A Study of PAD Followed by Autologous Stem Cell Transplantation (ASCT) to Treat Newly Diagnosed Multiple Myeloma

A Phase 2, Multicenter, Single Arm Study to Evaluate the Effect of PAD Followed by Autologous Stem-cell Transplantation(ASCT) on the Concentrations of Bone Metabolites in Patients With Newly Diagnosed Multiple Myeloma(MM)

This is a multicentre; single arm study in subjects with newly diagnosed multiple myeloma.

The primary objectives of this study is to assess the effect of bortezomib combination therapy (PAD regimen) followed by ASCT on bone metabolites in patients with newly diagnosed multiple myeloma, as measured by ELISA methodology as previously described analyzing the change in biochemical bone marker compared with the baseline value: bone formation marker- bone alkaline phosphatase(bALP) and osteoblast inhibitor- Dickkopf-1(DKK-1）.

The secondary objectives of this study are:

1. Subgroup analysis for the change from baseline in biochemical bone marker based on whether or not Bisphosphonate was used.
2. Assessment of other bone markers parameters: bone formation marker -carboxy terminal propeptide of type I procollagen (PICP); bone resorption markers -carboxy terminal telopeptide region of type I collagen ( ICTP); osteoclast stimulators -osteoprotegerin(OPG), soluble receptor activator of nuclear factor kappaB ligand(sRANKL);
3. To observe the effect of bortezomib on bone mineral density (BMD) as measured by repeated quantitative CT-scan;
4. The evaluation of Skeletal related events (SRE) and appearance of new bone lesions;
5. To determine progression free survival (PFS), 1 year survival, overall survival and safety profile following treatment with PAD and ASCT as first-line therapy.

After providing written informed consent, subjects will be evaluated for eligibility during a 14-day screening period. Eligible subjects will receive 4 cycles PAD treatment prior to ASCT. Bisphosphonate therapy can be administered as medically indicated and according to local practice.

After the end of the treatment phase, there will be 18 months follow-up period for every patient with visits at 4, 6, 12 and 18 months after the end of the treatment phase. In case the disease progresses before completing the 18 months of follow-up and once the subject started alternative MM treatment, study assessments will stop, except for survival follow-up which will be collected every 6 months by either a telephone call or a visit to the study site. The follow-up for survival will continue for all subjects until the last subject has completed follow-up. One interim analysis of efficacy and safety will be performed when all subjects have achieved the end of treatment. Safety will be assessed by the monitoring of adverse events, physical examination, vital signs measurements and clinical laboratory tests.

Inclusion Criteria:

1. Man or woman aged 18 to 65 years old;

2. Subjects are newly diagnosed MM patients which are scheduled by the investigators to be treated with vincristine, adriamycin and dexamethasone standard therapy. Stage II/III (according to Durie and Salmon criteria) with skeletal involvement, such as bone pain, bone lytic lesions, diffuse osteoporosis or pathologic fractures;

3. Life expectancy > 3 months;

4. Patient has measurable disease in which to capture response, defined as one or more of the following;

   • Serum M-protein level >10.0 g/L measured by serum protein electrophoresis or immunoglobulin electrophoresis; or
   • Urinary M-protein excretion > 1 g/24 hours; or
   • Bone marrow plasmacytosis of > 30% by bone marrow aspirate and/or biopsy; or
   • Serum free light chains (by the Freelite test) > 2 X the upper limit of normal (ULN), in the absence of renal failure.

5. Performance status (PS) of ECOG ≤2.0, unless PS of 3-4 based solely on bone pain;

6. Patients must have a Platelets count≥50×109 cells /L; Absolute neutrophil count (ANC)≥0.75×109 cells /L;

7. Patients must have adequate hepatic function defined as Alanine transaminase(ALT) ≤ 2.5 × upper limit of normal(ULN); Aspartate transaminase (AST) ≤2.5×ULN; Total bilirubin ≤2×ULN;

8. Patients must have adequate renal function defined as creatinine clearance >30 ml /min;

9. Subjects (or their legally acceptable representatives) must have signed a informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion Criteria:

1. Non-secretory MM, unless the patient has measurable lesions on computed tomography (CT), magnetic resonance imaging (MRI) and/or positron emission tomography (PET);
2. Peripheral neuropathy or neuropathy pain grade 2 or high as defined by National Cancer Institute Common Terminology Criteria for Adverse Events(NCI CTCAE) Version 3;
3. Uncontrolled or severe cardiovascular disease, including myocardial infarction (MI ) within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis;
4. History of allergy reaction attributable to compounds containing boron or mannitol;
5. Any serious, active disease or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol or the investigator's decision;
6. Concurrent treatment with another investigational agent;
7. Female subject who is pregnant or breast-feeding.