completed the day 80-120 evaluation assessments.

Arm/Group Title	Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant)	Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant)
Arm/Group Description	INDUCTION THERAPY: Patients receive amifostine IV over 3-5 minutes on days -3 and -2 followed by high-dose melphalan IV over 15-30 minutes on day 2. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.	INDUCTION THERAPY: Patients receive amifostine as in arm I and melphalan as in arm I at a lower dose. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.
Measure Participants	66	63
Number [percentage of participants]	39 59.1%	22 34.4%

2. Secondary Outcome

Title	Relative Toxicities Between Melphalan 280 mg/m^2 or Melphalan 200 mg/m^2
Description	Number of Grade 3-4 adverse events observed in each group from enrollment through the Day 80-120 evaluation. Grade 3-4 events are defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Time Frame	Up to day 56 after transplant

Outcome Measure Data

Analysis Population Description

Patients who were treated per protocol.

Arm/Group Title	Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant)	Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant)
Arm/Group Description	INDUCTION THERAPY: Patients receive amifostine IV over 3-5 minutes on days -3 and -2 followed by high-dose melphalan IV over 15-30 minutes on day 2. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.	INDUCTION THERAPY: Patients receive amifostine as in arm I and melphalan as in arm I at a lower dose. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.
Measure Participants	66	64
Number [Grade 3-4 adverse events]	20	10

Adverse Events

Arm/Group Title	Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant)		Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant)
Arm/Group Description	INDUCTION THERAPY: Patients receive amifostine IV over 3-5 minutes on days -3 and -2 followed by high-dose melphalan IV over 15-30 minutes on day 2. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.		INDUCTION THERAPY: Patients receive amifostine as in arm I and melphalan as in arm I at a lower dose. AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy.
All Cause Mortality
	Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant)		Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant)		Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/66 (0%)		0/64 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant)		Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/66 (21.2%)		7/64 (10.9%)
Cardiac disorders
Atrial fibrillation	0/66 (0%)	0	1/64 (1.6%)	1
Gastrointestinal disorders
Mucositis-Grade 3 or higher	7/66 (10.6%)	7	3/64 (4.7%)	3
Diarrhea	7/66 (10.6%)	7	3/64 (4.7%)	3
Nausea/Vomiting	7/66 (10.6%)	7	2/64 (3.1%)	2
Dehydration	0/66 (0%)	0	1/64 (1.6%)	1
Anorexia	1/66 (1.5%)	1	0/64 (0%)	0
Graft versus host disease of the gut	1/66 (1.5%)	1	0/64 (0%)	0
Nervous system disorders
Neutropenic fever	1/66 (1.5%)	1	0/64 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/66 (1.5%)	1	0/64 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 30 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication. In the event the sponsor decides a patent application should be filed, the embargo may extend up to an additional 60 days or until a patent application is filed.