High Dose Sequential Therapy and Autologous Stem Cell Rescue for Multiple Myeloma
High Dose Sequential Therapy and Autologous Stem Cell Rescue for Multiple Myeloma
The purpose of this phase II study is to assess the toxicity and efficacy of sequentially
 administered high dose chemotherapy followed by autologous stem cell rescue in the treatment
 of multiple myeloma. Prior studies have shown that dose-intensified melphalan can produce
 higher response rates and complete remission in some patients. Over the past several years,
 multiple phase II studies utilizing high dose chemotherapy or high dose chemo-radiotherapy
 with autologous marrow or peripheral blood stem cell rescue have demonstrated improved
 response rates and survival rates compared to historical controls. Recently a prospective
 randomized trial has demonstrated improved response rates, response duration and overall
 survival utilizing high dose therapy with autologous bone marrow support compared to standard
 chemotherapy. The primary cause of failure is relapse and it is unclear how many, if any,
 patients are cured by this approach. Based on observations of efficacy in Hodgkin's Disease,
 Non-Hodgkin's Lymphoma, and breast cancer, an approach utilizing sequential high dose
 chemotherapy in multiple myeloma was developed. This protocol tests the sequential regimen in
 multiple myeloma patients who have responded to a standard dose chemotherapy regimen prior to
 enrollment.
The purpose of this phase II study is to assess the toxicity and efficacy of sequentially
 administered high dose chemotherapy followed by autologous stem cell rescue in the treatment
 of multiple myeloma. Multiple myeloma is a chemotherapy sensitive disease but is not curative
 with standard therapy with a median survival of 2 to 4 years. Prior studies have shown that
 dose-intensified melphalan can produce higher response rates and complete remission in some
 patients. Over the past several years, multiple phase II studies utilizing high dose
 chemotherapy or high dose chemo-radiotherapy with autologous marrow or peripheral blood stem
 cell rescue have demonstrated improved response rates and survival rates compared to
 historical controls. Recently a prospective randomized trial has demonstrated improved
 response rates, response duration and overall survival utilizing high dose therapy with
 autologous bone marrow support compared to standard chemotherapy. The primary cause of
 failure is relapse and it is unclear how many, if any, patients are cured by this approach.
 Based on observations of efficacy in Hodgkin's Disease, Non-Hodgkin's Lymphoma, and breast
 cancer, an approach utilizing sequential high dose chemotherapy in multiple myeloma was
 developed. This protocol tests the sequential regimen in multiple myeloma patients who have
 responded to a standard dose chemotherapy regimen prior to enrollment. As originally written,
 eligible patients were required to have sensitive disease.

 The protocol was revised in August 1998 to allow entry of patients with newly diagnosed
 myeloma who had stable but not progressive disease following VAD chemotherapy. Patients with
 recurrent myeloma were still required to have chemotherapy sensitive disease. Eligible
 patients must also have pathologically confirmed multiple myeloma, no prior bone marrow
 transplantation and acceptable organ function (pulmonary, renal, hepatic, and cardiac). The
 recent revision of the protocol also allows entry of patients with renal insufficiency due to
 multiple myeloma to be enrolled on the protocol. Prior to initiating high dose therapy,
 patients must undergo a complete history and physical exam with routine lab work plus titers
 for HIV, CMV, HSV, and VCV: immunoglobulin levels, beta-2 microglobulin and serum protein
 electrophoresis as well as immunoelectrophoresis and bone marrow aspirates and biopsies.
 These studies are all standard for multiple myeloma patients. All patients require a double
 Human Hickman to be placed prior to the start of therapy. The protocol was originally written
 to include total body irradiation and high dose Melphalan as a preparative regimen for
 patients who had not received prior radiotherapy. Patients who were not eligible for TBI
 received high dose BCNU plus Melphalan. A revision removed the TBI Melphalan arm from the
 protocol after analysis of over 100 patients treated at Stanford University Medical Center on
 this same protocol showed no difference in event-free survival or overall survival between
 the TBI containing arm and the chemotherapy only preparative regimen. The TBI arm was dropped
 due to the increased cost and morbidity of TBI and the associated scheduling and logistics
 problems. The other revision to the protocol was the inclusion of CD34 stem cell selection on
 the stem cells collected by leukapheresis following high dose cyclophosphamide. This change
 was based on the results of a Phase III study which demonstrated that the degree of tumor
 cell contamination of these stem cell collections could be decreased by 3-6 logs with CD34
 cell selection. The dose of Melphalan was also increased to 200 mg/m2 after completion of a
 dose escalation study at Stanford.
Inclusion Criteria:

 -  All patients must receive multi-agent based chemotherapy, preferably VAD, as
 cytoreduction prior to transplantation. The time from the last chemotherapy
 administration must be greater than 21 days. Patients with recurrent myeloma must have
 sensitive disease as demonstrated by a decrease in serum or urine paraprotein levels
 of >50% or a decrease in bone marrow plasmacytosis to less than 20%. Patients with
 newly diagnosed myeloma may have stable (but not progressive) disease following VAD.

 -  Patients must have their pathology reviewed and the diagnosis of multiple myeloma
 confirmed at the transplant center. Patients with smoldering multiple myeloma or
 benign monoclonal gammopathy of unknown significance will be excluded from this study.

 -  Performance status: -CALGB 0.1 or Karnofsky greater than 70%

 -  Patients must have serum creatinine < 2 x upper limit of normal, bilirubin < 2 x upper
 limit of normal, transaminases < 2 x upper limit of normal, MUGA resting EF > 50% or
 more than a 5% increase with exercise if <50%, DLCO > 60%

 Exclusion Criteria:

 -  Patients who have undergone bone marrow transplantation previously will not be
 eligible.

 -  Patients with HIV, HBsAG positive

 -  Pregnant or lactating women

 -  Patients with other medical or psychiatric disorders which would seriously compromise
 tolerance to this protocol.