Clinical Trial Results:
Myeloma X Relapse (Intensive) - A randomised controlled trial to determine the role of a second autologous stem cell transplant as consolidation therapy in patients with relapsed multiple myeloma following prior high-dose chemotherapy and autologous stem cell rescue.
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Summary
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EudraCT number |
2006-005890-24 |
Trial protocol |
GB |
Global end of trial date |
16 Nov 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Nov 2017
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First version publication date |
30 Nov 2017
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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 |
HM05/7287
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Additional study identifiers
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ISRCTN number |
ISRCTN60123120 | ||
US NCT number |
NCT00747877 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Leeds Teaching Hospitals NHS Trust - Research & Innovation Department
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Sponsor organisation address |
Research & Innovation Centre, St James's University Hospital, Beckett Street, Leeds, United Kingdom, LS9 7TF
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Public contact |
Regulatory Affairs and Governance Manager, CTRU QA Department, 0113 3431477, medctruq@leeds.ac.uk
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Scientific contact |
Regulatory Affairs and Governance Manager, CTRU QA Department, 0113 3431477, medctruq@leeds.ac.uk
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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 |
20 Jan 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
16 Nov 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Nov 2016
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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 |
To determine the effect on freedom-from disease progression of a second autologous stem cell transplant (ASCT) compared with low-dose consolidation, following re-induction chemotherapy, in patients with relapsed myeloma previously treated with high-dose chemotherapy and ASCT.
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Protection of trial subjects |
Safety analyses will summarise the adverse event rates and serious adverse events separately for each of the re-induction and consolidation treatments. Safety data will be presented for patients receiving any of the relevant study treatment by treatment group and relationship to study treatment.
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Background therapy |
All trial participants received re-induction therapy of 2-4 cycles of PAD (Bortezomib, doxorubicin, dexamethasone) before proceeding to peripheral blood stem cell (PBSC) mobilisation and harvesting. Cyclophosphamide and granulocyte colony stimulating factor (G-CSF) were suggested for mobilisation. Mobilisation and harvest was optional for patients who already had sufficient stem cells stored from a previous harvest. Patients with an adequate number of PBSC collected were then randomised to the two different treatment arms. | ||
Evidence for comparator |
The trial will identify whether a second course of high dose melphalan and ASCT performed at relapse in myeloma patients results in an improved duration of response and survival outcome compared to a less intensive, alkylating agent therapy of cyclophosphamide-weekly. No RCTs have been done to assess the outcome of a second autologous transplant at relapse. Some patients will have achieved a good remission following their original ASCT and a second similar procedure undertaken following relapse may be an effective form of therapy. Together with pain and Quality of Life (QoL) assessments, it is proposed that the full effect of the differing treatment strategies on time to disease progression, key symptoms and QoL will assist in the development of an evidence based management plan for treatment of relapse in these patients and allow the best use of available resources. | ||
Actual start date of recruitment |
16 Apr 2008
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Long term follow-up planned |
No
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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 |
United Kingdom: 297
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Worldwide total number of subjects |
297
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EEA total number of subjects |
297
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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) |
206
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From 65 to 84 years |
91
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial opened at 51 centres across the United Kingdom. Between April 16 2008 and November 19 2012, 297 patients were registered and 174 were randomised. On the grounds of efficacy data reviewed by the DMEC, the trial was closed to recruitment on 21 November 2012. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Patients with multiple myeloma previously treated with standard chemotherapy and autologous stem cell transplant. Patients requiring therapy for first Progressive Disease & 12 months since 1st transplant. Written informed consent. | ||||||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
297 | ||||||||||||||||||||||||
Number of subjects completed |
293 | ||||||||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Consent withdrawn by subject: 3 | ||||||||||||||||||||||||
Reason: Number of subjects |
Received no treatment: 1 | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Re-Induction PAD and PBSC Harvest
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
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Arms
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Arm title
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Re-induction PAD and PBSC Harvest | ||||||||||||||||||||||||
Arm description |
All patients will be registered at trial entry and will receive re-induction therapy with 2-4 cycles of PAD. Following completion of re-induction therapy, the disease response will be re-assessed and all patients without progressive disease will then proceed to PBSC mobilisation and harvesting. Mobilisation and harvest is encouraged in all patients without progressive disease, but is optional in patients who have sufficient stem cells stored from a previous harvest. Those patients with an adequate number of PBSC (including those who do not mobilise or who were not mobilised but have stored PBSC from prior mobilisations) will be randomised. | ||||||||||||||||||||||||
Arm type |
Re-induction | ||||||||||||||||||||||||
Investigational medicinal product name |
Bortezomib
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Investigational medicinal product code |
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Other name |
Velcade
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intravenous bolus use
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Dosage and administration details |
Bortezomib is supplied as a 3.5 mg powder for solution for injection. It is administered as an intravenous bolous at a maximum dose of 1.3mg/m2 per day of treatment. Treatment days are days 1, 4, 8 and 11 of a 21 day cycle. A minimum of 2 cycles and a maximum of 4 cycles are given.
