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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Given IV
Given IV
Given IV
Undergo TMI
Given IV and orally
Given orally
Undergo allogeneic PBSC transplant
Correlative studies
City of Hope
Duarte, California, United States
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.
Time frame: 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
Time frame: 5 years post transplant
Frequency of clinical response (i.e., complete, partial, or very good partial response)
Response is evaluated based on a new International myeloma working group uniform response criteria.
Time frame: At 6 months and 1 year post transplant
Frequency of primary and secondary engraftment failure
Time frame: 6 weeks post transplant and 4 years post transplant
Time to neutrophil and platelet engraftment
Time frame: 100 days post transplant
Progression-free survival
Time from day 0 of transplant to the first observation or relapse or death due to any cause, assessed up to 4 years
Time frame: 4 years post transplant
Incidence of acute and chronic graft-versus-host disease
Time frame: At 6 months and 1 year post transplant up to 4 years post transplant
Overall survival
Time from first day of treatment to time of death due to any cause, assessed up to 4 years
Time frame: 4 years post transplant
Minimal residue disease
Assessed by flow cytometry
Time frame: At 6 months and 1 year post transplant
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