Ixazomib Plus Pomalidomide and Dexamethasone in Treating Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) of MLN9708 (ixazomib), when given in
combination with pomalidomide and dexamethasone, in patients with relapsed or
relapsed/refractory multiple myeloma. (Phase I) II. To estimate the response rate and to
evaluate the antitumor activity of the three drug combination: MLN9708 (at the RP2D),
pomalidomide and dexamethasone, in patients with relapsed or relapsed/refractory multiple
myeloma. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the safety of MLN9708 at each dose level when given as part of a three drug
combination by assessing the following: type, frequency, severity, attribution, time course
and duration of adverse events; and clinical laboratory tests at various points in the study.
(Phase I) II. To characterize and evaluate toxicities, including type, frequency, severity,
attribution, time course and duration, at the RP2D, for the three drug combination. (Phase
II) III. To obtain estimates of response duration, depth of response, clinical benefit
response, and survival (overall and progression-free), at the RP2D, for the three drug
combination. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of ixazomib followed by a phase II study.

Patients receive ixazomib orally (PO) on days 1, 8, and 15; dexamethasone PO on days 1, 8,
15, and 22; and pomalidomide PO on days 1-21. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

- Voluntary written informed consent must be given before performance of any study
related procedure not part of standard medical care, with the understanding that
consent may be withdrawn by the patient at any time without prejudice to future
medical care

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to and again
within 24 hours of starting pomalidomide or MLN9708 and must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
birth control, one highly effective method and one additional effective method AT THE
SAME TIME, at least 28 days before she starts taking pomalidomide or MLN9708 through
90 days after the last dose of study drug; FCBP must also agree to ongoing pregnancy
testing; men must agree to use a latex condom during sexual contact with a FCBP even
if they have had a vasectomy from the time of signing the informed consent form
through 90 days after the last dose of study drug; all patients must be counseled at a
minimum of every 28 days about pregnancy precautions and risks of fetal exposure

- All patients enrolled into this trial, must be registered in and must comply with all
requirements of the POMALYST (pomalidomide) Risk Evaluation and Mitigation Strategy
(REMS) program

- Patients must have a diagnosis of relapsed or relapsed and refractory multiple myeloma
with a minimum of one prior regimen and a maximum of 5 prior regimens

- Patients must have had therapy with a proteasome inhibitor and lenalidomide and be
refractory to lenalidomide according to the International Myeloma Working Group (IMWG)
criteria definition of refractory disease (progressive disease on or within 60 days of
stopping lenalidomide)

- Patients must have measurable disease defined as one of the following:

- Serum M protein >= 0.5 g/dL

- Urine M protein >= 200 mg/24 hours

- Serum free light chain >= 10 mg/dL provided the free light chain (FLC) ratio is
abnormal

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

- Absolute neutrophil count (ANC) >= 1,000/mm^3

- Platelet count >= 75,000/uL for patients in whom < 50% of bone marrow nucleated cells
are plasma cells; or a platelet count >= 50,000/uL for patients in whom >= 50% of bone
marrow nucleated cells are plasma cells; platelet transfusions are not allowed within
3 days of last platelet assessment to confirm eligibility

- Total bilirubin =< 1.5 × the institutional upper limit of the normal range (IULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 × IULN

- Calculated creatinine clearance >= 45 mL/min

Exclusion Criteria:

- Female patients who are pregnant or breastfeeding or have a positive serum pregnancy
test during the screening period

- Failure to have fully recovered (ie, =< grade 1 toxicity) from the reversible effects
of prior chemotherapy

- Prior therapy with a combination regimen containing pomalidomide except the 2 drug
combination of pomalidomide and dexamethasone

- Major surgery within 14 days before enrollment

- Radiotherapy within 14 days before enrollment; if the involved field is small, 7 days
will be considered a sufficient interval between treatment and administration of the
MLN9708

- Central nervous system involvement

- Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment

- Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months

- Systemic treatment, within 14 days before the first dose of MLN9708, with strong
inhibitors of cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2)
(fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450, family
3, subfamily A (CYP3A) (clarithromycin, telithromycin, itraconazole, voriconazole,
ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin,
rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo
biloba or St. John's wort

- Unable or unwilling to undergo antithrombotic prophylaxis

- Ongoing or active systemic infection, active hepatitis B or C virus infection, or
known human immunodeficiency virus (HIV) positive

- 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 of any agent

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

- Diagnosed or treated for another malignancy within 2 years before study enrollment or
previously diagnosed with another malignancy with 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

- Patient has > grade 2 peripheral neuropathy on clinical examination during the
screening period

- Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 21 days of the start of this trial and
throughout the duration of this trial (for all other standard therapies, no treatment
within 14 days of the start of this trial)

- Patients who are pomalidomide refractory, defined as patients who progress on or
within 60 days of pomalidomide when given as a single agent or with dexamethasone