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Investigational medicinal product name |
Doxorubicin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Doxorubicin is administered as a continuous intravenous infusion at a dose of 9mg/m2/day on days 1 to 4 of a 21 day cycle. A minimum of 2 cycles and a maximum of 4 cycles are given.
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Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Dexamethasone is in the form of tablets containing 2.0mg dexamethasone. It is administered at a dose of
40mg/day on days 1 to 4 of a 21 day cycle, for a minimum of 2 cycles and maximum of 4 cycles. It is also given on days 8-11 and 15-18 in cycle 1.
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Investigational medicinal product name |
Cyclophosphamide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Cyclophosphamide is in the form of powder for solution for injection. Each vial contains cyclophosphamide
monohydrate equivalent to 1000mg anhydrous cyclophosphamide. For stem cell mobilisation, it is administered as an intravenous infusion at a dose of 1.5-3g/m2 on day 0.
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Investigational medicinal product name |
G-CSF
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Investigational medicinal product code |
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Other name |
Granulocyte cell stimulating factor
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
G-CSF is administered at a dose of 5-10μg/kg/day, subcutaneously, from day +1 to time of stem cell
harvest.
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Period 2
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Period 2 title |
Consolidation Randomisation
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Is this the baseline period? |
Yes [1] | ||||||||||||||||||||||||
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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C-weekly | ||||||||||||||||||||||||
Arm description |
Oral cyclophosphamide 400 mg/m² per week for 12 weeks. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Cyclophosphamide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection, Tablet
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
For the C-weekly regimen, cyclophosphamide tablets, containing 50mg anhydrous cyclophosphamide, is
administered orally at 400mg/m2 weekly for 12 weeks. Alternatively, cyclophosphamide may be administered at a dose of 300mg/m2 intravenously, weekly for 12 weeks.
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Arm title
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High dose melphalan and ASCT | ||||||||||||||||||||||||
Arm description |
Single infusion of intravenous melphalan 200 mg/m² followed by ASCT after 24–48 h. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Melphalan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
High-dose melphalan is given as a 200mg/m2 short infusion (as per local protocol) in 100ml NaCL 0.9%.
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| Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: Period 1 relates to the trial treatment received prior to randomisation. Period 2 is the period following randomisation. In alliance with the publications this has been defined as our baseline period. |
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| Notes [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The worldwide number enrolled relates to the total number registered onto the trial. The baseline period relates to the total number randomised. As the trial had registration and randomisation stages these numbers are not identical. |
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Baseline characteristics reporting groups
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Reporting group title |
C-weekly
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Reporting group description |
Oral cyclophosphamide 400 mg/m² per week for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
High dose melphalan and ASCT
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Reporting group description |
Single infusion of intravenous melphalan 200 mg/m² followed by ASCT after 24–48 h. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Re-induction PAD and PBSC Harvest
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Reporting group description |
All patients will be registered at trial entry and will receive re-induction therapy with 2-4 cycles of PAD. Following completion of re-induction therapy, the disease response will be re-assessed and all patients without progressive disease will then proceed to PBSC mobilisation and harvesting. Mobilisation and harvest is encouraged in all patients without progressive disease, but is optional in patients who have sufficient stem cells stored from a previous harvest. Those patients with an adequate number of PBSC (including those who do not mobilise or who were not mobilised but have stored PBSC from prior mobilisations) will be randomised. | ||
Reporting group title |
C-weekly
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Reporting group description |
Oral cyclophosphamide 400 mg/m² per week for 12 weeks. | ||
Reporting group title |
High dose melphalan and ASCT
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Reporting group description |
Single infusion of intravenous melphalan 200 mg/m² followed by ASCT after 24–48 h. | ||
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End point title |
Time to disease progression | ||||||||||||
End point description |
Time to disease progression is defined as time from randomisation to first documented evidence of disease progression.
