Ixazomib in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib

PRIMARY OBJECTIVES:

I. To determine the confirmed overall response rate (>= partial response [PR]) of MLN9708
(ixazomib citrate), used as a single agent in patients with relapsed multiple myeloma, who
are proteasome inhibitor naïve (including bortezomib) naive OR have received less than 6
cycles of therapy with bortezomib and had a better than PR with no progression at the time of
discontinuation. (Arm A - Permanently closed to accrual as of Addendum 5) II. To determine
the confirmed overall response rate (>= PR) of MLN9708 at a 4 mg dose level in combination
with dexamethasone in patients with relapsed multiple myeloma, who are proteasome inhibitor
naïve (including bortezomib) naïve OR have received less than 6 cycles of therapy with
bortezomib and had a better than PR with no progression at the time of discontinuation. (Arm
B) III. To determine the confirmed overall response rate (>= PR) of MLN9708 at a 5.5 mg dose
level in combination with dexamethasone in patients with relapsed multiple myeloma, who are
proteasome inhibitor naïve (including bortezomib) naïve OR have received less than 6 cycles
of therapy with bortezomib and had a better than PR with no progression at the time of
discontinuation. (Arm C) IV. To determine the confirmed overall response rate (>= PR) of
MLN9708 in combination with cyclophosphamide and dexamethasone in patients with relapsed
multiple myeloma, who are proteasome inhibitor naive (including bortezomib) naïve OR have
received less than 6 cycles of therapy with bortezomib and had a better than PR with no
progression at the time of discontinuation. (Arm D)

SECONDARY OBJECTIVES:

I. To determine the overall response rate of MLN9708 in combination with dexamethasone, when
dexamethasone is added to MLN9708 for lack of response or for progression. (Arm A) II. To
determine the event free survival and overall survival among patients with relapsed myeloma
following treatment with MLN9708 with dexamethasone added for lack of response or
progression. (Arm A) III. To determine the event free survival and overall survival among
patients with relapsed myeloma following treatment with MLN9708 at two different doses, in
combination with dexamethasone. (Arms B and C) IV. To determine the event free survival and
overall survival among patients with relapsed myeloma following treatment with MLN9708 in
combination with cyclophosphamide and dexamethasone. (Arms D)

OUTLINE: Patients are randomized to 1 of 3 treatment arms (Arm A permanently closed to
accrual as of Addendum 5).

ARM A: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15. Patients with lack
of minor response by the end of the second course or lack of partial response by the end of
the fourth course also receive dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive ixazomib citrate PO on days 1, 8 and 15 and dexamethasone PO on days
1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

ARM C: Patients receive higher dose of ixazomib citrate PO on days 1, 8, and 15 and
dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

ARM D: Patients receive ixazomib citrate PO on days 1, 8, and 15, cyclophosphamide PO and
dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 or 12 months for 2
years.

Inclusion Criteria:

- Calculated creatinine clearance (using Cockcroft-Gault equation) >= 30 mL/min

- Absolute neutrophil count >= 1000/mL

- Untransfused platelet count >= 75000/mL

- Hemoglobin >= 8.0 g/dL

- Total bilirubin =< 1.5 x the upper limit of the normal range (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

- Patients with relapsed multiple myeloma who have already received one or more standard
treatment regimens

- Measurable disease of multiple myeloma as defined by at least ONE of the following:

- Serum monoclonal protein >= 1.0 g/dL

- >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis

- Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum
immunoglobulin kappa to lambda free light chain ratio

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2

- Patients should be proteasome inhibitor naïve (including bortezomib and carfilzomib)
OR have received less than 6 cycles of therapy with a bortezomib or carfilzomib
containing regimen and were not refractory to the bortezomib or carfilzomib based
regimen (less than a PR or progression on or within 60 days of discontinuation)

- Provide informed written consent

- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

- Willing to return to consenting Mayo Clinic institution for follow-up during the
Active Monitoring Phase of the study; Note: during the Active Monitoring Phase of a
study (i.e., active treatment and observation), participants must be willing to return
to the consenting institution for follow-up

- Recovered (i.e., < grade 1 toxicity) from the reversible effects of prior
antineoplastic therapy

Exclusion Criteria:

- Recent prior chemotherapy:

- Alkylators (e.g. melphalan, cyclophosphamide) =< 14 days prior to registration

- Anthracyclines =< 14 days prior to registration

- High dose corticosteroids, immune modulatory drugs (thalidomide or lenalidomide)
=< 7 days prior to registration

- Prior therapy with any proteasome inhibitor other than bortezomib or carfilzomib

- Concomitant high dose corticosteroids other than what is part of treatment protocol
(concurrent use of corticosteroids); EXCEPTION: patients may be on chronic steroids
(maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders
other than myeloma, i.e., adrenal insufficiency, rheumatoid arthritis, etc

- Diagnosed or treated for another malignancy within 2 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are
not excluded if they have undergone complete resection

- Any of the following:

- Pregnant women or women of reproductive ability who are unwilling to use 2
effective methods of contraception from the time of signing the informed consent
form through 90 days after the last dose of study drug

- Nursing women

- Men who are unwilling to use a condom (even if they have undergone prior
vasectomy) while having intercourse with any women, while taking the drug and for
30 days after stopping treatment

- Other co-morbidity which would interfere with patient's ability to participate in
trial, e.g. uncontrolled infection, uncompensated heart or lung disease

- Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered
investigational; NOTE: bisphosphonates are considered to be supportive care rather
than therapy, and are thus allowed while on protocol treatment

- Patient has >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical
examination during the screening period

- Major surgery within 14 days before study registration

- Systemic treatment with strong inhibitors of cytochrome P450, family 1, subfamily A
(CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,
phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the
first dose of study treatment

- Evidence of current uncontrolled cardiovascular conditions, including cardiac
arrhythmias, congestive heart failure, angina, or myocardial infarction within the
past 6 months; Note: prior to study entry, any electrocardiogram (ECG) abnormality at
screening must be documented by the investigator as not medically relevant

- Known human immunodeficiency virus (HIV) positive

- Known hepatitis B surface antigen-positive status, or known or suspected active
hepatitis C infection

- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol

- Known allergy to any of the study medications, their analogues or excipients in the
various formulations

- Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of MLN9708 including difficulty swallowing

- Diarrhea > grade 1, based on the National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) grading, in the absence of antidiarrheals