UARK 2012-02 Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission

Total therapy 5B will attempt to accelerate and sustain, at 2 years from starting therapy,
the proportion of subjects in complete remission by reducing host-imposed toxicity and
facilitating timely completion of highly synergistic 8-drug combination therapy, including
the next generation proteasome inhibitor, Carfilzomib. This will result in avoiding multiple
myeloma re-growth that, we postulate, ensued in Total therapy 3 during recovery phases from
severe de-conditioning. It is speculated that the incidence of positive minimal residual
disease will be reduced with the addition of one cycle of consolidation therapy. The
following approach will be implemented:

- apply a 4-day fractionated lower dose melphalan (80 mg/m2) together with CFZ-TD-PACE
regimen in MEL80-CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE as a hopefully
less toxic and more effective transplant regimen

- interspersed with 1 cycle of non-transplant supported MEL-20-CFZ-TD (carfilzomib,
thalidomide, dexamethasone) PACE (in lower doses than with transplant) inter-therapy
(reduced from two cycles due to prolonged thrombocytopenia)

- followed by CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE consolidation therapy
post transplant #2

- CFZ-RD (carfilzomib, lenalidomide and dexamethasone) maintenance for 1 year followed by
CFZ-D for an additional year

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.

- Patients must be either untreated or have not had more than one cycle of systemic MM
therapy, excluding bisphosphonates and localized radiation.

- Participants must have high-risk disease, as defined by GEP70 risk score of ≥ 0.66

- Zubrod ≤ 2, unless solely due to symptoms of MM-related bone disease.

- Patients must have a platelet count of ≥ 50,000/μL, unless lower levels are explained
by extensive bone marrow plasmacytosis.

- Patients must be at least 18 years of age and not older than 75 years of age at the
time of registration.

- Participants must have preserved renal function as defined by a serum creatinine level
of < 3 mg/dL.

- Participants must have an ejection fraction by ECHO or MUGA scan ≥ 45%

- Patients must have adequate pulmonary function studies > 50% of predicted on
mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) > 50% of predicted.
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 signed an IRB-approved informed consent indicating their
understanding of the proposed treatment and understanding that the protocol has been
approved by the IRB.

Exclusion Criteria:

- Does not have high-risk disease

- Poorly controlled hypertension, diabetes mellitus, or other serious medical illness or
psychiatric illness that could potentially interfere with the completion of treatment
according to this protocol.

- 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.

- Pregnant or nursing women may not participate. Women of childbearing potential must
have a negative pregnancy documented within one week of registration. Subjects of
reproductive potential may not participate unless they have agreed to use an effective
contraceptive method.