Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Symptoms and General Pathology

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Recurrence

Leukemia

Influenza, Human

Leukemia, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Plasma Cell Leukemia

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Amino Acids

Fludarabine

Fludarabine phosphate

Melphalan

Bortezomib

Tacrolimus

Sirolimus

Mechlorethamine

Temsirolimus

MTOR Inhibitors

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Calcineurin Inhibitors

Enzyme Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Phenylalanine

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.

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

bortezomib

fludarabine phosphate

melphalan

total marrow irradiation

tacrolimus

sirolimus

peripheral blood stem cell transplantation

laboratory biomarker analysis

Firoozeh Sahebi, MD

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.

PRIMARY OBJECTIVES:

I. To determine the feasibility of escalating doses of bortezomib with or without total marrow irradiation (TMI) at a fixed dose of 900 cGy in combination with fludarabine (FLU) and melphalan (MEL) as preparative regimen for allogeneic hematopoietic stem cell transplant in patients with high risk multiple myeloma who have human leukocyte antigen (HLA) matched donor (sibling or matched unrelated donor).

II. To describe toxicities, maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of this preparative regimen.

SECONDARY OBJECTIVES:

I. To evaluate the frequency of clinical response, i.e., complete response \[CR\], partial response \[PR\], very good partial response \[VGPR\]) at 6 month and 1 year post transplant.

II. To evaluate the frequency of primary and secondary engraftment failure.

III. To evaluate the time to neutrophil and platelet engraftment.

IV. To evaluate the incidence of acute and chronic graft-versus-host disease (GVHD).

V. To evaluate progression-free survival.

VI. To evaluate overall survival.

VII. To evaluate minimal residual disease (MRD) at 6 months and 1 year post transplant by flow cytometry in the bone marrow.

OUTLINE: This is a dose-escalation study of bortezomib. Patients are assigned to 1 of 2 treatment groups. GROUP I (patients eligible for TMI): Patients receive fludarabine phosphate intravenously (IV) on days -9 to -5 and melphalan IV on day -4. Patients also undergo TMI twice daily (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. GROUP II (patients ineligible for TMI): Patients receive fludarabine phosphate IV and melphalan IV as in Group I. Patients also receive bortezomib IV on days -6, -3, 1, and 4.

TRANSPLANT: All patients undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0.

GVHD PROPHYLAXIS: All patients receive tacrolimus IV or orally (PO) and sirolimus PO beginning on day -3.

After completion of study treatment, patients are followed up at day 100, 6 months, and then annually thereafter for up to 4 years.

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

Phase I Study of Bortezomib With or Without Total Marrow Irradiation (TMI) Using Intensity Modulated Radiation Therapy (IMRT) in Combination With Fludarabine (FLU) and Melphalan (MEL) as a Preparative Regimen for Allogeneic Hematopoietic Stem Cell (HSC) Transplantation in Patients With High Risk Multiple Myeloma

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.

Response is evaluated based on a new International myeloma working group uniform response criteria.

Time from day 0 of transplant to the first observation or relapse or death due to any cause, assessed up to 4 years

Time from first day of treatment to time of death due to any cause, assessed up to 4 years

National Cancer Institute (NCI)

City of Hope Medical Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	Autologous Hema... Loss of Chromos... Plasma Cell Leu... Recurrent Plasm... Refractory Plas...	bortezomib fludarabine pho... melphalan total marrow ir... tacrolimus sirolimus peripheral bloo... laboratory biom...	18 Years - 70 Years	City of Hope Medical Center
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	Autologous Hema... Loss of Chromos... Plasma Cell Leu... Recurrent Plasm... Refractory Plas...	bortezomib fludarabine pho... melphalan total marrow ir... tacrolimus sirolimus peripheral bloo... laboratory biom...	18 Years - 70 Years	City of Hope Medical Center

Spots Global Cancer Trial Database for autologous hematopoietic stem cell transplant recipient