Haploidentical Stem Cell Transplant With Prophylactic Natural Killer DLI for Lymphoma, Multiple Myeloma, and CLL

This is a single center Phase I trial of a new haploidentical stem cell transplant regimen
intended to assess safety. Two groups of patients are planned: patients with lymphoma and
patients with multiple myeloma. Each subject will receive a haploidentical stem cell
transplantation using peripheral blood stem cells. Bendamustine-fludarabine-rituximab-TBI
conditioning will be used, followed by stem cell infusion, with Post-Transplant
Cyclophosphamide and tacrolimus for GVHD prophylaxis. Patients will receive a CD56-selected
DLI on day +8. Evaluations will be taken at baseline and at each of the study visits.
Screening data will be reviewed to determine subject eligibility. Subjects who meet all
inclusion criteria and none of the exclusion criteria will be entered into the study. Total
duration of subject participation will be one year. Total duration of the study is expected
to be three years.

General Inclusion Criteria (For Treatment Groups)

- Patient age 18 - 75 years

- ECOG 0 - 2

- HIV-positive patients are allowed if these criteria are met:

1. No history of opportunistic infections

2. CD4+ cell count greater or equal to 250 cells/mm3

3. No history of non-malignancy AIDS-defining conditions other than historical low
CD4+ cell counts

4. Patient is on antiretroviral therapy with undetectable viral load. There must be
minimal interactions of the antiviral therapy with the experimental treatment
(antiretroviral such as ritonavir is potent CYP3A4 inhibitor and p-gp inducer may
interact with tacrolimus resulted in increased serum concentration of
tacrolimus).

- Patients must have a related donor or who is at minimum HLA haploidentical. The donor
and recipient must be identical at least one allele of each of the following genetic
loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is
therefore required, and will be considered sufficient evidence that the donor and
recipient share one HLA haplotype. An unrelated donor search is not required.
(Patients with a readily-available, suitable, fully-matched sibling donor less than
age 55 are not eligible for this trial, these patients should proceed to transplant
using the matched related donor as standard-of-care).

Criteria for Donor Eligibility

- Age greater than 12 years

- Donors must meet the selection criteria as defined by the Foundation for the
Accreditation of Hematopoietic Cell Therapy (FACT).

- In the event that two or more eligible donors are identified, the following order of
priority will be used to determine the preferred donor:

- Medically and psychologically fit and willing to donate

- For CMV seronegative recipients, a CMV seronegative donor

- Red blood-cell compatibility

- RBC cross-match compatible

- Minor ABO incompatibility

- Major ABO incompatibility

- If more than one preferred donor is identified and there is no medical, HLA- or KIR
ligand reason to prefer one of them, then the following guidelines are recommended:

If the patient is male, choose a male donor:

- Choose the youngest preferred donor

- If the patient and family express a strong preference for a particular donor, use that
one.

Inclusion Criteria (Lymphoma)

- Diagnosis of resistant or relapsed CLL, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, T-cell
lymphoma, NK or NK/T Lymphoma.

- Meets one of the following criteria:

- relapsed after auto-transplant, or

- failed to mobilize autologous stem cells, or

- for whom allogeneic stem cell transplant is deemed appropriate given disease risk
factors that make cure with autologous transplant seem unlikely, such as history
of chemotherapy refractoriness, high risk disease
features/mutations/translocations (e.g., Double Hit / Double Expressor DLBCL),
short remission after prior chemotherapy, or histologic transformation (see
below).

- For Patients with Aggressive Mantle Cell and Diffuse Large B Cell Lymphoma who have
not had a prior autologous transplant:

- Must have received at least 2 lines of prior therapy, and

- Have been exposed to anthracycline, and

- High and High-Intermediate aaIPI score (2 or 3 factors), and

- Have relapsed within one year of primary therapy

- For diagnosis of other aggressive lymphoma (e.g. NK/T Lymphoma, T Cell

Lymphoma, etc.):

- Must have received at least 2 lines of prior therapy, and

- Relapsed within 12 months of most recent therapy

- For low-grade lymphomas / CLL:

- Standard risk patients (absence of del(17p), absence of del(11q), no TP53
mutation and absence of complex karyotype) must have progressed on BCR inhibitor,
or undergone histologic transformation, to be eligible.

