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

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.

• DVD-R (Drug), also known as Decadron, Velcade, Doxil, Revlimid: 40 mg dexamethasone will be administered IV on Days 1, 4, 8, and 11 of each cycle. 1.0 mg/m2 Bortezomib will be administered IV over 3 to 5 seconds followed by a standard saline flush, on Days 1, 4, 8, and 11 immediately following the dexamethasone infusion. 4.0 mg/m2 PLD will be given as a 90 minute infusion on Day 1 of Cycle 1 and subsequent doses may be administered over 30 to 60 minutes on Days 4, 8 and 11 of Cycle 1 and on Days 1, 4, 8, and 11 of each subsequent cycle, following the bortezomib administration. 10 mg/day lenalidomide will be administered PO on days 1-14 of a 28-day treatment cycle, followed by a 14-day rest period, following the PLD administration.

Primary outcomes

• International Myeloma Working Group (IMWG) Response Criteria [Up to 7.5 months (eight 28-day cycles)]: The investigator will evaluate each patient for response to therapy according to criteria augmented from those developed by Bladé et al., 1998 presented below (Table 7-1). Assessment of disease response will be performed prior to drug administration on Day 1 of Cycles 2 8 and at the End of Study Treatment visit. If a patient is determined to have complete response (CR), very good partial response (VGPR), partial response (PR), or minor response (MR), then assessment of disease response is to be performed 4 weeks later to confirm the response.

Secondary outcomes

• Time to First Response [Up to 7.5 months (eight 28-day cycles)]
• Time to Best Response [Up to 7.5 months (eight 28-day cycles)]
• Duration of Response [First evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death.]
• Time to Progression [Time from the start of treatment to progressive disease]
• Progression-free Survival [Time from the start of treatment to progressive disease or until death]
• Follow-up Time [Follow-up visits for disease progression and overall survival every 3 months after study discontinuation. After progression, follow-up visits for survival status every 6 months or until alternate therapy needs to be started or death intervenes]: time that patients were monitored for disease progression and overall survival

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• International Myeloma Working Group (IMWG) Response Criteria (Primary), Number, participants: DVD-R Single Arm 8
• Time to First Response (Secondary), Median, months: DVD-R Single Arm 1 (1 to 5)
• Time to Best Response (Secondary), Median, months: DVD-R Single Arm 2 (1 to 6)
• Duration of Response (Secondary), Median, months: DVD-R Single Arm 12 (1 to 21)
• Time to Progression (Secondary), Median, months: DVD-R Single Arm 9 (1 to 22)
• Progression-free Survival (Secondary), Median, months: DVD-R Single Arm 9 (1 to 22)
• Follow-up Time (Secondary), Median, months: DVD-R Single Arm 11 (2 to 22)

Adverse events

Time frame: Severity and frequency of adverse events (AEs) were evaluated at each visit. Serious adverse events (SAEs) were followed until resolution or until clearly determined be unrelated to study treatment.

Serious adverse events by term

Other adverse events by term

• Results publication: Berenson JR, Yellin O, Kazamel T, Hilger JD, Chen CS, Cartmell A, Woliver T, Flam M, Bravin E, Nassir Y, Vescio R, Swift RA. A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma. Leukemia. 2012 Jul;26(7):1675-80. doi: 10.1038/leu.2012.51. Epub 2012 Feb 22. PMID 22354206

• James R. Berenson, MD, Principal investigator, James R. Berenson, MD, Inc.