High-Dose Melphalan and a Second Stem Cell Transplant or Low-Dose Cyclophosphamide in Treating Patients With Relapsed Multiple Myeloma After Chemotherapy

Multiple Myeloma and Plasma Cell Neoplasm Clinical Trial

Official title:

Myeloma X Relapse (Intensive): A Phase III Study 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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00747877
• Other study ID #: LCC-HM05/7287
• Secondary ID: CDR0000612567EU-
• Status: Recruiting
• Phase: Phase 3
• First received: September 4, 2008
• Last updated: August 9, 2013
• Start date: April 2008

Study information

• Verified date: June 2009
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Unspecified
• Study type: Interventional

Clinical Trial 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.

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.

• To compare the overall response rate of patients following high-dose melphalan chemotherapy and autologous stem cell transplantation with low-dose cyclophosphamide consolidation therapy.

• To assess the overall survival of patients treated with this regimen.

• To assess the safety and toxicity of a second ASCT in these patients.

• To assess the safety and toxicity of PAD in these patients.

• To assess the feasibility of stem cell collection following PAD in these patients.

• To determine the impact of this regimen on pain and quality of life in these patients.

OUTLINE: This is a multicenter study.

• 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.

• 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.

• 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.

• 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 460
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

DISEASE CHARACTERISTICS:

• Diagnosis of relapsed multiple myeloma

• Symptomatic disease, including non-secretory

• Previously treated with standard chemotherapy and autologous stem cell transplantation

• Requires therapy for first progressive disease AND at least 18 months since first stem cell transplantation

• Patients who were previously immunofixation-negative and are now immunofixation-positive must have > 5 g/L absolute increase in paraprotein

• Registered in the Myeloma X Relapse (Intensive) Trial and received 2-4 courses of PAD re-induction chemotherapy according to the protocol (consolidation phase)

• 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:

• ECOG performance status 0-2

• ANC = 1 x 10^9/L

• Platelet count = 50 x 10^9/L

• Creatinine clearance = 30 mL/min

• Total bilirubin < 2 times upper limit of normal (ULN)

• ALT or AST < 2.5 times ULN

• History of pulmonary disease allowed provided carbon monoxide diffusion in the lungs (KCO/DLCO) is = 50% and/or no requirement for supplementary continuous oxygen

• Left ventricular ejection fraction = 40% by ECG or MUGA scan

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 6 months after completion of study treatment

• No peripheral neuropathy = grade 2

• No known HIV or Hepatitis B or C positivity (testing is not required)

• No known resistance to combined bortezomib, doxorubicin hydrochloride, and dexamethasone therapy

• No known history of allergy to compounds containing boron or mannitol

• 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

• No medical or psychiatric condition which, in the opinion of the investigator, contraindicates the patient's participation in the study

• No other contra-indication to treatment that would make the patient ineligible for consolidation phase

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No other prior therapy for relapsed disease except for local radiotherapy, therapeutic plasma exchange, or = 200 mg of dexamethasone

• Radiotherapy since prior transplantation sufficient to alleviate or control pain of local invasion is permitted

• No hemi-body radiation since prior transplantation (consolidation phase)

• At least 4 weeks since prior and no concurrent investigational drugs

Study Design

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Neoplasms, Plasma Cell
• Plasmacytoma

Intervention

Drug:
• cyclophosphamide
Given orally
• melphalan
Given IV

Procedure:
• autologous hematopoietic stem cell transplantation
Patients undergo autologous hematopoietic stem cell transplantation on day 0.

