The patients are being offered a stem cell transplant. Stem cells are very early blood cells. They have not yet matured to become red or white blood cells or platelets. They have already received the standard treatment of chemotherapy and an autologous stem cell transplant. An autologous stem cell transplant is when the patient receives their infusion of their own cells. Thi will give the patient a better chance of curing the disease, this protocol includes an infusion of stem cells from the blood (or the bone marrow) of another person. This is called an allogeneic stem cell transplant. The stem cells will begin to grow in the bone marrow and produce new blood cells.

Allogeneic stem cell transplants can cause a condition called graft-versus-host disease or GVHD. In GVHD, a kind of white blood cell from the donor (graft) begins to attack the body (host). That blood cell is called a T-cell. It is a cell that normally helps to protects against things like bacteria and viruses. In this case, the donor's T-cells see the body as foreign in the same way they would see bacteria as foreign. GVHD can be fatal. In order to lower the chance that the patient will get GVHD this protocol treatment will remove the T-cells from the donor's cells. This is called T-cell depletion. The T cells are removed by a system called "Clinimacs". This method is still being evaluated through clinical trials and not been approved by the Federal Drug Administration (FDA) at this time.

Before the transplant, the physician will treat the bone marrow to get rid of the cancer. The physician uses three chemotherapy drugs plus ATG. The chemotherapy drugs (Busulfan, Melphalan and Fludarabine) kills the cancer. ATG gets rid of any of the patients T cells that survive the chemotherapy. This ensures that the donor stem cells are not rejected. The patient will also receive additional white blood cells called lymphocytes from the donor. This is called a donor lymphocyte infusion or DLI. These additional infusions will help cause a graft-versus-myeloma effect and can help the donor stem cells grow.

Inclusion Criteria:

• Patient must have multiple myeloma that has either relapsed or has high risk cytogenetics.

• Patients with relapsed multiple myeloma following autologous stem cell transplantation must have achieved at least partial response following additional chemotherapy (cohort 1):

• Patients are eligible if relapse occurs with complex/high-risk cytogenetics or occurs with normal cytogenetics but within 15 months following the autologous transplant.

• Patients with high risk cytogenetics at diagnosis must have achieved at least very good partial response following autologous stem cell transplantation (cohort 2):

  • Patients must have complex karyotype, 1q25, del17p, t4;14 and/or t14;16 by FISH and/or del13 by karyotyping.

DONOR: Patients must have a healthy HLA matched or mismatched related or unrelated donor who is willing to receive G-CSF injections and undergo apheresis for PBSC collection, or undergo a marrow harvesting procedure.

1. HLA-matched related and unrelated donors Patients who have an HLA-matched related or unrelated donor are eligible for entry on this protocol. This will include a healthy donor who is genotypically matched at all A, B, C, DRB1 and DQB1 locus, loci, as tested by DNA analysis.
2. HLA- mismatched related and unrelated donors Patients who do not have an HLA-matched donor but have a related or unrelated donor who have one antigen or one allele mismatch at the HLA A, B, C, DRB1 or DQB1 loci; or who have two mismatches, at HLA-DQB1 and at one other locus, will be eligible for entry on this protocol.

The following inclusion criteria are also required:

• Patients should be ≥ 21, < 73 years old.
• Patients may be of either gender or any ethnic background.
• Patients must have a Karnofsky (adult) or Performance Status ≥ 70%
• Patients must have adequate organ function measured by:

Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 50% and must improve with exercise. Hepatic: < 3x ULN ALT and ≤ 1.5 total serum bilirubin, unless there is congenital benign hyperbilirubinemia.

Renal: serum creatinine <1.2 mg/dl or if serum creatinine is outside the normal range, then CrCl > 40 ml/min (measured or calculated/estimated) with dose adjustment of Fludarabine for <70ml/min.

Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected for hemoglobin)

• Each patient must be willing to participate as a research subject and must sign an informed consent form.

Exclusion Criteria:

• Patients achieving < Partial Response following preceding chemotherapy (cohort 1) or < Very Good Partial Response following autologous stem cell transplantation (cohort 2).
• Patients with Plasma Cell Leukemia.
• Female patients who are pregnant or breast-feeding
• Active viral, bacterial or fungal infection
• Patient seropositive for HIV-I/II; HTLV -I/II
• Patients who have undergone prior allogeneic hematopoietic stem cell transplantation.
• Patients who have had a previous malignancy that is not in remission.
• Patients with known hypersensitivity to mouse proteins (murine antibodies in ISOLEX) if receiving SBA-E- bone marrow, or chicken egg products.