Autologous or Syngeneic Stem Cell Transplant Followed by Donor Stem Cell Transplant and Bortezomib in Treating Patients With Newly Diagnosed High-Risk, Relapsed, or Refractory Multiple Myeloma

NCT ID: NCT00793572

Last Updated: 2020-01-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-10-31
• Study Completion Date: 2016-10-31

Brief Summary

This phase II trial studies the side-effects and anti-cancer effects of giving an autologous or syngeneic stem cell transplant followed by an allogeneic donor stem cell transplant and bortezomib. Patients treated on this trial have newly diagnosed high-risk, relapsed, or refractory multiple myeloma (MM). Giving chemotherapy before an autologous stem cell transplant slows or stops the growth of cancer cells by preventing them from dividing or killing them. Stem cells that were harvested earlier from the patient's blood and frozen are then returned to the patient to replace the blood-forming cells that were destroyed by chemotherapy. Giving chemotherapy and total-body irradiation before an allogeneic donor stem cell transplant also prevents the patient's immune system from rejecting the donor's stem cells. Undergoing an autologous or syngeneic stem cell transplantation followed by an allogeneic donor stem cell transplant and bortezomib may be overall more effective in killing cancer cells.

Detailed Description

PRIMARY OBJECTIVES:

I. Progression-free survival (PFS) at 2 years after the autograft (=< 50% in historic controls).

SECONDARY OBJECTIVES:

I. Overall survival (OS) at 2 years after the autograft.

II. Non-relapse mortality (NRM) at 200 days and 1 year after allograft.

III. Incidence of grades II-IV acute graft-versus-host-disease (GVHD) and chronic extensive GVHD.

IV. Safety of bortezomib maintenance therapy after stem cell transplantation.

OUTLINE:

PERIPHERAL BLOOD STEM CELL (PBSC) MOBILIZATION: Patients undergo PBSC mobilization and collection using the preferred regimens at the participating institution.

CONDITIONING CHEMOTHERAPY AND AUTOLOGOUS OR SYNGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT): Patients receive high-dose melphalan intravenously (IV) on day -2 followed by an autologous or syngeneic HSCT on day 0.

NON-MYELOABLATIVE ALLOGENEIC HSCT: Beginning 40-180 days after autologous HSCT, patients receive 1 of the following regimens:

1. HLA-IDENTICAL RELATED DONOR: Patients receive cyclosporine IV or orally (PO) twice daily (BID) starting on days -3 to 56, and taper until day 180. Patients then undergo total-body irradiation (TBI) and non-myeloablative allogeneic HSCT on day 0. Four to six hours after completion of allogeneic HSCT, patients receive mycophenolate mofetil (MMF) PO BID on days 0-27.

2. HLA-UNRELATED DONOR: Patients receive fludarabine phosphate IV on days -4 to -2. Patients also receive cyclosporine IV or PO BID starting on days -3 to 100 and taper until day 180. Patients then undergo TBI and non-myeloablative allogeneic HSCT on day 0. Four to six hours after completion of allogeneic HSCT, patients receive MMF PO thrice daily (TID) on days 0-27 and then BID on days 27-40 with taper of MMF on days 40-96.

MAINTENANCE THERAPY: Beginning 60-120 days after allogeneic HSCT, patients receive bortezomib subcutaneously (SC) on days 1 and 4 of 14-day cycles for 9 months or for up to 18 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then annually for up to 5 years.

Conditions

Refractory Plasma Cell Myeloma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy

See Detailed Description

Group Type: EXPERIMENTAL

Autologous Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo transplantation

Bortezomib

Intervention Type: DRUG

Given SC

Cyclosporine

Intervention Type: DRUG

Given IV

Cyclosporine

Intervention Type: DRUG

Given PO

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Melphalan

Intervention Type: DRUG

Given IV

Mycophenolate Mofetil

Intervention Type: DRUG

Given PO

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo transplantation

Peripheral Blood Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo transplantation

Syngeneic Bone Marrow Transplantation

Intervention Type: PROCEDURE

Undergo transplantation

Total-Body Irradiation

Intervention Type: RADIATION

Undergo radiotherapy

Interventions

Autologous Hematopoietic Stem Cell Transplantation

Undergo transplantation

Intervention Type: PROCEDURE

Bortezomib

Given SC

Intervention Type: DRUG

Cyclosporine

Given IV

Intervention Type: DRUG

Cyclosporine

Given PO

Intervention Type: DRUG

Fludarabine Phosphate

Given IV

Intervention Type: DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Melphalan

