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High Dose Sequential Therapy and Autologous Stem Cell Rescue for Multiple Myeloma

Phase 2
18 Years
Not Enrolling
Multiple Myeloma

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Trial Information

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. 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

- 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

- 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

- Patients with HIV, HBsAG positive

- Pregnant or lactating women

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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the progression free survival at one year in multiple myeloma patients who receive sequentially administered high dose cyclophosphamide and VP-16 followed by high-dose BCNU (Carmustine) plus Melphalan

Outcome Time Frame:

4 years

Safety Issue:


Principal Investigator

Nelson Chao, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University Health System


United States: Institutional Review Board

Study ID:




Start Date:

May 1997

Completion Date:

February 2008

Related Keywords:

  • Multiple Myeloma
  • Multiple myeloma
  • Autologous Stem Cell Transplant
  • Multiple Myeloma
  • Neoplasms, Plasma Cell