Ixazomib in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib
Ixazomib in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib
This randomized phase II trial studies how well ixazomib (ixazomib citrate) works in treating
 patients with multiple myeloma that has returned after a period of improvement but is not
 resistant to bortezomib. Ixazomib citrate may stop the growth of cancer cells by blocking
 some of the enzymes needed for cell growth.
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.

 ARM E: Patient receive isazomib citrate PO on days 1,8 and 15, cyclophosphamide PO on days
 1,8,15 and 22. Daratumumab IV Days 1, 8, 15, 22 for cycles 1-2; Days 1, 15 for cycles 3-6;
 and Day 1 for subsequent cycles. Courses repeat every 28 days in the absence of disease
 progression or unacceptable toxicity.

 Dexamethasone IV (PO only if IV unavailable) days 1,8,15 and 22. *Dexamethasone is started
 Day 1 Cycle 1

 **Dexamethasone should be given IV (PO only if IV is unavailable), approximately 1 hour or
 less prior to daratumumab infusion. On days when subjects receive this dose of dexamethasone
 in the clinic, dexamethasone will not be self-administered at home. On days when daratumumab
 is not scheduled, PO may be taken at home.

 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