Given IV

Intervention Type: DRUG

Mycophenolate Mofetil

Given PO

Intervention Type: DRUG

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Undergo transplantation

Intervention Type: PROCEDURE

Peripheral Blood Stem Cell Transplantation

Undergo transplantation

Intervention Type: PROCEDURE

Syngeneic Bone Marrow Transplantation

Undergo transplantation

Intervention Type: PROCEDURE

Total-Body Irradiation

Undergo radiotherapy

Intervention Type: RADIATION

Other Intervention Names

Autologous Stem Cell Transplantation; [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid; LDP 341; MLN341; PS-341; PS341; Velcade; 27-400; Ciclosporin; CsA; Cyclosporin; Cyclosporin A; Neoral; OL 27-400; Sandimmun; Sandimmune; SangCya; 27-400; Ciclosporin; CsA; Cyclosporin; Cyclosporin A; Neoral; OL 27-400; Sandimmun; Sandimmune; SangCya; 2-F-ara-AMP; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Beneflur; Fludara; Oforta; SH T 586; Alanine Nitrogen Mustard; CB-3025; L-PAM; L-Phenylalanine Mustard; L-Sarcolysin; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; Cellcept; MMF; Non-myeloablative allogeneic transplant; Nonmyeloablative Stem Cell Transplantation; NST; PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; TOTAL BODY IRRADIATION; Whole-Body Irradiation

Eligibility Criteria

Inclusion Criteria

• Newly diagnosed patients must have received induction therapy (e.g., vincristine, doxorubicin, dexamethasone [VAD], thalidomide/dexamethasone) for a minimum of 4 cycles
• Must have the capacity to give informed consent
• Must have an human leukocyte antigen (HLA) genotypically identical sibling or a phenotypically matched relative or, at a minimum, a high likelihood of identifying an HLA-matched unrelated donor; the determination of availability of a suitable unrelated donor may be based on a World-Book search
• In addition, patients must meet at least one of the criteria A-I (A-G at time of diagnosis or pre-autograft):

• A) Any abnormal karyotype by metaphase analysis except for isolated t(11,14) and constitutional cytogenetic abnormality
• B) Fluorescence in situ hybridization (FISH) translocation 4;14
• C) FISH translocation 14;16
• D) FISH deletion 17p
• E) Beta2-microglobulin > 5.5 mg/L
• F) Cytogenetic hypodiploidy
• G) Plasmablastic morphology (>= 2%)
• DONOR: HLA genotypically identical sibling or phenotypically matched relative OR
• DONOR: HLA phenotypically matched unrelated donor (according to Standard Practice HLA matching criteria, Grade #2.1)

• Matched HLA-A, B, C, DRB1, and DQB1 alleles by high resolution typing.
• Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing

Exclusion Criteria

• Recurrent or non-responsive (less than partial response [PR]) MM after at least two different lines of conventional chemotherapy
• Progressive MM after a previous autograft
• Life expectancy severely limited by disease other than malignancy
• Seropositive for the human immunodeficiency virus (HIV)
• Females who are pregnant or breastfeeding
• Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
• Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
• Patients with fungal infection and radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
• Patients with the following organ dysfunction:

• Symptomatic coronary artery disease or ejection fraction < 40% or other cardiac failure requiring therapy; myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
• Ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease
• Diffusing lung capacity for carbon monoxide (DLCO) < 50%, forced expiratory volume in 1 second (FEV) < 50% and/or receiving supplementary continuous oxygen; the Fred Hutchinson Cancer Research Center (FHCRC) principle investigator (PI) of the study must approve of enrollment of all patients with pulmonary nodules
• Liver function abnormalities: Patient with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; the patient will be excluded if he/she is found to have fulminant liver failure; cirrhosis of the liver with evidence of portal hypertension; alcoholic hepatitis; esophageal varices; a history of bleeding esophageal varices; hepatic encephalopathy; uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time ascites related to portal hypertension; bacterial or fungal liver abscess; biliary obstruction; chronic viral hepatitis with total serum bilirubin > 3 mg/dL; and symptomatic biliary disease;
• Karnofsky score < 70% for adult patients
• Patient with poorly controlled hypertension and on multiple antihypertensives
• Patients with current >= grade 2 peripheral neuropathy
• Patient has an active bacterial or fungal infection unresponsive to medical therapy
• DONOR: Identical twin
• DONOR: Donors unwilling to donate PBSC
• DONOR: Pregnancy
• DONOR: Infection with HIV
• DONOR: Inability to achieve adequate venous access
• DONOR: Known allergy to G-CSF
• DONOR: Current serious systemic illness
• DONOR: Failure to meet FHCRC criteria for stem cell donation
• DONOR: Age < 12 years
• DONOR: A positive anti-donor cytotoxic crossmatch
• DONOR: Patient and donor pairs must not be homozygous at mismatched allele

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Marco Mielcarek

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Marco Mielcarek

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Locations

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Seattle, Washington, United States

Countries

United States

References

Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.

Reference Type: DERIVED

PMID: 32499241 (View on PubMed)

Green DJ, Maloney DG, Storer BE, Sandmaier BM, Holmberg LA, Becker PS, Fang M, Martin PJ, Georges GE, Bouvier ME, Storb R, Mielcarek M. Tandem autologous/allogeneic hematopoietic cell transplantation with bortezomib maintenance therapy for high-risk myeloma. Blood Adv. 2017 Nov 9;1(24):2247-2256. doi: 10.1182/bloodadvances.2017010686. eCollection 2017 Nov 14.

Reference Type: DERIVED

PMID: 29296873 (View on PubMed)

Other Identifiers

NCI-2009-01473

Identifier Type: REGISTRY

Identifier Source: secondary_id

MPI X05251

Identifier Type: -

Identifier Source: secondary_id

2070.00

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA015704

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2070.00

Identifier Type: -

Identifier Source: org_study_id