Clinical Trial Results:
A phase III national, multicentre, randomized open-label study with Lenalidomide/Dexamethasone versus Lenalidomide/Dexamethasone and autologous stem cell transplantation followed by Lenalidomide
maintenance therapy for patients with relapsed Multiple Myeloma
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Summary
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EudraCT number |
2009-013856-61 |
Trial protocol |
DE |
Global end of trial date |
30 Jun 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Jul 2022
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First version publication date |
16 Jul 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ReLApsE_RV-MM-GMMG-340
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Additional study identifiers
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ISRCTN number |
ISRCTN16345835 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University Hospital Heidelberg
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Sponsor organisation address |
Im Neuenheimer Feld 672, Heidelberg, Germany, 69120
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Public contact |
GMMG-Studiensekretariat, GMMG Study Office , 0049 6221568198, studiensekretariat.gmmg@med.uni-heidelberg.de
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Scientific contact |
GMMG-Studiensekretariat, GMMG Study Office , 0049 6221568198, studiensekretariat.gmmg@med.uni-heidelberg.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
24 May 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Jun 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jun 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Proof of significant prolongation of the progression-free survival (PFS, time from randomization until disease progression or death from any cause) through an induction therapy with Lenalidomide/Dexamethasone followed by high-dose chemotherapy with Melphalane, autologous blood stem cell transplantation and
maintenance therapy with Lenalidomide in contrast to conventional therapy with Lenalidomide/Dexamethasone.
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Protection of trial subjects |
- reporting and assessment of serious adverse events (SAE)
- reporting and assessment of adverse events (AE)
AEs are assessed according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).
List of safety parameter according to protocol :
• laboratory parameters (hematology, blood chemistry incl. creatinine, urea, ASAT, ALAT, γ-GT, hCG for women of childbearing potential)
• physical examination
• medical history
• ECG
Implementation of "pregnancy prevention programme"
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Background therapy |
Following randomization, all patients received reinduction treatment consisting of 3 Rd cycles of 28 days each (oral lenalidomide 25 mg on days 1-21, oral dexamethasone 40 mg on days 1, 8, 15, 22). Subsequently, all patients that did not have available stem cells from earlier harvesting (≥ 2*106 CD34+ cells*kg bw-1) underwent peripheral blood stem cell mobilization and harvesting. Stem cell mobilization consisted of cyclophosphamide (2 g*m-2 i.v. daily on days 1 and 2) and G-CSF (filgrastim 10 µg*kg-1*d-1 or lenograstim 300 µg*m-2*d-1 s.c. from day 5 until the end of apheresis). Patients in standard arm A then continued on consecutive Rd cycles (same dosages and intervals as reinduction treatment). | ||
Evidence for comparator |
standard therapy for relapsed multiple myeloma | ||
Actual start date of recruitment |
02 Dec 2010
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy | ||
Long term follow-up duration |
7 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 282
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Worldwide total number of subjects |
282
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EEA total number of subjects |
282
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
188
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From 65 to 84 years |
94
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85 years and over |
0
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Recruitment
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Recruitment details |
FPI (first patient in): 02-DEC-2010 LPI (last patient in): 18-MAR-2016 | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
The investigations required for checking the eligibility criteria and for enrollment usually are consistent with the routine medical care for relapsed myeloma patients and prior to start of relapse treatment. Routine data obtained up to 4 weeks prior to randomization could be used for screening. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Standard arm A | |||||||||||||||||||||||||||||||||
Arm description |
In the standard arm A, patients received continuous treatment with Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1,8,15,22; 4 week cycles). | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Lenalidomide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
25mg per day on day 1-21 of 28 day cycle
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Arm title
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Experimental arm B | |||||||||||||||||||||||||||||||||
Arm description |
In the experimental arm B, patients received re-induction treatment with 3 cycles of Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1,8,15,22; 4 week cycles). Patients proceeded to high dose chemotherapy (melphalan 100 mg/m2 on days -3 and -2) and autologous stem cell transplantation (≥2x10^6 CD34+ cells/kg on day 0) followed by Lenalidomide maintenance (10 mg daily). | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Lenalidomide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
25mg per day on day 1-21 of 28 day cycle (induction cycles 1-3); 10mg per day continously (maintenance)
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Investigational medicinal product name |
autologous stem cells
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
≥2x10^6 CD34+ cells/kg body weight, i.v., day 0
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Baseline characteristics reporting groups
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Reporting group title |
Standard arm A
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Reporting group description |
In the standard arm A, patients received continuous treatment with Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1,8,15,22; 4 week cycles). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Experimental arm B
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Reporting group description |
In the experimental arm B, patients received re-induction treatment with 3 cycles of Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1,8,15,22; 4 week cycles). Patients proceeded to high dose chemotherapy (melphalan 100 mg/m2 on days -3 and -2) and autologous stem cell transplantation (≥2x10^6 CD34+ cells/kg on day 0) followed by Lenalidomide maintenance (10 mg daily). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
intent-to-treat (ITT) population
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The intent-to-treat (ITT) population includes all patients randomized with written informed consent, excluding patients with violation of major eligibility criteria. Patients in the ITT population are analyzed as randomized.
