Clinical trial NCT00747877: High-Dose Melphalan and a Second Stem Cell Transplant or Low-Dose Cyclophosphamide in Treating Patients With Relapsed Multiple Myeloma After Chemotherapy
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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Multiple Myeloma and Plasma Cell Neoplasm
Keywords: stage II multiple myeloma
stage III multiple myeloma
refractory multiple myeloma
stage I multiple myeloma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-09-05
Enrollment: 460
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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.

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.
* 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to disease progression
Secondary outcomes:
measure: Response rate to bortezomib, doxorubicin hydrochloride, and dexamethasone (PAD)
measure: Overall response rate following randomized treatments
measure: Overall survival
measure: Progression-free survival
measure: Toxicity and safety of autologous stem cell transplantation
measure: Toxicity and safety of weekly cyclophosphamide
measure: Toxicity and safety of PAD therapy
measure: Feasibility of stem cell collection
measure: Pain
measure: Quality of life
Other outcomes:
Locations:
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire NHS Foundation Trust
state: England
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
state: England
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: England
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
state: England
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
state: England
city: Bristol
country: United Kingdom
facility: Frenchay Hospital
state: England
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Carshalton
country: United Kingdom
facility: St. Helier Hospital
state: England
city: Cheltenham
country: United Kingdom
facility: Gloucestershire Oncology Centre at Cheltenham General Hospital
state: England
city: Chichester
country: United Kingdom
facility: Saint Richards Hospital
state: England
city: Colchester
country: United Kingdom
facility: Colchester General Hospital
state: England
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital
state: England
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
state: England
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: England
city: Gloucester
country: United Kingdom
facility: Gloucestershire Royal Hospital
state: England
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
state: England
city: Leeds
country: United Kingdom
facility: Leeds Cancer Centre at St. James's University Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
state: England
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: London
country: United Kingdom
facility: Guy's Hospital
state: England
city: London
country: United Kingdom
facility: King's College Hospital
state: England
city: London
country: United Kingdom
facility: St. George's Hospital
state: England
city: London
country: United Kingdom
facility: University College of London Hospitals
state: England
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
state: England
city: Manchester
country: United Kingdom
facility: Christie Hospital
state: England
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
state: England
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
state: England
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
state: England
city: Oxford
country: United Kingdom
facility: Oxford Radcliffe Hospital
state: England
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: England
city: Reading
country: United Kingdom
facility: Berkshire Cancer Centre at Royal Berkshire Hospital
state: England
city: Rotherham
country: United Kingdom
facility: Rotherham General Hospital
state: England
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
state: England
city: Torquay
country: United Kingdom
facility: Torbay Hospital
state: England
city: Wirral
country: United Kingdom
facility: Arrowe Park Hospital
state: England
city: Belfast
country: United Kingdom
facility: Belfast City Hospital Trust Incorporating Belvoir Park Hospital
state: Northern Ireland
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
city: Ayr
country: United Kingdom
facility: Ayr Hospital
state: Scotland
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
state: Scotland
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
state: Scotland
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
state: Scotland
city: Kilmarnock
country: United Kingdom
facility: Crosshouse Hospital
state: Scotland
city: Wakefield
country: United Kingdom
facility: Pinderfields General Hospital
state: Scotland
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
state: Wales
city: Rhyl, Denbighshire
country: United Kingdom
facility: Glan Clwyd Hospital
state: Wales
city: Swansea
country: United Kingdom
facility: Singleton Hospital
state: Wales
Study officials:
affiliation: Leeds Cancer Centre at St. James's University Hospital
name: Gordon Cook, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. doi: 10.1016/S2352-3026(16)30049-7.
citation: Parrish C, Morris CTCM, Williams CD, Cairns DA, Cavenagh J, Snowden JA, Ashcroft J, Cavet J, Hunter H, Bird JM, Chalmers A, Brown JM, Yong K, Schey S, Chown S, Cook G; National Cancer Research Institute Haemato-Oncology Clinical Studies Group. Stem Cell Harvesting after Bortezomib-Based Reinduction for Myeloma Relapsing after Autologous Transplantation: Results from the British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X (Intensive) Trial. Biol Blood Marrow Transplant. 2016 Jun;22(6):1009-1016. doi: 10.1016/j.bbmt.2016.01.016. Epub 2016 Jan 28.
citation: Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. doi: 10.1016/S1470-2045(14)70245-1. Epub 2014 Jun 16.
citation: Michaelis LC, Saad A, Zhong X, Le-Rademacher J, Freytes CO, Marks DI, Lazarus HM, Bird JM, Holmberg L, Kamble RT, Kumar S, Lill M, Meehan KR, Saber W, Schriber J, Tay J, Vogl DT, Wirk B, Savani BN, Gale RP, Vesole DH, Schiller GJ, Abidi M, Anderson KC, Nishihori T, Kalaycio ME, Vose JM, Moreb JS, Drobyski W, Munker R, Roy V, Ghobadi A, Holland HK, Nath R, To LB, Maiolino A, Kassim AA, Giralt SA, Landau H, Schouten HC, Maziarz RT, Mikhael J, Kindwall-Keller T, Stiff PJ, Gibson J, Lonial S, Krishnan A, Dispenzieri A, Hari P; Plasma Cell Disorders Working Committee of the Center for International Blood and Marrow Transplant Research. Salvage second hematopoietic cell transplantation in myeloma. Biol Blood Marrow Transplant. 2013 May;19(5):760-6. doi: 10.1016/j.bbmt.2013.01.004. Epub 2013 Jan 5.