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

Refractory Plasma Cell Myeloma Clinical Trial

Official title:

Tandem Autologous HCT/Nonmyeloablative Allogeneic HCT From HLA-Matched Related and Unrelated Donors Followed by Bortezomib Maintenance Therapy for Patients With High-Risk Multiple Myeloma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00793572
• Other study ID #: 2070.00
• Secondary ID: NCI-2009-01473MP
• Status: Completed
• Phase: Phase 2
• Start date: October 2008
• Est. completion date: October 2016

Study information

• Verified date: January 2020
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: October 2016
• Est. primary completion date: October 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Refractory Plasma Cell Myeloma

Intervention

Procedure:
• Autologous Hematopoietic Stem Cell Transplantation
Undergo transplantation

Drug:
• Bortezomib
Given SC
• Cyclosporine
Given IV
• Cyclosporine
Given PO
• Fludarabine Phosphate
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Melphalan
Given IV
• Mycophenolate Mofetil
Given PO

Procedure:
• Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo transplantation
• Peripheral Blood Stem Cell Transplantation
Undergo transplantation
• Syngeneic Bone Marrow Transplantation
Undergo transplantation

Radiation:
• Total-Body Irradiation
Undergo radiotherapy

Locations

Country	Name	City	State
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center	Millennium Pharmaceuticals, Inc., National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients Surviving Progression-free	Number of subjects surviving without progressive disease post-transplant.; Progressive disease criteria: Greater than 25% increase in serum (absolute increase must be =0.5 g/dL) or urine (absolute increase must be =200 mg/24h) M proteins compared to best response status after autologous transplant.; Appearance of new lytic bone lesions or plasmacytomas.	At 2 years after the autograft
Secondary	Number of Patients With Grade II-IV Acute GVHD	Number of patients who developed acute GVHD post allogeneic transplant.; aGVHD Stages; Skin: - a maculopapular eruption involving < 25% BSA; - a maculopapular eruption involving 25 - 50% BSA; - generalized erythroderma; - generalized erythroderma w/ bullous formation and often w/ desquamation; Liver: - bilirubin 2.0 - 3.0 mg/100 mL; - bilirubin 3 - 5.9 mg/100 mL; - bilirubin 6 - 14.9 mg/100 mL; - bilirubin > 15 mg/100 mL; Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall.; aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death	100 days post allo transplant
Secondary	Number of Patients With Chronic GVHD	Number of subjects with classic chronic or chronic extensive GVHD post allogeneic transplant.	1 year post allo
Secondary	Number of Patients With Toxicities Related to Bortezomib Maintenance Therapy	Number of subjects with toxicities related to bortezomib maintenance therapy post-transplant.	Up to 100 days after the autograft or allograft
Secondary	Number of Patients With Non-relapse Mortality	Number of subjects with non-relapse mortalities post allogeneic transplant.	200 and 365 days after allo
Secondary	Number of Patients Surviving Overall	Number of subjects surviving two years post autologous transplant.	At 2 years after the autograft