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

Purpose

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	Intervention	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Drug: cyclophosphamide Drug: melphalan Procedure: autologous hematopoietic stem cell transplantation	Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Masking: Open Label Primary Purpose: Treatment
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.

Resource links provided by NLM:

Genetics Home Reference related topics: multiple myeloma

MedlinePlus related topics: Multiple Myeloma

Drug Information available for: Cyclophosphamide Melphalan Melphalan hydrochloride

Genetic and Rare Diseases Information Center resources: Multiple Myeloma Anaplastic Plasmacytoma

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Time to disease progression [ Designated as safety issue: No ]

Secondary Outcome Measures:

Response rate to bortezomib, doxorubicin hydrochloride, and dexamethasone (PAD) [ Designated as safety issue: No ]
Overall response rate following randomized treatments [ Designated as safety issue: No ]
Overall survival [ Designated as safety issue: No ]
Progression-free survival [ Designated as safety issue: No ]
Toxicity and safety of autologous stem cell transplantation [ Designated as safety issue: Yes ]
Toxicity and safety of weekly cyclophosphamide [ Designated as safety issue: Yes ]
Toxicity and safety of PAD therapy [ Designated as safety issue: Yes ]
Feasibility of stem cell collection [ Designated as safety issue: No ]
Pain [ Designated as safety issue: No ]
Quality of life [ Designated as safety issue: No ]


Estimated Enrollment:	460
Study Start Date:	April 2008
Estimated Primary Completion Date:	April 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

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


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00747877

Show 53 Study Locations

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.


ClinicalTrials.gov Identifier:	NCT00747877 History of Changes
Other Study ID Numbers:	LCC-HM05/7287 CDR0000612567 EU-20873 ISRCTN60123120 EudraCT-2006-005890-24
Study First Received:	September 4, 2008
Last Updated:	August 9, 2013
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):


stage II multiple myeloma stage III multiple myeloma refractory multiple myeloma stage I multiple myeloma

Additional relevant MeSH terms:


Multiple Myeloma Neoplasms, Plasma Cell Plasmacytoma Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders	Immunoproliferative Disorders Immune System Diseases Cyclophosphamide Melphalan Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists

ClinicalTrials.gov processed this record on September 30, 2016