Bortezomib With Melphalan and Prednisone for Multiple Myeloma

Based on the need to improve front-line therapy for patients less likely to undergo
transplant, the promising recent in vitro and clinical work on melphalan and bortezomib, we
propose a prospective trial with bortezomib added to standard melphalan and prednisone
therapy for previously untreated patients with multiple myeloma. Bortezomib 1.3 mg/m2 will
be given twice weekly for two weeks and will be added to standard melphalan and prednisone
on a 4-week cycle. This three-drug combination will be compared to historical data. We have
treated 2 patients with relapsed disease following >2 prior regimens including high-dose
therapy with autologous stem cell support. Each patient received melphalan, prednisone, and
bortezomib as described below and both had marked declines in M-protein within 2 cycles.
These responses have been sustained for at least 3 months and treatment was well tolerated.

Eligible patients will have histologically confirmed Multiple Myeloma (MM) having not
received prior systemic therapy given with the intent to induce remission, be adults, have
life expectancy greater than 3 months, adequate performance status, organ and marrow
function as described in the protocol, not be pregnant, HIV positive, or taking any
investigational agents. Patients must not have history of allergic reactions to study drugs
or similar compounds or have uncontrolled intercurrent illness or social situation that
would limit compliance with study requirements. Patients must also have the ability to give
informed consent.

Study drugs will be administered on an inpatient or outpatient basis. Bortezomib 1.3 mg/m2
is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day
cycle. Six cycles are planned. On days when both melphalan and bortezomib are given,
melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered
orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is
administered orally daily on days 1-7 of each cycle. Supportive care measures such as
antiemetics and growth factors may be given.

Inclusion Criteria:

- Patients must have histologically confirmed multiple myeloma, defined as at least one
of the following major criteria and one minor criterion or at least three minor
criteria:

Major Criteria Minor Criteria Plasmacytoma on tissue biopsy Marrow plasmacytosis 10-29%
Marrow plasmacytosis ≥ 30% Monoclonal protein present, less than major criteria Monoclonal
protein: Lytic bone lesions

Immunoglobulin G (IgG) > 3.5 g/dl Decrease in uninvolved immunoglobulins:

Immunoglobulin A (IgA) > 2 g/dl Immunoglobulin M (IgM) < 50 mg/dl Bence Jones ≥ 1 g/24 hr
IgA < 100 mg/dl IgG < 600 mg/dl

- No prior therapy

- Life expectancy greater than 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status <3 (Karnofsky >40%

- Patients must have normal organ and marrow function. Patients with severe
pancytopenia due to myeloma involvement of the bone marrow and patients with renal
insufficiency (creatinine > 2 mg/dl) due to myeloma will also be included.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Pregnant women

- Patients may not be receiving any other investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to bortezomib, melphalan, or other agents used in the study.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Patients with immune deficiency are at increased risk of lethal infections when
treated with marrow-suppressive therapy. Therefore, HIV-positive patients receiving
combination anti-retroviral therapy are excluded from the study because of possible
pharmacokinetic interactions with bortezomib or other agents administered during the
study.