Tandem Auto Transplantation in Myeloma Patients With <12 Months of Prior Treatment
Tandem Auto Transplantation in Myeloma Patients With <12 Months of Prior Treatment
This study is designed to decrease toxicity associated with prior tandem transplant protocols
 by reducing the intensity of induction, consolidation and maintenance therapy, while
 increasing event-free survival by adding bortezomib (Velcade®), thalidomide, gemcitabine and
 carmustine to the transplant regimens to down-regulate the rescue of myeloma cells by the
 micro-environment and to prevent DNA repair post high-dose alkylating agent therapy. By
 reducing drug resistance, it is hoped that 3-year event-free survival will be increased
 significantly when compared to Total Therapy II. Additionally, participants will have the
 option of providing biospecimens for a sub-study evaluating gene expression profiling at
 specific timepoints to better understand drug-resistance in myeloma, and to determine whether
 there are genes or gene products in the resistant population that can be targeted by novel
 therapies.
This study is targeted towards patients who have been diagnosed with Multiple Myeloma,
 POEMS(Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes),
 or myeloma plus amyloidosis and have had no more than 12 months of prior treatment.
 Furthermore, participants cannot have had a prior autologous or allogeneic transplant. The
 study schema consists of one round of induction chemotherapy, two transplants, one round of
 consolidation chemotherapy, and two years of maintenance treatment. This study design differs
 from its historical predecessors in the following manner:

 -  In contrast to Total Therapy II and III, which only allow enrollment of patients with
 one cycle or one month of treatment prior to enrollment, the proposed study allows
 enrollment of participants with up to 12 months of prior treatment.

 -  Induction therapy has been reduced to a single cycle.

 -  Bortezomib and thalidomide have been added to the transplant regimen.

 -  Carmustine is added to the second transplant.

 -  Gemcitabine is added to the second transplant regimen.

 -  Consolidation treatment has been reduced to a single cycle.

 -  The first year of maintenance consists of 12 28-day cycles of bortezomib,dexamethasone,
 and either thalidomide, lenalidomide, or cyclophoshamide. The second year of maintenance
 therapy consists of lenalidomide and dexamethasone.

 -  The novel agents thalidomide and bortezomib are not introduced upfront, but only with
 transplantation, consolidation, and maintenance.
Inclusion Criteria:

 1. Participants must have had a diagnosis of symptomatic MM, MM + amyloidosis, or POEMS
 (osteosclerotic myeloma: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal
 protein, Skin changes) requiring treatment. Participants with a previous history of
 smoldering myeloma will be eligible if there is evidence of progressive disease
 requiring chemotherapy. Note that study participants do not need to have active
 disease at the time of study entry, as participants may have received up to 12 months
 of prior chemotherapy, which might have induced a response.

 2. Protein criteria must be present (quantifiable M-component of IgG, IgA, IgD, or IgE
 and/or urinary kappa or lambda light chain, Bence-Jones protein, or Free Kappa Light
 Chain or Free Lambda Light Chain) in order to evaluate response. Non-secretory
 participants are eligible provided the participant has > 20% plasmacytosis OR multiple
 (>3) focal plasmacytomas or focal lesions on MRI.

 3. Participants must have received no more than 12 months of prior chemotherapy for this
 disease. Participants may have received prior radiotherapy provided approval has been
 obtained from the PI.

 4. Participants must not have had a prior transplant.

 5. Participants must be 18-80 years of age at the time of study entry.

 6. Ejection fraction by ECHO or MUGA of ≥ 40% performed.

 7. Participants must have adequate pulmonary function studies, > 50% of predicted on
 mechanical aspects (FEV1, FVC) and diffusion capacity (DLCO) > 50% of predicted
 (adjusted for hemoglobin). If the participant is unable to complete pulmonary function
 tests due to disease related pain or condition, a participant may still be enrolled
 provided that the PI or enrolling investigator documents that the participant is a
 transplant candidate.

 8. Participants must have a creatinine < 3 mg/dl and a calculated creatinine clearance
 >30mL/min. The Cockroft-Gault equation may be used to obtain calculated creatinine
 clearance.

 9. Participants must have a performance status of 0-2 based on ECOG criteria.
 Participants with a poor performance status (3-4)based solely on bone pain will be
 eligible, provided there is documentation to verify this.

 10. Participants must sign the most current IRB-approved study ICF (Informed Consent
 Form).

 Exclusion Criteria:

 1. Prior autologous or allogeneic transplant.

 2. Platelet count < 30 x 109/L, unless myeloma-related. If MM-related, the enrolling
 investigator must document this.

 3. > grade 3 neuropathy.

 4. Known hypersensitivity to bortezomib, boron, or mannitol.

 5. Uncontrolled diabetes.

 6. Recent (< 6 months) myocardial infarction, unstable angina, difficult to control
 congestive heart failure, uncontrolled hypertension, or difficult to control cardiac
 arrhythmias.

 7. Participants must not have light chain deposition disease-related renal failure or
 creatinine >3 mg/dl.

 8. Participants must not have a concurrent malignancy unless it can be adequately treated
 by surgical, non-chemotherapeutic intervention. Participants may have a history of
 prior malignancy, provided that he/she has not had any treatment within 365 days of
 study entry AND that life expectancy exceeds 5 years at the time of study entry.

 9. Participants must not have life-threatening co-morbidities.

 10. Women of child-bearing potential must have a documented negative pregnancy test
 documented within one week of study entry. Women and men of reproductive potential may
 not participate unless they have agreed, by signing the study ICF, to use effective
 contraceptive method(s) as outlined in that form.