Documented evidence of progression is defined as:
- Progression confirmed by central review (blind to treatment) by the central reviewer.
- Progression unconfirmed by central review if central review unable to determine whether or not a patient suffered progression
- Death primarily due to progression
Patients who die prior to documentation of disease progression will be censored in the analysis. Patients not reaching disease progression at the time of analysis will be censored at the last date known to be progression-free. Patients dying from causes not primarily due to progression will also be censored in the disease progression analysis.
The results of this endpoint are based on the final data download on 20/01/2017.
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End point type |
Primary
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End point timeframe |
Time to disease progression is defined as time from randomisation to first documented evidence of disease progression.
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Statistical analysis title |
Time to disease progression | ||||||||||||
Statistical analysis description |
Cox regression will be used to analyse time to progression accounting for the stratification factors (length of first remission or plateau and response to PAD re-induction therapy), and whether or not mobilisation therapy was received. Patients not reaching disease progression at the time of analysis will be censored at the last date known to be progression-free. Patients dying from causes not primarily due to progression will also be censored.
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Comparison groups |
High dose melphalan and ASCT v C-weekly
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.29 | ||||||||||||
upper limit |
0.56 | ||||||||||||
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End point title |
Response rate to PAD | ||||||||||||||||||
End point description |
Response to treatment will be assessed according to the international uniform response criteria for multiple myeloma.
For all analyses, responses will be categorised into the following five groups: Complete Response (sCR and CR), Partial Response (VGPR and PR), Stable Disease (SD), Progressive Disease (PD) and early death.
For response rate to PAD, early death is defined as death between registration and up to and including 21 days post date last PAD cycle started.
Results for this endpoint are based on the first data cut off of 9/7/2013.
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End point type |
Secondary
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End point timeframe |
This is measured following re-induction treatment with PAD.
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Overall response rate following randomised treatments | ||||||||||||||||||||||||||||||
End point description |
Response to treatment will be assessed according to the international uniform response criteria for multiple myeloma.
For all analyses, responses will be categorised into the following five groups: Complete Response (sCR and CR), Partial Response (VGPR and PR), Stable Disease (SD), Progressive Disease (PD) and early death.
At 100 days post transplant or 30 days post end of C-weekly treatment, early death is defined as death between randomisation and up to and including 100 days post randomisation.
Results for this endpoint are based on the first data cut off of 9/7/2013.
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End point type |
Secondary
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End point timeframe |
Response rate is measured following the completion of the randomised treatments (100 days post transplant or 30 days post end of C-weekly treatment).
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Statistical analysis title |
Overall response rate | ||||||||||||||||||||||||||||||
Statistical analysis description |
Treatment groups will be compared using ordinal logistic regression to adjust for the stratification factors (length of first remission or plateau and response to PAD re-induction therapy) and whether or not mobilisation therapy was received.
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Comparison groups |
High dose melphalan and ASCT v C-weekly
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||||||||
P-value |
= 0.0069 | ||||||||||||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||||||||||||
Point estimate |
0.42
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.22 | ||||||||||||||||||||||||||||||
upper limit |
0.79 | ||||||||||||||||||||||||||||||
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End point title |
Overall Survival | ||||||||||||
End point description |
Overall survival is defined as the time from randomisation to death from any cause. If a patient is still alive at the time of analysis or lost to follow-up, they will be treated as censored at the date last known to be alive.
The analysis of this end point is based off data from the final download 20/1/2017.
The upper 95% confidence interval limit was not reached for the median survival time in the high dose melphalan and ASCT arm, this has been indicated by 999.
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End point type |
Secondary
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End point timeframe |
Overall survival is defined as the time from randomisation to death from any cause.
