With this study - Total Therapy IIIB - researchers are extending the findings of Total Therapy III based what they have learned from the first two studies (Total Therapy I and II), with new research strategies designed to explore why chromosome abnormalities found in persons with multiple myeloma affect the outcome of drug therapy used in this disease."

It is well known that myeloma patients with chromosome abnormalities are at higher risk because their disease tends to be more aggressive and does not respond to treatment as well as patients without chromosome abnormalities. When researchers at the Myeloma Institute looked at the results of Total Therapy II, they found that although research subjects with chromosome abnormalities had better outcomes (how many responded, and how long they survived) than those treated with standard chemotherapy; still their outcomes did not improve significantly with Total Therapy II, when compared to Total Therapy I.

The research in this new study is designed to target this high-risk group of individuals with chromosomal abnormalities. However, it is hoped that both groups of research participants - those with and without chromosome abnormalities - will derive benefit from changes made in this new research study.

Inclusion Criteria:

• Patients must have newly diagnosed active MM requiring treatment. Patients with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy.
• Protein criteria must be present (quantifiable serum M-component of IgG, IgA, IgD, or IgE; urinary kappa or lambda light chain; or serum free light chain (SFLC) levels in order to evaluate response. Non-secretory patients are eligible provided the patient has > 20% plasmacytosis OR multiple (>3) focal plasmacytomas or focal lesions on MRI OR diffuse hyperintense signal on STIR images in the absence of hematopoietic growth factors.
• Patients must have received no more than one cycle or one month of prior chemotherapy for this disease. Patients may have received prior radiotherapy provided approval has been obtained by the Principal Investigator.
• Patients must be <75 years of age at the time of initial registration.
• Ejection fraction by ECHO or MUGA ≥ 40% performed within 60 days prior to registration.
• Patients must have adequate pulmonary function studies > 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) > 50% of predicted, within 60 days of registration. If the patient is unable to complete pulmonary function tests due to MM related pain or condition, exception may be granted if the principal investigator documents that the patient is a candidate for high dose therapy.
• Patients must have a performance status of 0-2 based on SWOG criteria. Patients with a poor performance status (3-4), based solely on bone pain, will be eligible.
• All patients must be informed of the investigational nature of this study and must have signed an IRB-approved informed consent in accordance with institutional and federal guidelines.

Exclusion Criteria:

• Platelet count < 30 x 109/L, unless myeloma-related.
• 5.1.2.2 Grade > 2 peripheral neuropathy.
• Hypersensitivity to bortezomib, boron, or mannitol.
• Uncontrolled diabetes.
• Recent (< 6 months) myocardial infarction, unstable angina, difficult to control congestive heart failure, uncontrolled hypertension, or difficult to control cardiac arrhythmias.
• Evidence of chronic obstructive or chronic restrictive pulmonary disease.
• Patients must not have light chain deposition disease or creatinine > 3 mg/dl
• Patients must not have prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has not received treatment for one year prior to enrollment. Other cancers will only be acceptable if the patient's life expectancy exceeds five years.
• Patients must not have significant co-morbid medical conditions or uncontrolled life threatening infection.
• Pregnant or nursing women. Women of child-bearing potential must have a negative pregnancy test documented within one week of registration. Women and men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.