Autologous or Syngeneic Stem Cell Transplant Followed by Donor Stem Cell Transplant and Bortezomib in Treating Patients With Newly Diagnosed High-Risk, Relapsed, or Refractory Multiple Myeloma
Condition: Refractory Plasma Cell Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Autologous Hematopoietic Stem Cell Transplantation; Bortezomib; Cyclosporine; Cyclosporine; Fludarabine Phosphate; Laboratory Biomarker Analysis; Melphalan; Mycophenolate Mofetil; Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Peripheral Blood Stem Cell Transplantation; Syngeneic Bone Marrow Transplantation; Total-Body Irradiation
Intervention description: Undergo transplantation; Given SC; Given IV; Given PO; Given IV; Correlative studies; Given IV; Given PO; Undergo transplantation; Undergo transplantation; Undergo transplantation; Undergo radiotherapy
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Fludarabine; Fludarabine phosphate; Bortezomib; Melphalan; Mechlorethamine; Nitrogen Mustard Compounds; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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