A Randomized Trial to Compare Busulfan + Melphalan 140 mg/m2 With Melphalan 200 mg/m2 as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01413178
• Collaborator: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Enrollment: 205
• Location: 1
• Arms: 2
• Actual Duration (Months): 89.3
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to compare Busulfex (busulfan) with or without Alkeran (melphalan) to learn which study therapy may be better at helping to control MM in patients who will receive an autologous stem cell transplant. The safety of this combination therapy will also be studied.

Melphalan and busulfan are designed to damage the DNA (genetic material) of cells, which may cause cancer cells to die.

Condition or Disease	Intervention/Treatment	Phase
Myeloma	Drug: Busulfan; Drug: Melphalan; Other: Questionnaire; Drug: G-CSF; Drug: High Dose Melphalan; Procedure: Stem cell transplant	Phase 3

Detailed Description

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups.

• Group 1 will receive melphalan and busulfan.

• Group 2 will receive melphalan.

Both groups will have a stem cell transplant.

Study Drug Administration:

If you are in Group 1, you will first receive an additional low-level "test" dose of busulfan given by vein to check how your blood levels change over time. This information will be used to decide the next dose that is needed to reach a target blood level of busulfan. Blood (about 1 teaspoon each time) will be drawn up to 11 times during the next 11 hours after the test dose and the first high-dose busulfan treatment.

A heparin lock line will be placed in a vein to lower the number of needle sticks needed for these draws.

This test dose of busulfan can be given as an outpatient before you are admitted to the hospital, or you will be admitted on Day -10 (10 days before your transplant) and will receive the test dose on Day -9. If it is not possible for these blood level tests to be performed for technical or scheduling reasons, you will receive the standard, fixed (unchanging) dose of busulfan.

Eight (8) or 10 days before the transplant, you will be admitted to the hospital and given hydration fluids by vein.

On Days -7, -6, -5, and -4, you will receive busulfan by vein over 3 hours. You will receive melphalan on Days -2 and -1 by vein over 30 minutes. You will receive the stem cell transplant through the CVC on Day 0.

If you are in Group 2, you may be admitted to the hospital 3 days before the transplant. You will receive hydration fluids by vein. Two (2) days before the transplant, you will receive melphalan by vein over 30 minutes. You will not receive melphalan the day before the transplant.

Stem Cell Transplant:

The day that you receive the stem cell transplant is called Day 0. The stem cells will be given by vein through the CVC. The cells will travel to your bone marrow where they are designed to start making healthy, new blood cells after several weeks. You will sign a separate consent for the collection of your stem cells.

Beginning 5 days after the transplant, you will receive filgrastim (G-CSF) through a needle under your skin 1 time each day until your blood cell levels return to normal. Filgrastim is designed to help with the growth of white blood cells.

You will be in the hospital after the transplant for about 2-4 weeks.

Questionnaire:

You will be asked to complete a quality-of-life questionnaire before starting the study drugs and then once a week during Weeks 1, 2, and 4 after the stem cell transplant. The questionnaire will take about 15 minutes to complete.

Follow-Up Visits:

About 3 months after the transplant, you will have a bone marrow aspiration and biopsy to check the status of the disease. To collect a bone marrow aspiration and biopsy, an area of the hip is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle.

Every 3 months during the first year after the transplant, blood (about 1-2 tablespoons) will be drawn to check your immune response and status of the disease.

About 1 year after the transplant, you will have a bone scan if the doctor thinks it is needed.

Length of Study:

One (1) year after the transplant, your participation in this study will be over.

If intolerable side effects from the chemotherapy occur or there is sign of disease after the transplant, you will be taken off study. If you have intolerable side effects after you receive chemotherapy, then you will still have the transplant. If you are taken off study early, you still may need to return for routine post-transplant follow-up visits, if your transplant doctor decides it is needed.

This is an investigational study. Busulfan and melphalan are commercially available and FDA approved for the treatment of myeloma. The use of melphalan alone before an autologous stem cell transplant is considered standard of care. Using busulfan with melphalan is investigational.

