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)