Combined Bone Marrow Transplantation (BMT) and Renal Transplant for Multiple Myeloma (MM) With End Stage Renal Disease (ESRD)

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, a plasma cell malignancy for which the only known cure is
allogeneic bone marrow transplantation. Standard bone marrow transplantation is associated
with frequent toxicity in patients with multiple myeloma, and is generally no considered an
option for those patients with end stage renal disease. Myeloma patients are excluded from
conventional renal transplantation protocols because of their underlying malignancy. A less
toxic bone marrow transplantation protocol, combined with renal transplantation, could
provide an opportunity for cure of the myeloma and correction of ESRD in patients with this
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 would be spared the
disabling complications of indefinite immunosuppression, which include infections, cataracts,
osteoporosis, diabetes, atherosclerosis, hypertension, and malignancy

Recipient Inclusion Criteria

1. Participants with end-stage renal failure due to or in association with greater than
or equal to stage II multiple myeloma

2. Males or females 18 - 65 years of age.

3. Participants must have an HLA-matched or one of six HLA A, B, or DR antigen-mismatched
related donor, with high resolution molecular DR allele determination.

4. 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.

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

6. Participants must receive medical clearance by a cardiologist prior to conditioning
for transplant.

7. Life expectancy greater than or equal to 6 months.

8. Recipient ability to understand and provide informed consent.

Recipient Exclusion Criteria:

1. 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.

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

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

4. Serologic positivity to HIV, HCV, or HbsAg positivity.

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

6. Malignancy within the past two years other than multiple myeloma, excluding basal cell
carcinoma of the skin and carcinoma in situ of the cervix.

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

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

9. Cardiac ejection fraction < 40% by echocardiogram; individual assessment if ejection
fraction between 40% and 50%.

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

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

Donor Inclusion Criteria:

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

2. ECOG performance status 0 or 1.

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

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

5. Compatible ABO blood group.

6. Negative donor lymphocyte crossmatch.

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

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

9. Donor ability to understand and provide informed consent.