E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Multiple Myeloma |
Myelomatose |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To assess the efficacy of VMP versus high-dose therapy and stem cell transplantation (HDT) in patients with previously untreated multiple myeloma, as measured by the progression free survival.
- To evaluate the effect of consolidation with VRD followed by Lenalidomide maintenance with no consolidation but Lenalidomide maintenance alone on progression free survival.
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E.2.2 | Secondary objectives of the trial |
-To compare VMP versus single HDT+ ASCT; or VMP versus tandem HDT + ASCT; or single versus tandem HDT + ASCT.
-To compare overall response rate and CR + VGPR (complete and very good partial response) after induction therapy, after VMP or HDT, after consolidation and during maintenance.
-To evaluate overall survival.
-To assess safety and toxicity
-To assess the prognostic value of risk factors at diagnosis, including b2-microglobulin, FISH abnormalities del1p, ampli 1q, t(4;14), t(14;16), t(11;14), ampli 9, del13q/13-, del17p as analyzed in purified bone marrow plasma cells with respect to progression free survival.
-To analyze the prognostic value of myeloma gene expression profiles on the overall response on induction of all patients and of patients treated in the different randomization arms.
- To assess quality of life |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1 Observation Of Asymptomatic Patients (chapter 20)
• evaluation of time to progression in symptomatic myeloma
• evaluation of prognostic factors that can influence the time to progression
• evaluation of role of MRI to predict time to progression
• evaluation of role of PET-CT to predict time to progression and on skeletal related events (optional)
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E.3 | Principal inclusion criteria |
- Patients with a confirmed diagnosis of symptomatic multiple myeloma stage I to III according to the International Staging System ISS (see appendix A), i.e. at least one of the CRAB criteria should be present;
-Measurable disease as defined by the presence of M-protein in serum or urine (serum M-proteïn > 10 g/l or urine M-proteïn > 200 mg/24 hours) or abnormal free light chain ratio with involved free light chain (FLC) > 100 mg/l or proven plasmacytoma by biopsy
- Age 18-65 years inclusive;
- WHO performance status 0-3 (WHO=3 is allowed only when caused by MM and not by co-morbid conditions)
- Negative pregnancy test at inclusion if applicable;
- Written informed consent.
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E.4 | Principal exclusion criteria |
- Known intolerance of Boron;
- Systemic AL amyloidosis;
- Primary Plasmacell Leukemia;
- Non-secretory MM;
- Previous chemotherapy or radiotherapy except local radiotherapy in case of local myeloma progression or corticosteroids maximum 5 days for symptom control;
- Severe cardiac dysfunction (NYHA classification II-IV, see appendix E);
- Significant hepatic dysfunction (serum bilirubin >= 30 mmol/l or transaminases >= 2.5 times normal level), unless related to myeloma;
- Patients with GFR <15 ml/min,
- Patients known to be HIV-positive;
- Patients with active, uncontrolled infections;
- Patients with neuropathy, CTC grade 2 or higher;
- Patients with a history of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
- Patients who are not willing or capable to use adequate contraception during the therapy (all men, all pre-menopausal women);
-Lactating women;
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E.5 End points |
E.5.1 | Primary end point(s) |
- For all registered patients: progression free survival (PFS) as defined by time from registration to progression or death from any cause whichever occurs first).
-F or all patients included in R1; PFS as defined by time from randomization R1 to progression or death from any cause whichever comes first
- For all patients included in R2; PFS as defined by time from randomization R2 to progression or death from any cause whichever comes first
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Two interim analyses are planned for each randomization, primarily to guard against unfavorable results in the HDM and in the VRD consolidation arms. Results of the interim analyses will be presented confidentially to an independent data and safety monitoring board (DSMB). Only if the DSMB recommends that the study should be stopped or modified the results will be made public to the principal investigators for further decisions. The interim analyses are planned after 33% and 66% of the events with regard to PFS from R1 and R2 have been observed (240/480 resp. 172/343), which are the primary endpoints for these analyses. |
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E.5.2 | Secondary end point(s) |
- Response (PR, VGPR, CR and stringent CR), and improvement of response during the various stages of the treatment.
- Overall survival measured from the time of registration/randomization R1/ randomization R2. Patients still alive or lost to follow up are censored at the date they were last known to be alive.
- Toxicity.
- Quality of life as defined by the EORTC QLQ-C30 and QLQ-MY20 definitions. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Two interim analyses are planned for each randomization, primarily to guard against unfavorable results in the HDM and in the VRD consolidation arms. Results of the interim analyses will be presented confidentially to an independent data and safety monitoring board (DSMB). Only if the DSMB recommends that the study should be stopped or modified the results will be made public to the principal investigators for further decisions. The interim analyses are planned after 33% and 66% of the events with regard to PFS from R1 and R2 have been observed (240/480 resp. 172/343), which are the primary endpoints for these analyses. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
other treatment strategy (standard treatment) |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 60 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 300 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Israel |
Austria |
Estonia |
Finland |
Iceland |
Poland |
Sweden |
Netherlands |
Switzerland |
Czechia |
Germany |
Greece |
Italy |
Belgium |
Croatia |
Denmark |
Hungary |
Ireland |
Norway |
Portugal |
Slovakia |
Slovenia |
Turkey |
Serbia |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |