Pegylated Liposomal Doxorubicin, Bortezomib, Dexamethasone and Lenalidomide for Relapsed/Refractory Multiple Myeloma

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 (MM). 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.

Studies have shown that combinations of PLD and bortezomib have striking synergy in preclinical studies and impressive response rates (73 \& 89%) in early clinical trials for MM patients with relapsed/refractory disease as well as first-line therapy. In addition, the efficacy of PLD with bortezomib in anthracycline-insensitive patients has been greater than single-agent bortezomib when comparing across studies. The immunomodulatory drugs, thalidomide and lenalidomide, target the tumor cell microenvironment, are antiangiogenic, have an immune activation effect and also exert a direct cytotoxic effect on myeloma cells. A phase 1 clinical study by our group also demonstrated that low dose PLD, administered at a more frequent dosing schedule, in combination with bortezomib, and dexamethasone (DVD regimen) is well tolerated and associated with high response rates and durable responses. In this phase II prospective trial, we will evaluate this regimen and show that this change enhances the DVD-R regimen's safety and efficacy for patients with relapsed/refractory MM.

Eligibility Criteria:
Inclusion Criteria:

1. Has a diagnosis of multiple myeloma (MM) based on standard criteria (Durie 1986)
2. Currently has MM with measurable disease (serum m protein \> 1.0g/dl and/or 24 hr urine m protein \> 200mg/24 hr)
3. Currently has progressive MM that has relapsed or is refractory
4. Voluntarily signed an informed consent
5. Age 18 years
6. Eastern Cooperative Oncology Group (ECOG) performance \< 2
7. Life-expectancy \> 3 months
8. Laboratory test results within these ranges:

   * Absolute neutrophil count (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)
   * Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) 3 x ULN or 5 x ULN if hepatic metastases are present
   * Serum potassium within the normal range
9. 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
10. Registered into the mandatory RevAssist® program, willing and able to comply with the requirements of RevAssist®.
11. 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.
12. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid (ASA) may use warfarin or low molecular weight heparin)

Exclusion Criteria:

1. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes syndrome
2. Plasma cell leukemia
3. Grade 2 peripheral neuropathy within 14 days before enrollment
4. Impaired cardiac function or clinically significant cardiac diseases, including 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 Multigated acquisition(MUGA) scan evidence of left ventricular ejection fraction (LVEF) below institutional normal within 28 days prior to enrollment, electrocardiographic (ECG) 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.
5. Severe hypercalcemia, i.e., serum calcium 12 mg/dL (3.0 mmol/L) corrected for albumin
6. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
7. 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
8. 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).
9. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide)
10. 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, except localized radiation therapy
    * Use of any other experimental drug or therapy within 28 days of enrollment
11. Known hypersensitivity to compounds of similar to thalidomide, doxorubicin, bortezomib, boron or mannitol.
12. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
13. Concurrent use of other anti-cancer agents or treatments
14. Known positivity for human immunodeficiency virus (HIV) or hepatitis B or C; baseline testing for HIV and hepatitis B or C is not required