Phase I study of Bortezomib with ?DT-PACE? for induction and Stem Cell collection of Newly Diagnosed Multiple Myeloma patients

I

This study represents a phase I trial to determine the safety and tolerance of the investigational agent VELCADE in combination with (DT-PACE) followed by stem cell collection and tandem auto-transplants with melphalan 200 mg/m2. It builds on the experience with DT-PACE; probably the most effective regimen today to treat myeloma patients, in an attempt to increase the incidence of CR and extend CR duration, event free and overall survival for newly diagnosed patients with multiple myeloma up to age 70. The following specific objectives will be pursued:

1.1 To determine the MTD of VELCADE (Bortezomib) in combination with thalidomide-based regimen (DT-PACE: dexamethasone, thalidomide, platinum, Adriamycin, cyclophosphamide and etoposide).

1.2 To evaluate the effects of VELCADE on stem cell collection as evaluated by the cellular composition of the graft for CD-34, Cloning efficiency, T & NK cell subsets (CD 3, 4, 8, 16, 56, 25) and B-cell clones (CD-19, 20)

• Patients must have newly diagnosed active multiple myeloma requiring treatment.
• Patients with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy.
• Protein criteria must be present (quantifiable M-component of IgG, IgA, IgD, or IgE and/or urinary kappa or lambda light chain or Bence Jones protein) in order to evaluate response. Non-secretory patients are eligible provided the patient has > 20% plasmacytosis.
• Patients must have received no more than two cycles (e.g. VAD, thalidomide, dexamethasone) of prior chemotherapy for this disease.
• Patients must be <70 years of age at the time of registration.
• Patients must have a performance status of 0-2 based on ECOG criteria. Patients with a poor performance status (3-4), based solely on bone pain, will be eligible.
• All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

Exclusion Criteria

• Patients must not have significant co-morbid medical conditions or uncontrolled life threatening infection.
• If medically appropriate, patients with pathologic fractures, pneumonia at diagnosis or hyperviscosity with shortness of breath should have these conditions attended to prior to registration.
• Patients with renal failure (creatinine > 2 mg/dl), are not eligible for this trial.
• Patients must not have uncontrolled diabetes.
• Patients with recent (< 6 months) myocardial infarction, unstable angina, difficult to control congestive heart failure, uncontrolled hypertension, or difficult to control cardiac arrhythmia are ineligible. Ejection fraction by ECHO or MUGA should be within the institutional normal range and must be performed within 42 days prior to registration.
• Patients must not have a history of chronic obstructive or chronic restrictive pulmonary disease. Patients must have adequate pulmonary function studies > 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) > 50% of predicted. Patients unable to complete pulmonary function tests due to myeloma related pain or fracture must have a high resolution CT scan of the chest and must also have acceptable arterial blood gases defined as P02 greater than 70.
• No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease free for at least three years. Prior malignancy is acceptable provided there has been no evidence of disease within the three-year interval and there must be no prior treatment with cytotoxic drugs that could potentially be assigned on this protocol.
• Pregnant or nursing women may not participate. Women of child-bearing potential must have a negative pregnancy documented within one week of registration. Women/men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

Dexamethasone 40 mg P.O. q day x 4 days

Thalidomide 100-400 mg P.O. q day x 8 days

Cyclophosphamide 400 mg/m2 per day

Etoposide (VP-16) 40 mg /m2 per day

Cisplatin 10 mg/m2 per day

Adriamycin 10 mg/m2 per day

G-CSF day 5 until ANC > 2000/ completion of stem cell collection

Bortezomib as per dose escalation schedule

Day 1, 4 and 8 of each cycle
Bortezomib Dose Escalation
Level 1 0.7 mg/m2
Level 2 1.0 mg/m2
Level 3 1.3 mg/m2

College Park, Maryland
University of Maryland, MD
Marlene and Stewart Greenebaum Cancer
Ashraf Badros, M.D.
410-328-1230