RATIONALE: Giving chemotherapy and total marrow irradiation before a donor umbilical cord blood or hematopoietic stem cell transplant helps stop the growth of cancer cells. It may also 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase I trial is studying the side effects and best dose of total marrow irradiation when given together with combination chemotherapy and umbilical cord blood hematopoietic stem cell transplant in treating patients with acute leukemia, acute myeloid leukemia or multiple myeloma that did not respond to previous therapy.

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of total marrow irradiation (TMI) delivered by image-guided tomographic intensity-modulated radiotherapy when administered in combination with myeloablative chemotherapy in patients undergoing double umbilical cord blood (UCB) transplantation or hematopoietic stem cell for refractory acute leukemia.

Secondary

• Determine the incidence of engraftment (defined as achievement of neutrophil count > 500/uL at 42 days after transplantation).
• Determine the incidence of platelet engraftment at 6 months and at 1 year after transplantation.
• Evaluate the incidence of complete donor chimerism and the relative contribution of each UCB unit to donor engraftment within the first 100 days after transplantation.
• Determine the incidence of transplantation-related mortality (TRM) at 6 months after treatment with a TMI-containing myeloablative conditioning regimen.
• Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at 100 days after transplantation.
• Determine the incidence of chronic GVHD at 1 year after transplantation.
• Determine the incidence of relapse at 1 year after transplantation.
• Determine the survival and disease-free survival at 1 and 2 years after transplantation.
• Assess the durability of remission based on presence of rapid early response (defined by clearance of leukemic blasts from the bone marrow at 21 days after transplantation).

OUTLINE: This is a dose-escalation study of total marrow irradiation (TMI).

• Myeloablative conditioning regimen: Patients receive fludarabine phosphate IV over 1 hour once daily for 3 days between days -12 and -6 and cyclophosphamide IV once daily for 2 days between days -11 and -6. Patients undergo TMI once daily for 4-8 days between days -8 and -1.
• Donor umbilical cord blood (UCB) transplantation: Patients undergo single-unit or double-unit donor UCB transplantation on day 0. Patients receive filgrastim (G-CSF) IV or subcutaneously once daily beginning on day 1 and continuing until blood counts recover.
• Related Donor: Related donor bone marrow will be collected (target cell dose 5x10^8 nucleated cells/kg recipient weight, minimum 3x10^8 nucleated cells/kg recipient weight) and infused without processing on day 0.
• Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours or orally 2-3 times daily beginning on day -3 and continuing until day 100, followed by a taper until day 180, in the absence of GVHD. Patients also receive mycophenolate mofetil IV or orally 2-3 times daily beginning on day -3 and continuing until day 30 (or 7 days after engraftment), in the absence of acute GVHD.

Patients are followed periodically for up to 2 years after transplantation.

Inclusion Criteria:

• Acute lymphoblastic leukemia

  • ≥ Complete remission 2 (CR2) (adults ≥ 18 years and ≤ 55 years)
  • CR2 in pediatrics (defined as <18 years) and <12 months duration of first remission
  • ≥ CR3 or not in remission (pediatric patients <18 years)
  • T cell leukemia ≥ CR2
  • Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH or cytogenetics

• Myelodysplastic syndrome

  • ≤ 55 years of age and ≥ 10% blasts, not responsive to hypomethylating agents and/or conventional therapy

• Acute myeloid leukemia

  • Not in remission (pediatric patients <18 years)
  • Not in remission (10-30% blasts in the bone marrow for adult patients ≥18 years and ≤ 55 years)
  • Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH or cytogenetics

• Multiple myeloma

  • No prior autologous transplant and fitting into one of the following disease categories:

    • Early disease stage (CR1/PR1) with high-risk molecular features
    • Early disease stage (CR1/PR1) with high-risk clinical features
    • Late disease stage (CR2/PR2+) with high-risk clinical features

• Other high risk hematologic malignancies - to be approved by 2 or more hematology/oncology and BMT physicians

• Patients with prior CNS involvement are eligible provided that it has been treated and is in remission. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the protocol.

• Have acceptable organ function within 14 days of study registration defined as:

  • Renal: glomerular filtration rate > 60ml/min/1.73m2
  • Hepatic: bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal (ULN)
  • Pulmonary function: Carbon Monoxide Diffusing Capacity corrected (DLCOcorr) > 50% of normal, (oxygen saturation [>92%] can be used in child where pulmonary function tests (PFT's) cannot be obtained)
  • Cardiac: left ventricular ejection fraction ≥ 45% by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)

• Karnofsky performance status (PS) >80% for ages 16 years and older or Lansky Play Score >50 for < 16 years

• An acceptable source of stem cells according to current University of Minnesota BMT program guidelines:

  • UCB graft will be composed of two partially HLA matched units. Each unit must be matched at 4-6 HLA loci to the recipient and to each other. If two matched units are not available, then a single HLA 4-6 matched unit may be used if of adequate cell dose - total graft dose must be >3 x 107 MNC/kg
  • HLA-matched related donor (6/6 or 5/6 antigen match)
  • HLA-matched unrelated adult donor (if previously identified)

• Women of childbearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment.

• Voluntary written consent

Exclusion Criteria:

• Active uncontrolled infection at time of enrollment or documented fungal infection within 3 months.
• Evidence of Human immunodeficiency virus (HIV) infection
• Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.
• Prior myeloablative transplant within the last 6 months
• Prior total body irradiation (TBI) making total marrow irradiation (TMI) not feasible