High-Dose Melphalan and a Second Stem Cell Transplant or Low-Dose Cyclophosphamide in Treating Patients With Relapsed Multiple Myeloma After Chemotherapy
Study Details
Study Description
Brief Summary
RATIONALE: Giving chemotherapy and bortezomib before a peripheral stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as G-CSF, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy and bortezomib. It is not yet known whether high-dose melphalan given together with a second stem cell transplant is more effective than low-dose cyclophosphamide in treating patients with relapsed multiple myeloma.
PURPOSE: This randomized phase III trial is studying giving high-dose melphalan together with a second stem cell transplant to see how well it works compared with low-dose cyclophosphamide in treating patients with relapsed multiple myeloma after chemotherapy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
OBJECTIVES:
Primary
- To determine the effect on freedom from disease progression in patients with relapsed multiple myeloma treated with re-induction therapy comprising bortezomib, doxorubicin hydrochloride, and dexamethasone (PAD) followed by a second autologous stem cell transplantation (ASCT) with high-dose melphalan vs low-dose cyclophosphamide consolidation therapy.
Secondary
-
To assess the response rate of PAD in patients following a previous autograft.
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To compare the overall response rate of patients following high-dose melphalan chemotherapy and autologous stem cell transplantation with low-dose cyclophosphamide consolidation therapy.
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To assess the overall survival of patients treated with this regimen.
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To assess the safety and toxicity of a second ASCT in these patients.
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To assess the safety and toxicity of PAD in these patients.
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To assess the feasibility of stem cell collection following PAD in these patients.
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To determine the impact of this regimen on pain and quality of life in these patients.
OUTLINE: This is a multicenter study.
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Re-induction (PAD) therapy: Patients receive bortezomib IV on days 1, 4, 8, and 11, doxorubicin hydrochloride IV continuously on days 1-4, and oral dexamethasone on days 1-4 (and days 8-11 and 15-18 of course 1 only). Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
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Peripheral blood stem cell (PBSC) mobilization and harvest: Within 6-12 weeks, some patients receive cyclophosphamide IV on day 0 and filgrastim (G-CSF) subcutaneously (SC) beginning on day 1 and continuing to time of PBSC harvest. PBSCs are then collected.
Patients who successfully complete re-induction therapy and have adequate PBSC mobilization are stratified according to length of first remission or plateau (≤ vs ≥ 24 months) and response to PAD re-induction therapy (stable disease vs ≥ partial response). Patients are randomized to 1 of 2 arms.
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Arm I (high-dose melphalan consolidation therapy): Patients receive high-dose melphalan IV on day -1 followed by autologous stem cell transplantation (ASCT) on day 0.
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Arm II (low-dose cyclophosphamide consolidation therapy): Patients receive low-dose cyclophosphamide IV or orally once a week for 12-20 weeks for a total of 12 courses.
Patients complete the EORTC QLQ-C30 and EORTC QLQ-MY20, the Brief Pain Inventory Short Form (BPI-SF), and the Leeds Assessment of Neuropathic Symptoms and Signs (Self Assessment) Pain Scale (S-LANSS) questionnaires at baseline and after completion of re-induction therapy.
Patients are followed monthly for up to 100 days after ASCT or at 30 days after low-dose cyclophosphamide and then every 3 months for 5 years.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm I Patients receive high-dose melphalan IV on day -1 followed by autologous stem cell transplantation (ASCT) on day 0. |
Drug: melphalan
Given IV
Procedure: autologous hematopoietic stem cell transplantation
Patients undergo autologous hematopoietic stem cell transplantation on day 0.
