Ixazomib Citrate, Lenalidomide, and Dexamethasone in Treating Patients With POEMS Syndrome
Ixazomib Citrate, Lenalidomide, and Dexamethasone in Treating Patients With POEMS Syndrome
This phase II trial studies how well ixazomib citrate, lenalidomide, and dexamethasone work
 in treating patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal
 gammopathy, and skin changes (POEMS) syndrome. Ixazomib citrate may stop the growth of cancer
 cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy,
 such as lenalidomide and dexamethasone, work in different ways to stop the growth of cancer
 cells, either by killing the cells, by stopping them from dividing, or by stopping them from
 spreading. Giving ixazomib citrate, lenalidomide, and dexamethasone may work better in
 treating patients with POEMS syndrome.
PRIMARY OBJECTIVE:

 I. Normalization of VEGF after 3 cycles of therapy.

 SECONDARY OBJECTIVES:

 I. Toxicity and safety of the combination of ixazomib citrate (ixazomib), lenalidomide, and
 dexamethasone.

 II. Hematologic response after 3 cycles of therapy. III. Hematologic response rates and/or
 VEGF response at 12 months. IV. Overall survival.

 EXPLORATORY OBJECTIVES:

 I. Improvement of peripheral neuropathy (Overall Neuropathy Limitations Scale [ONLS],
 Modified Neurological Impairment Score for POEMS [mNIS+7POEMS], and performance score),
 ascites/effusions, diffusing capacity of the lungs for carbon monoxide (DLCO) after 3 cycles
 of therapy.

 II. Improvement of peripheral neuropathy (ONLS, mNIS+7POEMS, and performance score),
 ascites/effusions, DLCO, and positron emission tomography (PET)-scan (if abnormal at
 baseline) at 12 months (both groups) and at 24 and 36 months (group 2 only).

 III. Time to VEGF response, hematologic response, and clinical response. IV. Time to VEGF
 progression, hematologic progression, and clinical progression.

 V. Doses delivered will be tabulated to establish tolerance of study drugs.

 CORRELATIVE RESEARCH OBJECTIVES:

 I. To describe changes in bone biomarkers with treatment of ixazomib, lenalidomide, and
 dexamethasone.

 OUTLINE: Patients are assigned to 1 of 2 groups.

 GROUP I: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15, lenalidomide PO
 once daily (QD) on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment
 repeats every 28 days for up to 3 cycles in the absence of disease progression or
 unacceptable toxicity. Patients undergo standard of care autologous stem cell transplant
 (ASCT) after completing 3 cycles of treatment.

 GROUP II: Patients receive ixazomib citrate PO, lenalidomide PO QD, and dexamethasone PO as
 in Group I. Treatment repeats every 28 days for up to 13 cycles in the absence of disease
 progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 3 months until disease
 progression and then every 6 months for up to 36 months.
Inclusion Criteria:

 -  POEMS syndrome requiring therapy, previously treated or untreated

 -  Plasma vascular endothelial growth factor (VEGF) > 2 x upper limit of normal (ULN)

 -  Presence of a plasma cell clone (any of the following):

 -  Monoclonal protein in the serum or urine

 -  Measurable light chains by free light chain assay

 -  Measurable plasmacytoma

 -  Monoclonal plasma cells in bone marrow

 -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2, or 3

 -  Absolute neutrophil count (ANC) >= 1000/uL obtained =< 14 days prior to registration

 -  Platelet count (PLT) >= 75,000/uL obtained =< 14 days prior to registration

 -  Total bilirubin =< 2.0 mg/dL unless due to known Gilbert's disease obtained =< 14 days
 prior to registration

 -  NOTE: If total bilirubin is > 2 mg/dL, a direct bilirubin should be performed and
 must be < 1.5 mg/dL for Gilbert's to be diagnosed

 -  Alanine aminotransferase (ALT/serum glutamic pyruvic transaminase [SGPT]) and
 aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) =< 3
 x upper limit of normal (ULN) obtained =< 14 days prior to registration

 -  Creatinine clearance >= 30 mL/min/1.73 m^2 (as determined by Cockcroft-Gault equation)
 obtained =< 14 days prior to registration

