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

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

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma; End Stage Renal Disease
• Intervention / Treatment: Drug: Cyclophosphamide, anti-thymocyte globulin; Procedure: Kidney transplant; Radiation: Thymic irradiation; Procedure: Bone marrow transplant from a related donor

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Bone marrow and renal transplant; 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

Drug: Cyclophosphamide, anti-thymocyte globulin; 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; Other Names: Cyclosporine; Procedure: Kidney transplant; On Day 0 the renal transplant is performed according to standard surgical techniques, preferably using an iliac fossa, extraperitoneal approach; Radiation: Thymic irradiation; Thymic irradiation 7 Gy on Day -1; Procedure: Bone marrow transplant from a related donor; • 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Remission status of multiple myeloma	3 years
Renal allograft acceptance and ability to discontinue immunosuppressive therapy	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Graft versus host disease (GVHD)	3 years
Opportunistic infections	3 years
T cell recovery and immune reconstitution	3 years

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: Thomas R Spitzer, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start: August 1, 2001
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: February 27, 2009
• First Submitted That Met QC Criteria: March 2, 2009
• First Posted (Estimate): March 3, 2009

Study Record Updates

• Last Update Posted (Actual): March 4, 2020
• Last Update Submitted That Met QC Criteria: March 2, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Multiple myeloma; Renal failure; Kidney transplant
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Urologic Diseases; Hematologic Diseases; Renal Insufficiency; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Renal Insufficiency, Chronic; Kidney Diseases; Multiple Myeloma; Neoplasms, Plasma Cell; Kidney Failure, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Cyclophosphamide; Antilymphocyte Serum; Cyclosporine; Cyclosporins
• Other Study ID Numbers: NKD01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No