A Study of Pegylated Liposomal Doxorubicin (PLD), Bortezomib, Dexamethasone and Lenalidomide for Patients With Relapsed/Refractory Multiple Myeloma (DVD-R)

• Adverse Events [ Time Frame: up to 36 weeks ] [ Designated as safety issue: Yes ]
  Occurrence of adverse events throughout the study using CTCAE ctriteria version 3.0.
• Clinical laboratory [ Time Frame: up to 32 weeks ] [ Designated as safety issue: Yes ]
  • Hematology (hematocrit, hemoglobin, RBC count, WBC count, with differential, platelet count.
  • Serum electrolyte and glucose panel (sodium, potassium, chloride, calcium, and glucose).
  • Serum beta human chorionic gonadotropin pregnancy test for women of child-bearing potential
  • Chemistry [BUN, serum creatinine, bilirubin (total), alkaline phosphatase, total protein, albumin, AST (SGOT), ALT (SGPT)]
  • Amylase
• Vital signs [ Time Frame: up to 32 weeks ] [ Designated as safety issue: Yes ]
  Pulse, blood pressure, respiratory rate, and body temperature
• Medical history [ Time Frame: up to 32 weeks ] [ Designated as safety issue: Yes ]
• Physical Examination [ Time Frame: up to 32 weeks ] [ Designated as safety issue: Yes ]
  Body weight measurements
• Eastern Cooperative Oncology Group (ECOG) performance status [ Time Frame: up to 32 weeks ] [ Designated as safety issue: Yes ]

  SCORE DESCRIPTION 0 Fully active, able to carry on all pre-disease performance without restriction.

  1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.
  2. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.
  3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
  4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
  5. Dead.
• Concomitant medication usage [ Time Frame: up to 32 weeks ] [ Designated as safety issue: Yes ]

This is a phase II, multicenter, open label, nonrandomized study to evaluate the efficacy and safety of lenalidomide at a dose of 10 mg/dose in combination with bortezomib at 1.0 mg/m2/dose, pegylated liposomal doxorubicin (PLD) at 4.0 mg/m2/dose, and intravenous (IV) dexamethasone at 40 mg/dose in adult patients with relapsed/refractory multiple myeloma. The study consists of a screening period, followed by up to eight 28 day open label treatment cycles, a final assessment to occur 28 days after the end of the last treatment cycle, and a follow-up period.

Inclusion Criteria:

• Each patient must meet all of the following inclusion criteria to be enrolled in the study:

  1. Has a diagnosis of multiple myeloma based on standard criteria (Durie 1986)
  2. Currently has multiple myeloma with measurable disease (serum m protein > 1.0g/dl and/or 24 hr urine m protein > 200mg/24 hr)
  3. Currently has progressive multiple myeloma that has relapsed or is refractory
  4. Voluntarily signed an informed consent
  5. Age 18 years
  6. Able to adhere to the study visit schedule and other protocol requirements
  7. ECOG performance < 2
  8. Life-expectancy > 3 months

  9. Laboratory test results within these ranges:

     • ANC 1.5 x 109/L; if the bone marrow is extensively infiltrated (> 70% plasma cells) then 1.0 x 109/L
     • Platelet count 75 x 109/L; if the bone marrow is extensively infiltrated (> 70% plasma cells) then 50 x 109/L
     • Hg > 8 g/dL
     • Calculated or measured creatinine clearance > 30 mL/minute.
     • Total bilirubin 2.0 x upper limit of normal (ULN)
     • AST (SGOT) and ALT (SGPT) 3 x ULN or 5 x ULN if hepatic metastases are present
     • Serum potassium within the normal range
  10. Disease free of prior malignancies for 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast
  11. Registered into the mandatory RevAssist® program, willing and able to comply with the requirements of RevAssist®.
  12. Females of childbearing potential must have a negative serum or urine pregnancy test and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control.
  13. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin)

Exclusion Criteria:

• Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

  1. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes syndrome
  2. Plasma cell leukemia
  3. Non-measurable multiple myeloma
  4. Grade 2 peripheral neuropathy within 14 days before enrollment

  5. Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:

     • Myocardial infarction within 6 months prior to enrollment
     • New York Heart Association (NYHA) Class II or greater heart failure
     • Uncontrolled angina
     • Clinically significant pericardial disease
     • Severe uncontrolled ventricular arrhythmias
     • Echocardiogram or MUGA evidence of LVEF below institutional normal within 28 days prior to enrollment
     • Electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
  6. Severe hypercalcemia, i.e., serum calcium 12 mg/dL (3.0 mmol/L) corrected for albumin
  7. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
  8. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
  9. Undergone major surgery within 28 days prior enrollment or has not recovered from side effects of such therapy (Kyphoplasty is not considered to be a major surgery; however, the investigator is to discuss enrollment of a patient with a recent history of kyphoplasty with the medical monitor).
  10. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide)

  11. Received the following prior therapy:

      • Chemotherapy within 3 weeks of enrollment (6 wks for nitrosoureas)
      • Corticosteroids (>10 mg/day prednisone or equivalent) within 3 weeks of enrollment
      • Immunotherapy or antibody therapy as well as thalidomide, lenalidomide, arsenic trioxide or bortezomib within 21 days before enrollment
      • Radiation therapy within 28 days before enrollment, receipt of localized radiation therapy does not preclude enrollment
      • Use of any other experimental drug or therapy within 28 days of enrollment
  12. Known hypersensitivity to compounds of similar chemical or biological composition to thalidomide, doxorubicin, bortezomib, boron or mannitol.
  13. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
  14. Concurrent use of other anti-cancer agents or treatments
  15. Known positivity for human immunodeficiency virus (HIV) or hepatitis B or C; baseline testing for HIV and hepatitis B or C is not required