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Cyclophosphamide, anti-thymocyte globulin, thymic irradiation conditioning and kidney transplant and bone marrow transplant from a related donor for patients with multiple myeloma and end stage renal disease with cyclosporine for graft versus host disease prophylaxis

Cyclophosphamide 60 mg/kg IV on Day -5, -4 Anti-thymocyte globulin 20 mg/kg IV on Day -1, Day +1, +3, +5

Cyclosporine starting on Day -1 at 5 mg/kg daily I.V. and reduced to 3 mg/kg on Day +4, and adjusted to provide a trough whole blood concentration of 250-400 ng/mL. The route of administration will be changed to oral as soon as the patient is able to tolerate oral medications

Cyclophosphamide, anti-thymocyte globulin

On Day 0 the renal transplant is performed according to standard surgical techniques, preferably using an iliac fossa, extraperitoneal approach

Kidney transplant

Thymic irradiation

• Donor bone marrow (\> 2 x 108 nucleated cells/kg of recipient body weight) is prepared for infusion according to the standard procedure at the medical center. A total of 15,000 Units of heparin is mixed with the marrow, which is infused at a rate of 300-500 cc/hr. The infusion begins in the operating room as soon as the vascular anastomosis of the renal allograft has been completed. Protamine, 25 mg, is administered I.V. after completion of the first half of the bone marrow infusion. If a partial thromboplastin time measured after completion of the marrow infusion is \> 60 seconds, the protamine treatment shall be repeated

Bone marrow transplant from a related donor

Thomas R Spitzer, MD

The primary objective is to cure multiple myeloma with less toxic allogeneic bone marrow transplantation while inducing renal allograft tolerance through mixed chimerism in patients with end stage renal failure and multiple myeloma

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

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

Combined HLA-matched Bone Marrow and Kidney Transplantation for Multiple Myeloma With Renal Failure

Massachusetts General Hospital

Nutritional and Metabolic Diseases

Amyloidosis

Proteostasis Deficiencies

Metabolic Diseases

Tacrolimus

combined bone marrow and kidney transplantation

Equine Anti-thymocyte globulin

On Day 0 the renal transplant is performed according to standard surgical techniques.

Kidney transplant from a related donor

Donor bone marrow (\> 2 x 10e8 nucleated cells/kg of recipient body weight) is prepared for infusion according to the standard procedure. The infusion begins in the operating room as soon as the vascular anastomosis of the renal allograft has been completed.

Total body irradiation 400 centigray (200 cGy X 2)

This pilot trial offers the unique opportunity for both the treatment of multiple myeloma or systemic AL amyloidosis for which hematopoietic stem cell transplantation would be ordinarily indicated and the reversal of end-stage renal failure, while avoiding the risks associated with long-term standard anti-rejection therapy used in renal transplantation. The primary objectives of this study are to assess renal allograft tolerance (that is, the acceptance of the kidney without the need for anti-rejection therapy), assess anti-tumor response rates in multiple myeloma and AL amyloidosis, and assess complication rates for genetically (HLA) matched related donor combined bone marrow and kidney transplantation using a low dose total body irradiation based preparative regimen.

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.

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

Combined HLA-Matched Bone Marrow and Kidney Transplantation for Multiple Myeloma or Other Hematologic Disorders With End Stage Renal Disease

There is no plan to share IPD, including the study protocol and consent form with other researchers.

Any publication that results from this trial will not include any patient identifiers.

The Primary Outcome is: the incidence of renal allograft rejection at 6 months post-transplant

This is measurement is summarized via bone marrow biopsy results and blood assays through 3 years.

Anti-tumor response is assessed according to Center for International Blood and Marrow Transplant Research (CIBMTR.org) criteria.

For multiple myeloma, based on assessment of serum and urine immunofixation, the presence or absence of soft tissue plasmacytomas and analyses of bone marrow aspirate and biopsy samples, response categories include stringent complete remission (sCR), complete remission (CR), near CR (nCR) very good partial response (VGPR), partial response (PR), stable disease (SD), and progressive disease (PD).

For AL amyloidosis, based on assessment of serum and urine immunofixation and serum free light chain ratio, hematologic response categories include complete response, very good partial response, partial response, no response/stable disease and progressive disease. Organ responses are also assessed according to organ specific criteria.

Director, Bone Marrow Transplant Program

Adverse event information was assessed by study investigators and entered into an internal Bone Marrow Transplant database.

Single arm combined bone marrow and kidney transplantation

Tacrolimus: Tacrolimus starting on Day -1

Equine Anti-thymocyte globulin: 20 mg/kg IV on Days -3, -1, +1, +3

Kidney transplant from a related donor: On Day 0 the renal transplant is performed according to standard surgical techniques.

Bone marrow transplant from a related donor: Donor bone marrow (\> 2 x 10e8 nucleated cells/kg of recipient body weight) is prepared for infusion according to the standard procedure. The infusion begins in the operating room as soon as the vascular anastomosis of the renal allograft has been completed.

Total body irradiation 400 centigray (200 cGy X 2): On transplant day -1

Bone Marrow and Kidney RECIPIENT

Kidney transplant from a related donor: On Day 0 the renal transplant is performed according to standard surgical techniques.

Bone marrow transplant from a related donor: Donor bone marrow (\> 2 x 10e8 nucleated cells/kg of recipient body weight) is prepared for infusion according to the standard procedure.

Bone Marrow and Kidney DONOR

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

1 transplant recipient and their donor were enrolled.

Thomas Spitzer, MD

Bone Marrow and Kidney RECIPIENTS

One bone marrow/kidney transplant recipient was enrolled and treated on this trial.

Number of Participants Without Renal Allograft Rejection at 6 Months Post-transplant

One bone marrow/kidney recipient was enrolled and treated on this trial.

Anti-Tumor Response Rate

Donor nephrectomy and bone marrow harvest (\> 2X10e8/kg nucleated cells/kg recipient body weight) on Day 0

Bone Marrow and Kidney DONORS

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Combined Bone Marrow Transplantation (BMT) and Renal Transplant for Multiple Myeloma (MM) With End Stage Renal Disease (ESRD)	NCT00854139	Multiple Myelom... End Stage Renal...	Cyclophosphamid... Kidney transpla... Thymic irradiat... Bone marrow tra...	18 Years - 65 Years	Massachusetts General Hospital
Combined Bone Marrow and Renal Transplantation for Hematologic Disorders With End Stage Renal Disease	NCT02158052	Multiple Myelom... Amyloidosis	Tacrolimus Equine Anti-thy... Kidney transpla... Bone marrow tra... Total body irra...	18 Years - 65 Years	Massachusetts General Hospital

Spots Global Cancer Trial Database for bone marrow transplant from a related donor