UARK 2013-13, Total Therapy 4B - Formerly 2008-01 - A Phase III Trial for Low Risk Myeloma

The major treatment-related toxicities in TT3 pertained to the high-dose melphalan 200mg/m2
(MEL200)-based tandem transplant approach, consisting of mucosal and other toxicities.

For the TT4 trial, we are proposing to compare standard TT3 (S-TT3) to TT3-Lite (L-TT3).
L-TT3 will employ various strategies aimed at improving the therapeutic Index of S-TT3 by
reducing toxicities while maintaining the superior results reported for S-TT3 in terms of
frequency and duration of CR, EFS, and. The following strategies will be utilized in L-TT3:

- Applying only 1 instead of 2 cycles of induction and consolidation therapy prior to and
after tandem transplant. This is supported by the well known association between prior
exposure to mucotoxic therapies4, 5 and worse post-transplant mucositis, particularly
when etoposide is used in the mobilizing regimen6 such as in VDTPACE.

Note: Randomization has been discontinued and accrual is closed to the L-TT3 arm. This trial
is currently enrolling as a single-arm trial for patients to receive S-TT3.

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 low-risk disease, as defined by any of the following:

- GEP risk score of < 0.66

- lack of GEP-defined TP53 deletion (Affymetrix signal <727)

- No metaphase based abnormalities of 1q or 1p

- LDH <360 U/L Rule out hemolysis, infection, and contact PI for Clarification

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

- 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 ≥ 40%

- 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:

- High risk disease defined by high-risk gene array features as determined by any of the
following:

- GEP risk score of ≥ 0.66 or

- Presence of GEP-defined TP53 deletion, or

- Presence of abnormalities of chromosome 1 (amp1q, del 1p).

- 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.

- Platelet count < 30 x 109/L, unless myeloma-related.

- Grade > 2 peripheral neuropathy.

- Hypersensitivity to bortezomib, boron, or mannitol.

- 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

- No prior malignancy is allowed except for adequately treated basal cell or squamous
cell skin cancer, in situ cervical cancer, or other cancer for which the patient has
been disease free for at least three years. Prior malignancy is acceptable provided
there has been no evidence of disease within the three-year interval or if the
malignancy is considered much less life threatening than the myeloma.

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