Up to 205 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 205 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Trial to Compare Busulfan + Melphalan 140 mg/m2 With Melphalan 200 mg/m2 as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma
• Actual Study Start Date: Sep 30, 2011
• Actual Primary Completion Date: Mar 10, 2019
• Actual Study Completion Date: Mar 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Busulfan + Melphalan Busulfan test dose (32 mg/m^2) on day -9 then 130 mg/m^2 intravenous (IV) Days -7, -6, -5, and -4 + Melphalan 70 mg/m2 IV on Days -2 and -1. Stem Cell Transplant (SCT) Day 0.	Drug: Busulfan; Test dose (32 mg/m^2) on day -9 then 130 mg/m^2 by vein or adjusted dose on Days -7, -6, -5, and -4.; Other Names: Busulfex Myleran ; Drug: Melphalan; 70 mg/m2 by vein over 30 minutes minutes on Days -2 and -1.; Other Names: Alkeran ; Other: Questionnaire; Quality of Life (QOL) questionnaire before starting the study drugs and then once every 4 weeks after the stem cell transplant, taking about 15 minutes to complete.; Other Names: Survey ; Drug: G-CSF; Approximately 5 mcg/kg/day subcutaneously beginning on Day +5.; Other Names: Filgrastim NeupogenTM ; Procedure: Stem cell transplant; Stem cell infusion on Day 0.; Other Names: ABMT autologous bone marrow transplantation Peripheral Blood Progenitor Cells PBPCs
Experimental: Melphalan High-dose Melphalan 200 mg/m2/day IV over 30 minutes on day -2. SCT Day 0.	Other: Questionnaire; Quality of Life (QOL) questionnaire before starting the study drugs and then once every 4 weeks after the stem cell transplant, taking about 15 minutes to complete.; Other Names: Survey ; Drug: G-CSF; Approximately 5 mcg/kg/day subcutaneously beginning on Day +5.; Other Names: Filgrastim NeupogenTM ; Drug: High Dose Melphalan; 200 mg/m2 by vein over 30 minutes on Day -2.; Other Names: Alkeran ; Procedure: Stem cell transplant; Stem cell infusion on Day 0.; Other Names: ABMT autologous bone marrow transplantation Peripheral Blood Progenitor Cells PBPCs

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) [3 years after transplant]

   Participants that are still alive and without Multiple Myeloma 3 years after Stem cell Transplantation.

Secondary Outcome Measures

1. Number of Participants With Complete Response (CR) [Evaluated 90 days from transplant.]

   Complete response (CR), evaluated 90 days from transplant, defined as (i) negative immunofixation of the multiple myeloma (MM) protein in urine and serum, (ii) disappearance of any soft tissue plasmacytomas, and (iii) less than 5% plasma MM cells in the bone marrow. International Myeloma Working Group uniform response criteria.

2. Treatment-Related Mortality (TRM) Between 2 Arms. [100 days post treatment]

3. Number of Participants That Had Grade 3-4 Toxicities. [At day 90 post SCT (Stem Cell Transplantation)]

4. Overall Survival (OS) [From time of ASCT to 3 years]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Patients with multiple myeloma in complete remission (CR), partial remission (PR), or very good partial remission (VGPR), or symptomatic stable disease (no evidence of progression) including patients with light chain MM detected in the serum by free light chain assay.

2. Patients with non-secretory multiple myeloma [absence of a monoclonal protein (M protein) in serum as measured by electrophoresis (SPEP) and immunofixation (SIFE) and the absence of Bence Jones protein in the urine (UPEP) defined by use of conventional electrophoresis and immunofixation (UIFE) techniques] but with measurable disease on imaging studies like MRI, CT scan or PET scan.

3. Who have received at least two cycles of initial systemic therapy and are within 2 to 12 months of the first dose. Mobilization therapy is not considered initial therapy.

4. 70 years of age or younger.

5. Karnofsky performance score 70% or higher.

6. Cardiac function: left ventricular ejection fraction at rest > 40% within 3 months of registration.

7. Hepatic function: bilirubin < 2x the upper limit of normal and ALT and AST < 2.5x the upper limit of normal.

8. Renal function: creatinine clearance of >/= 40 mL/min, estimated or calculated.

9. Pulmonary function: DLCO, FEV1, FVC >/= 50% of predicted value (corrected for hemoglobin) within 3 months of registration

10. Signed informed consent form.

Exclusion Criteria:

1. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms).

