Stem Cell Transplantation in Individuals With Multiple Myeloma (BMT CTN 0102)

Multiple myeloma (MM), characterized by malignant plasma cell proliferation, bone
destruction, and immunodeficiency, is a disease with a median age at diagnosis of
approximately 65 years. It is responsible for about 1 percent of all cancer-related deaths in
Western Countries. Conventional treatments with chemotherapy and radiation therapy are
non-curative but improve quality of life and duration of survival. Attempts to cure myeloma
through high-dose therapy followed by autografting or allografting have largely failed due to
a combination of relapsed disease or transplant related mortality (TRM). High-dose therapy
with autologous transplantation is safe and has low TRM (less than 5%), but is associated
with a continuing and nearly universal risk of disease progression and relapse. Even so,
autologous transplantation is superior to continued conventional chemotherapy. Recent data
indicate that tandem autologous transplants are superior to a single procedure. Even with
this approach, patients remain at risk of relapse and additional approaches are needed.

DESIGN NARRATIVE:

The overall study design is that of biologic assignment, based on the availability of an
HLA-matched sibling, to one of two treatment strategies for MM patients. Patients without an
HLA-matched sibling will undergo tandem autologous transplants. Patients with an HLA-matched
sibling will undergo an autologous transplant followed by a non-myeloablative allogeneic
transplant. In addition, the tandem autologous transplant recipients will be randomized to
either observation or one year of maintenance therapy to begin following the second
autologous transplant. The large number of MM patients without an HLA-matched sibling enables
us to evaluate the role of maintenance therapy following tandem autologous transplants.

Inclusion Criteria:

- Meeting the Durie and Salmon criteria for initial diagnosis of MM

- Stage II or III MM at diagnosis or anytime thereafter

- Symptomatic MM requiring treatment at diagnosis or anytime thereafter

- Received at least three cycles of initial systemic therapy and are within 2-10 months
of initiation of the initial therapy (this time frame excludes the time for
mobilization therapy)

- If receiving chemotherapy-based mobilization regimens, must be able to receive
high-dose melphalan between 2 and 8 weeks after the initiation of mobilization therapy
whether delivered at the transplant center or at a referring center

- Adequate organ function as measured by:

1. Cardiac: Left ventricular ejection fraction at rest greater than 40%

2. Hepatic: Bilirubin less than 2 times the upper limit of normal and alanine
transaminase (ALT) and aspartate transaminase (AST) less than 3 times the upper
limit of normal

3. Renal: Creatinine clearance greater than 40 ml/min (measured or
calculated/estimated)

4. Pulmonary: Carbon monoxide diffusion (DLCO), Volume forcibly exhaled in one
second (FEV1), and Forced Vital Capacity (FVC) greater than 50% of predicted
value (corrected for hemoglobin), or O2 saturation greater than 92% of room air

- An adequate autologous graft defined as a cryopreserved PBSC graft containing at least
4.0 x 106 CD34+ cells/kg patient weight; if prior to enrollment it is known that a
patient will be on the auto-allo arm (i.e., a consenting, eligible HLA-matched sibling
donor is available), the required autograft must contain at least 2.0 x 10^6 CD34+
cells/kg patient weight; the graft may not be CD34+ selected or otherwise manipulated
to remove tumor or other cells; the graft can be collected at the transplanting
institution or by a referring center; for patients without an HLA-matched sibling
donor, the autograft must be stored so that there are two products each containing at
least 2 x 10^6 CD34+ cells/kg patient weight

Exclusion Criteria:

- Never advanced beyond Stage I MM since diagnosis

- Non-secretory MM (absence of a monoclonal protein [M protein] in serum as measured by
electrophoresis and immunofixation and the absence of Bence Jones protein in the urine
defined by use of conventional electrophoresis and immunofixation techniques)

- Plasma cell leukemia

- Karnofsky performance score less than 70%, unless approved by the Medical Monitor or
one of the Protocol Chairs

- Uncontrolled hypertension

- Uncontrolled bacterial, viral, or fungal infections (currently taking medication and
progression of clinical symptoms)

- Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma
in situ; cancer treated with curative intent less than 5 years previously will not be
allowed unless approved by the Medical Monitor or one of the Protocol Chairs; cancer
treated with curative intent more than 5 years previously will be allowed

- Pregnant or breastfeeding

- Seropositive for the human immunodeficiency virus (HIV)

- Unwilling to use contraceptive techniques during and for 12 months following treatment

- Prior allograft or prior autograft

- Received mid-intensity melphalan (more than 50 mg IV) as part of prior therapy

- Prior organ transplant requiring immunosuppressive therapy