Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Multiple Myeloma

OBJECTIVES: I. Determine the toxicity and potential efficacy of intensive high dose
chemotherapy consisting of melphalan, topotecan, and etoposide phosphate followed by
autologous stem cell transplantation in patients with stage II or III multiple myeloma or
stage I with evidence of progressive disease. II. Determine the maximum tolerated dose of
topotecan in combination with melphalan and etoposide phosphate in this patient population.
III. Determine response rates and time to treatment failure in these patients when treated
with this regimen. IV. Determine the pharmacokinetic profiles of these drugs and investigate
the pharmacodynamic relationships with respect to the efficacy and toxicity of this regimen
in these patients. V. Determine whether the sequencing of this chemotherapy regimen is
appropriate and optimal in these patients.

OUTLINE: This is a dose escalation study of topotecan. Patients are primed with
cyclophosphamide IV over 2 hours for 2 days. Peripheral blood stem cells (PBSC) are
collected. Approximately 4 weeks after PBSC collection, patients receive melphalan IV over 30
minutes and topotecan IV over 30 minutes on days -7 to -5. Etoposide phosphate IV is
administered over 4 hours on days -4 and -3. PBSC are reinfused on day 0. Cohorts of 4-12
patients receive escalating doses of topotecan until the maximum tolerated dose (MTD) is
determined. The MTD is defined as the dose preceding that at which 6 of 12 patients
experience dose limiting toxicities. Patients are followed 2-3 times a week for approximately
1 month, then at 3, 6, and 12 months.

PROJECTED ACCRUAL: A total of 34-60 patients will be accrued for this study within 24-36
months.

DISEASE CHARACTERISTICS: Histologically confirmed multiple myeloma Newly diagnosed, drug
sensitive (i.e., greater than 50% response to standard chemotherapy), and poor prognostic
indicators (e.g., Salmon-Durie stage III, serum beta-2-microglobulin greater than 3.0 ug/L,
high proliferative fraction, or hypodiploidy) OR Relapsed after a response to standard
chemotherapy OR Primary refractory disease No active leptomeningeal involvement History of
prior CSF tumor involvement without symptoms or signs allowed provided CSF is now free of
disease on lumbar puncture and MRI of brain shows no tumor involvement No severe
symptomatic CNS disease of any etiology

PATIENT CHARACTERISTICS: Age: 15 to 69 Performance status: ECOG 0-1 ECOG 3-4 secondary to
bone pain or a potentially reversible disease related problem eligible at investigator's
discretion Life expectancy: At least 12 weeks Hematopoietic: Not specified Hepatic:
Bilirubin no greater than 2.0 mg/dL SGOT/SGPT no greater than 2.5 times upper limit of
normal No history of severe hepatic dysfunction Renal: Creatinine no greater than 2.0 mg/dL
OR Creatinine at least 40 mL/min No hemodialysis or peritoneal dialysis Cardiovascular: No
evidence of severe cardiac dysfunction Ejection fraction at least 50% by MUGA scan No major
heart disease Essential hypertension controlled with medications allowed Pulmonary: DLCO at
least 50% of normal No symptomatic obstructive or restrictive pulmonary disease Other: Not
pregnant or nursing Negative pregnancy test Fertile patients must use effective
contraception No psychosocial disorder that would preclude study compliance No active
infections No uncontrolled insulin dependent diabetes mellitus No uncompensated major
thyroid or adrenal dysfunction No other prior malignancy except for nonmelanoma skin cancer
HIV negative

PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior total dose
of doxorubicin or daunorubicin greater than 450 mg/m2 No prior topotecan or any other
topoisomerase I inhibitor, etoposide, etoposide phosphate, or teniposide Endocrine therapy:
Not specified Radiotherapy: Not specified Surgery: Not specified Other: No concurrent
nitroglycerin preparations for angina pectoris No concurrent antiarrhythmic drugs for major
ventricular dysrhythmias