Combined Bone Marrow and Renal Transplantation for Hematologic Disorders With End Stage Renal Disease

The induction of transplantation tolerance involves the specific elimination of the immune
response to the transplant but not to other antigens. In the realm of kidney transplantation,
tolerance means that the recipient is unable to detect the donor transplant kidney as
foreign, and therefore the recipient is unable to reject the kidney. Donor bone marrow
engraftment leads to kidney graft tolerance in animal models. Renal failure is a major
complication of multiple myeloma and AL amyloidosis for which the only known cure is
allogeneic bone marrow transplantation. Standard bone marrow transplantation is associated
with prohibitive toxicities in patients with end stage renal disease, and is generally not
considered an option for those patients. Patients with multiple myeloma and AL amyloidosis
are excluded from conventional renal transplantation protocols because of their underlying
malignancy. A less toxic bone marrow transplantation protocol, utilizing low dose total body
irradiation and anti-thymocyte globulin, combined with renal transplantation, could provide
an opportunity for cure of the myeloma or amyloidosis and correction of end stage renal
disease. In addition, successful marrow engraftment may be expected to lead to a state of
tolerance. Successful implementation of tolerance would be a major benefit to transplant
recipients. The significance of developing tolerance is that the patient could be spared the
disabling complications of indefinite immunosuppression, which include infections, cataracts,
osteoporosis, diabetes, atherosclerosis, hypertension, and malignancy.

Participant Inclusion Criteria

- Participants with end-stage renal failure due to or in association with multiple
myeloma or systemic AL amyloidosis which hematopoietic cell transplantation is
appropriate and a ≥ 50% five-year survival probability with transplantation is
expected. This includes, but is not limited to:

- Multiple myeloma (MM), ISS stage II or III in complete or very good partial remission

- AL amyloidosis without significant cardiac disease

- Males or females 18 - 65 years of age.

- Participants must have an HLA-matched or one of six HLA A, B, or DR antigen-mismatched
related donor, with high resolution molecular class I and II allele typing.

- Men and women of reproductive potential must agree to use a reliable method of birth
control during the treatment, and women should do so for a period of 2 years following
the transplant.

- Participants should be on dialysis or have a CrCl <20 ml/min.

- Patients should not have evidence of renal recovery of their renal failure over a 90
day period of therapy for their underlying malignancy or other blood disorder.

- Patients with a history of other malignancies excluding basal cell carcinoma of the
skin and carcinoma in situ of the cervix with a disease-free survival interval of >2
years. Patients with the following malignancies must demonstrate a 5 year disease-free
survival:

- Breast cancer with positive nodes

- Malignant melanoma (other than in situ)

- Colorectal cancer (other than Dukes Stage A or B1)

- Patients with multiple myeloma must have received previous treatment with a
bortezomib-based regimen.

Patients with AL amyloidosis must have received previous treatment with a bortezomib-based
regimen and/or autologous stem cell transplantation

- Patients with a history of malignant melanoma must be reviewed by an independent
oncologist prior to enrollment.

- Recipient ability to understand and provide informed consent.

Participant Exclusion Criteria

- Evidence of active infection as defined by: a) clinical syndrome consistent with viral
or bacterial infection (e.g., influenza, URI, UTI) or b) fever with a clinical site of
infection identified, or c) microbiologically documented infection, including, but not
limited to, bacteremia or septicemia.

- Participation in other investigational drug use at the time of enrollment.

- Contraindication to therapy with any one of the proposed agents (e.g., history of
allergy to horse serum in ATG).

- Serologic positivity to HIV or HCV.

- Women of childbearing age in whom adequate contraception cannot be maintained.

- AST/ALT > 3 x normal or bilirubin > 1.5 x normal (unless due to Gilbert's syndrome).

- Pregnancy or uncontrolled serious medical illness not related to underlying myeloma.

- Cardiac ejection fraction < 40% by echocardiogram.

- FEV1 < 50% predicted or corrected DLCO < 50% predicted.

- ABO blood group incompatibility in the host-vs-graft direction.

- Diagnosis of myelodysplastic syndrome

Donor Inclusion Criteria

- HLA-matched or one of six HLA A, B, or DR antigen-mismatched related male or female
donor 18-65 years of age.

- ECOG performance status 0 or 1.

- Excellent health per conventional pre-donor history (medical and psychosocial
evaluation).

- Acceptable laboratory parameters (hematology in normal or near-normal range; liver
function < 2 times the upper limit of normal and normal creatinine).

- Compatible ABO blood group.

- Negative donor lymphocyte crossmatch.

- No positive testing for viral infection (HbsAg, HIV, HCV, HTLV-1).

- Cardiac/Pulmonary evaluation within normal limits (CXR, EKG).

- Donor ability to understand and provide informed consent.