ITT patients with violations of exclusion criteria are excluded from further analyses. As per principle investigator decision, randomized patients who received high-dose chemotherapy and autologous stem cell transplantation in fi rst-line therapy and duration of resulting remission <12 months after transplantation (inclusion criterion 10) or patients with previous salvage autologous transplantation (exclusion criterion 14) are excluded from ITT population and all further analyses.
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End points reporting groups
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Reporting group title |
Standard arm A
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Reporting group description |
In the standard arm A, patients received continuous treatment with Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1,8,15,22; 4 week cycles). | ||
Reporting group title |
Experimental arm B
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Reporting group description |
In the experimental arm B, patients received re-induction treatment with 3 cycles of Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1,8,15,22; 4 week cycles). Patients proceeded to high dose chemotherapy (melphalan 100 mg/m2 on days -3 and -2) and autologous stem cell transplantation (≥2x10^6 CD34+ cells/kg on day 0) followed by Lenalidomide maintenance (10 mg daily). | ||
Subject analysis set title |
intent-to-treat (ITT) population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The intent-to-treat (ITT) population includes all patients randomized with written informed consent, excluding patients with violation of major eligibility criteria. Patients in the ITT population are analyzed as randomized.
ITT patients with violations of exclusion criteria are excluded from further analyses. As per principle investigator decision, randomized patients who received high-dose chemotherapy and autologous stem cell transplantation in fi rst-line therapy and duration of resulting remission <12 months after transplantation (inclusion criterion 10) or patients with previous salvage autologous transplantation (exclusion criterion 14) are excluded from ITT population and all further analyses.
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End point title |
progression-free survival (PFS) | ||||||||||||
End point description |
The primary objective is to compare therapy efficacy in standard arm A and experimental arm B with respect to PFS.
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End point type |
Primary
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End point timeframe |
PFS times are defined from randomization until progression or death from any cause whichever occurs first. Patients without progression at the time of analysis are censored at the time of last evaluable response assessment.
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Statistical analysis title |
PFS | ||||||||||||
Statistical analysis description |
Progression-free survival (PFS) times are compared between arm A and arm B as primary endpoint. PFS
times are defined from randomization until progression or death from any cause whichever occurs first. Patients without progression
at the time of analysis are censored at the time of last evaluable response assessment.
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Comparison groups |
Standard arm A v Experimental arm B
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Number of subjects included in analysis |
277
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
P-value |
= 0.34 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.87
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
0.65 | ||||||||||||
upper limit |
1.16 | ||||||||||||
| Notes [1] - inferiority of PFS in standard arm A vs. experimental treatment arm B |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events (AE) had to be reported from start of study treatment up to 30d after last dose of study treatment or start of subsequent therapy.
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Adverse event reporting additional description |
Grade 1 AE of negligible clinical significance (e.g. fatigue, obstipation, night sweats) did not have to be reported. Hematotoxicity had to be reported only if grade ≥3; leukocytopenia only if grade ≥4.
All SAE had to be reported independent from CTCAE grade.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
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Reporting groups
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Reporting group title |
Safety population
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Reporting group description |
The safety population consisted of all patients who received at least one dose of study treatment: 145 patients in the control arm and 135 patients in the transplant arm. Patients were analyzed as treated. Patients randomized to the transplant arm but proceeding in the control arm after induction were analyzed in the control arm. Safety and toxicity variables were analyzed by Fisher’s exact test. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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18 Jul 2012 |
Key change in regard to Exclusion criteria (EC).
EC #13:
- Patients with prior therapy with Lenalidomide (LEN) will be excluded if they had
- no response (SD) to LEN,
- PD during treatment with LEN or PD within 6o days after end of treatment with LEN,
- in case of response MR or better (and PD > 60 days): PD within 6 months after end of treatment with LEN.
(prior treatment with LEN was excluded in earlier protocol version)
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21 Nov 2013 |
Key changes in Inclusion (IC) and Exclusion criteria.
IC #2:
- increase of upper limit of age at time of inclusion from 70 years to 75 years
(inclusion of patients >= 71 years only in case there are at time of inclusion suitable autologous blood stem cell transplants available from earlier mobilization).
EC #2:
- patients with asecretory Multiple Myeloma (with normal sFLC ratio) without radiological assessable (e.g. MRI) extramedullary disease
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16 Jul 2014 |
- Adaption of recruitment period and overall trial duration:
Since the recruitment rate was lower than originally assumed, a modification of the initial planned patient number became necessary. Assuming uniform recruitment in the 18 trial sites initiated during the course of the study, the required 282 patients should be reached after a total of 5 years of recruitment (originally 3 years of recruitment were planned). The expected duration of study was 6.25 years (5 years of recruitment plus 1.25 years of minimum follow-up) instead of 5 years (3 years of recruitment plus 2 years of minimum follow-up).
- Change in Inclusion criterion #6 (in line with SmPc Revlimid®):
Platelets >= 75 x 10 exp 9/L or, depending on bone marrow infiltration by plasma cells, platelets >= 30 x 10 exp 9/L.
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18 Aug 2016 |
- Implementation of updated Pregnancy Prevention Programme (PPP).
- Prolongation of SAE reporting period for Second primary malignancies (SPM) until at least 3 years after last dose LEN (prior protocol versions defined time frame until 30 days after last dose LEN).
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/32694619 |
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