Tandem Auto Transplantation in Myeloma Patients With <12 Months of Prior Treatment

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.