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

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.

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.

Study Overview

• Status: Unknown
• Conditions: Multiple Myeloma and Plasma Cell Neoplasm
• Intervention / Treatment: Drug: melphalan; Drug: cyclophosphamide; Procedure: autologous hematopoietic stem cell transplantation

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.

• Study Type: Interventional
• Enrollment (Anticipated): 460
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • England
    • Basingstoke, England, United Kingdom, RG24 9NA
      • Recruiting
      • Basingstoke and North Hampshire NHS Foundation Trust
      • Contact: Contact Person; Phone Number: 44-125-631-4793
    • Birmingham, England, United Kingdom, B9 5SS
      • Recruiting
      • Birmingham Heartlands Hospital
      • Contact: Contact Person; Phone Number: 44-121-424-2000
    • Birmingham, England, United Kingdom, B15 2TH
      • Recruiting
      • Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
      • Contact: Contact Person; Phone Number: 44-121-472-1311
    • Bournemouth, England, United Kingdom, BH7 7DW
      • Recruiting
      • Royal Bournemouth Hospital
      • Contact: Contact Person; Phone Number: 44-202-303-626
    • Bradford, England, United Kingdom, BD9 6RJ
      • Recruiting
      • Bradford Royal Infirmary
      • Contact: Contact Person; Phone Number: 44-1274-542-200
    • Bristol, England, United Kingdom, BS2 8ED
      • Recruiting
      • Bristol Haematology and Oncology Centre
      • Contact: Contact Person
    • Bristol, England, United Kingdom, BS16 1LE
      • Recruiting
      • Frenchay Hospital
      • Contact: Contact Person; Phone Number: 44-117-970-1212
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Recruiting
      • Addenbrooke's Hospital
      • Contact: Contact Person; Phone Number: 44-1223-245-151
    • Carshalton, England, United Kingdom, SM5 1AA
      • Recruiting
      • St. Helier Hospital
      • Contact: Contact Person; Phone Number: 44-20-8296-2000
    • Cheltenham, England, United Kingdom, GL53 7AN
      • Recruiting
      • Gloucestershire Oncology Centre at Cheltenham General Hospital
      • Contact: Contact Person; Phone Number: 44-8454-222-222
    • Chichester, England, United Kingdom, P019 4SE
      • Recruiting
      • Saint Richards Hospital
      • Contact: Contact Person; Phone Number: 44-1243-788-122
    • Colchester, England, United Kingdom, CO4 5JL
      • Recruiting
      • Colchester General Hospital
      • Contact: Contact Person; Phone Number: 44-1206-747-474
    • Dorchester, England, United Kingdom, DT1 2JY
      • Recruiting
      • Dorset County Hospital
      • Contact: Contact Person; Phone Number: 44-1305-251-150
    • Dudley, England, United Kingdom, DY1 2HQ
      • Recruiting
      • Russells Hall Hospital
      • Contact: Contact Person; Phone Number: 44-1384-456-111
    • Exeter, England, United Kingdom, Ex2 5DW
      • Recruiting
      • Royal Devon and Exeter Hospital
      • Contact: Contact Person; Phone Number: 44-1392-411-611
    • Gloucester, England, United Kingdom, GL1 3NN
      • Recruiting
      • Gloucestershire Royal Hospital
      • Contact: Contact Person; Phone Number: 44-8454-222-222
    • Ipswich, England, United Kingdom, IP4 5PD
      • Recruiting
      • Ipswich Hospital
      • Contact: Contact Person; Phone Number: 44-1473-712-233
    • Leeds, England, United Kingdom, LS9 7TF
      • Recruiting
      • Leeds Cancer Centre at St. James's University Hospital
    • Liverpool, England, United Kingdom, L7 8XP
      • Recruiting
      • Royal Liverpool University Hospital
      • Contact: Contact Person; Phone Number: 44-151-706-2000
    • Liverpool, England, United Kingdom, L9 7AL
      • Recruiting
      • Aintree University Hospital
      • Contact: Contact Person; Phone Number: 44-151-525-5980
    • London, England, United Kingdom, SW17 0QT
      • Recruiting
      • St. George's Hospital
      • Contact: Contact Person; Phone Number: 44-208-672-1255
    • London, England, United Kingdom, EC1A 7BE
      • Recruiting
      • Saint Bartholomew's Hospital
      • Contact: Contact Person; Phone Number: 44-20-7601-8391
    • London, England, United Kingdom, SE5 9RS
      • Recruiting
      • King's College Hospital
      • Contact: Contact Person; Phone Number: 44-20-3299-9000
    • London, England, United Kingdom, SE1 9RT
      • Recruiting
      • Guy's Hospital
      • Contact: Contact Person; Phone Number: 44-20-7188-7188
    • London, England, United Kingdom, WIT 3AA
      • Recruiting
      • University College of London Hospitals
      • Contact: Contact Person; Phone Number: 44-20-7636-8333
    • Manchester, England, United Kingdom, M20 4BX
      • Recruiting
      • Christie Hospital
      • Contact: Contact Person; Phone Number: 44-845-226-3000
    • Manchester, England, United Kingdom, M13 9WL
      • Recruiting
      • Manchester Royal Infirmary
      • Contact: Contact Person; Phone Number: 44-161-276-1234
    • Middlesbrough, England, United Kingdom, TS4 3BW
      • Recruiting
      • James Cook University Hospital
      • Contact: Contact Person; Phone Number: 44-1642-850-850
    • Newcastle-Upon-Tyne, England, United Kingdom, NE1 4LP
      • Recruiting
      • Royal Victoria Infirmary
      • Contact: Contact Person; Phone Number: 44-191-233-6161
    • Norwich, England, United Kingdom, NR4 7UY