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Statistical analysis title |
Overall Survival | ||||||||||||
Statistical analysis description |
Cox regression analysis will be used to analyse overall survival accounting for the stratification factors (length of first remission or plateau and response to PAD re-induction therapy) and whether or not mobilisation therapy was received.
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Comparison groups |
High dose melphalan and ASCT v C-weekly
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0435 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.64
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.42 | ||||||||||||
upper limit |
0.99 | ||||||||||||
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End point title |
Progression-Free Survival | ||||||||||||
End point description |
Disease progression will be determined according to the international uniform response criteria for multiple myeloma. Progression-free survival is defined as the time from randomisation to first documented evidence of disease progression or death from any cause. Patients who do not progress will be censored at the last date they were known to be alive and progression free.
The analysis of this end point is based off data from the final download on 20/1/2017.
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End point type |
Secondary
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End point timeframe |
Progression-free survival is defined as the time from randomisation to first documented evidence of disease progression or death from any cause.
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Statistical analysis title |
Progression-Free Survival | ||||||||||||
Statistical analysis description |
Cox regression analysis will be used to analyse progression-free survival accounting for the stratification factors (length of first remission or plateau and response to PAD re-induction therapy) and whether or not mobilisation therapy was received.
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Comparison groups |
High dose melphalan and ASCT v C-weekly
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.41
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.3 | ||||||||||||
upper limit |
0.58 | ||||||||||||
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End point title |
Feasibility of stem cell collection | ||||||||||
End point description |
The feasibility of stem cell collection will be determined by the satisfactory mobilisation of an adequate number of peripheral blood stem cells (≥10 CD34+ cells/µl blood) and the subsequent harvest of sufficient numbers of stem cells to support high-dose chemotherapy (≥2.0x106 CD34+ cells/kg or ≥2.0x108 PBMC/kg).
Note that any results relating to this endpoint are based on data downloaded following the original data lock on 9/7/2013.
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End point type |
Secondary
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End point timeframe |
This is measured following PAD re-induction therapy only in patients who had PBSC mobilisation and harvest as part of the trial.
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| Notes [1] - Only 100 participants completed PBSC mobilisation and harvest on the trial. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Effect of type of PBSC mobilisation and harvest on time to disease progression [2] | ||||||||||||||
End point description |
Type of PBSC mobilisation and harvest is categorised as: pre-relapse harvest with no mobilisation therapy received post-relapse; pre-relapse harvest with mobilisation therapy received post-relapse; post-relapse harvest; or mixed harvest. Mobilisation therapy includes re-mobilisation therapy.
The results relating to this endpoint are based off data from the first follow-up analysis download, dated 14/7/15.
The upper 95% confidence interval limit was not reached for the median survival time in the mixed harvest group, this has been indicated by 999.
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End point type |
Secondary
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End point timeframe |
Time to disease progression is measured from randomisation to the first documented evidence of disease progression.
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| Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only applicable to those who underwent an ASCT following randomisation and therefore values are only given for one arm. |
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| Notes [3] - Information on this endpoint was not available for 7 participants. |
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| No statistical analyses for this end point | |||||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Adverse reactions were collected from the time of registration until 100 days post-ASCT or 30 days post cyclophosphamide.
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||
Dictionary version |
3
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| Frequency threshold for reporting non-serious adverse events: 0% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Leeds Institute of Clinical Trials Research is an academic trials unit where full MedDRA coding is not the standard. It has therefore not been possible for adverse event data to be accurately entered into the full data view within EudraCT as all mandatory categories cannot be completed. |
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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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07 Aug 2007 |
Protocol version 2 and PIS version 2, with updates to clarify exclusion criteria and correct mistakes.
Addition of sites. |
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02 Nov 2007 |
Protocol version 3 and PIS version 3 |
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01 Apr 2008 |
Protocol version 4 |
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07 Nov 2008 |
Protocol version 5 |
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20 Oct 2010 |
Protocol version 6 |
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10 Oct 2011 |
Protocol version 7 |
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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. | |||
| On the grounds of efficacy data reviewed by the DMEC, the trial was closed to recruitment on 21 November 2012. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/24033132 http://www.ncbi.nlm.nih.gov/pubmed/24948586 http://www.ncbi.nlm.nih.gov/pubmed/27374467 http://www.ncbi.nlm.nih.gov/pubmed/26827659 |
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