90 Y-BC8-DOTA Monoclonal Antibody, Fludarabine Phosphate, and Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Multiple Myeloma

PRIMARY OBJECTIVES:

I. To assess the tissue localization of 111In-BC8-DOTA antibody therapy (Ab) and establish
reproducibly favorable biodistribution.

II. To estimate the maximum tolerated dose (MTD) of radiation delivered via 90Y-BC8-DOTA Ab
when combined with fludarabine phosphate (FLU) and 2 Gy total-body irradiation (TBI) as a
preparative regimen followed by human leukocyte antigen (HLA)-matched, related or unrelated
hematopoietic cell transplant (HCT) for patients with multiple myeloma.

SECONDARY OBJECTIVES:

I. To assess the potential efficacy of this approach, within the limits of a phase I study,
by examining disease response, duration of remission, disease free survival (DFS), and
overall survival (OS).

OUTLINE: This is a dose-escalation study of yttrium Y 90 anti-CD45 monoclonal antibody BC8
(90Y-BC8 Ab).

Patients receive 90Y-BC8 Ab intravenously (IV) on day -12 and fludarabine phosphate IV on
days -4 to -2. Patients undergo TBI and allogeneic peripheral blood stem cell transplant on
day 0. Patients also receive graft-vs-host disease prophylaxis comprising cyclosporine orally
(PO) twice daily (BID) on days -3 to 56 with taper to day 180 or on days -3 to 100 with taper
to 180; and mycophenolate mofetil IV or PO BID on days 0-27, or 0-40 with taper to 96.

After completion of study treatment, patients are followed up every 6 months for 2 years, and
then annually thereafter.

Inclusion Criteria:

- Patients must have history of symptomatic myeloma requiring treatment and meet one of
the following requirements:

- Have at least 1 high risk feature at diagnosis (including deletion 13 or
hypodiploidy by conventional cytogenetics, t(4;14), t(14;16) or deletion 17 by
fluorescence in situ hybridization [FISH], beta 2 microglobulin > 3.5, lactate
dehydrogenase [LDH] greater than 1.5 x upper limit of normal [ULN], history of
plasma cell leukemia) (prior to chemotherapy); OR

- Have progressive disease on primary therapy with or without prior autologous stem
cell transplant; OR

- Have persistent or progressive disease following autologous transplant; it is
acceptable for these patients to have a second transplant for disease reduction

- Bone marrow cellularity of >= 50% of age defined normal values by core biopsy;
cellularity must be evaluated within 90 days of the dosimetry infusion and at least 21
days after receiving any cytoreductive/myelosuppressive chemotherapy

- Eastern Cooperative Oncology Group (ECOG) =< 2

- Measured creatinine clearance > 50 ml/min or estimated creatinine clearance > 50
ml/min

- For females of childbearing potential, must have a negative pregnancy test

- Patients must have a human leukocyte antigen (HLA)‐matched related donor or an
unrelated donor who meets standard Seattle Cancer Care Alliance (SCCA) and or National
Marrow Donor Program (NMDP) or other donor center criteria for peripheral blood stem
cell (PBSC) donation, or bone marrow donation as follows:

- Related donor related to the patient and genotypically or phenotypically
identical for HLA-A, B, C, DRB1 and DQB1; phenotypic identity must be confirmed
by high-resolution typing

- Unrelated donor:

- Matched for HLA‐A, B, C, DRB1 DQB1 by high resolution typing; OR

- Mismatched for a single allele without antigen mismatching at HLA‐A, B, or C
as defined by high resolution typing but otherwise matched for HLA‐A, B, C,
DRB1 and DQB1 by high resolution typing

- Patient and donor pairs homozygous at a mismatched allele, in the graft
rejection vector are considered a two‐allele mismatch, i.e., the patient is
A*0101 and the donor is A*0102, and this type of mismatch is not allowed

- Donors are excluded when preexisting immunoreactivity is identified that would
jeopardize donor hematopoietic cell engraftment; this determination is based on
the standard practice of the individual institution; the recommended procedure
for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain panel
reactive antibody (PRA) screens to class I and class II antigens for all patients
before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell
cytotoxic cross matches should be obtained; the donor should be excluded if any
of the cytotoxic cross match assays are positive; for those patients with an HLA
Class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches
should be obtained regardless of the PRA results; a positive anti‐donor cytotoxic
crossmatch is an absolute donor exclusion

- Ability to provide informed consent

- DONOR: Patients must have an HLA matched donor as well as standard Seattle Cancer Care
Alliance (SCCA) and or National Marrow Donor Program (NMDP)/other donor center
criteria for PBSC donation

- DONOR: Donors must consent and be eligible to undergo granulocyte colony-stimulating
factor (GCSF) mobilization and PBSC harvest; marrow is not allowed as a source of stem
cells on this study

Exclusion Criteria:

- Patients with the following organ dysfunction:

- Left ventricular ejection fraction < 35%

- Corrected diffusion capacity of carbon monoxide (DLCO) < 35% or receiving
supplemental continuous oxygen

- Liver abnormalities: fulminant liver failure, cirrhosis of the liver with
evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic
encephalopathy, uncorrectable hepatic synthetic dysfunction as evidences by
prolongation of the prothrombin time, ascites related to portal hypertension,
bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis,
or symptomatic biliary disease

- Pregnant or breast-feeding females

- Circulating antibody against mouse immunoglobulin (HAMA)

- Prior allogeneic transplant

- Plasmacytomas > 1 cm in marrow areas measured by magnetic resonance imaging (MRI) or
extramedullary plasmacytomas (radiated lesions are exempt from this criteria);
patients may receive cytoreductive therapy, including allogeneic stem cell transplant
(ASCT) (if high risk) or second ASCT (if failed a prior ASCT) to achieve disease
control, but may not receive any cytoreductive therapy within 30 days of the dosimetry
infusion and must have bone marrow cellularity meeting inclusion criteria obtained at
least 21 days after any cytoreductive/myelosuppressive chemotherapy was last
administered

- Prior radiation to maximally tolerated levels to any critical normal organ, or > 20 Gy
prior radiation to large areas of the bone marrow (e.g., external radiation therapy to
whole pelvis)

- Patients who are known to be seropositive for human immunodeficiency virus (HIV)

- Fertile men and women unwilling to use contraceptives during and for 12 months
post-transplant

- Active central nervous system (CNS) disease at the time of treatment