      • Recruiting
      • Norfolk and Norwich University Hospital
      • Contact: Contact Person; Phone Number: 44-603-286-286
    • Nottingham, England, United Kingdom, NG5 1PB
      • Recruiting
      • Nottingham City Hospital
      • Contact: Contact Person; Phone Number: 44-115-969-1169
    • Oxford, England, United Kingdom, 0X3 9DU
      • Recruiting
      • Oxford Radcliffe Hospital
      • Contact: Contact Person; Phone Number: 44-1865-64841
    • Plymouth, England, United Kingdom, PL6 8DH
      • Recruiting
      • Derriford Hospital
      • Contact: Contact Person; Phone Number: 44-175-277-7111
    • Reading, England, United Kingdom, RG1 5AN
      • Recruiting
      • Berkshire Cancer Centre at Royal Berkshire Hospital
      • Contact: Contact Person; Phone Number: 44-118-322-7878
    • Rotherham, England, United Kingdom, S60 2UD
      • Recruiting
      • Rotherham General Hospital
      • Contact: Contact Person; Phone Number: 44-1709-820-000
    • Salisbury, England, United Kingdom, SP2 8BJ
      • Recruiting
      • Salisbury District Hospital
      • Contact: Contact Person; Phone Number: 44-1722-336-262
    • Sheffield, England, United Kingdom, S1O 2JF
      • Recruiting
      • Royal Hallamshire Hospital
      • Contact: Contact Person; Phone Number: 44-114-271-1900
    • Southampton, England, United Kingdom, SO16 6YD
      • Recruiting
      • Southampton General Hospital
    • Sutton, England, United Kingdom, SM2 5PT
      • Recruiting
      • Royal Marsden - Surrey
      • Contact: Contact Person; Phone Number: 44-20-8642-6011
    • Taunton, England, United Kingdom, TA1 5DA
      • Recruiting
      • Musgrove Park Hospital
      • Contact: Contact Person; Phone Number: 44-1823-333-444
    • Torquay, England, United Kingdom, TQ2 7AA
      • Recruiting
      • Torbay Hospital
      • Contact: Contact Person; Phone Number: 44-1803-614-567
    • Wirral, England, United Kingdom, CH49 5PE
      • Recruiting
      • Arrowe Park Hospital
      • Contact: Contact Person; Phone Number: 44-151-678-5111
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT8 8JR
      • Recruiting
      • Belfast City Hospital Trust Incorporating Belvoir Park Hospital
      • Contact: Contact Person; Phone Number: 44-2890-699-069
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZN
      • Recruiting
      • Aberdeen Royal Infirmary
      • Contact: Contact Person; Phone Number: 44-84-5456-6000
    • Ayr, Scotland, United Kingdom, KA6 6DX
      • Recruiting
      • Ayr Hospital
      • Contact: Contact Person; Phone Number: 44-1292-610-555
    • Dundee, Scotland, United Kingdom, DD1 9SY
      • Recruiting
      • Ninewells Hospital
      • Contact: Contact Person; Phone Number: 44-1382-660-111
    • Glasgow, Scotland, United Kingdom, G12 0YN
      • Recruiting
      • Beatson West of Scotland Cancer Centre
      • Contact: Contact Person; Phone Number: 44-141-211-2123
    • Inverness, Scotland, United Kingdom, 1V2 3UJ
      • Recruiting
      • Raigmore Hospital
      • Contact: Contact Person; Phone Number: 44-1463-704-000 ext. 4310
    • Kilmarnock, Scotland, United Kingdom, KA2 OBE
      • Recruiting
      • Crosshouse Hospital
      • Contact: Contact Person; Phone Number: 44-1563-521-133
    • Wakefield, Scotland, United Kingdom, WF1 4DG
      • Recruiting
      • Pinderfields General Hospital
      • Contact: Contact Person; Phone Number: 44-84-4811-8110
  • Wales
    • Bangor, Wales, United Kingdom, LL57 2PW
      • Recruiting
      • Ysbyty Gwynedd
      • Contact: Contact Person; Phone Number: 44-1248-370-007
    • Rhyl, Denbighshire, Wales, United Kingdom, LL 18 5UJ
      • Recruiting
      • Glan Clwyd Hospital
    • Swansea, Wales, United Kingdom, SA2 8QA
      • Recruiting
      • Singleton Hospital
      • Contact: Contact Person; Phone Number: 44-1792-285-501

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time to disease progression

Secondary Outcome Measures

Outcome Measure
Progression-free survival
Overall survival
Quality of life
Pain
Response rate to bortezomib, doxorubicin hydrochloride, and dexamethasone (PAD)
Overall response rate following randomized treatments
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

Collaborators and Investigators

• Sponsor: 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

Publications and helpful links

General Publications

• 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.
• 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.
• 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. Erratum In: Lancet Oncol. 2014 Aug;15(9):e365. Dosage error in article text.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (Anticipated): April 1, 2012

Study Registration Dates

• First Submitted: September 4, 2008
• First Submitted That Met QC Criteria: September 4, 2008
• First Posted (Estimate): September 5, 2008

Study Record Updates

• Last Update Posted (Estimate): August 12, 2013
• Last Update Submitted That Met QC Criteria: August 9, 2013
• Last Verified: June 1, 2009

More Information

Terms related to this study

• Keywords: stage II multiple myeloma; stage III multiple myeloma; stage I multiple myeloma; refractory multiple myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Melphalan
• Other Study ID Numbers: LCC-HM05/7287; CDR0000612567 (Registry Identifier: PDQ (Physician Data Query)); EU-20873; ISRCTN60123120; EudraCT-2006-005890-24