OUTLINE: This is a dose-escalation study of ²¹¹At-OKT10-B10. Patients are assigned to 1 of 2
arms.
ARM A: Patients with HLA-matched related or unrelated donors receive ²¹¹At-OKT10-B10
intravenously (IV) on day -7 (day -10 to -5) and fludarabine IV over 30 minutes on days -4 to
-2. Patients then undergo TBI and allogeneic HCT on day 0.
ARM B: Patients with HLA-matched haploidentical donors receive ²¹¹At-OKT10-B10 IV on day -8
(day -14 to -7), fludarabine IV over 30 minutes on days -6 to -2, and cyclophosphamide IV
over 1 hour on day -6 and -5. Patients then undergo TBI on day -1 and allogeneic HCT on day
0.
Inclusion Criteria:
- Patients with newly diagnosed or relapsed/refractory multiple myeloma
- Patients with multiple myeloma must have at least one of the following high-risk
features:
- t(4;14), t(14;16), t(14;20) or deletion 17p, gain in chromosome 1q (> 3 copies of
CKS1b) by fluorescence in situ hybridization (FISH); hypodiploidy; complex
karyotype
- Revised International Staging System III
- Plasmablastic morphology
- History of primary or secondary plasma cell leukemia
- Patients must start ²¹¹At-OKT10-B10 within 40-180 days of autologous stem cell
transplant (either as part of their induction, or as salvage)
- Patients must have an estimated creatinine clearance greater than 50/ml per minute
measured by 24-hour urine collection
- Total bilirubin < 2 times the upper limit of normal
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2 times the
upper limit of normal)
- Patients must have an Eastern Cooperative Oncology Group (ECOG) =< 2 or Karnofsky >=
70
- Patients must have CD38+ myeloma cells as demonstrated by either flow cytometry or
immunohistochemistry in most recent bone marrow that had evidence of clonal plasma
cells
- For patients of childbearing potential, must have a negative urinary pregnancy test on
the day of and prior to infusion of ²¹¹At-OKT10-B10
- Ability to provide informed consent
- Patients must have an HLA-matched related donor or an HLA-matched 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) 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 and 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
- Donors are excluded when preexisting immunoreactivity is identified that
would jeopardize donor hematopoietic cell engraftment. 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
- 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
- Patients without an HLA-matched related or unrelated donor available must have a
related donor who is identical for one HLA haplotype and mismatched at the HLA-A, -B
or DRB1 loci of the unshared haplotype with the exception of single HLA-A, -B or DRB1
mismatches
Exclusion Criteria:
- History of central nervous system involvement by multiple myeloma
- Presence of circulating plasma cells in the peripheral blood of 5% or more by flow
cytometry or morphology
- Prior radioimmunotherapy or radiation of > 20 Gy to pelvis or at maximally tolerated
levels to any critical normal organ
- Prior allogeneic HCT
- More than two prior autologous HCTs
- Patients with plasmacytomas > 1 cm in bone marrow or any extramedullary plasmacytoma.
Previously fludeoxyglucose F-18 (FDG) avid mass lesions by positron emission
tomography (PET) that are no longer hypermetabolic following the most recent cycle of
therapy are exempt, as are plasmacytomas irradiated with curative intent (>= 35 Gy)
- Patients with symptomatic coronary artery disease defined as having angina or anginal
equivalent, and/or arrhythmias requiring anti-arrhythmics for rhythm control
- History of reactive airway disease and clinically significant asthma requiring ongoing
treatment
- Patients with the following organ dysfunction:
- Left ventricular ejection fraction < 40% in patients with HLA-matched or
unrelated donor or < 45% in patients with an HLA-haploidentical donor
- New York Heart Association (NYHA) class > 1 heart failure
- Corrected diffusing capacity of the lungs for carbon monoxide (DLCO) < 50% or
receiving supplemental continuous oxygen. When pulmonary function tests cannot be
obtained, the 6-minute walk test (6MWT, also known as exercise oximetry) will be
used: Any patient with oxygen saturation on room air of < 90% during a 6MWT will
be excluded
- 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 evidenced 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
- Patients who are known to be seropositive for human immunodeficiency virus (HIV)
- Perceived inability to tolerate diagnostic or therapeutic procedures
- Women of childbearing potential who are pregnant (beta-human chorionic gonadotropin
[HCG]+) or breast feeding
- Fertile men and women unwilling to use contraceptives during and for 12 months
post-transplant
- Uncontrolled or untreated active infection
- Patients with known AL subtype amyloidosis
- Inability to understand or give an informed consent
- Known allergy to murine-based monoclonal antibodies
- Known contraindications to radiotherapy
- History of another primary malignancy that has not been in remission for at least 2
years. The following are exempt from the 2-year-limit: nonmelanoma skin cancer,
curatively treated localized prostate cancer, or cervical carcinoma in situ or
squamous intraepithelial lesion on papanicolaou (PAP) smear
- Therapy with anti-CD38 monoclonal antibody within 3 months of ²¹¹At-OKT10-B10 infusion
- Prior therapy with radiolabeled monoclonal antibodies
- Any history of treatment with checkpoint inhibitor/s
