Bortezomib, Doxorubicin Hydrochloride Liposome, and Dexamethasone Followed by Thalidomide and Dexamethasone With or Without Bortezomib in Treating Patients With Multiple Myeloma

OBJECTIVES:

• Determine the efficacy and safety of bortezomib, pegylated doxorubicin hydrochloride liposome, and dexamethasone followed by thalidomide and dexamethasone with or without bortezomib in patients with symptomatic high-risk or primary resistant multiple myeloma.

OUTLINE: Patients receive BDD comprising bortezomib IV on days 1, 4, 8, and 11; pegylated doxorubicin hydrochloride liposome IV over 60-90 minutes on day 4; and oral dexamethasone on day 1, 2, 4, 5, 8, 9, 11, and 12. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients achieving response to BDD receive oral thalidomide on days 1-28 and oral dexamethasone on days 1-4, 9-12, and 17-20. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Patients experiencing stable or progressive disease on BDD receive oral thalidomide on days 1-28; oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, 12, and 17-21; and bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.

DISEASE CHARACTERISTICS:

• Histologically and serologically confirmed multiple myeloma meeting one of the following criteria:

• High-risk myeloma, defined as symptomatic International Staging System (ISS) stage 2 or 3 multiple myeloma
• Soft-tissue involvement with myeloma in the form of a soft-tissue plasmacytoma
• Extension of a plasmacytoma into soft tissues
• Primary resistant myeloma, defined as unchanged or progressive myeloma despite two courses of standard treatment
• No ISS stage 1 multiple myeloma without soft-tissue involvement
• No smoldering myeloma

PATIENT CHARACTERISTICS:

• ECOG performance status 0-3
• Life expectancy > 16 weeks
• Absolute granulocyte count ≥ 1,500/mm³ (unless low granulocyte counts are due to multiple myeloma)
• Platelet count ≥ 100,000/mm³ (unless low platelet counts are due to multiple myeloma)
• Bilirubin ≤ 2.0 mg/dL
• AST and ALT < 3 times upper limit of normal (ULN)
• Alkaline phosphatase < 3 times ULN
• LVEF ≥ 50% by MUGA or ECHO
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception 4 months prior to, during, and for 4 weeks after completion of study treatment
• No active thromboembolic disease on anticoagulation
• No active angina or myocardial infarction within the past 6 months
• No pre-existing neuropathy or sensory or neuropathic pain ≥ grade 2
• No concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ of the cervix

• Prior malignancies that have not required antitumor treatment within the past 24 months allowed
• Patients with a history of stage I or II (T1a/b) prostate cancer (detected incidentally at transurethral resection of prostate [TURP] and comprising < 5% of resected tissue) allowed if the prostate-specific antigen has remained normal since TURP
• No known HIV positivity or AIDS-related illness
• No other medical condition or reason that, in the opinion of the investigator, would preclude study compliance
• No history of hypersensitivity reactions attributed to a conventional formulation of doxorubicin hydrochloride or to components of pegylated doxorubicin hydrochloride liposome, bortezomib, boron, or mannitol

PRIOR CONCURRENT THERAPY:

• Prior radiotherapy allowed
• No more than 2 courses of prior initial chemotherapy for multiple myeloma
• No prior bortezomib
• No prior high-dose steroids (not including taper) for more than 1 month in duration for emergent indications, such as hypercalcemia or life-threatening lesions (e.g., spinal cord compromise) (in high-risk patients)