The purpose of this study is to determine whether intravenous busulfan and melphalan as a conditioning regimen is effective in the treatment of multiple myeloma undergoing autologous stem cell transplantation.

Title

• A phase 2, open-label, prospective, multicenter study to evaluate the efficacy of intravenous busulfan and melphalan as a conditioning regimen in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT)

Principal Investigator

• Je-Jung Lee (Chonnam National University Hwasun Hospital)

Co-investigators

• Hyeon Seok Eom (National Cancer Center)
• Kihyun Kim (Samsung Medical Center)
• Chang Ki Min (Seoul St. Mary's Hospital)
• Soo Jung Kim (Severance Hospital)
• Sung Soo Yoon (Seoul National University Hospital)
• Jae Hoon Lee (Gachon University Gil Hospital)
• Yeung-Chul Mun (Ewha Womans University Mokdong Hospital)

Duration

• 2 years

Study phase

• Phase II

Patients

• Patients with multiple myeloma who undergo autologous stem cell transplantation

Objectives(end points)

• Primary objective:

  1. Treatment response up to 2 months after ASCT
  2. Safety and toxicity (frequency of grade 3 or worse toxicities) of the conditioning regimen

• Secondary objective:

  1. Progression free survival (PFS)
  2. Overall survival (OS)

Total patients

• Initial 105 evaluable patients
• Complete Response (CR) rate of 200mg/m2 melphalan conditioning chemotherapy followed by ASCT in patients with newly diagnosed MM was about 26% and CR rate of busulfan and melphalan conditioning chemotherapy followed by ASCT in patients with newly diagnosed MM was about 40%. If the CR rate of busulfan and melphalan conditioning chemotherapy followed by ASCT is more than 40%, this combination will be accepted as active conditioning regimen that may be worth for investigating in phase III trial. But, if the CR rate of this regimen is lower than 26%, this has not a merit than 200mg/m2 melphalan conditioning chemotherapy. Based upon the above assumption, this trial was designed by using Simon's optimal two-stage testing procedure. Assuming a target level of interest, p1=0.4, and a lower activity level, p0=0.26 and drop rate 0.1. Initially 44 patients will be accrued. If 13 or more CR rate were observed, the trial will be continued. Accrual will be planned to a total of 105 patients, If total 35 or more patients were assessed as CR, busulfan and melphalan conditioning regimen will be accepted as active regimen, This design provides probability ≤ 0.05 of accepting drugs worse than p0 and probability ≤ 0.20 of rejecting drugs better than p1.if we assume that drop-out rate is 10%, total accrual patient will be 105

Treatment Schedule

• Busulfan 3.2 mg/kg/day iv once daily over 3 hours(day-6 ~ day-4)
• Melphalan 70 mg/m2/day iv once daily over 30 minutes(day-3 ~ day-1). If Creatinine Clearance (mL/min) < 50, reduce to 50 mg/m2. If Creatinine Clearance (mL/min) < 30, excluded from the this trial

Informed consent

• Written informed consent must be obtained before any study-specific screening procedures are performed

Screening

• Baseline assessments should be made within 28 days before treatment start:

  1. Demographic data (date of birth and sex)
  2. Eastern Cooperative Oncology Group performance status
  3. Vital signs and physical examination (including height, and weight)
  4. Medical history (including previous diseases/treatments and concomitant diseases/ treatments)
  5. Hematology - complete blood counts with differential count examination
  6. Serum electrolytes (Na, K, Cl, Ca, phosphorus)
  7. Serum lactate dehydrogenase
  8. Hepatitis B virus/hepatitis C virus/HIV serology (If serologic tests were conducted within 6 months prior to screening, retests are not required)
  9. Serum Beta2-microglobulin
  10. Quantitative serum M-protein (Serum protein electrophoresis), including immunofixation or immune electrophoresis
  11. Quantitative urine M-protein in 24 hrs urine (Urine protein electrophoresis), including immunofixation or immune electrophoresis
  12. Serum free light chain assay
  13. Creatinine clearance if increased serum creatinine
  14. ECG
  15. multigated radionuclide angiography or 2D ECHO
  16. Chest X-ray, Radiographic skeletal survey including skull, pelvis, vertebral column and long bones
  17. Bone marrow aspiration and biopsy with chromosome study, and flow cytometry or immunohistochemistry

Assessment

• Primary outcome measure

  1. To evaluate the objective responses after ASCT, the guidelines from the International Myeloma Working (IMW) Group uniform response criteria will be used
  2. Response Criteria for Multiple Myeloma the guidelines from the IMW Group uniform response criteria + Add for criteria of near CR (Immunofixation positive CR)
  3. Serum free light chain study will be added at the every evaluation of response
  4. To confirm the stringent complete response (sCR) after ASCT, flow cytometry or immunohistochemistry will be used
  5. NCI Common Toxicity Criteria for Adverse Effects version 4.0 will be used for the examination of toxicities

• Secondary outcome measure

  1. PFS will be defined from the time of ASCT to the time of first sign of disease progression or death
  2. OS will be defined as the period from the time of ASCT to the date of the last follow-up or death from any cause

Inclusion Criteria:

• Patients with a confirmed diagnosis of MM
• Symptomatic MM
• Age 20 - 65 years
• The MM patients who performed the stem cell collection with appropriate stem cell counts, cluster of differentiation 34 positive cells more than 2 x 10^6 /kg
• Eastern Cooperative Oncology Group 0 - 2
• The MM patients who received induction chemotherapy regardless of types of induction
• Patient has measurable disease when the patients started the primary induction therapy, defined as follows: Measurable disease is defined as serum M-protein more than 1 g/dL, urine M-protein more than 200 mg/24 hours, or free light chain more than 100 mg/L
• Adequate liver functions before ASCT Transaminase less than 3 x upper normal value Bilirubin less than 2 x upper normal value
• Adequate hematological function - Platelet count more than 50,000 /microliter, hemoglobin more than 8 g / dL but, Prior red blood cell transfusion or recombinant human erythropoietin use is allowed, absolute neutrophil count more than 1,000 / microliter
• Expected survival: 6 months or more
• Informed consent

Exclusion Criteria:

• Systemic amyloid light chain amyloidosis, smoldering multiple myeloma or monoclonal gammopathy of undetermined significance
• Patient with plasma cell leukemia
• Patients who received an extensive radiation therapy within 4 weeks
• Patient is known to be Human Immunodeficiency Virus positive
• Patient has known clinically active Hepatitis B or C
• Pregnant or lactating women, women of childbearing potential not employing adequate contraception
• Other serious illness or medical conditions Uncontrolled or severe cardiovascular disease, including myocardial infarction, within 6 months of enrollment, New York Heart Association Class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis History of significant neurological or psychiatric disorders including dementia or seizures Active uncontrolled infection Active ulcers detected at gastroscopy Other serious medical illnesses
• Known hypersensitivity to any of the study drugs or its ingredients concomitant administration of any other experimental drug under investigation, or concomitant chemotherapy, hormonal therapy, or immunotherapy