*To assess the efficacy of VMP versus high-dose therapy (HDT) and stem cell transplantation in patients with previously untreated multiple myeloma, as measured by the progression free survival.**To evaluate the effect of consolidation with VRD…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- For all registered patients: progression free survival (PFS) as defined by
time from registration to progression or death from any cause whichever occurs
first).
- For 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
Secondary outcome
- 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 R !/
randomization R2.
- Toxicity
- Quality of life defined by the EORTC QLQ-C30 and QLQ-MY20 definitions.
Background summary
This is a phase III study to test the efficacy and feasibility of Bortezomib
combined with Melphalan and Prednisone (VMP) versus intensive treatment (HDM)
followed by ASCT(s) and secondly to evaluate the role of short term
consolidation treatment with VRD (Bortezomib, Lenalidomide, Dexamethasone)
versus no consolidation. In a subgroup of patients, 2 cycles of HDM + ASCT will
be compared to 1 cycle of HDM + ASCT. Finally, the overall efficacy of these
treatments in relation to clinical and molecular prognostic factors in multiple
myeloma will be evaluated.
The rationale for including Bortezomib in VCD induction chemotherapy is based
on the different mechanisms of actions and the potential synergism of
Bortezomib with Cyclophosphamide and/or Dexamethasone. It has been shown that
Bortezomib (1.3 mg/m2) can be safely combined with Doxorubicin and/or
Dexamethason (BD, PAD) or Cyclophosphamide and/or Dexamethasone. Furthermore
the combination of Bortezomib, Lenalidomide and Dexamethasone has been used for
induction in refractory/relapsed as well as previously untreated patients with
good results
Bortezomib has also been combined with Melphalan/Prednisone for patients who
were not eligible for transplantation resulting in an high CR (35 %) and
significant prolongation of remission duration and survival
These results have prompted the rationale for the use of Bortezomib during
induction therapy of MM. In addition, it seems feasible to compare the
standard treatment of induction followed by high-dose therapy and stem cell
transplantation with a Bortezomib based approach that includes the same
induction followed by VMP.
Secondly, it is time to examine whether consolidation treatment using an
effective combination of Bortezomib and Lenalidomide (VRD) may further improve
the CR rate, progression-free survival and overall survival.
Study objective
*To assess the efficacy of VMP versus high-dose therapy (HDT) and stem cell
transplantation 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.
*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.
Study design
Prospective, multicenter, intrergroup, randomized phase 3
Intervention
All patients will be treated with 3 induction cycles with VCD, followed by
cyclophosphamide for stem cell mobilization and collection.
After induction patients will be randomized to compare two intensification
regimens VMP vs. HDM (R1), except if a patient will proceed to allogenic SCT.
In hospitals with a policy of double intensification, all patients will be
randomized at R1 between VMP, 1 HDM and 2 HDM, in order also to evaluate 1 HDM
vs. 2 HDM
After intensification treatment there will be a 2nd randomization to compare
VRD consolidation vs. no consolidation (R2), followed by lenalidomide
maintenance in both arms.
Study burden and risks
No extra risk.
Longer duration of treatment with VMP
de Boelelaan 1117
Amsterdam 1081 HV
NL
de Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
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.
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;
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-017903-28-NL |
| ClinicalTrials.gov | NCT01208766 |
| CCMO | NL31466.078.10 |