Patients are being asked to take part in this research study because they have multiple
myeloma which has relapsed after (come back), or is refractory to (unaffected by), initial
For patients who have relapsed or are refractory to therapy, there is no agreed upon
standard treatment. Treatment options include chemotherapy and, for some patients, bone
marrow transplants. None of the available treatments are curative and investigators are
continually looking for more effective treatments. This study involves treatment with a new
combination of standard drugs: VELCADE, Doxil, and Dexamethasone. Preliminary results from
a study using a combination of VELCADE with Doxil showed high response rates (disease
reduction). Two other studies showed that an addition of Dexamethasone to VELCADE in
patients not responding to VELCADE alone improved response rate. The proposed combination
of all three drugs may improve efficacy and response.
VELCADE is approved by the Food and Drug Administration (FDA) for use in multiple myeloma.
Doxil is not approved for use in multiple myeloma but is an approved drug for use in
patients with some other cancers. Several published clinical trials provide evidence that
Doxil is an active agent in multiple myeloma and it is used in treatment combinations for
multiple myeloma in general practice. Dexamethasone is approved for use in multiple
myeloma. The combination of all three drugs is experimental (not FDA approved).
The goals of this study are to determine if this new combination therapy with VELCADE, Doxil
and Dexamethasone is an effective treatment, and also to determine the side effects that
occur when this combination treatment is given.
Multiple myeloma remains a non-curable disease. Combination therapies such as VAD have been
effective, with partial response rates in ~40-60% range and tolerable toxicity. A recent
study showed that substituting Doxil for Doxorubicin in a regimen similar to VAD (DVd)
resulted in an improved toxicity profile and similar efficacy. The most active agents in VAD
(and presumably in DVd) are Doxorubicin (or Doxil) and Dexamethasone, while Vincristine adds
little, if at all to the efficacy of these regimen(s). One of the new active agents in
multiple myeloma is VELCADE (bortezomib, formerly known as VELCADE). This molecule has a
novel mechanism of action by specifically inhibiting the proteasome. A recently reported
Phase II trial showed that VELCADE as a single agent induced at least minimal responses
(i.e. > 25% reduction in monoclonal protein) in 35% of patients and at least a stabilization
of the disease in 59% of patients with relapsed/refractory multiple myeloma using strict
SWOG criteria. An additional 18% responded when Dexamethasone was added to VELCADE.
Pre-clinical observations showed that the addition of VELCADE to other chemotherapeutic
agents, such as doxorubicin, enhances cytotoxicity of multiple myeloma cells. Preliminary
results from Phase I study of combination of VELCADE with Doxil showed 60% response rate
(i.e. > partial response) with acceptable toxicity. In this study we propose to combine
three active agents, i.e. Doxil, Dexamethasone (two most active agents from DVd), and
VELCADE. The ultimate goal is to show that this combination of drugs is more efficacious
than VAD or VELCADE with either Dexamethasone or Doxil and without additional toxicity.
Each patient must meet all of the following inclusion criteria to be enrolled in the
- An Institutional Review Board (IRB)-approved signed informed consent
- Patient is, in the investigator's opinion, willing and able to comply with the
- Age greater than or equal to 18 years
- Female patient is either postmenopausal or surgically sterilized or willing to use an
acceptable method of birth control (i.e. hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study
- Male patient agrees to use an acceptable method of contraception for the duration of
- Expected survival greater than or equal to 3 months
- Pre-study Karnofsky performance status > 60%
- Histologic confirmation of multiple myeloma
- Patient was previously diagnosed with stage II or III multiple myeloma based on
standard criteria and currently requires second or higher line therapy because of
progression of disease (PD), defined as a 25% increase in M-protein; development of
new or worsening of existing lytic lesions or soft tissue plasmacytomas; or
hypercalcemia (> 11.5 mg/dl); or relapse from complete response (CR) or because of
refractory disease, defined as less than minimal response (MR) after 2 cycles of the
most recent treatment, including first line of therapy.
- Patients with measurable disease defined as: serum monoclonal protein greater than 1
g/dl for IgG type and greater than 0.5 g/dl for IgA type, and, where applicable,
greater than 0.2 g/24 hour urine light chain excretion.
- Patients with oligosecretory or nonsecretory myeloma will be eligible if measurable
disease can be established, such as measurable soft tissue plasmacytoma greater than
2 cm, by either physical examination and/or applicable radiographs (i.e. magnetic
resonance imaging [MRI], computed tomography [CT]-scan) and/or bone marrow
involvement greater than 20%.
- Patients refractory or relapsing after treatment with any one or two of the agents
used in this protocol will be allowed.
- Prior radiation therapy will be allowed but radiation therapy must be completed 2
weeks prior to registration.
- Left ventricular ejection fraction (LVEF) > 50% by multiple-gated acquisition (MUGA)
or echocardiogram (ECHO)
- Patients previously on investigational drugs if no long-term toxicity is expected,
and the patients have been off the drugs for one or more weeks
- Patient has received less than 250 mg/m2 cumulative dose of doxorubicin or
- Patient has the following laboratory values at and within 14 days before Baseline
(Day 1 of Cycle 1, before study drug administration):
- Platelet count > 50 x 10^9/L without transfusion support within 7 days before
the laboratory test (> 30 x 10^9/L if significant bone marrow [BM] involvement
- Hemoglobin > 7.5 x 10^9/L, without transfusion support within 7 days before the
- Absolute neutrophil count (ANC) > 1.0 x 10^9/L, without the use of colony
- Corrected serum calcium < 14 mg/dl (3.5 mmol/L);
- Aspartate transaminase (AST): < 2.5 x upper limit of normal (ULN);
- Alanine transaminase (ALT): < 2.5 x ULN;
- Alkaline phosphatase: <1.5 x the ULN;
- Total bilirubin: < 1.5 x the ULN; and
- Calculated or measured creatinine clearance: > 20 mL/minute.
Patients meeting any of the following exclusion criteria are not to be enrolled in the
- Patient had major surgery within 3 weeks before enrollment.
- Patient had a myocardial infarction within 6 months of enrollment or clinical
evidence of congestive heart failure.
- Patient is known to be human immunodeficiency virus (HIV)-positive (patients assessed
to be at risk should be tested).
- Patient is known to be hepatitis B surface antigen-positive or has known active
hepatitis C infection (patients assessed by the investigator to be at risk should be
- Patient has >= Grade 2 peripheral neuropathy within 14 days before enrollment.
- Patient has hypersensitivity to bortezomib, boron or mannitol, or other study drugs.
- Serious nonmalignant disease, including uncontrolled diabetes mellitus (DM) or
hypertension (HTN), or infection which, in the opinion of the investigator and/or the
sponsor, would compromise other protocol objectives