Locations

Country	Name	City	State
United Kingdom	Aberdeen Royal Infirmary	Aberdeen	Scotland
United Kingdom	Ayr Hospital	Ayr	Scotland
United Kingdom	Ysbyty Gwynedd	Bangor	Wales
United Kingdom	Basingstoke and North Hampshire NHS Foundation Trust	Basingstoke	England
United Kingdom	Belfast City Hospital Trust Incorporating Belvoir Park Hospital	Belfast	Northern Ireland
United Kingdom	Birmingham Heartlands Hospital	Birmingham	England
United Kingdom	Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust	Birmingham	England
United Kingdom	Royal Bournemouth Hospital	Bournemouth	England
United Kingdom	Bradford Royal Infirmary	Bradford	England
United Kingdom	Bristol Haematology and Oncology Centre	Bristol	England
United Kingdom	Frenchay Hospital	Bristol	England
United Kingdom	Addenbrooke's Hospital	Cambridge	England
United Kingdom	St. Helier Hospital	Carshalton	England
United Kingdom	Gloucestershire Oncology Centre at Cheltenham General Hospital	Cheltenham	England
United Kingdom	Saint Richards Hospital	Chichester	England
United Kingdom	Colchester General Hospital	Colchester	England
United Kingdom	Dorset County Hospital	Dorchester	England
United Kingdom	Russells Hall Hospital	Dudley	England
United Kingdom	Ninewells Hospital	Dundee	Scotland
United Kingdom	Royal Devon and Exeter Hospital	Exeter	England
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow	Scotland
United Kingdom	Gloucestershire Royal Hospital	Gloucester	England
United Kingdom	Raigmore Hospital	Inverness	Scotland
United Kingdom	Ipswich Hospital	Ipswich	England
United Kingdom	Crosshouse Hospital	Kilmarnock	Scotland
United Kingdom	Leeds Cancer Centre at St. James's University Hospital	Leeds	England
United Kingdom	Aintree University Hospital	Liverpool	England
United Kingdom	Royal Liverpool University Hospital	Liverpool	England
United Kingdom	Guy's Hospital	London	England
United Kingdom	King's College Hospital	London	England
United Kingdom	Saint Bartholomew's Hospital	London	England
United Kingdom	St. George's Hospital	London	England
United Kingdom	University College of London Hospitals	London	England
United Kingdom	Christie Hospital	Manchester	England
United Kingdom	Manchester Royal Infirmary	Manchester	England
United Kingdom	James Cook University Hospital	Middlesbrough	England
United Kingdom	Royal Victoria Infirmary	Newcastle-Upon-Tyne	England
United Kingdom	Norfolk and Norwich University Hospital	Norwich	England
United Kingdom	Nottingham City Hospital	Nottingham	England
United Kingdom	Oxford Radcliffe Hospital	Oxford	England
United Kingdom	Derriford Hospital	Plymouth	England
United Kingdom	Berkshire Cancer Centre at Royal Berkshire Hospital	Reading	England
United Kingdom	Glan Clwyd Hospital	Rhyl, Denbighshire	Wales
United Kingdom	Rotherham General Hospital	Rotherham	England
United Kingdom	Salisbury District Hospital	Salisbury	England
United Kingdom	Royal Hallamshire Hospital	Sheffield	England
United Kingdom	Southampton General Hospital	Southampton	England
United Kingdom	Royal Marsden - Surrey	Sutton	England
United Kingdom	Singleton Hospital	Swansea	Wales
United Kingdom	Musgrove Park Hospital	Taunton	England
United Kingdom	Torbay Hospital	Torquay	England
United Kingdom	Pinderfields General Hospital	Wakefield	Scotland
United Kingdom	Arrowe Park Hospital	Wirral	England

Sponsors (1)

Lead Sponsor	Collaborator
Leeds Cancer Centre at St. James's University Hospital

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to disease progression			No
Secondary	Response rate to bortezomib, doxorubicin hydrochloride, and dexamethasone (PAD)			No
Secondary	Overall response rate following randomized treatments			No
Secondary	Overall survival			No
Secondary	Progression-free survival			No
Secondary	Toxicity and safety of autologous stem cell transplantation			Yes
Secondary	Toxicity and safety of weekly cyclophosphamide			Yes
Secondary	Toxicity and safety of PAD therapy			Yes
Secondary	Feasibility of stem cell collection			No
Secondary	Pain			No
Secondary	Quality of life			No