Doxil® + Melphalan + Velcade (DMV) in Relapsed/Refractory Multiple Myeloma

Phase I/II Study of Liposomal Doxorubicin (Doxil®)/Melphalan/Bortezomib (Velcade®) in Relapsed/Refractory Multiple Myeloma

The median overall survival (OS) of relapsed/refractory multiple myeloma (MM) is less than nine months. However, phase II data with the proteasome inhibitor bortezomib (Velcade®) has been heartening, with 35% overall response rates and median survival of 16 months. In-vitro data has shown that this agent dramatically increases the sensitivity to chemotherapeutic agents. Liposomal doxorubicin (Doxil), melphalan, and bortezomib all have different mechanisms of action and toxicity profiles. Clinical studies employing two drug combinations with these agents in patients with refractory MM have found favorable efficacy (nearly no progression of disease) and tolerance data. Thus, the investigators are initiating a phase I/II study to examine the safety and efficacy of combining all three agents into the regimen DMV (Doxil® + melphalan + Velcade).

Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2

Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2

Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2

Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2

Adjunctive therapy with a bisphosphonate, either pamidronate or zoledronic acid, will be given monthly.

Dose Escalation Schedule: Dose escalation will occur only after patients have completed at least two cycles at a given dose level.

1. If 0/3 experience DLT (as defined in attachment Section 6.0), the next three patients will be escalated by one dose level.

2. If 1/3 experience DLT, 3 additional patients enrolled at this dose level.

   • If 0, 1, or 2 of these additional patients experience DLT (i.e. total 3/6), the dose will be escalated.
   • If 3/3 experience DLT (i.e. total 4/6) then the next lower dose will be considered the MTD..

3. If 2/3 experience DLT, 3 additional patients enrolled at this dose level.

   • If 0 or 1 of these additional patients experience DLT (i.e. total 3/6), the dose will be escalated.
   • If 2 or more/3 experience DLT (i.e. total more than 3/6) then the next lower dose level is MTD

Inclusion Criteria:

Disease Characteristics:

1. Patient previously diagnosed with multiple myeloma; Durie-Salmon Stage I, II, or III based on standard criteria
2. Progressive disease. For non-secretory multiple myeloma, progressive disease is defined as bone marrow biopsy with > 25% increase in plasma cells or an absolute increase of at least 10% over prior known level. Alternatively, development of new or worsening of existing lytic bone lesions or soft tissue plasmacytomas, or hypercalcemia (serum calcium >11.5 mg/dL), or relapse from complete response.

Patient Characteristics:

1. 18 yrs or older

2. Patient has given voluntary written informed consent.

3. Unless post-menopausal or surgically sterilized, a female must be willing to use an acceptable method of birth control

4. Male patient must agree to use an acceptable method for contraception for the duration of the study.

5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.

6. Life expectancy is at least 3 months.

7. • Absolute Neutrophil Count (ANC) over 1,000/ul without the use of colony stimulating factors

   • Platelets over 50,000/ul without transfusion support 7 days
   • Bilirubin 2.0 mg/dl or less
   • aspartate aminotransferase (AST) 4 times or less upper limit normal Prior Therapy for Multiple Myeloma: Patients must have had at least 2 prior therapeutic regimens

Exclusion Criteria:

• Pregnant or breast feeding
• History of allergic reaction to compounds containing boron or mannitol.
• Active uncontrolled viral (including HIV), bacterial, or fungal infection.
• Grade III or IV toxicity due to previous anti-neoplastic therapy
• More than Grade 2 motor or sensory neuropathy
• Myocardial infarction within 6 months of enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled arrhythmias, or electrocardiographic evidence of acute ischemia.
• For any patients whose lifetime cumulative doxorubicin dose exceeds 400mg/m2, patients with left ventricular ejection fraction (LVEF) less than 35% by multigated acquisition (MUGA) .
• Concurrent administration of liposomal doxorubicin, melphalan, and bortezomib (single or two drug combinations of these are permissible)
• Less than 3 weeks since most recent chemotherapy or concurrent chemotherapy
• Use of corticosteroids (mroe than 10 mg prednisone/day or equivalent)