- Patients with high risk disease (del(17p) or TP53 mutations and/or complex
phenotype) who relapse after frontline therapy, demonstrate refractory disease to
second line therapy (not BCR inhibitors), but show an objective response to BCR
inhibitors are eligible to be taken off BCR inhibitors in order to proceed to
alloHSCT on trial. Patients with high risk disease who relapse after frontline
therapy, demonstrate refractory disease to second line therapy including BCR
inhibitors (not BCL-2 inhibitors), but show an objective response to BCL-2
inhibitors (venetoclax) are eligible to be taken off BCL-2 inhibitors in order to
proceed to alloHSCT on trial.

- For aggressive lymphomas, partial or complete remission (PR or CR) is required
prior to alloHSCT.

- Regarding CD20 expression: Patients with B cell malignancies that were CD20+ at
any level at the time of relapse diagnosis (including partial / dim staining on
IHC or partial / low level expression by flow cytometry) will receive rituximab
as part of allogeneic transplant conditioning. Patients with primary-refractory
disease who were CD20+ at any level at the time of diagnosis will likewise
receive rituximab. Patients with histologies that were CD20- will not receive
rituximab (T cell lymphoma, NK/T lymphoma, etc.). Fresh tissue / repeat biopsy is
not required; the most recent biopsy will be reviewed to assess CD20 status.

Inclusion Criteria (Multiple Myeloma)

- Patient age 18 - 75 years with:

- Early relapse (less than 24 months) after primary therapy that included an autologous
HSCT, or

- High risk multiple myeloma defined as t(4;14), del(17p), -13, t(14;16), amp (1q21),
chromosome 8q24.1/c-MYC abnormality, or LDH > ULN at diagnosis, provided patients
respond favorably to salvage therapy before enrollment for alloHSCT on trial and
patient is age < 55, or

- Patients failing to mobilize peripheral blood stem cells for autologous
transplantation, or

- Extramedullary disease at diagnosis or relapse, or

- Plasma-cell leukemia with chemosensitive disease

Inclusion Criteria - Control Patients (specimen collection, only)

- Age 18-75 years

- Undergoing standard-of-care reduced-intensity peripheral blood allogeneic stem cell
transplantation (any indication, donor source, conditioning regimen) using PTCy GVHD
prophylaxis.

- Willing to provide longitudinal blood samples per Control Specimen Collection Calendar
for correlative studies (for comparison to specimens from patients treated on the
trial).

- Agrees to let study personnel collect excess bone marrow aspirate whenever a bone
marrow biopsy is performed for clinical purposes, and use for research.

Exclusion Criteria

- Patient has a readily-available, suitable, fully-matched sibling donor (MRD) less than
age 55. 'Suitable' means no high-titre donor-specific antibodies present, and negative
IDM testing with no contraindications.

- Patient has a clinically-significant donor-specific antibody for the selected donor
(DSA clearance is not allowed).

- Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA
or ECHO.

- Symptomatic pulmonary disease. Poor pulmonary function: FEV1, FVC, and DLCO <50%
predicted (corrected for hemoglobin) for patients who have not received thoracic or
mantle irradiation. For patients who have received thoracic or mantle irradiation,
FEV1 and FVC <70% predicted or DLCO < 50 of predicted.

- Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary
malignancy). ALT or AST > 5 x laboratory upper normal limits.

- Poor renal function: Creatinine >2.0mg/dl or creatinine clearance (calculated
creatinine clearance is permitted) < 60 mL/min based on Traditional Cockcroft-Gault
formula

- Women of childbearing potential who currently are pregnant (Β-HCG+) or who are not
practicing adequate contraception.

- Uncontrolled viral, bacterial, or fungal infections. Patients with symptoms consistent
with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed
for the above viruses and if positive are not eligible for the trial until they are no
longer symptomatic (patients may have continued assay positivity for a period of time
post resolution of symptoms secondary to the nature of the assay).

- Uncontrolled CNS involvement by malignancy (patients with prior history of CNS disease
controlled with intrathecal chemotherapy or prior systemic therapy are allowed).

- Patients who have any debilitating medical or psychiatric illness which would preclude
their giving informed consent or their receiving optimal treatment and follow-up.

Exclusion Criteria - Control Patients (specimen collection, only)

- Undergoing myeloablative alloHSCT.

- Non-PTCy GVHD prophylaxis.

- Non-PBSC transplant (bone marrow stem cell source).

- Not willing to give longitudinal blood specimens for research use or not willing to
allow access to medical records for non-clinical purposes.