|
| Experimental: Arm II Patients receive low-dose cyclophosphamide IV or orally once a week for 12-20 weeks for a total of 12 courses. |
Drug: cyclophosphamide
Given orally
|
Outcome Measures
Primary Outcome Measures
- Time to disease progression []
Secondary Outcome Measures
- Response rate to bortezomib, doxorubicin hydrochloride, and dexamethasone (PAD) []
- Overall response rate following randomized treatments []
- Overall survival []
- Progression-free survival []
- Toxicity and safety of autologous stem cell transplantation []
- Toxicity and safety of weekly cyclophosphamide []
- Toxicity and safety of PAD therapy []
- Feasibility of stem cell collection []
- Pain []
- Quality of life []
Eligibility Criteria
Criteria
DISEASE CHARACTERISTICS:
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Diagnosis of relapsed multiple myeloma
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Symptomatic disease, including non-secretory
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Previously treated with standard chemotherapy and autologous stem cell transplantation
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Requires therapy for first progressive disease AND at least 18 months since first stem cell transplantation
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Patients who were previously immunofixation-negative and are now immunofixation-positive must have > 5 g/L absolute increase in paraprotein
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Registered in the Myeloma X Relapse (Intensive) Trial and received 2-4 courses of PAD re-induction chemotherapy according to the protocol (consolidation phase)
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Adequate stem cell mobilization available for transplantation defined as ≥ 2x10^6 CD34
- cells/kg or ≥ 2x10^8 PBMC/kg including cells stored from a previous harvest (consolidation phase)
PATIENT CHARACTERISTICS:
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ECOG performance status 0-2
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ANC ≥ 1 x 10^9/L
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Platelet count ≥ 50 x 10^9/L
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Creatinine clearance ≥ 30 mL/min
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Total bilirubin < 2 times upper limit of normal (ULN)
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ALT or AST < 2.5 times ULN
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History of pulmonary disease allowed provided carbon monoxide diffusion in the lungs (KCO/DLCO) is ≥ 50% and/or no requirement for supplementary continuous oxygen
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Left ventricular ejection fraction ≥ 40% by ECG or MUGA scan
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Not pregnant or nursing
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Negative pregnancy test
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Fertile patients must use effective contraception during and for 6 months after completion of study treatment
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No peripheral neuropathy ≥ grade 2
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No known HIV or Hepatitis B or C positivity (testing is not required)
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No known resistance to combined bortezomib, doxorubicin hydrochloride, and dexamethasone therapy
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No known history of allergy to compounds containing boron or mannitol
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No other previous or concurrent malignancies except for appropriately treated localized epithelial skin cancer or carcinoma in situ of the cervix, or remote histories of other cured tumors within the past 5 years
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No medical or psychiatric condition which, in the opinion of the investigator, contraindicates the patient's participation in the study
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No other contra-indication to treatment that would make the patient ineligible for consolidation phase
PRIOR CONCURRENT THERAPY:
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See Disease Characteristics
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No other prior therapy for relapsed disease except for local radiotherapy, therapeutic plasma exchange, or ≤ 200 mg of dexamethasone
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Radiotherapy since prior transplantation sufficient to alleviate or control pain of local invasion is permitted
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No hemi-body radiation since prior transplantation (consolidation phase)
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At least 4 weeks since prior and no concurrent investigational drugs
