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.

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.

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