Patients with newly diagnosed symptomatic multiple myeloma according to the International Myeloma Working Group Diagnostic Criteria (Kyle 2009)
Conditions
Interventions
Trade Name: Adriamycin
Product Name: doxorubicin
Pharmaceutical Form: Concentrate and solvent for solution for infusion
Trade Name: Cyclophosphamide
Product Name: Cyclophosphamide
Pharmaceutical Form
Sponsors
Vejle Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion Criteria: 1. Male or female subjects ³ 18 years at the time of signing informed consent. 2. Subject is diagnosed with symptomatic multiple myeloma based on the International Myeloma Working Group Diagnostic Criteria (Kyle 2009): a. Monoclonal plasma cells in the bone marrow =10% and/or presence of a biopsy-proven plasmacytoma. b. Monoclonal protein present in the serum and/or urine. If no monoclonal protein is detected (non-secretory disease), then =30% monoclonal bone marrow plasma cells and/or a biopsy-proven plasmacytoma is required. c. Myeloma-related organ dysfunction (1 or more)*: o [C] Calcium elevation in the blood (Ionized serum calcium > 0.25 mmol/l above the upper limit of normal) o [R] Renal insufficiency (Serum creatinine > 173 µmol/l) o [A] Anemia (Hemoglobin 30% 4. Subject has a Karnofsky performance status of = 60 (Appendix 10). 5. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. 6. Subject is willing and able to comply with the protocol as judged by the investigator. Are the trial subjects under 18? no Number of subjects for this age range: 30 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 15
Exclusion criteria
Exclusion criteria: 1. Any prior systemic therapy for multiple myeloma. 2. Other therapies such as biologic therapy and chemotherapy less than 3 months prior to screening. 3. Concurrent or recent (less than 2 weeks prior to Screening) radiotherapy or surgery. 4. Prior glucocorticoid treatment of multiple myeloma exceeding dexamethasone 20mg/day for a maximum of 7 days. Topical glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted. 5. More than or equal to grade 2 peripheral neuropathy according to the NCI-CTC criteria on clinical examination within 14 days before enrollment (Day 1 of Cycle 1). 6. Evidence of mucosal or internal bleeding and/or platelet counts 2 x ULN. 10. Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class IV heart failure (see Appendix 15), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant. 11. Clinically relevant active infection or serious co-morbid medical conditions, such as chronic obstructive or chronic restrictive pulmonary disease, and cirrhosis. 12. Any condition, including laboratory abnormalities, that in the opinion of the Investigator places the subject at unacceptable risk if he/she were to participate in the study. 13. Prior malignancy (within the last 3 years) except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, in situ breast cancer, in situ prostate cancer or other cancer for which the subject has been disease-free for at least 3 years. 14. Female subject is pregnant or breast-feeding. The first serum pregnancy test to be done within 10-14 days prior to the study treatment start and repeated serum pregnancy test to be done within 24 hours prior to the start of study treatment. 15. Female subjects who are of childbearing potential (biologically capable of becoming pregnant) or men with partners of childbearing potential, who are unwilling or unable to use effective means of contraception. The means of contraception must either commit to continued abstinence from sexual intercourse or begin TWO acceptable methods of birth control, one highly effective method (hormonal contraceptives pills, injections or implants, tubal ligation, partner’s vasectomy) and one additional effective method (condom, diaphragm, cervical cap) AT THE SAME TIME, at least 28 days before she starts ACVDL and for at least 28 days after the last dose of ACVDL. 16. Serious medical or psychiatric illness likely to interfere with participation in this clinical study. 17. Uncontrolled diabetes mellitus at the discretion of the investigator. 18. Hypersensitivity and/or contraindication to any one of the Investigational Medicinal Products (IMP), acyclovir or similar anti-viral drug. 19. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and ski
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Secondary Objective: Efficacy: To determine the clinical efficacy as measured by response rate (sCR plus CR plus VGPR) of the combination of doxorubicin, cyclophosphamide, bortezomib, dexamethasone and lenalidomide in patients with newly diagnosed multiple myeloma at 4-weeks after completion of 8 cycles of ACVDL, and 3 months after 4 cycles of ACVDL followed by high-dose melphalan. Safety: To evaluate the safety profile of the combination of doxorubicin, cyclophosphamide, bortezomib, dexamethasone and lenalidomide in newly diagnosed multiple myeloma patients. ;Primary end point(s): Efficacy The response rate of stringent complete response (sCR) or complete response (CR) or very good partial response (VGPR) at 4-weeks after completion of 8-cycle ACVDL, and 3 months post 4-cycle ACVDL followed by high-dose melphalan and stem cell transplantation. The response rate is defined as the percentage of patients who achieve either a sCR or CR or VGPR using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma (Durie et al. 2006). Safety The following parameters will be used to evaluate the safety of the ACVDL therapy 1. Vital signs 2. Physical examination 3. Peripheral neuropathy assessment 4. FACT/GOG-Neurotoxicity Questionnaire 5. ECG & Echocardiography 6. Serum haematology, biochemistry and immunology 7. Urinalysis for protein and glucose 8. Adverse events (NCI Common Terminology Criteria for Adverse Events, Version 4.0) ;Timepoint(s) of evaluation of this end point: Safety: Patients are evaluable for safety when they have received at least one dose of study treatment. Efficacy: The response rate of stringent complete response (sCR) or complete response (CR) or very good partial response (VGPR) at 4-weeks after completion of 8-cycle ACVDL, and 3 months post 4-cycle ACVDL followed by high-dose melphalan and stem cell transplantation. The response rate is defined as the percentage of patients who achieve either a sCR or CR or VGPR using I | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. The percentage of patients who achieve either a sCR or a CR using IMWG Response Criteria 2006 after completion of 4-cycle ACVDL, 4 weeks after completion of the 8-cycle ACVDL (non-SCT patients), and 3 months post 4-cycle ACVDL followed by high-dose melphalan and stem cell transplantation (SCT patients). The endpoint will also be evaluated by baseline stage of myeloma according to ISS 2005 when allowed by sample size. 2. The percentage of patients who achieve a VGPR using IMWG Response Criteria 2006 after completion of 4-cycle ACVDL, 4 weeks after completion of the 8-cycle ACVDL (non-SCT patients), and 3 months post 4-cycle ACVDL followed by high-dose melphalan and stem cell transplantation (SCT patients). The endpoint will also be evaluated by baseline stage of myeloma according to ISS 2005 when allowed by sample size. 3. Time to progression (TTP) measured from date of first dose of the ACVDL therapy until documentation of disease progression according to IMWG Response Criteria 2006. The TTP will be stratified by the baseline stage of myeloma according to ISS 2005. Death due to cause other than progression will be censored. Patient without an event will be censored at date last known progression-free. 4. Progression-free survival (PFS) defined as the start of the ACVDL therapy until documentation of disease progression according to IMWG Response Criteria 2006 or death due to any cause. The PFS will be stratified by the baseline stage of myeloma according to ISS 2005. Patients without an event will be censored at date last known progression-free. ;Timepoint(s) of evaluation of this end point: 1. The percentage of patients who achieve either a sCR or a CR or a VGPR using IMWG Response Criteria 2006 after completion of 4-cycle ACVDL, 4 weeks after completion of the 8-cycle ACVDL (non-SCT patients), and 3 months post 4-cycle ACVDL followed by high-dose melphalan and stem cell transplantation (SCT patients). 2. Time to progression (TTP | — |
Countries
Denmark
Contacts
Public ContactLena Bjerre
Vejle Hospital
Outcome results
None listed