2. Patients seropositive for the human immunodeficiency virus (HIV).

3. Patients with history of myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.

4. Patients participating in an investigational new drug protocol within 14 days before enrollment.

5. Female patients who are pregnant (positive b-HCG) or breastfeeding.

6. Prior stem cell transplantation allogeneic or autologous.

7. Prior organ transplant requiring immunosuppressive therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

• Principal Investigator: Muzaffar H. Qazilbash, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 14, 2015

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01413178
• Other Study ID Numbers: 2010-0071; NCI-2011-02760
• First Posted: Aug 10, 2011
• Last Update Posted: Apr 21, 2020
• Last Verified: Apr 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Myeloma; Multiple Myeloma; Light chain Multiple Myeloma; MM; Autologous Hematopoietic Stem Cell Transplantation; Busulfan; Busulfex; Myleran; Melphalan; Alkeran; G-CSF; Filgrastim; NeupogenTM; Questionnaire; Survey; Quality of Life; QOL
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Melphalan; Busulfan

Study Results

Participant Flow

Recruitment Details	All participants were registered in MD Anderson Cancer.

Arm/Group Title	Busulfan + Melphalan	Melphalan
Arm/Group Description	Busulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplant	High-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
Period Title: Overall Study
STARTED	105	100
COMPLETED	104	98
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Busulfan + Melphalan	Melphalan	Total
Arm/Group Description	Busulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplant.	High-dose Melphalan 200 mg/m2/day followed by a stem cell transplant	Total of all reporting groups
Overall Participants	104	98	202
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	58.9	59.5	59.2
Sex: Female, Male (Count of Participants)
Female	43 41.3%	43 43.9%	86 42.6%
Male	61 58.7%	55 56.1%	116 57.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	5 4.8%	1 1%	6 3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	15 14.4%	24 24.5%	39 19.3%
White	75 72.1%	67 68.4%	142 70.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	9 8.7%	6 6.1%	15 7.4%
Region of Enrollment (participants) [Number]
United States	104 100%	98 100%	202 100%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS)
Description	Participants that are still alive and without Multiple Myeloma 3 years after Stem cell Transplantation.
Time Frame	3 years after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Busulfan + Melphalan	Melphalan
Arm/Group Description	Busulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplant	High-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
Measure Participants	104	98
Count of Participants [Participants]	72 69.2%	50 51%

2. Secondary Outcome

Title	Number of Participants With Complete Response (CR)
Description	Complete response (CR), evaluated 90 days from transplant, defined as (i) negative immunofixation of the multiple myeloma (MM) protein in urine and serum, (ii) disappearance of any soft tissue plasmacytomas, and (iii) less than 5% plasma MM cells in the bone marrow. International Myeloma Working Group uniform response criteria.
Time Frame	Evaluated 90 days from transplant.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Busulfan + Melphalan	Melphalan
Arm/Group Description	Busulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplant	High-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
Measure Participants	104	98
Count of Participants [Participants]	12 11.5%	15 15.3%

3. Secondary Outcome

Title	Treatment-Related Mortality (TRM) Between 2 Arms.
Time Frame	100 days post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Busulfan + Melphalan	Melphalan
Arm/Group Description	Busulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplant	High-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
Measure Participants	104	98
Count of Participants [Participants]	0 0%	0 0%

4. Secondary Outcome

Title	Number of Participants That Had Grade 3-4 Toxicities.
Time Frame	At day 90 post SCT (Stem Cell Transplantation)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Busulfan + Melphalan	Melphalan
Arm/Group Description	Busulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplant	High-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
Measure Participants	104	98
Grade 3 - Diarrhea	5 4.8%	4 4.1%
Grade 3 - Elevated ALT	3 2.9%	0 0%
Grade 3 - Elevated Tbili	2 1.9%	0 0%
Grade 3 - Infection	16 15.4%	5 5.1%
Grade 3 - Mucositis	15 14.4%	0 0%
Grade 3 - Nausea	5 4.8%	2 2%
Grade 3 - Neuropathy	1 1%	0 0%
Grade 3 - Neutropenic fever	73 70.2%	32 32.7%
Grade 3 - Pneumonia	1 1%	1 1%
Grade 3 - Tachycardia	1 1%	0 0%
Grade 3 - Transient blindness	1 1%	0 0%
Grade 3 - Anorexia	1 1%	0 0%
Grade 3 - Myocardial ischemia	1 1%	1 1%
Grade 3 - Pleural effusion	0 0%	1 1%
Grade 3 - Rash	0 0%	1 1%

5. Secondary Outcome

Title	Overall Survival (OS)
Time Frame	From time of ASCT to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Busulfan + Melphalan	Melphalan
Arm/Group Description	Busulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplant	High-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
Measure Participants	104	98
Count of Participants [Participants]	91 87.5%	79 80.6%

Adverse Events

Time Frame	From the time of ASCT until 12 months.
Arm/Group Title	Busulfan + Melphalan		Melphalan
Arm/Group Description	Busulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplant		High-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
All Cause Mortality
	Busulfan + Melphalan		Melphalan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/104 (22.1%)		21/98 (21.4%)
Serious Adverse Events
	Busulfan + Melphalan		Melphalan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/104 (70.2%)		32/98 (32.7%)
Cardiac disorders
Myocardial ischemia	1/104 (1%)		1/98 (1%)
Tachycardia	1/104 (1%)		0/98 (0%)
Eye disorders
Transient blindness	1/104 (1%)		0/98 (0%)
Gastrointestinal disorders
Diarrhea	5/104 (4.8%)		4/98 (4.1%)
Mucositis	15/104 (14.4%)		0/98 (0%)
Nausea	5/104 (4.8%)		2/98 (2%)
Hepatobiliary disorders
Elevated ALT	3/104 (2.9%)		0/98 (0%)
Elevated Tbili	2/104 (1.9%)		0/98 (0%)
Infections and infestations
Infection	16/104 (15.4%)		6/98 (6.1%)
Neutropenic fever	73/104 (70.2%)		32/98 (32.7%)
Nervous system disorders
Neuropathy	1/104 (1%)		0/98 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/104 (1%)		0/98 (0%)
Pleural effusion	0/104 (0%)		1/98 (1%)
Skin and subcutaneous tissue disorders
Rash	0/104 (0%)		1/98 (1%)
Other (Not Including Serious) Adverse Events
	Busulfan + Melphalan		Melphalan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	101/104 (97.1%)		98/98 (100%)
Blood and lymphatic system disorders
Elevated creatinine	3/104 (2.9%)		0/98 (0%)
Cardiac disorders
Arrhythmia	1/104 (1%)		0/98 (0%)
Atrial fibrillation	1/104 (1%)		1/98 (1%)
Fluid overload	63/104 (60.6%)		22/98 (22.4%)
Hypertension	16/104 (15.4%)		5/98 (5.1%)
Hypotension	1/104 (1%)		0/98 (0%)
Tachycardia	4/104 (3.8%)		1/98 (1%)
Myocardial ischemia	0/104 (0%)		1/98 (1%)
Ear and labyrinth disorders
Tinnitus	1/104 (1%)		0/98 (0%)
Gastrointestinal disorders
Diarrhea	57/104 (54.8%)		82/98 (83.7%)
Mucositis	86/104 (82.7%)		49/98 (50%)
Nausea	99/104 (95.2%)		98/98 (100%)
Hepatobiliary disorders
Elevated ALT	31/104 (29.8%)		1/98 (1%)
Elevated AST	1/104 (1%)		1/98 (1%)
Elevated Tbili	8/104 (7.7%)		9/98 (9.2%)
Infections and infestations
Fever	17/104 (16.3%)		8/98 (8.2%)
Infection	18/104 (17.3%)		17/98 (17.3%)
Neutropenic fever	1/104 (1%)		33/98 (33.7%)
Musculoskeletal and connective tissue disorders
Weakness of extremities	1/104 (1%)		0/98 (0%)
involuntary leg movements	0/104 (0%)		1/98 (1%)
Nervous system disorders
Dizziness	1/104 (1%)		0/98 (0%)
Headache	2/104 (1.9%)		0/98 (0%)
Neuropathy	0/104 (0%)		1/98 (1%)
Psychiatric disorders
Anorexia	0/104 (0%)		3/98 (3.1%)
Renal and urinary disorders
Hematuria	3/104 (2.9%)		2/98 (2%)
Reproductive system and breast disorders
Dysuria	1/104 (1%)		0/98 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	5/104 (4.8%)		4/98 (4.1%)
Pulmonary edema	2/104 (1.9%)		0/98 (0%)
Pleural effusion	0/104 (0%)		1/98 (1%)
Shortness of breath	0/104 (0%)		1/98 (1%)
Skin and subcutaneous tissue disorders
Chemo burns	3/104 (2.9%)		0/98 (0%)
Rash	5/104 (4.8%)		4/98 (4.1%)
Lip ulcer	0/104 (0%)		1/98 (1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.