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

• 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 [ Time Frame: 6 weeks post transplant ] [ Designated as safety issue: Yes ]
  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.
  
  
• 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 ] [ Designated as safety issue: No ]
  

• Frequency of clinical response (i.e., complete, partial, or very good partial response) [ Time Frame: At 6 months and 1 year post transplant ] [ Designated as safety issue: No ]
  Response is evaluated based on a new International myeloma working group uniform response criteria.
  
  
• Frequency of primary and secondary engraftment failure [ Time Frame: 6 weeks post transplant ] [ Designated as safety issue: No ]
  
• Time to neutrophil and platelet engraftment [ Time Frame: 100 days post transplant ] [ Designated as safety issue: No ]
  
• Progression-free survival [ Time Frame: 4 years post transplant ] [ Designated as safety issue: No ]
  
• 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 ] [ Designated as safety issue: No ]
  
• Overall survival [ Time Frame: 4 years post transplant ] [ Designated as safety issue: No ]
  
• Minimal residue disease [ Time Frame: At 6 months and 1 year post transplant ] [ Designated as safety issue: No ]
  

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 bortezomib intravenously (IV) on days -6 and -3 and undergo TMI twice daily (BID) on days -9 to -7. Patients also receive fludarabine phosphate IV on days -9 to -5 and melphalan IV on day -4. GROUP II (patients ineligible for TMI): Patients receive bortezomib IV on days -6, -3, 1, and 4. Patients also receive fludarabine phosphate IV and melphalan IV as in Group I.

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.