• To test a new combination (VMD) and compare the effects (good and bad) to the VTD combination [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
  

• To study how many subjects' myeloma responds to treatment on this study, and how many subjects survive after treatment with these two regimens [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  

A new drug (bortezomib [VelcadeTM PS-341]) has been shown in recent studies to be effective in subjects with advanced multiple myeloma. There is also research that shows this drug may be even more effective when used in combination with other drugs that have been used to treat myeloma for many years (melphalan, thalidomide, and dexamethasone). This study is being done to find out if the combination of VelcadeTM with melphalan and dexamethasone (VMD) will be as effective, or even more effective as it is in combination with thalidomide and dexamethasone (VTD).

Inclusion Criteria:

• History of histologically documented MM previously enrolled on UARK 98-026 with relapsed or progressive disease after at least one autologous transplant.
• Patient has measurable disease in which to capture response, defined as:
• Serum M-protein level > 1.0 gm/dl (10.0 g/L) measured by serum protein electrophoresis or immunoglobulin electrophoresis
• Urinary M-protein excretion > 200 mg/24 hrs
• Bone marrow plasmacytosis of > 30percent by bone marrow aspirate and/or biopsy
• Serum Free Light Chains (By the Freelite test) > 10 mg/dL with an abnormal kappa/lambda ration.
• 50percent increase in size of lytic and/or focal lesions or development of new lesions recognized by radiographic studies.
• Performance status of 2 as per SWOG scale, unless PS of 3-4 based solely on bone pain.
• Patients must have a platelet count 50,000/mm3, unless the low platelet count is due to documented (>30 percent) extensive myeloma infiltration of the bone marrow.
• Patients must have adequate renal function defined as serum creatinine < 2.5 mg/dl.
• Patients must have adequate hepatic function defined as serum transaminases and direct bilirubin < 2 x the upper limit of normal.
• Pregnant or nursing women may not participate. Women of childbearing potential must have a negative pregnancy documented within one week of registration. Women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
• Male or female adults of at least 18 years of age.
• Patients must have signed and IRB-approved written informed consent form and demonstrate willingness to meet follow-up schedule and study procedure obligations
• > 5 x 106 CD34 cells/kg in storage strongly desired, but not mandated

Exclusion Criteria:

• Not previously enrolled on UARK 98-026.
• Has received salvage therapy after coming off UARK 98-026.
• Evidence of POEMS Syndrome..
• Significant neurotoxicity interfering with ADL.
• Platelet count < 50,000/mm3
• Clinically significant hepatic dysfunction as noted by bilirubin or AST >3 times the upper normal limit or clinically significant concurrent hepatitis.
• New York Hospital Association (NYHA) Class III or Class IV heart failure.
• Myocardial infarction within the last 6 months.
• Truly non-secretory MM (no increase in serum free-light chains) in the absence of bone marrow plasmacytosis and MRI-defined focal lesions with CT-FNA-proven MM
• Uncontrolled, active infection requiring IV antibiotics.
• Patients with a history of treatment for clinically significant ventricular cardiac arrhythmias.
• Poorly controlled hypertension, diabetes mellitus, or other serious or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol.
• Pregnant or potential for pregnancy. Women of childbearing potential will have a pregnancy test at screening, and will be required to use a medically approved contraceptive method. Pregnancy testing will be performed prior to administration of each dose of study drug.
• Breast-feeding women may not participate.