Ixazomib Citrate, Pomalidomide, Dexamethasone, and Stem Cell Transplantation in Treating Patients With Relapsed or Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. To estimate the rate of progression free survival at 18 months from study entry after
therapy with ixazomib citrate (ixazomib [MLN9708]) in combination with pomalidomide and
dexamethasone followed by a single autologous stem cell transplantation (ASCT) and
consolidation with ixazomib in combination with pomalidomide and dexamethasone and
maintenance with ixazomib in relapsed refractory ASCT naive multiple myeloma (MM) patients.

SECONDARY OBJECTIVES:

I. To determine the best overall response rates (>= partial response [PR]) and deep responses
(very good partial response [VGPR], complete response [CR], stringent complete response
[sCR]) at various stages of treatment: after induction, after stem cell transplantation
(SCT), after consolidation and during maintenance.

II. To determine the overall survival from study entry.

TERTIARY OBJECTIVES:

I. Assessment of minimal residual disease (MRD) by flow cytometry at various stages of
treatment: after induction, day # 100 after SCT, after consolidation and during maintenance
at year 1 and 2 from initiation of maintenance therapy.

II. To determine the engraftment kinetics (white blood cells [WBC] and platelet) following
single salvage ASCT for relapsed disease.

OUTLINE:

INDUCTION (COURSES 1-4): Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15,
pomalidomide (PO) on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment
repeats every 28 days (courses 1-3) and 56 days (course 4) for up to 4 courses in the absence
of disease progression or unacceptable toxicity.

TRANSPLANTATION (COURSE 5): Between 2-4 weeks following Induction, patients undergo ASCT.

CONSOLIDATION (COURSES 6-9): Beginning 60-120 days following ASCT, patients receive ixazomib
citrate, pomalidomide, and dexamethasone as in Induction. Treatment repeats every 28 days
(courses 6-8) and 56 days (course 9) for up to 4 courses in the absence of disease
progression or unacceptable toxicity.

MAINTENANCE (COURSES 10+): Beginning 0-4 weeks following Consolidation, patients receive
ixazomib citrate as in Induction. 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 until
progressive disease, and then every 6 months for 3 years.

Inclusion Criteria:

- Previously treated ASCT naive MM patients, currently with relapsed or refractory
disease who are being considered for single ASCT for relapsed disease; patients must
be eligible to undergo a stem cell transplant as per institutional criteria for
selection at the time of registration

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

- Absolute neutrophil count (ANC) >= 1000/mm^3

- Platelet count >= 75 x 10^9/L unless the participant has >= 50% bone marrow
infiltration in which case a platelet count of >= 50 x 10^9/L is allowed

- Hemoglobin >= 9.0 g/dL

- Total bilirubin =< 1.5 x the upper limit of the normal range (ULN) or if total
bilirubin is > 1.5 x ULN, the direct bilirubin must be =< 2.0 mg/dL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN or < 5
x ULN if liver involvement

- Patients with measurable disease defined as at least one of the following:

- Serum monoclonal protein >= 1.0 g/dL by protein electrophoresis

- >= 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 or 2

- Willing to provide informed written consent

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

- Willing to follow strict birth control measures

- Persons of childbearing potential, agree to one of the following:

- Practice 2 effective methods of contraception, at the same time, from the time of
signing the informed consent form through 90 days after the last dose of study
drug, AND must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred and
usual lifestyle of the subject; (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception)

- Persons able to father a child: even if surgically sterilized (i.e., status
post-vasectomy), must agree to one of the following:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 90 days after the last dose of study drug, OR

- Must also adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred and
usual lifestyle of the subject; (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception)

- Willing to follow the requirements of the Pomalyst REMS program

- Willing to return to return to enrolling institution for follow-up (during the Active
Monitoring Phase of the study)

- Willing to provide bone marrow samples under Institutional Review Board (IRB)#521-93
for correlative research purposes

Exclusion Criteria:

- Diagnosed or treated for another malignancy =< 2 years prior to registration or
previously diagnosed with another malignancy and have any evidence of residual disease

- NOTE: If there is a history or prior malignancy, patient must not be receiving
other specific treatment for their cancer; patients with non-melanoma skin cancer
or carcinoma in situ of any type, or low-risk prostate cancer after curative
therapy, are not excluded if they have undergone complete resection

- NOTE: Platelet transfusions to help patients meet eligibility criteria are not
allowed =< 3 days prior to study registration

- Any of the following:

- Pregnant persons

- Nursing persons

- Persons of childbearing potential who are unwilling to employ adequate
contraception

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens; NOTE: this includes uncompensated heart or lung disease

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm; NOTE: Bisphosphonates are considered to be supportive care
rather than therapy and are allowed while on protocol treatment

- Patient has >= grade 2 peripheral neuropathy, or grade 1 with pain on clinical
examination during the screening period

- Major surgery =<14 days prior to registration

- Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin,
carbamazepine, phenytoin, phenobarbital) or use of Ginkgo biloba or St. John?s wort =<
14 days prior to registration

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements. NOTE: Any electrocardiogram (ECG) abnormality at screening must be
documented by the investigator as not medically relevant

- Corrected QT (QTc) > 470 milliseconds (msec) on a 12-lead ECG obtained during the
screening period; Note: If a machine reading is above this value, the ECG should be
reviewed by a qualified reader and confirmed on a subsequent ECG

- Known human immunodeficiency virus (HIV) positive

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

- 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 study treatment including difficulty swallowing

- Diarrhea > grade 1, based on the National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) version (v) 4.0 grading, in the absence of
antidiarrheals

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

- Radiotherapy =< 14 days prior to registration; NOTE: If the involved field is small, 7
days will be considered a sufficient interval between treatment and administration of
the ixazomib

- Central nervous system involvement with disease under study (myeloma), or concurrent
AL amyloidosis or plasma cell leukemia

- Patients that have previously been treated with ixazomib, or participated in a study
with ixazomib whether treated with ixazomib or not

- Prior stem cell transplantation for myeloma