Bortezomib, Total Marrow Irradiation, Fludarabine Phosphate, and Melphalan in Treating Patients Undergoing Donor Peripheral Blood Stem Cell Transplant For High-Risk Stage I or II Multiple Myeloma

NCT01163357 | Completed Phase 1 DMC

• 2 other identifiers: 09171NCI-2010-01610
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving chemotherapy drugs, such as fludarabine phosphate and melphalan, and total marrow irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when given together with fludarabine phosphate and melphalan with or without total marrow irradiation in treating patients undergoing donor peripheral blood stem cell transplant for high-risk stage I or II multiple myeloma.

Conditions

Autologous Hematopoietic Stem Cell Transplant Recipient; Loss of Chromosome 17p; Plasma Cell Leukemia; Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose of bortezomib as defined as the highest dose tested in which none or only one patient experiences dose limiting toxicity attributable to the study regimen

  Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose-limiting toxicity will be defined using Bearman Scale for events that occur.

  6 weeks post transplant

• Feasibility of escalating doses of bortezomib with or without TMI in combination with FLU and MEL as preparative regimen for allogeneic hematopoietic stem cell transplant in patients with high risk multiple myeloma

  5 years post transplant

Secondary Outcomes (7)

• Frequency of clinical response (i.e., complete, partial, or very good partial response)

  At 6 months and 1 year post transplant

• Frequency of primary and secondary engraftment failure

  6 weeks post transplant and 4 years post transplant

• Time to neutrophil and platelet engraftment

  100 days post transplant

• Progression-free survival

  4 years post transplant

• Incidence of acute and chronic graft-versus-host disease

  At 6 months and 1 year post transplant up to 4 years post transplant

Study Arms (2)

Group I (bortezomib, fludarabine phosphate, TMI, melphalan)

EXPERIMENTAL

Patients receive fludarabine phosphate IV on days -9 to -5 and melphalan IV on day -4. Patients also undergo TMI BID on days -9 to -7. If no DLT is observed in the first cohort, bortezomib IV will be added on days -6 and -3 for subsequent cohorts.

Drug: bortezomib; Drug: fludarabine phosphate; Other: melphalan; Radiation: total marrow irradiation; Drug: tacrolimus; Drug: sirolimus; Procedure: peripheral blood stem cell transplantation; Other: laboratory biomarker analysis

Group II (bortezomib, fludarabine phosphate, melphalan

EXPERIMENTAL

Patients receive fludarabine phosphate IV and melphalan IV as in Stratum I. Patients also receive bortezomib IV on days -6, -3, 1, and 4.

Drug: bortezomib; Drug: fludarabine phosphate; Other: melphalan; Drug: tacrolimus; Drug: sirolimus; Procedure: peripheral blood stem cell transplantation; Other: laboratory biomarker analysis

Interventions

bortezomib DRUG

Given IV

Also known as: LDP 341, MLN341, PS-341, VELCADE

Group I (bortezomib, fludarabine phosphate, TMI, melphalan); Group II (bortezomib, fludarabine phosphate, melphalan

fludarabine phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, Beneflur, Fludara

Group I (bortezomib, fludarabine phosphate, TMI, melphalan); Group II (bortezomib, fludarabine phosphate, melphalan

melphalan OTHER

Given IV

Also known as: Alkeran, CB-3025, L-PAM, L-phenylalanine mustard, L-Sarcolysin, Melfalan

Group I (bortezomib, fludarabine phosphate, TMI, melphalan); Group II (bortezomib, fludarabine phosphate, melphalan

total marrow irradiation RADIATION

Undergo TMI

Group I (bortezomib, fludarabine phosphate, TMI, melphalan)

tacrolimus DRUG

Given IV and orally

Also known as: Advagraf, FK 506, Prograf, Protopic

Group I (bortezomib, fludarabine phosphate, TMI, melphalan); Group II (bortezomib, fludarabine phosphate, melphalan

sirolimus DRUG

Given orally

Also known as: AY 22989, RAPA, Rapamune, rapamycin, SILA 9268A, SLM

Group I (bortezomib, fludarabine phosphate, TMI, melphalan); Group II (bortezomib, fludarabine phosphate, melphalan

peripheral blood stem cell transplantation PROCEDURE

Undergo allogeneic PBSC transplant

Also known as: PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell

Group I (bortezomib, fludarabine phosphate, TMI, melphalan); Group II (bortezomib, fludarabine phosphate, melphalan

laboratory biomarker analysis OTHER

Correlative studies

Group I (bortezomib, fludarabine phosphate, TMI, melphalan); Group II (bortezomib, fludarabine phosphate, melphalan

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Recipient must have signed a voluntary, informed consent in accordance with institutional and federal guidelines
• Recipients must have histopathologically confirmed diagnosis of multiple myeloma
• Age:
• Stratum I (TMI containing arm): 18-60 years of age
• Stratum II (non TMI arm): 18-70 years of age
• Patients with primary progressive disease on induction therapy with new targeted therapies
• Relapsed/refractory disease on new targeted therapies, i.e. thalidomide, lenalidomide, bortezomib, or other new novel agents such as carfilzomib, pomalidomide
• Patients with relapsed multiple myeloma following previous autologous stem cell transplant
• Plasma cell leukemia at diagnosis
• High-risk patients with presence of chromosome 17p deletion (\> 60%) in the bone marrow by fluorescence in situ hybridization (FISH); patients are not required to have prior autologous stem cell transplant
• Able to lie supine for approximately 60 minutes, the anticipated duration of each treatment session
• Performance status evaluated by Eastern Cooperative Oncology Group (ECOG) or Karnofsky Performance Scales (KPS) patients must have a score of 0-II (ECOG) or \>= 70% (KPS)
• Cardiac ejection fraction \>= 50% by multiple gate acquisition (MUGA) scan and/or by echocardiogram
• Forced expiratory volume in one second (FEV1) \>= 50%
• Diffusing lung capacity for carbon monoxide (DLCO) \>= 50%

You may not qualify if:

• Patients with peripheral neuropathy greater than grade II
• Major medical or psychiatric disorders that would seriously compromise patient tolerance of this regimen
• Human immunodeficiency virus (HIV) infection, active hepatitis B or C infection, or evidence of liver cirrhosis
• Active viral, bacterial or fungal infection unless adequately treated. For fungal infection, patient should have completed full course of antifungal therapy with resolution of infection.
• Patients with radiographic changes including pulmonary disease, including but not limited to: pulmonary nodules, infiltrates, pleural effusion are excluded unless cleared by pulmonary biopsy showing no evidence for pulmonary infection
• Patients with renal insufficiency or cr clearance \< 60 ml/min
• DONOR: Donors will be excluded if for medical or psychological reasons they are unable to tolerate the procedure of peripheral stem cell donation

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope

Duarte, California, 91010, United States

Location

MeSH Terms

Conditions

Chromosome 17 deletion; Leukemia, Plasma Cell; Multiple Myeloma

Interventions

Bortezomib; fludarabine phosphate; Melphalan; Tacrolimus; Sirolimus; Peripheral Blood Stem Cell Transplantation

Condition Hierarchy (Ancestors)

Leukemia; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Plasma Cell; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Macrolides; Lactones; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative

Study Officials

• Firoozeh Sahebi, MD

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 14, 2010
• First Posted: July 15, 2010
• Study Start: January 28, 2011
• Primary Completion: July 20, 2019
• Study Completion: May 20, 2024
• Last Updated: March 26, 2025

Record last verified: 2025-03

Locations

US (1)