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

 -  NOTE: Females of reproductive potential must adhere to the scheduled pregnancy
 testing as required in the Revlimid Risk Evaluation and Mitigation Strategy
 (REMS) program

 -  Birth control

 -  Female patients of childbearing potential must be willing to use 2 methods of
 birth control or be surgically sterile, or abstain from heterosexual activity for
 the course of the study through 120 days after the last dose of study medication

 -  NOTE: Patients of childbearing potential are those who have not been
 surgically sterilized or have not been free from menses for > 1 year

 -  Male patients must agree to use an adequate method of contraception starting with
 the first dose of study therapy through 120 days after the last dose of study
 therapy

 -  NOTE: Abstinence is acceptable (for either males or females) if this is the
 established and preferred method of contraception for the subject

 -  Willing to adhere to the guidelines of the Revlimid REMS (formerly known as RevAssist)
 program

 -  NOTE: The counseling must be documented

 -  Provide written informed consent

 -  Willing to return to enrolling 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

 -  No contraindication to be on a minimum of 81 mg aspirin a day (or other anticoagulant
 therapy as prescribed) for thromboembolism prophylaxis

 -  Willing to provide mandatory blood and bone marrow samples for research purposes

 -  Ability to complete questionnaire(s) by themselves or with assistance

 Exclusion Criteria:

 -  Recent prior chemotherapy:

 -  Newly diagnosed patients (regardless of group); any prior chemotherapy for POEMS
 with the following exceptions:

 -  Prior immunomodulators like azathioprine, cyclosporin, and/or
 corticosteroids are not exclusionary therapies if used for prior diagnosis
 of chronic inflammatory demyelinating polyneuropathy

 -  Prior chemotherapy directed at a "myeloproliferative neoplasm" like
 hydroxyurea is not exclusionary

 -  Previously treated patients (group 2)

 -  Alkylators (e.g. melphalan, cyclophosphamide) =< 28 days prior to
 registration

 -  Anthracyclines =< 28 days prior to registration

 -  High dose corticosteroids, immune modulatory drugs (thalidomide or
 lenalidomide), or proteosome inhibitors (e.g. ixazomib or bortezomib) =< 28
 days prior to registration

 -  Requirement for concomitant high dose corticosteroids

 -  EXCEPTION: Patients may be on chronic steroids (maximum dose 20 mg/day prednisone
 equivalent) if they are being given for adrenal insufficiency, rheumatoid
 arthritis, etc

 -  Receiving any other investigational agent, which would be considered as a treatment
 for the primary neoplasm

 -  Participation in other clinical trials, including those with other investigational
 agents not included in this trial, =< 30 days prior to registration and throughout the
 duration of this trial

 -  Prior refractoriness to proteasome inhibitor or immunomodulatory drugs (IMiD)

 -  Any of the following because this study involves an agent that has known genotoxic,
 mutagenic and teratogenic effects:

 -  Pregnant women

 -  Nursing women

 -  Men or women of childbearing potential who are unwilling to employ adequate
 contraception

 -  Other active malignancy =< 3 years prior to registration

 -  EXCEPTIONS: Non-melanotic skin cancer, ductal carcinoma in-situ, or
 carcinoma-in-situ of the cervix

 -  NOTE: If there is a history of prior malignancy, they must not be receiving other
 specific treatment for their cancer

 -  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, e.g. uncontrolled infection (infection requiring systemic
 antibiotic therapy or other serious infection =< 14 days prior to registration); or
 uncompensated heart or lung disease

 -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
 positive and currently receiving antiretroviral therapy

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

 -  History of myocardial infarction =< 6 months prior to registration, or congestive
 heart failure requiring use of ongoing maintenance therapy for life-threatening
 ventricular arrhythmias

 -  Radiotherapy =< 14 days prior to registration

 -  Major surgery =< 14 days prior to registration

 -  Failure to fully recover (i.e. =< grade 1 adverse event [AE]) from the reversible
 effects of prior chemotherapy

 -  Known allergy to any of the study medications, their analogs, 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 the study drugs including difficulty swallowing

 -  Ongoing or active systemic infection or active hepatitis B or C virus infection