Inclusion Criteria:

• Multiple Myeloma Criteria = Newly diagnosed with drug sensitive disease (>50% tumor response to standard chemotherapy) and poor prognostic indicators, such as Salmon-Durie stage III, serum b-2-microglobulin >3.0 mg/L, high proliferative fraction or hypodiploidy. Relapsed patients after a response to standard chemotherapy. Patients with primary refractory disease. Patients with non-secretory multiple myeloma are eligible for enrollment on this study. They will be followed for toxicity, survival and molecular endpoint analyses, but will not be followed for response. Patients with plasma cell leukemia, either occurring de novo or arising from existing multiple myeloma, are ineligible for this study.
• Patients greater than or equal to 18 years of age are eligible.
• Patients must have histologically confirmed diagnosis by a pathologic review at the H. Lee Moffitt Cancer Center and Research Institute.
• Patients must have undergone a complete psychosocial evaluation and been considered capable of compliance.
• Patients willing and able to receive palifermin (young cohort only)

Exclusion Criteria:

• Patients with a DLCO less than 50% (adjusted) of normal or with symptomatic obstructive or restrictive disease are ineligible.
• Patients with a serum creatinine of greater than 2.0 mg/dL OR a creatinine clearance of less than 40 ml/minute. Creatinine clearance can be measured or calculated. Patients with renal dysfunction secondary to multiple myeloma may be enrolled at the discretion of the principal investigator. However, patients on hemodialysis or peritoneal dialysis are ineligible.
• Patients with a total bilirubin greater than 2.0 mg/dL and SGOT or SGPT greater than two and a half times normal (unless due to primary malignancy), or a history of severe hepatic dysfunction are ineligible.
• Patients who have evidence of severe cardiac dysfunction are ineligible. A gated blood pool (MUGA) scan must show an ejection fraction of at least 50%. Patients must be free of major heart disease. Patients are ineligible if they have received a total dose of doxorubicin of greater than 450 mg/m2 (or daunorubicin equivalent) unless the left ventricular ejection fraction by MUGA scan is at least 50%. Patients must not be taking nitroglycerin preparations for angina pectoris or antiarrhythmic drugs for major ventricular dysrhythmias. Patients with essential hypertension controlled with medications are eligible for study. Any patient with congenital or acquired heart disease or cardiac arrhythmias will have a cardiology consult and evaluation.
• Patients with active infections are ineligible.
• Patients who are HIV antibody positive are ineligible.
• Patients with active leptomeningeal involvement are ineligible. Patients with a history of previous CSF tumor involvement without symptoms or signs are eligible provided the CSF is now free of disease on lumbar puncture and MRI of the brain shows no tumor involvement. Patients with severe symptomatic CNS disease of any etiology are ineligible.
• Patients with uncontrolled insulin-dependent diabetes mellitus or uncompensated major thyroid or adrenal dysfunction are ineligible.
• Patients with an ECOG performance status of > or = 2 are ineligible. Patients with ECOG performance status 2 to 3 secondary to bone pain may be enrolled at the discretion of the institutional investigator. Patients with ECOG performance status 2 to 3 secondary to a potentially reversible disease-related problem may be enrolled at the discretion of the institutional investigator.
• Patients who are pregnant or lactating are ineligible.
• Patients with any previous malignancy other than non-melanoma skin cancer are ineligible, unless the patient is without evidence of disease > or = 5 years after the treatment for the cancer was completed.
• Patients previously treated with topotecan or any other topoisomerase I inhibitor.