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Basingstoke and North Hampshire NHS Foundation Trust | Basingstoke | England | United Kingdom | RG24 9NA |
| 2 | Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust | Birmingham | England | United Kingdom | B15 2TH |
| 3 | Birmingham Heartlands Hospital | Birmingham | England | United Kingdom | B9 5SS |
| 4 | Royal Bournemouth Hospital | Bournemouth | England | United Kingdom | BH7 7DW |
| 5 | Bradford Royal Infirmary | Bradford | England | United Kingdom | BD9 6RJ |
| 6 | Frenchay Hospital | Bristol | England | United Kingdom | BS16 1LE |
| 7 | Bristol Haematology and Oncology Centre | Bristol | England | United Kingdom | BS2 8ED |
| 8 | Addenbrooke's Hospital | Cambridge | England | United Kingdom | CB2 2QQ |
| 9 | St. Helier Hospital | Carshalton | England | United Kingdom | SM5 1AA |
| 10 | Gloucestershire Oncology Centre at Cheltenham General Hospital | Cheltenham | England | United Kingdom | GL53 7AN |
| 11 | Saint Richards Hospital | Chichester | England | United Kingdom | P019 4SE |
| 12 | Colchester General Hospital | Colchester | England | United Kingdom | CO4 5JL |
| 13 | Dorset County Hospital | Dorchester | England | United Kingdom | DT1 2JY |
| 14 | Russells Hall Hospital | Dudley | England | United Kingdom | DY1 2HQ |
| 15 | Royal Devon and Exeter Hospital | Exeter | England | United Kingdom | EX2 5DW |
| 16 | Gloucestershire Royal Hospital | Gloucester | England | United Kingdom | GL1 3NN |
| 17 | Ipswich Hospital | Ipswich | England | United Kingdom | IP4 5PD |
| 18 | Leeds Cancer Centre at St. James's University Hospital | Leeds | England | United Kingdom | LS9 7TF |
| 19 | Royal Liverpool University Hospital | Liverpool | England | United Kingdom | L7 8XP |
| 20 | Aintree University Hospital | Liverpool | England | United Kingdom | L9 7AL |
| 21 | Saint Bartholomew's Hospital | London | England | United Kingdom | EC1A 7BE |
| 22 | Guy's Hospital | London | England | United Kingdom | SE1 9RT |
| 23 | King's College Hospital | London | England | United Kingdom | SE5 9RS |
| 24 | St. George's Hospital | London | England | United Kingdom | SW17 0QT |
| 25 | University College of London Hospitals | London | England | United Kingdom | WIT 3AA |
| 26 | Manchester Royal Infirmary | Manchester | England | United Kingdom | M13 9WL |
| 27 | Christie Hospital | Manchester | England | United Kingdom | M20 4BX |
| 28 | James Cook University Hospital | Middlesbrough | England | United Kingdom | TS4 3BW |
| 29 | Royal Victoria Infirmary | Newcastle-Upon-Tyne | England | United Kingdom | NE1 4LP |
| 30 | Norfolk and Norwich University Hospital | Norwich | England | United Kingdom | NR4 7UY |
| 31 | Nottingham City Hospital | Nottingham | England | United Kingdom | NG5 1PB |
| 32 | Oxford Radcliffe Hospital | Oxford | England | United Kingdom | 0X3 9DU |
| 33 | Derriford Hospital | Plymouth | England | United Kingdom | PL6 8DH |
| 34 | Berkshire Cancer Centre at Royal Berkshire Hospital | Reading | England | United Kingdom | RG1 5AN |
| 35 | Rotherham General Hospital | Rotherham | England | United Kingdom | S60 2UD |
| 36 | Salisbury District Hospital | Salisbury | England | United Kingdom | SP2 8BJ |
| 37 | Royal Hallamshire Hospital | Sheffield | England | United Kingdom | S1O 2JF |
| 38 | Southampton General Hospital | Southampton | England | United Kingdom | SO16 6YD |
| 39 | Royal Marsden - Surrey | Sutton | England | United Kingdom | SM2 5PT |
| 40 | Musgrove Park Hospital | Taunton | England | United Kingdom | TA1 5DA |
| 41 | Torbay Hospital | Torquay | England | United Kingdom | TQ2 7AA |
| 42 | Arrowe Park Hospital | Wirral | England | United Kingdom | CH49 5PE |
| 43 | Belfast City Hospital Trust Incorporating Belvoir Park Hospital | Belfast | Northern Ireland | United Kingdom | BT8 8JR |
| 44 | Aberdeen Royal Infirmary | Aberdeen | Scotland | United Kingdom | AB25 2ZN |
| 45 | Ayr Hospital | Ayr | Scotland | United Kingdom | KA6 6DX |
| 46 | Ninewells Hospital | Dundee | Scotland | United Kingdom | DD1 9SY |
| 47 | Beatson West of Scotland Cancer Centre | Glasgow | Scotland | United Kingdom | G12 0YN |
| 48 | Raigmore Hospital | Inverness | Scotland | United Kingdom | 1V2 3UJ |
| 49 | Crosshouse Hospital | Kilmarnock | Scotland | United Kingdom | KA2 OBE |
| 50 | Pinderfields General Hospital | Wakefield | Scotland | United Kingdom | WF1 4DG |
| 51 | Ysbyty Gwynedd | Bangor | Wales | United Kingdom | LL57 2PW |
| 52 | Glan Clwyd Hospital | Rhyl, Denbighshire | Wales | United Kingdom | LL 18 5UJ |
| 53 | Singleton Hospital | Swansea | Wales | United Kingdom | SA2 8QA |
Sponsors and Collaborators
- Leeds Cancer Centre at St. James's University Hospital
Investigators
- Principal Investigator: Gordon Cook, MD, PhD, Leeds Cancer Centre at St. James's University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- LCC-HM05/7287
- CDR0000612567
- EU-20873
- ISRCTN60123120
- EudraCT-2006-005890-24