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

• ClinicalTrials.gov Identifier: NCT01852799
• Recruitment Status: Completed
• First Posted: May 14, 2013
• Results First Posted: August 10, 2018
• Last Update Posted: August 10, 2018
• Sponsor: Shanghai Changzheng Hospital
• Information provided by (Responsible Party): Jian Hou, Shanghai Changzheng Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: PAD Followed by ASCT	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: December 2012
• Actual Primary Completion Date: September 2016
• Actual Study Completion Date: January 2017

Arms and Interventions

Arm

Intervention/treatment

Experimental: PAD Followed by ASCT; Drug: Bortezomib, Adriamycin (Doxorubicin) /Epidoxorubicin(EPI), Dexamethasone. After received induction therapy, patients will proceed to receive ASCT based on the willing of the patients and the decision of the investigators.

Drug: PAD Followed by ASCT; Drug: Bortezomib, Bortezomib (1.3mg/m2, iv, on day 1, 4, 8, 11, of each 28 day cycle) Drug: Adriamycin (Doxorubicin) /EPI, Adriamycin (Doxorubicin) (9 mg/m2, iv, on days 1-4 of each 28 day cycle) or EPI (15mg/m2, iv, on days 1-4 of each 28 day cycle) Drug: Dexamethasone, Dexamethasone (20mg, iv, on days 1-4, 8-11of each 28 day cycle) After received induction therapy, patients will proceed to receive ASCT based on the willing of the patients and the decision of the investigators.; Other Names: Induction Therapy (4 cycles); ASCT

Outcome Measures

Primary Outcome Measures :

1. Bone Formation Markers Measurement [ Time Frame: Up to Cycle 4 with 28 days per cycle ]
   The bone formation marker- bone alkaline phosphatase(bALP) and osteoblast inhibitor- Dickkopf-1(DKK-1）are measured on serum samples by ELISA methodology at baseline, on day 28 of cycles 1,4, and after 4, 6, 12 and 18 months of follow-up or until start of alternative multiple myeloma(MM) treatment, if earlier.

Secondary Outcome Measures :

1. Measurement of Bone Mineral Density [ Time Frame: At baseline, on day 28 of cycles 1,4, and after 4, 6, 12 and 18 months of follow-up or until start of alternative MM treatment ]
   The effect on bone mineral density（BMD） will be measured by quantitative analysis of qCT scans of the intra-individual same region [lumbar spine and hip] at baseline, on day 28 of cycles 4, and after 4, 6, 12 and 18 months of follow-up or until start of alternative MM treatment, if earlier.
2. Skeletal Related Events' Evaluation [ Time Frame: At baseline, on day 28 of cycles 4, and after 4, 6, 12 and 18 months of follow-up or until start of alternative MM treatment ]
   Skeletal survey of the skeleton using plain radiography will be performed at baseline, on day 28 of cycle 4, and after 6, 12 and 18 months of follow-up or until start of alternative MM treatment, if earlier. SREs, such as pathological fractures, need for radiation therapy or surgery will be recorded at the time of the event.

Other Outcome Measures:

1. Evaluation of Responses [ Time Frame: At baseline, on day 28 of cycles 4, and after 4, 6, 12 and 18 months of follow-up ]
   Evaluation of responses was performed every cycle. Responses were assessed according to the european group for blood and marrow transplantation（EBMT） criteria (An attempt will be made to collect data for the assessment of stringent complete response (sCR) if these data are available.). Other efficacy parameters including PFS and 1-year overall survival rate and overall survival will be evaluated by normal methodology. According to EBMT criteria, responses were assessed by changes in the level of the serum paraprotein and/or urinary light chain excretion.The specific assessment rules may refer to EBMT criteria for MM.
2. Safety Evaluation [ Time Frame: Starting with informed consent signature through study completion, an average of 1 year ]
   Safety evaluations will be based on scheduled physical examinations, Eastern Cooperative Oncology Group(ECOG) scores, vital signs (blood pressure, heart rate) and clinical laboratory tests.
3. Evaluation of Responses(PFS) [ Time Frame: From date of signing informed consent form until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months ]
   Efficacy parameters PFS will be evaluated by normal methodology. PFS =（date of signing informed consent form minus the date of first documented progression or date of death from any cause plus 1）/30.5（months）

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

China, Shanghai

Shanghai Changzheng Hospital

Shanghai, Shanghai, China

Sponsors and Collaborators

Shanghai Changzheng Hospital

Investigators

• Principal Investigator: Jian Hou, PhD; Shanghai Changzheng Hospital

More Information

• Responsible Party: Jian Hou, Chief Physician, Professor of Shanghai Changzheng Hospital, Shanghai Changzheng Hospital
• ClinicalTrials.gov Identifier: NCT01852799
• Other Study ID Numbers: 26866138MMY2074
• First Posted: May 14, 2013
• Results First Posted: August 10, 2018
• Last Update Posted: August 10, 2018
• Last Verified: November 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Jian Hou, Shanghai Changzheng Hospital:

Multiple myeloma; PAD; ASCT; Bone metabolites; Bone marker

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases